Note from the Author

The knowledge that this book conveys may revolutionize cancer and AIDS therapy in the coming years. After having read this book, no responsible doctor should continue to provide such harmful therapy to the patients in his/her care and trust. This book will inform them about the fatal mistakes of their previous therapies, of which until now they were the unwitting victims.

Additionally, this book is indispensable reading for the patient afflicted with cancer or AIDS. Herein for the first time, the exact reasons are revealed to the world why neither cancer nor AIDS must inevitably result in death. These two illnesses are the natural result of a systemic imbalance, which not only can be halted, but can also be healed.

Dedicated to the memory of my teacher and friend:

Prof. Dr. med. Alfred HÄSSIG (1921-1999)

As a long-standing head of the central laboratory of the Swiss Red Cross, Professor of Immunology at Berne, Advisor to the World Health Organization in all continents, President of the International Society for Blood Transfusion, and Chairman of the Study Group for Nutrition and Immunity, Alfred Hässig was an eminent pioneer in the field of hematology, immunology and stress-medicine.

With an exemplary medical ethic, he tirelessly and courageously made clear the uncertainty of the so-called HIV test and the fatal consequences of toxic AIDS and cancer therapy. In spite of legal persecution up until his death, he imparted the practical alternatives of biological regulation therapy.

Patients around the world will owe their survival to the doctor and researcher Alfred Hässig, who has liberated them from the fatal mistakes of HIV/AIDS medicine. His impressive reminder—that the service to health must always take priority over profit from illness—remains a lasting legacy and lesson, not only for his friends and colleagues but also for his opponents, who are as skilled and resourceful as they are stubbornly misinformed.

Examining all the major research data since the 1940s, this book challenges two orthodox medical models: HIV as the cause of AIDS, and random genetic mutations as the cause of cancer. Based on the recent findings from Evolutionary Biology and Nitric Oxide research, it presents a fundamentally new understanding of the human cell, its double genome split between the cell nucleus and the mitochondria, and the role of energy production and signal modulation for immune reactions and carcinogenesis. Finally, it explains the concept of a new Cell Symbiosis Therapy® for the treatment of all chronic diseases, including cancer. Now available in English for the first time, this book is a must-read for doctors, patients and anyone following the cutting edge of biology and immunology. With the blasting open of such doors of knowledge, the medical world will never again be the same.

Heinrich Kremer, MD, Medical Director Emeritus was, from 1968-1975, head of social therapy for addicts, sexual offenders and people with personality disorders at the Berlin Tegel prison which was the pilot project for the reform of the German penal system. In 1988 he resigned as medical director of a model clinic specializing in youth drug addiction due to differences on medical ethics regarding the HIV test and AIDS therapy. From 1993-1999 as collaborating member of the Study Group for Nutrition and Immunity (Bern) he investigated together with Prof. Alfred Hässig the mechanisms occurring in AIDS defining illnesses and in cancer. Since the publication of this book in German in 2001 he has been in demand as a lecturer on the treatment of chronic diseases, working today as senior consultant in a growing medical network for Cell Symbiosis Therapy®. [Source]

Alive and Well WHALE

Copyright © 2012 by Heinrich Kremer; Barcelona (Spain) and by David Lowenfels, San Francisco (USA)
for “The Dual Strategy of the Immune Response”

ISBN: Ebook 978-1-4771-0419-4

All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without permission in writing from the copyright owner.

Editor: Felix A. de Fries, Zürich, Study Group AIDS Therapy, Zürich (Switzerland)
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
Translator: Jamie Mc Intosh, Freiburg (Germany)
Proofreading: David Lowenfels and Dorion Sagan, San Francisco (USA)

German edition: Heinrich Kremer: Die stille Revolution der Krebs—und AIDS—Medizin Ehlers Verlag, Wolfratshausen (Germany) 2001

Italien edition: Heinrich Kremer: La Rivoluzione Silenziosa della Medicina del Cancro e dell’ AIDS, Macroedizioni, Diegaro di Cesena (Italy) 2003

We would like to thank Monique Altmann, Benglen (Switzerland) for her sponsoring of the English edition of this book and the Macroedizioni Publishing House for permission to use the illustrations made for the Italian edition.

To order additional copies of this book, contact: Xlibris Corporation
1-888-795-4274
www.Xlibris.com
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• Chapter I — A Disastrous Decision
  20 years of abusing nitric gases for sexual enhancement—the seemingly mysterious consequences … 1
• Chapter II — The Sensational Discovery
  Gaseous Nitrogen Monoxide as bioenergetic regulator within and between living cells——the gas war between humans and microbes … 8
• Chapter III — The AIDS Mystery
  Why the AIDS diseases were misinterpreted—inhibition of the gaseous defense is the cause of acquired immune cell weakness … 19
• Chapter IV — AIDS is not a Contagious Disease
  Opportunistic infections and Kaposi’s sarcoma were well known long before the AIDS era—a variety of causes trigger the same immune response, as programmed by biological evolution. … 32
• Chapter V — Challenging the Previously Valid Immunity Theories
  How acquired immune cell impairment actually develops … 60
• Chapter VI — The Most Successful Fusion in the History of Evolution
  How the micro-Gaian milieu functions—the vital role of the mitochondria … 88
• Chapter VII — Collective Tunnel Vision
  Why “HIV characteristics” are the outcome of evolutionary biological programming, and are not specific causes of strong and/or continuous immune stress—what the “HIV test” really measures. … 123
• Chapter VIII — The Solution to the Cancer Puzzle
  Why normal cells become cancerous—the degeneration of cancer cells back to an embryonic state is programmed by evolutionary biology, and is the result of mitochondrial inactivation. … 137
• Chapter IX — HIV/AIDS Medicine Run Amok
  Why AIDS drugs cause cancer, degenerative changes in muscular and nervous cells, and even AIDS itself-the explanation of how AZT, Bactrim/Septra, and their ilk actually work. … 179
• Chapter X — The Daunting Task of Reconsideration
  The fundamental malpractices of AIDS and cancer medicine—why patients die by chemotherapeutic poisoning … 204
• Chapter XI — The Lifesaving Knowledge of Healing
  On the practice of diagnosing, preventing, and treating AIDS, cancer, and other systemic diseases—rebalancing instead of eradication … 260
• Chapter XII — Resistance against Mass Poisoning in Africa
  The international initiative of President Mbeki—answers from the South African government’s open discussion: on the causes of AIDS in the West and developing nations, on the nontoxic prevention and therapy for AIDS, on AZT’s true mechanism of action, and the global terror epidemic spread by physicians and the media—the international HIV cartel’s refusal to join the discussion, and the disinformation campaign it launched. … 292
• Appendix A — The Secret of Cancer: “Short-Circuit” in the Photon Switch
  Change in the medical world-view of tumorology—The rational Cell Symbiosis Therapy concept … 300
• Appendix B — The Concept of Cell Symbiosis Therapy
  The Way Out of the Therapeutic Dead End … 305
• Appendix C — The Dual Strategy of the Immune Response
  A Review of Heinrich Kremer’s Research on the Pathophysiology of AIDS, Cancer, and Other Chronic Immune Imbalances … 311
• Bibliography … 319
• Tables … 343

Chapter 4:

• Table I The pathogenesis of AIDS according to the retroviral theory … 343
• Table II Actual clinical manifestations … 344

Chapter 5:

• Table III The double strategy of the immune response … 345

Chapter 6:

• Table IV Diagram of the fusion between an archacum and a proteobacterium … 346
• Table V The alternating switch between OXPHOS and aecobic Glycolysis … 347
• Table VI Compensated/decompensated oxidative and nitrosative Stress … 348
• Table VII Cellular symbiosis and dyssymbiosis subject to NO and ROS production … 349
• Table VIII Clinical examples of cellular dyssymbioses … 350

Chapter 7:

• Table IX The phantom “HIV” … 351
• Table X The experimental findings of the Montaigner team as counter-evidence to the “HIV causes AID and AIDS” theory … 352
• Table XI The experimental findings of the Gallo team as counter-evidence to the “HIV causes AID and AIDS” theory … 353

Chapter 8:

• Table XII Diagram of the mitochondrial channels … 354
• Table XIII The channel rhythm in mitochondrion … 355
• Table XIV Programmed cell death in metastatic tumor cells after the transfer of a functional iNOS gene … 356
• Table XV Programmed cell death in metastatic tumor cells after repeated injection of synthetic lipopeptides and induction of the iNOS enzyme for the synthesis of iNO … 357
• Table XVI Examples of the progressive decline in disease and mortality rates via infectious illnesses from 1838-1970 … 358

Chapter 10:

• Table XVII Typical Laboratory findings in cumulative wasting syndrome … 359

1-25 26-50 51-78

In scientific research, the following principle applies: a theory enables valid claims only if it describes as many model observations as possible (using as few unproven assumptions as possible) and makes verifiable predictions regarding future observations.

In 1916, the biochemist Mitchell observed that humans excrete more nitrites and nitrates than they could have ingested from food. However, Mitchell and his colleagues could not locate the source of nitrite and nitrate excretion in the human body. Mitchell made an astute statement, the validity of which would only be acknowledged 70 years later: “The problem is of peculiar theoretical interest, since the production of an oxidized radicle [sic] by animal tissues would be unique” (Mitchell 1916). Mitchell’s prediction regarding the “uniqueness” referred to the fundamental acceptance that nitrogen oxides could not be formed in the environment of mammalian cells. This belief remained unquestioned for decades.

In 1978, the synthesis of nitrites and nitrates was thought to be explained by the activities of microbes in the human small intestine (Tannenbaum 1978). Soon thereafter, the same research group corrected this interpretation, using evidence that rats purged of gut bacteria still produced nitrates in the small intestine. From this finding it was concluded that nitrites and nitrates are actually synthesized in mammalian cells in their own unique metabolic pathway (Green 1981). Thus it was for the first time demonstrated, in opposition to a long-held dogma, that nitrites and nitrates are actually created internally (endogenously) by mammalian cells, independent of the exogenous supply of organic nitrites and nitrates, that is, from outside the body, (i.e. from food, medicine, or “Poppers”).

At the same time, important realizations were made regarding the biological action of exogenous nitrites and nitrates. In 1973, the action of orally ingested organic nitrates was tested; they could not be found in the bloodstream after consumption, so it was assumed that they were rapidly metabolized. Beginning in 1976, however, the US research groups of Diamond and Murad showed that the vasodilatory effect of organic nitrates was based on the activation of ferrous enzymes (Diamond 1976, Murad 1978). In this context, Murad first hypothesized that the endothelial cells of the blood vessels release nitric oxide (NO). Ignarro’s research group confirmed this by demonstrating that NO bound with iron in the enzyme guanylate cyclase. This in turn activates the production of a messenger substance, cyclic guanosine phosphate, in the vascular smooth muscle cells. In this way the blood vessel is relaxed, thus lowering the blood pressure (Gruetter 1979). Ignarro and his colleagues also made the pivotal connection that organic nitrites must be metabolized into gaseous NO, in order to create the vasodilatory effect. They showed that molecules of NO bind with sulfur-containing molecules in the cellular metabolism, to create nitrosothiols (Ignarro 1981). This finding would later turn out to be extremely relevant to AIDS research; the exhaustion of thiol by nitroso-bonding, for example, caused by a continual surplus of exogenous nitrite/NO (Poppers!) and/or endogenous NO (chronic infectiosity), would lead to extreme reactions and counter-reactions in the immune cells, in addition to other consequences. Unfortunately, at the time of the first publicized clinical cases of AIDS in 1981, the research of Murad and Ignarro was not yet acknowledged; prominent cardiac researchers were still quite convinced that NO could not be synthesized in mammalian cells (Ignarro 1992). It was not until 1998 that, together with Furchgott, they were awarded the Nobel Prize for Medicine for the discovery of the biological role of NO (Ignarro 1992).

The Furchgott research group got lucky when, somewhat accidentally, they discovered further crucial findings in 1980. The pharmacologists found that the smooth muscle relaxation of blood vessels in response to vasodilatory nitrogen compounds is dependent on intact endothelial cells. Some of the endothelial cells were accidentally damaged in preparation, which prevented vasodilation from occurring. This accidental damage led to the conclusion that only intact endothelial cells were able to deliver the vasodilatory signalling chemical to the neighboring smooth muscle cells. This messenger compound was dubbed endothelium-derived relaxing factor (EDRF) (Furchgott 1980). Finally, in 1986 Ignarro and Furchgott independently postulated that EDRF was identical to gaseous NO. In 1987, the laboratories of Ignarro and Moncada furnished the first direct biochemical proof that NO is formed by the endothelial cells, and diffuses through the cellular membrane into the nearby smooth muscle cells (Ignarro 1987, Palmer 1987).

This time the skeptical researchers finally suspended their disbelief, because research in immunology had already proven that mammals could actually synthesize endogenous nitric oxide. The same research group that in 1981 proved the biosynthesis of nitrates in mammalian intestinal mucosa detected very high quantities of nitrate in the urine of an experimental subject with diarrhea. The researchers concluded correctly that the nitrate had formed from inflammatory reactions caused by the diarrhea. This was verified by injecting rats with bacterial proteins called endotoxins, which are biochemical lipopolysaccharides (LPS) composed of fat and sugar. The rats exhibited increased quantities of nitrate in their urine (Wagner 1983). Thus fortuitously the researchers had come to discover one of the most important immune-cell reactions: the production of nitrogen compounds in immune cells after stimulation by toxic microbial proteins. In 1985, American laboratory researchers furnished the unique proof in studies with mice; they found that macrophages (cells which digest foreign matter), present all throughout the body, exercise a central function for the non-specific immune defense; in response to contact with bacterial LPS, the cells form a gas cloud of nitrites and nitrates, which penetrates the bacterial membrane and disrupts its metabolic processes. The cell-killing (cytotoxic) effect of nitrogen compounds, as a defensive weapon of mammalian cells against bacteria, had been discovered at last (Stuehr 1985). In subsequent studies, other researchers demonstrated that the amino acid L-arginine, present in every cell of the body as a building block for protein synthesis, was also necessary for the synthesis of the cytotoxic nitrogen compounds used by macrophages (Hibbs 1987).

A short while later it was published that macrophages, if activated by special cellular communication proteins synthesized by all immune cells and other bodily cells, oxidize L-arginine into nitrite and nitrate, forming NO gas as an intermediary product (Marletta 1988). These communication proteins are called cytokines, since they act within and between cells to precisely regulate important cellular functions. Currently, about a dozen cellular proteins are recognized as members of the cytokine family. Later that year, Moncada et al. proved that endothelial cells in walls of the blood vessels also synthesize NO gas from L-arginine (Palmer 1988).

Because of the research findings secured in 1988, a crucial question arose as to whether the functional disturbances that the AIDS patients demonstrated (among certain immune cells, resulting in “opportunistic infections”; and within endothelial cells in the walls of blood and lymph vessels, resulting in the cancer-like Kaposi’s sarcoma and lymphoma) could be triggered by plausible nonviral causes.

AIDS researchers failed to ask the following crucial questions:

1. Whether the long-term inhalation of organic nitrites in combination with the intake of medicines that enhance the formation of NO and nitrosamine could lead to supra-elevated production of NO or its decay product nitrosamine?
2. Whether exposure to microbial toxins through chronic infection could lead to increased NO and nitrosamine production?
3. Whether an imbalance in cytokine synthesis as the net effect of exogenous and endogenous stimulation could result in production of NO gas and its biochemical decay products?
4. Whether the binding of overproduced NO to nitrosamine and/or sulfonamide detoxification metabolites to form nitrosothiol could result in the long-term exhaustion of the thiol pool?

These precise biochemical and bioenergetic crucial questions were not asked by the experimental and clinical AIDS researchers. The “tragic premature consensus” (Root-Bernstein 1993) blocked these plausible questions in favor of the consequence-fraught disease theory of a “new infectious agent” (Haverkos 1982).

Parallel to the realizations in immunological and cardiac research, NO gas was shown to be a neurotransmitter in the central and peripheral nervous system. In 1982, a research group found that the activation of cyclic guanosine monophosphate mediated the inhibition of impulses between nerves and muscles—similar to the processes between the endothelial cells and the smooth muscle fibers in the blood vessels (Bowman 1982). This inhibitor was identified as NO in 1988 (Martin 1988); the same year, published findings showed that if certain neurons in the brain were stimulated by the excitatory neurotransmitter glutamate, they delivered a messenger substance to nearby cells, which as in the muscle cells activated the ferrous enzyme guanylate cyclase, causing the formation of the important secondary messenger substance cyclic guanosine monophosphate (Garthwaite 1988). One year later, it was proven that nitrite and nitrate were synthesized from L-arginine in brain cells from cattle (Schmidt 1989). This finding was corroborated by evidence that NO is synthesized from L-arginine in the brain cells of rats (Garthwaite 1989). A further important discovery was made by American brain researchers, who in 1990 established for the first time in mammalian brain cells, the enzyme which uses molecular oxygen (O₂) to liberate gaseous NO from L-arginine. This process also requires the presence of calcium (Ca²⁺). The calcium ion, when bound to a protein called calmodulin, was found to control the activity of this newly discovered enzyme called NO synthase (NOS) (Bredt 1990).

A short time later came the proof of an NO synthase in endothelial cells, which is also regulated by Ca²⁺ and calmodulin. The NOS enzyme of the endothelial cells was found to have a slightly different structure than the NOS enzyme of the nerve cells (Pollock 1991).

At the same time, a third NO synthase was isolated in activated macrophages (Stuehr 1991). This NOS enzyme is fundamentally different from the Ca²⁺-dependent NO synthases in the endothelial and neuronal cells; it can produce NO gas in large quantities and for a longer time, as long as the stimulation persists and the supply of L-arginine and other factors are provided.

The pioneering work of NO researchers in immunology, cardiology, and neurology released an unparalleled explosion of research (overview Lincoln 1997). In 1992, the prominent research journal “Science” named NO as the molecule of the decade. In 1998, the Nobel Prize was awarded to the American physician Murad and the American pharmacologists Ignarro and Furchgott, for their innovative discoveries in nitric oxide (NO) research. The Nobel Prize committee spoke of a “sensation.”

Why were the discovery of the existence, and the various functions of gaseous nitrogen monoxide (NO) in mammalian cells systems, including humans, so sensational?

Nitrogen monoxide = nitric oxide = NO is one of the smallest molecules found in nature. It consists of a nitrogen and an oxygen atom. From this molecular combination, an unpaired electron results. NO is thus a radical: it can snatch away an electron from other atoms and molecules, thereby oxidizing them. The uptake of an electron (as well as a positively charged hydrogen ion, a.k.a. proton) by a receiving molecule is called reduction; conversely, the donation of an electron (as well as a hydrogen ion) is called oxidation. In living cells, the effective proportion of reduced substances to oxidized substances is called the redox balance. The redox potential can be measured in millivolts, for instance at the membrane of cells or their organelles.

A distinguishing feature of living cells is the dynamic maintenance of energy flows away from thermodynamic equilibrium. This is done via constant electron transfer, which at the same time produces proton gradients to increase or decrease the electromotive force.

A fundamental principle of evolutionary biology states that the more complex an organism has evolved, the more reduced it must be. In order to ensure the necessary predominance of the reduction status, any oxidation of a molecule or an atom (in each case by other molecules which can deliver electrons and protons) must quickly be reduced again. In living cells, this takes place particularly by means of sulfur-containing amino acids, sulfurous peptides with low molecular weight, and other sulfurous molecules. These sulfur molecules, biochemically termed thiols, together form a bodily reservoir known as the thiol pool. Thiols possess sulfur-hydrogen bonds, which contain an unpaired electron. This gives them a reductive capacity, in which they can exchange protons and electrons with other atoms and molecules. In this manner thiols can neutralize oxygen radicals and NO radicals. If the thiols are consumed by strong formation of oxygen and/or NO radicals, and free radicals can be no longer sufficiently controlled and neutralized, substantial shifts in the redox status will occur either in the entire cell or its component structures. Vital molecules such as proteins, nucleic acids, fatty acids and many other biological substances are damaged by reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are created by oxidative and nitrosative stress reactions. Too much damage can give rise to mutations and under certain conditions lead to cell death. Between these extreme responses to pro-oxidation (oxidative and/or nitrosative stress), various pathophysiological states can occur; dependent on the cell type, the extracellular environment, and a variety of counterregulations. These counterregulations, called into action by thiol deficiency resulting from strong ROS and RNS production, can occur temporarily or on a long-term basis. Knowledge of the regulation and counterregulations, controlled by the thiol-depletion sensor, is critical in solving the mystery of AIDS and cancer.

Since an unpaired electron develops during the formation of NO from L-arginine and molecular O₂, NO is a paramagnetic monoxide radical (NO⁰). In addition, it can also assume other redox statuses yielding different characteristics and reactivity: NO⁺ (nitrosium) and NO^–(nitrosyl anion). This free-radical characteristic enables NO to bind to metals such as iron in metallic enzymes and in other proteins (metalloproteins). Many enzymes in living cells contain such metalloproteins. Because of this, NO was already used more than 50 years ago to demonstrate metalloenzymes by means of Electron Paramagnetic Resonance (EPR) spectroscopy; in 1983, this procedure demonstrated that bacteria release NO after they come into contact with nitrites. The NO then binds to bacterial metalloenzymes and in this way causes their death (Lancaster 1992). However at that point in time, it did not occur to check whether nitrites and the NO formed from them are also produced in human immune cells as a diffusive gas for microbial defense. The mental block still existed that nitrogen oxides were not formed in mammalian cells. Thus the window of opportunity was missed by a few years in light of the mass poisoning of millions by organic nitrites as a sexual doping agent (poppers), to realize that the provocation of NO synthesis not only inhibits bacterial metalloenzymes, but with excessive and long-term inhalation of poppers also results in substantial regulation and counterregulation of the human immune and other cell systems (acquired immunodeficiency syndrome). Experiments with mice and rats were executed, by fumigation with organic nitrites or nitrosamine supplied via intranasal drip. It would have been possible to prove unique toxic effects in a variety of immune cell types after exposure to nitrites via animal experimentation or small groups of volunteer subjects, but the actual biochemical mechanism had not yet been recognized (overview Haverkos 1988).

NO is not the most reactive of free-radicals, since it cannot react with itself. In the aqueous solution of biological cell systems, in presence of O₂, it has a half-life of less than 30 seconds. Since NO is electrically neutral however, it can disperse freely within and between cells, and diffuse unhindered across the membranes of cells and their organelles. These characteristics led to the long-held assumption that NO was not a suitable candidate for an intracellular messaging substance.

Until the end of the ’80s, it was assumed that only complex molecular structures, emitted by precisely controlled mechanisms, could relay messages to complementary receptive target structures. In this manner a large distance between the message source and the receptor cells can be overcome, as is the case with hormones in the bloodstream. It was also known that transmission pathways of a very short range existed, as is the case with biochemical signal transmission between nerve cells (neurotransmitters). For hormonal messengers, special receptors on the cell membrane are not necessarily needed, as they can also penetrate into the target cell and interact with internal receptors (e.g. the hormone cortisol). In contrast, neurotransmitters do their work at receptor sites on the target cell. In both cases, the messenger molecule must make contact with a specific receptor. Therefore only specialized target systems should be able to synthesize the compatible messenger materials. Yet some exceptions to this biological rule are known. For example, prostaglandins occurring in many cell types, and adenosine triphosphate (ATP), the key molecule for energy metabolism synthesized in all living cells; both act as functional messengers between different cell types. Thus, molecules can play an important role in the metabolism of individual cells, as well as fulfil highly specialized functions between different cell types. A prerequisite, however, is that these molecules, active throughout the cells, once outside the cell boundaries find specific receptors on or in the recipient cells.

So far unique throughout evolutionary biology however, is the fact that NO, after synthesis and release from the originating cell to the adjoining cells, can cause a specific modification of the redox processes—without having to bind, for this purpose, to highly complex receptor molecules. These neighboring cells can be normally differentiated body cells, red blood corpuscles, tumor cells or any kind of microbial cells. The effects which NO produces in living cells, either within or between them, depend therefore not on the molecular shape, but solely on the characteristic of being a paramagnetic radical (Snyder 1992).

Contrary to the simple structure of NO, three isoforms of the NO-synthesizing enzyme, NO-synthase (NOS), were discovered, the first one in 1991. Close examination showed that these enzymes had a unique structure never before seen in mammalian cells. It was demonstrated that these enzymes are actually a combination of two different enzymes. This assertion applies both to the calcium-dependent isoforms, nNOS (first discovered in nerve cells) and eNOS (first discovered in endothelial cells), and to the calcium-independent isoform, iNOS (first discovered in phagocytes). One half of the NOS enzymes supplies the electrons for the synthesis of NO by means of O₂ from arginine, while the other half carries out the actual synthesis. A comparable enzyme that donates electrons has so far only been found in bacteria (Marletta 1993).

Comparative investigations of the three isoforms of NOS show a 50% commonality between the structures of the NOS subtypes. Furthermore, a comparison of these NOS isoforms in various mammalian species demonstrated a 90% structural equality. Thus, from an evolutionary-biological perspective, the structure of the NOS enzymes has been highly conserved (Knowles 1994, Nathan 1994, Sessa 1994).

The central findings of NO research can be summarized as follows:

• The unique function of the NO molecule in all living cells, from bacteria to humans.
• The uniqueness of the NO-synthesizing enzyme among thousands of enzymes in mammalian cells, human cells included, with the only occurrence of a similar enzyme being found in bacterial cells.
• The high degree of structural equality between the isoforms of the NO-synthesizing enzyme throughout evolution favors the perspective that NO gases and their synthesizing enzymes are an age-old communication principle within and between single-celled organisms, a principle which was retained by multi-cellular organisms and has thus been evolutionary and biologically conserved. This regulatory strategy works via the short-term modification of redox statuses, as NO is a paramagnetic radical which can, as an uncharged molecule, diffuse freely within and between cells; it binds with metalloproteins, especially ferrous enzymes. The bioenergetic modification of the redox potentials caused by this process are counter-regulated by sulfurous bonds (nitrosothiol), especially by high concentrations of low-molecular weight sulfur bonds, for example glutathione and cysteine, which together with other thiols form an anti-oxidative resevoir against ROS and RNS.

Over the course of the evolution, two strategies of NO production developed:

• Synthesis of small amounts, dependent on the level of intracellular calcium, has been proven in practically all human cell systems and is involved in a multiplicity of physiological and pathophysiological processes (Moncada 1991).
• The inducible large-quantity and long-lasting NO production, which is carried out by activation of the calcium-independent enzyme iNOS. The iNOS enzyme and the corresponding high output of NO gas clouds were proven in numerous non-specific and specific cell types of the human immune cell network, especially in macrophages and monocytes, microglial cells of the brain, Kupffer’s cells, spleen cells, neutrophilic leukocytes and T-cells (overview Kroencke 1995, Lincoln 1997).

Due to the realization that immune cells produce cytotoxic (cell-restraining or cell-killing) NO gas, the question of crucial interest was whether an elimination of NO synthesis within mammalian immune cells would cause a measurable reduction of the immune defense against microbial agents. This question, central to infectious-disease medicine, was tested in numerous cleverly devised experiments.

For example, a research group working with knock-out mice blocked the gene responsible for the protein biosynthesis (expression) of the inducible NOS enzyme. These mice could no longer produce cytotoxic NO gas in the appropriate immune cells. In other experiments, the cytotoxic NO synthesis in immune cells was prevented by iNOS inhibitors. These types of experiments all showed the same thing: that without sufficient production of cytotoxic NO gas, the ability of the immune cells to restrain or kill microbial agents was heavily suppressed. These particular knock-out mice were shown to be extremely susceptible to bacterial and parasitic infections, since due to NO inhibition their activated macrophages could no longer kill bacteria (Wei 1995 a, MacMicking 1995, overview Lincoln 1997). Such experiments led to another important realization: macrophages of knock-out mice in which iNOS synthesis was blocked could no longer restrain the growth and uncontrolled cell division of lymphomas (= rampant cancerous growth of lymphocytes, among other things an AIDS-indicating illness). Likewise, macrophages with blocked iNOS synthesis cannot restrain tumor cells in co-cultivated cell cultures (MacMicking 1995). On the other hand, the expression of iNOS in tumor cells from a multiplicity of cancerous human tissues was demonstrated, for example in ovary, uterine, and breast cancer (Henry 1993, Nussler 1993, Bani 1995, Thomsen 1995).

These findings and many others (overview Kroencke 1995, Lincoln 1997) were supplemented by the proof that the following cell systems, including mobile immune cells, can produce cytotoxic NO gas:

• Mucous membrane cells (stomach, intestine, kidney, lung, and many others),
• Endothelial cells,
• Vascular smooth muscle cells,
• Cardiac muscle cells,
• Cartilage cells,
• Bone cells (osteoblasts),
• Fibroblasts of the connective tissue,
• Keratinocytes of the skin,
• Liver cells,
• Pancreatic cells,
• Astrocytes in the brain,
• Peripheral nerve cells (overview Kroencke 1995, Lincoln 1997).

Within a few years it could be demonstrated to the world that in practically all cell systems of the human organism, with appropriate stimulation, the universal diffusive messenger gas NO plays a crucial role in the regulation of the redox potentials, both within cells and between neighboring cells, e.g.: between immune cells and microbes, local mucous membrane cells and microbes, normally differentiated cells and cancerously transformed cells.

Since that time, experimental and clinical study of gaseous nitrogen monoxide and its biochemical descendants in human cell systems has had a profound impact on the understanding of elementary disease processes.

Below is a partial list, with some references, of the medical fields affected by the new nitrogen research:

• Immunology (von Rooijen 1997, MacMicking 1997, Zidek 1998, Kolb 1998),
• Infectious disease (Clark 1996, 1997; Alexander 1997, Mayers 1997, Liew 1997, Peterhans 1997, Akaike 1998),
• Hematology (Yonetani 1998),
• Oncology (Tamir 1996. Xie 1996, Chinje 1997),
• Cardiology (Habib 1996, Birks 1997, Dewanjee 1997, Matsumori 1997, McQuaid 1997, Wever 1998),
• Diabetes research (McDaniel 1996, Rabinovitch 1998, Sjoeholm 1998),
• Hepatology (Suematsu 1996, Stadler 1996, Ceppi 1997, Taylor 1998, Khatsenko 1998),
• Sepsis research (Beizhuizen 1998, Ketteler 1998, Kirkeboen 1999),
• Lung research (Singh 1997, Sanders 1999),
• Tuberculosis research (Kwon 1997),
• Organ transplantation research (Krenger 1996),
• Rheumatology (Mijasaka 1997, Ralston 1997, Amin 1998),
• Brain and nerve research (Bolanas 1997, Leist 1998, Vincent 1998, Minghetti 1998, Murayama 1998),
• Multiple Sclerosis research (Parkinson 1998, Santiago 1998),
• Stress and hormone research (McCann 1998 a, 1998 b; Rivier 1998),
• Sleep research (Liew 1995 b),
• Sexual medicine (Guiliano 1997).

The universal function of the cytotoxic NO gasification and of the metabolites derived from this pervasive bio-molecule, as an archaic regulatory principle in human cell systems, has placed into question all previous disease theories—particularly those of AIDS and cancer. However, in light of a dynamic evolutionary view of these disease phenomena, an abundance of findings can be integrated into a revised holistic conceptual understanding.

On June 5, 1981, the first medical report regarding lethal opportunistic infections in US homosexual men was published by the supervising authority for diseases, the Center for Disease Control (CDC), in the weekly report on morbidity and mortality (CDC 1981 a). Of note were five “active homosexuals” between the ages of 29 and 36, who were treated in two Los Angeles hospitals between October 1980 and May 1981. These five patients had no sexual contact with each other. They all suffered from a fungal infection of the lung, which led to a rare form of pneumonia called Pneumocystis carinii pneumonia (PCP), as well as previous or current infections with cytomegalovirus (CMV) and a fungal infection of the mucous membranes called candidiasis. Two of the patients had died.

In three of the five patients, tests were run to determine the quantity and reactivity of the immune cells in their blood serum. “All three patients had profoundly depressed in vitro [in the test tube] proliferative responses [inhibited maturation] to mitogens [substances which energize the cell division] and antigens [substances which activate the T-helper immune cells]” (CDC 1981 a).

The report did not give any details of prior consumption of antibiotics, antifungals, antiparasitics, antivirals, chemotherapeutic agents, or corticosteroids. It was only stated succinctly that “the 5 did not have comparable histories of sexually transmitted disease.” The complete oversight or inadequate investigation of the prior use of antibiotics, etc. (whether medically or self-prescribed), would become an unfortunate hallmark of subsequent AIDS medicine and corresponding clinical publications.

In the case of the five patients in Los Angeles, four of them previously had hepatitis B, as determined by serological investigation, but had no current hepatitis S surface antigens. Without any further explanation or discussion, it was casually noted in one sentence that “all 5 reported using inhalant drugs, and 1 reported parenteral drug abuse.”

     Half a year after this historic medical report on AIDS-indicating illnesses in homosexual patients, the attending physicians of the UCLA clinic published a follow-up report on four of the original five patients (Gottlieb 1981). This second report had more specific detail regarding immunological data and clinical procedures.

“These patients presented a distinct and unusual clinical syndrome. All were exclusively homosexual and had been in excellent health before late 1980. Their medical histories did not suggest preexisting immunodeficiency. All were anergic and had infections in which cell-mediated immunity plays the major part in host defense. P. carinii pneumonia, extensive mucosal candida infections, and chronic viral shedding were uniformly present … The most striking abnormalities were the nearly total elimination of Leu-3+ [CD4+] helper/inducer cells and an abnormally increased percentage of Leu-2+ [CD8+] suppressor/cytotoxic cells … The absolute numbers of cells in both subsets were decreased … The virtual absence of the Leu-3+ subset was undoubtedly the major contributing factor to the severe immune deficiency observed in our patients. The mechanism of this differential effect on the Leu-3+ subset is still unclear, since cytomegalovirus has not been shown to infect subpopulations of lymphocytes directly … We acknowledge the possibility that cytomegalovirus infection was a result rather than a cause of the T-cell defect, and that some other exposure to an undetected microorganism, drug, or toxin made these patients susceptible to infection with opportunistic organisms, including cytomegalovirus … The explanation for the elevated IgA levels in these patients remains unclear” (Gottlieb 1981).

     In summary the University physicians observed: “All patients were anergic and lymphopenic; they had no lymphocyte proliferative responses to soluble antigens, and their responses to phytohemagglutinin [a mitogen] were markedly reduced” (Gottlieb 1981).

At the same time, these clinical and immunological findings were acknowledged by several medical centers in New York in sexually active homosexual patients with AIDS-indicating diseases: “None of the patients had cutaneous reactivity to any of the antigens tested. This anergy was present during the acute illness, and it persisted in the patients who were tested for delayed hypersensitivity [DTH, a routine test for the reactivity of the immune cells in the skin, tested by means of a variety of microbial toxins and other substances] more than two weeks after the P. carinii pneumonia had clinically resolved … The patients had lower proliferative responses [of the T-helper cells] to various mitogens, antigens, and allogeneic cells [all of which are materials that energize the activation and division of lymphocytes] than did a simultaneously tested age-matched control group. These responses represent the maximal lymphocyte proliferation that could be elicited with a range of concentrations of stimulating substances and cells. Since only pooled normal human serum was used to supplement the lymphocyte-culture mediums, it is not possible that serum suppressor factors had a role in these abnormally low responses. An impaired cellular immune response in the patients, as compared with the controls, was observed in in vitro studies of lymphocytes cultured with non-specific inducers of T-lymphocyte activation: phytohemagglutinin, concanavalin A, and the T-cell-dependent inducer of mitosis in B-cells, pokeweed mitogen. Lymphocyte responses to the microbial activators C. albicans, Staph. aureus, Esch. coli, and purified protein derivative of tuberculin were also depressed … These tests of lymphocyte proliferation were performed when the patients were not acutely ill. In addition, repeated evaluation more than one month after the first evaluation confirmed the same type of abnormally depressed responses” (Masur 1981).

These historic medical reports clearly show the lack of knowledge in the fields of immunology and clinical infectious medicine in the early ’80s; the fact that the T-helper immune cells in AIDS patients were drastically diminished in number and could not be stimulated, was incongruent with the fact that simultaneously the production of certain antibodies was increased. According to the then-valid immune theory, B-cells (B for bone), which mature in the bone marrow, need to receive an activation signal from the T-helper lymph cells which mature in the thymus (T for thymus) in order to produce antibodies against a microbial antigen detected by the T-cells; therefore the designation “helper.”

What immunologists and clinicians did not yet know in 1981 was the fact that there are two kinds of T-helper cells: type 1 and type 2, defined accordingly as Th1 and Th2. These two kinds of T-cells behave in markedly different ways:

• Th1 cells are produced and stimulated, compared with Th2, by a different profile of signal and communication proteins from the large family of cytokines. The cytokine profiles of type 1 have the particular characteristic that they stimulate production of cytotoxic NO gas in the Th1-immune cells, as a defense against intracellular microbes. In contrast, the type 2 cytokines cause T-cells to mature into Th2 cells, which produce no cytotoxic NO gas but rather take on the actual helper function, to activate the B-cells and thereby stimulate anti-body production. The type 2 cytokines of the Th2 cells even inhibit the protein expression (biosynthesis) of the enzyme for inducible NO synthesis (overview Lincoln 1997).
• The central study of cytokines only intersected with NO research at the beginning of the 1990s. Unaware of the basic facts regarding the existence of the type 1 and type 2 cytokine-producing T-cells, AIDS doctors were inevitably perplexed by the immunological and clinical findings of their homosexual patients. In the context of this medical helplessness, it can be understood why a hypothetical retrovirus, whose existence was maintained solely as a result of indirect laboratory markers, was so readily accepted as the cause of AIDS.

Now the crucial question to be asked is why does this dual strategy for immune defense exist? This question can only be answered in the context of evolutionary biology, namely the development of the immune defense in invertebrate and vertebrate organisms.

The equivalent of T-cells are first seen in primitive invertebrate animals, for example the sponges, evolving more than 500 million years ago (Roitt 1985). Upon contact with bacterial toxins, T-cells form a cloud of NO gas that diffuses across the bacterial membrane and binds to metalloenzymes or thiol-peptides, paralyzing the energetic metabolism of the invaders and thus rendering them lame or dead. A similar process occurs when macrophages or other special cells present fragments of protein chains (peptides) to the T-cells, as molecular antigen signals. These peptide fragments come from intracellular bacteria, viruses, parasites, or fungi, which were cleaved by protein-splitting enzymes in the antigen-presenting cells. After activation by the antigen signal, the T-cells produce specific cytokines, mature and propagate identically (as clones), and under influence of type 1 cytokines continuously synthesize large amounts of cytotoxic NO. The NO gas diffuses into the antigen-containing cells, which die along with their intracellular passengers. The mouth-like cells of the immune system, the macrophages, usually devour the remaining cellular debris.

When vertebrate animals developed from invertebrates after a long evolutionary epoch, they needed more than just the singular immune response against bacteria, viruses, parasites, and fungi as they were themselves invaded by invertebrate animals, namely worms. Such invaders could not be captured by the macrophages and presented to the T-cells as “fillets.” Compared to the single-celled microbes and the smaller multi-cellular parasites, the invertebrate parasites are enormous. Such quantities of the gas-cocktail would have been required from the gas-producing T-cells that the integrity of the defending organism’s own cellular systems would be compromised. The host animals would have been damaged and destroyed by their own gas defense.

     Thus arose the need for a more modern immune response, and so the immune defense was retrofitted by evolution with the (specific and non-specific) cell-mediated defense, known as the humoral immunity (from the Latin: humor = liquid). The humoral immune response has both a specific and nonspecific component. The nonspecific part is called the complement system, which involves a series of proteins occurring in the blood plasma and intracellular fluids, and can be activated in different ways via an intricate cascade of chain reactions. In a very complex way, the complement system is counterregulated by inhibitors and control proteins. The end result of the activated complement cascade is the perforation (opsonization) of cellular membranes, for example those of bacteria, resulting in their destruction. The non-specific complement system is closely coupled to the specific humoral defense system by immunoglobulins: glycoprotein antibodies that are custom manufactured by a special class of lymph cells called the B-cells. As they mature, the B-cells go through a complicated developmental sequence. On their surface, mature B-cells carry cell-bound immunoglobulin (antibody). If a soluble antigen (for example a protein molecule from microbes or the host, or a non-protein molecule) binds to a corresponding antibody-mature B-cell, this antigen is recognized as abnormal and an activation signal is released to other B-cells. Under the influence of the nonspecific (by macrophages) and specific (by T-cells) immune responses, the B-cells divide (by clonal expansion) and mature into antibody-producing plasma cells, which can set their immunoglobulins free as soluble antibodies.

Human antibodies are differentiated into five immunoglobulin (Ig) classes: IgM, IgG, IgA, IgD and IgE. Formation of IgM is the initial response in a humoral immune reaction; IgG and the other sub-classes are formed as a secondary response. Only IgG can cross the placental barrier, conveying protection to the newborn child in the first phase of its life until the development of its own antibodies. The antibodies of the IgA class are found in the serum, and in secretions, for instance in the breathing passages, the digestive tract, and breast milk. IgD is used as receptors on the surface of B-cells in their early maturation phase. IgE plays an important role in parasitic worm infections and allergic reactions.

The plasma cells can manufacture an extraordinary variety of custom-made immunoglobulin proteins, using a relatively small number of genes for synthesis by aggregate combination and rearrangement; these proteins can selectively react with as many abnormal foreign and self proteins and with other molecules. However, due to sophisticated surface properties, specific antibodies can also bind non-specifically with divergent antigens (foreign or self molecules), and conversely the same antigen can interact with many different antibodies (cross-reactivity).

In invertebrate animals, humoral immune factors are called antisomes, and resemble the enzymes of the complement system. With more highly developed invertebrates such as crabs and spiders, these humoral complement factors are already substantially evolved. However, antibody-producing lymphocytes are only possible with the development of bone marrow and a sophisticated circulatory system, which can be traced back to the first amphibians (anurans) and fish (Roitt 1985).

Thus through different stages of biological development, the human immunity evolved different components that require precise coordination. The harmonization between the T-cell system and the antibody-producing B-cells is regulated via cytokine patterns. Like genetic expression (protein biosynthesis), cytokine expression is also redox-dependent (Senn 1996). If the redox status changes, so does the cytokine pattern. If the expressed pattern leans towards type 2 cytokine dominance, more Th2 cells are produced. The consequence is increased antibody formation by the B-cells, since the stimulating relationship between T-helper lymph cells and B-cells is predominantly controlled via the Th2 cells; Th1 cells control only a small branch of antibody production.

In the context of evolutionary biology, the development of the complement system and B-cell antibody production are to be regarded as extracellular assistance for the T-cell network (which is responsible for intracellular disposal). Historically in research, however, certain T-cells were regarded as helper cells for the B-cells and therefore were named accordingly. The control circuit behind the cellular immune network, and within the network of organ cells enabled for NO synthesis is, however, far more complex.

Over the course of evolution, the autopoietic (from the Greek: auto = self + poiein = make, meaning: self-organizing) maintenance of the reduction potential potency, apart from states of scarcity and hunger, naturally proved to be threatened by too great a load of microbial antigens. The unique diffusivity of NO within cells, for the short-term modification of the redox status by means of binding to metalloproteins, could additionally be used as a cell-penetrating cytotoxic defense. NO gas is a double-edged molecular sword: under excessive and/or prolonged antigen presentation, the T-cells are substantially stimulated and produce too many type 1 cytokines. These in turn further energize the cytotoxic NO synthesis, namely by interferon-γ. At the same time, especially by the production of type 1 cytokines, tumor necrosis factor is increased, which in turn increases the formation of oxygen radicals in the mitochondrial respiration chain. The reactive oxygen species (ROS) include, among other things, the superoxide anion (O₂^*), peroxides (hydrogen peroxide (H₂O₂), lipoperoxides) and hydroxyl groups (OH); together the NO radical and the superoxide anion form peroxynitrite, which in large quantities is more toxic than NO.

Excessive production of nitrogen oxides and ROS must be counterregulated against, in order to protect the organism from serious cellular damage due to loss of the reductive potency by hyperoxidization. Thus at this critical juncture, multiple counterregulation programs will intervene. The pivotal control variable is the thiol pool. Since sulfur and oxygen are in the same series of the Periodic Table of Elements [have the same number of valence electrons], reduced thiol electrons (and at the same time protons) can transfer to the radical oxides (NO, CO₂^*–). In this way, the redox equilibrium is adjusted within the cell in cooperation with antioxidative enzymes, vitamins and certain coenzymes.

Since the more complex cells of mammals and humans exhibit a greater antioxidative reduction potency than microbes, they can usually adjust to the state of oxidative emergency caused by the chain reaction of antigen stimulation. However, the cells that are directly bombarded with large quantities of NO gas by T-cells suffer programmed cell death, bringing down with them the microbes settled inside. Crucial, however, is the circumstance that the oxidized thiols are brought back to a reduced state by certain enzymes and coenzymes in order to maintain their function as redox regulators. However, if this rebalancing does not occur (perhaps, because the ratio of reduced to oxidized thiols shifted too much towards oxidization; or the supply of available reduced thiol was exhausted, for example by heavy nitrosothiol binding; or due to an insufficient exogenous supply of sulfurous amino acids such as methionine and cysteine, or other thiols) then the low level of thiol pool antioxidants will trigger counterregulations in the particularly redox-sensitive immature T-helper cells. This T-cell sensor, now below a critical threshold, triggers genetic counterregulations that switch the expression of cytokines from type 1 to type 2. The consequence is that the natural equilibrium between the type 1 cytokine T-cells (Th1) and the type 2 cytokine T-cells (Th2), shifts in favor of increased Th2 cells. This means that the immune reaction is relocated predominantly into the extracellular sphere, to the detriment of the intracellular microbial defense. Not enough of the NO-synthesizing Th1 cells are available, and the intracellular microbial defense is weakened. By the increase of the Th2 cells, whose type 2 cytokines suppress NO synthesis, antibody production is increased in the B-cells. Just like the Th1 cells, Th2 cells become activated after antigen stimulation by antigen-presenting cells (APCs, e.g. the ubiquitous dendritic APCs and the macrophages). The difference lies in the fact that unlike Th1 cells, the Th2 immune cells do not spray cytotoxic NO gas, but rather set the antibody synthesis into motion by cytokine signalling to the B-cells. Put casually, the immune defense thus switches from an ancient NO gas war, to the subsequently evolved biological missile attack of the antibodies.

This dualistic strategy, however, has pros and cons for the infected organism. On one hand, cell systems are protected against heavy nitrogenous and oxidative stress in the case of excessive and/or prolonged burden by antigens and microbial toxins. On the other hand, the complement and antibody defense are not sufficient against a multiplicity of microbes. Bacteria (with the exception of mycobacteria, the agent of leprosy, tuberculosis and other infections) are held relatively well in check by the complement antibody reaction, since their cell membranes are vulnerable to antibodies. However, fungi and parasites possess a more complex cell wall and often have developed their own molecular defense. In mammals and humans they must, just as with mycobacteria and intracellular viruses, be restrained or killed by sufficient NO gasification by the Th1 immune cells, the neutrophilic leukocytes, the macrophages, microglial cells in the brain (which act there as mouth-like cells), and others.

The crucial matter, which thus gives the “opportunity” of infectious seeding to the fungi, parasites, mycobacteria, and intracellular viruses which cause opportunistic infections in AIDS patients, is to determine the cause of the switching from a Th1 response to a predominant Th2 response. This switch is almost certainly related to a suppression of the cytotoxic NO gasification for lack of type 1 cytokines. Additionally, the production of type 2 cytokines further attenuates NO synthesis, and results in increased antibody levels in the blood serum and extracellular fluids.

The immunological observations (anergy and strong reduction in number of T-cells, combined with elevated antibody levels) in the homosexual patients with opportunistic infections in Los Angeles and New York, first published in 1981 (CDC 1981 a, Gottlieb 1981, Masur 1981) must be interpreted retrospectively as the Th1-Th2 switch. The acquired immune deficiency syndrome (AIDS) is the consequence of an acquired exhaustion of the antioxidative thiol pool in the T-helper immune cells and other cell systems. Immunologically, this thiol deficiency syndrome manifests itself by the type 2 cytokine pattern (Th1-Th2 switch), and clinically by opportunistic fungal and parasitic infections, due to reduced production of cytotoxic NO gas by the T-helper immune cells and by increased antibody formation due to successful inhibition of bacterial infections (with the exception of mycobacteria). The cause is an unusually excessive and prolonged nitrogenous and oxidative stress load from:

• nitrite inhalation
• microbial antigen and toxin stimulation
• immunotoxic medicines
• many other stress factors (outline to the pathophysiological stressors of homosexual patients with Root-Bernstein 1993, Haverkos 1988).

For the understanding of AIDS-indicating diseases, it is crucial to realize that the evolutionary and biologically programmed flipping of the cytokine switch is caused by depletion of the thiol pool, independent of the source of NO gas hyperproduction. Thiol exhaustion—as both a sign of excessive and/or prolonged nitrogenous and oxidative stress, and a sensor for the protection of the cell systems by modification of the redox status—switches the pattern of cytokine expression in all cases identically. This occurs, for example, due to excessive and/or prolonged NO production after stimulation with microbial antigens and toxins, and likewise after inhalation of nitrites. The latter is metabolized in the bloodstream into nitrate, and intracellularly as NO. NO can further be bound as nitrosothiol, and stored stably in special cell organelles called lysosomes (Ignarro 1992).

Thus long-term nitrite inhalation simulates the same net effect on the T-helper immune cells as NO gas hyperproduction in response to microbial antigens or toxin exposure. Starting from a critical threshold value in the particularly redox-sensitive and short-lived immature T-helper cells, the predominant cytokine synthesis pattern is adjusted in response to the changed redox environment, and the Th1-Th2 switch flips towards Th2 cell dominance.

This process happens in two phases: a preliminary phase of NO gas hyperproduction with corresponding antioxidative thiol consumption, followed by a phase of the restriction of NO gas production by type 1 cytokine inhibition in the T-helper immune cells and other cell systems. The result is a partial weakness of the cell-mediated immunity, which can be temporary or long lasting.

As to the AIDS clinicians who in 1981 diagnosed the first homosexual AIDS patients with immunological anomalies, the lack of T-helper cells and their anergy is thus plausibly explained by an imbalance of the Th1/Th2 immune cells favoring the type 2 cytokine pattern. The stimulation of the T-helper cells by the usual mitogens and antigens presupposes the presence of certain type 1 cytokines, namely interleukin-2. Anergy is thus primarily based on interleukin-2 insufficiency. The relative total number of T-helper cells, measured only in a sample of blood serum by means of monoclonal antibodies, can be misleading as to the quantity of T-helper cells actually available in the organism. The quantity of T-cells in the blood serum depends on many factors, and is not constant over time. For example, the cortisol level explains the fact that T-cell counts in the morning can be up to 100% lower than in the evening and night hours. This explains the well-known fact that inflammatory illnesses can worsen at night because of the higher Th1 cell quantity and thus higher NO synthesis, which is central to inflammatory processes. Usually only 2-4% of the T-helper cells circulate in the bloodstream; within 24 hours they progress through the lymph fluids in a dormant state (so long as they are not activated to function as effector cells), and flow back into the bloodstream. With a Th1-Th2 switch, the T-cell count in the bloodstream changes. The function of the Th2 lymphocytes is the cytokine-supported stimulation of B-cells for antibody production. Thus they are predominantly outside the bloodstream at their actual work place in the neighborhood of the B-cells, instead of uselessly roaming the bloodstream. The ratio of the B-cells to the T Helper lymphocytes in the bloodstream amounts to 1:6, even though in adults, more B-cells are produced in the marrow than T-helper cells are in the thymus, an organ which usually deteriorates continuously starting from the first year of life.

The AIDS medical profession falsely interpreted, albeit unwittingly, the clinical and immunological findings of:

• The cytotoxic NO synthesis of the Th1 helper cells,
• the inhibition of the cytotoxic NO synthesis by the switch from Th1-Th2 dominance,
• the change of the cytokine pattern from type 1 to type 2,
• the migration of Th2 helper cells into the domain of the B-cells, and
• the evolutionary-biological program of the Th1-Th2 switch controlled by the thiol pool as redox regulator.

Based on the level of knowledge at that time, they believed that the snapshot of a depleted T-helper cell count in circulating blood, combined with anergic reactions in both the DTH skin test and test tube stimulation, was a sign of a T-helper cell defect. As possible reasons for the assumed immune cell defect they considered:

• an unknown microorganism,
• drugs (pharmaceutical or recreational), or
• a toxin (Gottlieb 1981, Masur 1981).

Yet a serious difference exists between an immune cell defect and an immune cell imbalance as the consequence of a systemic functional adjustment of the cellular immune network in response to a changed redox environment. If the cause of the postulated immune cell defect is, for example, an unknown microorganism in the form of a virus that infected the T-helper cells, then this virus would also propagate with each natural cell division of the T-cells, and the subsequently matured T-cells would be defective as well. Additionally, the danger exists that the viruses will migrate from the defective T-helper cells and infect healthy T-cells. The result will be difficult-to-treat opportunistic infections by fungi and parasites. The healing of this progressive immune defect can only occur if one succeeds in medically restraining or killing the assumed viruses in the T-helper cells without destroying the immune cells themselves. If one assumes that the carriers of virus-infected T-helper cells can transfer these through sexual intercourse by means of semen to a sexual partner, or by transfer of blood and blood products to recipients, or from virus-infected pregnant women to their children, then this logic induces the existence of a potentially deadly mass epidemic with unpredictable consequences.

However something important could not be explained by this scenario of a T-cell defect induced by a hypothetical virus: the increased antibody production of the B-cells. In the early 1980s, the dominant paradigm of immunology rightfully held that such defective and decimated T-helper cells could not possibly activate B-cells. Thus the hypothesis of a virally induced T-cell defect resulted in an unsolvable contradiction, which was labelled with the term: “intriguing AIDS puzzle” (Friedman-Kein 1984).

Yet if an imbalance of the immune cells is postulated to be the cause of the clinical and immunological anomalies, then the findings can be explained without contradiction: the cell-mediated immune response of the T-helper cells involving NO synthesis is restrained by the acquired lack of thiol, thus the cytokine patterns are reprogrammed and the resulting Th2 dominance stimulates B-lymphocyte activity for increased antibody production; this acquired immune cell imbalance is not contagious, and thus gives no massive viral epidemic transmitted by sex or blood. What can be transferred however, are fungi, parasites, viruses, and bacteria, which in humans with a preexisting immune cell imbalance can lead to opportunistic infections.

     We have encountered these illnesses since the beginning of mankind, since the Th1-to-Th2 switch represents an ancient evolutionary-biological mechanism for adjustment to extreme nitrogenous and oxidative stress. Modern medicine only relabelled these symptoms as AIDS, when a subset of homosexual men experimented with a previously unknown combination of nitrite inhalation, consumption of immunotoxic medicines and drugs, as well as multi-infectious antigen and toxin exposure, causing immune cell imbalance as the inevitable outcome. It was the unusual provocation of the immune system that was new, not its response according to evolutionary-biological principles.

If the crucial connection between the role of NO gas, the cytokine patterns, the immune cell switch, and the sulfur detoxification molecules in human cell types, had already been investigated 15 years ago, the alleged “most frightening epidemic illness of the 20th Century” (Gallo 1991) would never have occurred as such. The diagnosis and treatment of Acquired Immuno-Dysbalance Syndrome in place of an Acquired Immuno-Deficiency Syndrome would not have necessitated the presumption of an “undetected microorganism” as cause of the disease (Gottlieb 1981).

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In 1909, the Brazilian microbiologist Chagas published his findings about a particular parasite in the lungs of an infant and termed it trypanosoma infection. Trypanosomes are, among other things, the pathogens of sleeping sickness. Research on animals initially substantiated the diagnosis. In 1912 the Italian microbiologist Carini defined a similar pathogen in the lungs of rats as Trypanosoma lewisi. The husband and wife team Delanoe in Paris compared the findings of Carini with the results of research on the lungs of sewer rats and proved that they were not trypanosomes but an independent pathogen, which they named Pneumocystis carinii (Cantwell 1984, Armengol 1995).

It took almost a generation until this pathogen was recognized as clinically relevant in non-bacterial (atypical) pneumonia in premature babies and newborn infants with dystrophy. The latter denotes a protein-energy deficiency syndrome, frequently combined with vitamin deficiencies. The first published reports of cases of Pneumocystis carinii pneumonia (PCP, also known as pneumocystis of the lungs) in infants appeared in Germany (Ammich 1938, Benecke 1938). Before the introduction of sulphonamides as anti-bacterial chemotherapy by Domagk (Nobel Prize for Medicine 1939), most of the premature and dystrophic infants died of bacterial infections within the first weeks of life. However, the pharmaceutical containment of the bacterial sepsis precipitated the development of pneumocystis, which was especially prevalent in orphanages. Between the years 1941 and 1948, alone in Switzerland, more than 700 cases of infant pneumocystis were reported, in Hamburg between 1950 and 1954 it was more than 190. This was mainly due to epidemics in orphanages, which began to end around 1960 as a result of considerable improvements in nourishment. Individual cases of PCP, however, were reported from all countries carrying out systematic autopsies on deaths of premature and newborn infants, except the USA (Vanec 1952, 1953, Deamer 1953, Weller 1956, Gajdusek 1957, Dutz 1970, Pifer 1978, Cantwell 1984, Armengol 1995). A Canadian pathologist stated: “PCP is much more common in this country than we thought, we just have to open our eyes to see it” (Berdnikov 1970). In 1970, PCP in newborn infants was classified differently than PCP in older children and adults.

• Diffuse and bronchial PCP was diagnosed in premature and newborn infants in overcrowded paediatric wards and orphanages. Immunological analysis showed a pronounced immune imbalance, mostly between the first 10 to 28 weeks of life, as a result of prematurity, starvation or inadequate nutrition, frequent intermittent debilitative infections with antibiotic therapy, and recurrent diarrhoea in conjunction with artificial feeding and vitamin resorption deficiencies.
• PCP occurred with a congenital immunity imbalance in older children, as a result of insufficient T-cell ripening in the thymus and an underproduction of the immunoglobulin Ig class G.

PCP developed in children and adults in three forms of acquired immunodeficiency (AID):

1. In cancer and organ transplant patients treated with immunotoxins.
2. After long term treatment with corticosteroid hormones for patients with rheumatoid arthritis, connective tissue diseases, dermatosis, allergies, haemolytic anaemia, organ transplants and cancer diseases.
3. In patients with disorders of immunoglobulin formation, especially immunoglobulin class G, malignant degeneration of the B-cells (multiple myeloma and all forms of lymphoma), tissue macrophages (histiocytoma) and white blood cells (all forms of leukaemia).

It must be emphasized that PCP, whether caused by congenital or acquired immunity deficiency, very often appears in conjunction with fungal and viral infections (Dutz 1970, Pifer 1978).

Extensive animal experiments have been carried out since the 1950s. Experiments on rats, dosed with antibiotics after corticosteroid treatment, demonstrated that pneumocystis could be provoked. Sterile rats in isolators did not develop PCP after corticosteroid and tetracycline treatment, but with the same treatment plus a protein-free diet the animals displayed signs of a pneumonitis, like PCP, but no PCP pathogens were found in the lungs after death. However, when the immunosuppressed animals, under corticosteroid treatment, came into contact with non-sterile animals they developed a pronounced pneumocystis with evidence of PCP pathogens. The PCP pathogens were carried through the air from animal to animal without affecting the non-immunosuppressed animals (Weller 1956, Sheldon 1959, Frenkel 1966).

In Western countries, pneumocystis diagnoses among dystrophic infants (as a result of starvation or malnutrition) point to the millions of statistically unmeasured illnesses and deaths in the Third World through acute or chronic protein-energy malnutrition syndromes (PEM): “In the tropical developing countries very frequent and socially highly significant, nutritional diseases emerge—a distinction is made between marasmus (caloric undernourishment corresponding to infant dystrophy) and kwashiorkor (protein deficiency syndrome corresponding to a flour-based nutritional disturbance). Hybrids and combinations of vitamin deficiency are frequent, only a fraction of the nutritional disturbances become clinically manifest. They account indirectly for a sharp increase in infant and child mortality, in that they weaken resistance against acute infectious diseases. Therapy: Introduction of a diet with sufficient energy and proteins. Prophylaxis: improvement of the social situation, improvement in farming and nutritional counselling” (Pschyrembel 1990).

This definition of PEM stems from the Klinisches Wörterbuch (Clinical Dictionary) commonly used by German-speaking doctors. Apart from the inept therapy recommendations (which from the viewpoint of affluent Western society gives the impression that people from the Third World are starving as a result of ignorance), there is no reference, whatsoever, to concrete opportunistic infections as a result of PEM. They are the typical AIDS-indicator diseases like PCP, other fungal infections, mycobacterioses like miliary tuberculosis, and viral infections inclusive of cytomegalo and herpes viral infections with concurrent thymus atrophy as a result of a cell-mediated T-cell immunity dysbalance (Purtilo 1975). Significantly, this form of thiol deficiency syndrome resulting from the absence of the sulfurous amino acids, methionine and cysteine is extensively referred to as “nutritional AIDS” (Beisel 1992, 1996).

According to long-term statistics of the WHO, which are based on incomprehensible estimates, 90% of the AIDS sufferers worldwide live in the African countries south of the Sahara. Scandalously, the cause of this is not considered to be the “very frequent and socially highly significant, nutritional diseases” due to protein and vitamin deficiencies, but a new retrovirus that is presumed to have been transmitted to humans by apes. Since the 1980s, this virus is now supposed to have triggered the opportunistic infections that have been observed for centuries.

Patients having undergone an organ transplant are of special interest. Since the 1960s patients have been treated with immunotoxic substances in order to prevent rejection of the transplanted organs through cell-mediated immunity. Some of the patients developed a distinct immunity dysbalance, opportunistic infections like PCP, fungal and viral infections, and Kaposi’s sarcoma and lymphoma, in particular of the central nervous system. The clinical symptoms were identical to the AIDS-indicating illnesses of homosexual men that were diagnosed since 1978 and published since 1981. To inhibit the reaction of the immune system, three groups of substances were deployed:

• Azathioprine
• Corticosteroids
• Cyclosporine A

In the 1940s, biochemists focused on how the biosynthesis of the basic structure of nucleic acids could be medicinally altered to inhibit or block the growth and proliferation of microbes or tumor cells. The genes contained in the human cell nucleus are assembled from nucleic acids, biochemically synthesized as deoxyribonucleic acid (DNA). Within certain genetic sections, transcripts are produced as coded building blocks for the synthesis of amino acids into protein molecules, which is carried out in the cytoplasm. This transcript moves from the nucleus to specialized protein synthesis structures (ribosomes) as messenger RNA (mRNA). RNA is a modified form of DNA. Other forms of RNA are used for protein and other biosyntheses.

The idea back then was to attack one of the nucleic acid’s building blocks, biochemically termed bases, by substituting a false or analogue molecule. The nucleic acid of the DNA contains four different bases, which combine in the DNA chain to produce the alphabet of the DNA code. There are two purine bases (adenine and guanine) and two pyrimidine bases (cytosine and thymine). A fifth pyrimidine base, uracil, is only present in RNA.

In addition to the obligatory base, the individual building blocks of nucleic acids contain ribose sugar, and are coupled to each other by phosphate. Such a macromolecule is called a nucleotide. These nucleotides also play an essential role in co-enzymes for many biosyntheses, e.g. NO synthesis in T-cells and in all other cell systems.

     It is important to have a basic understanding of the role of nucleotides in NO synthesis, in order to comprehend what happens to patients with organ transplants, opportunistic infections, and certain forms of cancer; immunotoxic interventions on such patients with excessive NO constitutes the model for the development of AIDS in homosexuals and other patients, without the primary cause of a hypothetical virus.

In his acceptance speech for the 1988 Nobel Prize in Medicine, the American biochemist Hitchings, whose team among other things developed the immunotoxic drug Azathioprine, spoke of synthetic nucleotide analogues for introduction into the nucleus instead of natural nucleotides: “Now we have the chemotherapeutic agents; we need only to find the diseases in which they will be active” (Hitchings 1989).

One such chemotherapeutic analogue, Azathioprine, inhibits the synthesis of the purine bases, adenosine and guanine, rendering them ineffective and thereby disrupting the synthesis of DNA, RNA and the nucleotides. Azathioprine is called a purine blocker as its mercaptopurine metabolite blocks the body’s natural amino purines. Even though Hitchings had already stated, in 1989, that this mechanism could transform certain cells into cancer cells, Azathioprine was prescribed to patients whom had undergone kidney, heart, liver or bone marrow transplants. 6% of the kidney-transplant patients developed Kaposi’s sarcoma and T-cell lymphoma, as well as lymphomas of the central nervous system. The malignant cell mutation appeared after 30 months on average, with a variability between a few weeks and 13 years. The average patient age was 40.

Opportunistic infections like PCP, fungal and viral infections including cytomegalic infections were common. The immunologic function of T-helper cells was drastically reduced: the DTH skin reaction after antigenic stimulation, as well as mitogenic and antigenic stimulation in vitro, was strongly anergic (overview Penn 1979, Penn 1981, Zisbrod 1980, Schooley 1982, Harwood 1984, Levine 1984, Friedman-Kein 1984). These patients developed an immunotoxically-induced immune dysbalance with typical indicator illnesses, fully analogous to homosexual patients, whose illnesses would just a few years later be called AIDS.

“Malignancies have been occurring with astonishing frequency in patients receiving grafts of kidneys and hearts in recent years, and the only plausible explanation for this is the routine, mandatory use of immune suppressive drugs. It became clear that a substantial number of brand new cancers were occurring in the course of the intensive treatment of not only graft recipients with immune suppressive drugs, but also in patients treated with the same drugs for other reasons. The cancers have been of all types: Kaposi’s sarcoma, lymphomas and carcinomas. Some have appeared in or near the graft areas, others at distant sites. The most remarkable feature of the phenomena, apart from the cancers themselves, has been that a few of these spontaneous tumors regressed when the immune suppressive drugs were discontinued. On a few occasions, malignant growths the size of a hen’s egg or larger, some with already established lymph node metastases, some of them Kaposi’s have been reported to melt away after stopping the drugs. Transplant patients who developed neoplasms were routinely maintained on immune suppressive drugs, usually a combination of Azathioprine and prednisone. Krikorian summarized the results of Stanford experience with heart transplants three years ago. Out of the 143 transplanted patients who survived for three months or longer, 10 developed cancer, 6 lymphomas, 3 carcinomas and 1 acute leukaemia. All of these patients were under forty which indicates that the incidence of de novo cancer was really extraordinarily high” (Thomas 1984, Krikorian 1978).

Azathioprine (a.k.a. Imuran), when administered experimentally to research animals in combination with exogenous antigenic stimuli, caused a high occurrence of lymphomas. When Azathioprine was administered to mice bred for autoimmune dysfunction, a high rate of lymphomas was also seen.

The findings of the simultaneous provocation of opportunistic infections and cancer cell transformations by medically administered immune cell-inhibiting substances were presented at a historically decisive conference. In March 1983 more than 500 specialists from the USA, Canada, Europe and Africa discussed: “AIDS: The Epidemic of Kaposi’s sarcoma and Opportunistic Infections.” The conference was organized by the New York University Medical Center and in the words of the organizers, was to, “present a broad overview of the disease as it is currently understood.” At this point in time in the USA there were just over 1,200 patients, mostly homosexuals, who had been clinically diagnosed with AIDS; worldwide there were also some 500 further AIDS patients, again mostly homosexuals. The organizers pointed out that “the world was witnessing the emergence of a new disease—a devastating disease which within two years would reach epidemic proportions in the United States” (Fernandez 1984).

However this “profound, unexplained impairment of cell-mediated immunity” was not a uniform disease, in that Kaposi’s sarcoma was diagnosed solely in homosexual men, with and without opportunistic infections. Most homosexual AIDS patients suffered however not from Kaposi’s sarcoma but had developed opportunistic infections, predominantly PCP. But other patients with anomalies in their immune cells together with one or more opportunistic infections (even those without PCP but with, for instance, candida infections) were also counted as AIDS patients: “Haitians, hemophiliacs, intravenous drug users, blood transfusion recipients, and female sexual partners of men with this disease” (Fernandez 1984). This listing of the patient groups shows the power of suggestion of the implicit assumption that every anomaly in the immunocells associated with one or more opportunistic fungal or parasitical infections, must always be caused by “this presumably contagious illness” (Fernandez 1984).

We are not talking about a “new disease” (Fernandez 1984), but well-known anomalies of cell-mediated immune response and its resulting symptoms. These could arise from a number of root causes as supported by the quoted medical examples. What was new was the possibility, with technical advances, to differentiate between the T-helper cells and other T-cells in blood samples using monoclonal antibodies. To take such laboratory findings and then to claim that all opportunistic illnesses must be caused by this “presumably contagious illness” was arbitrary and digressive as the immune cell network and other cell networks respond to every toxic, traumatic, infectious, nutritive, psychological or other stress related overload with an evolutionary biologically programmed counterregulation.

Kaposi’s sarcoma (KS) also was not new. The disease symptoms have been familiar in Africa for centuries, particularly among the Bantu tribes in South Africa and an endemic belt located in equatorial Africa (overview Freidman-Kein 1984 a). KS was rarely found in people of European or Asian descent, even in areas of Africa where KS was relatively common among the indigenous population. In Uganda, for example, 9% of all tumors were diagnosed as KS (Taylor 1971). In Africa, KS is most common in adults between the ages of 25 and 45 with a male to female ratio of 17:1, the benign nodular form being more common. There is also an extremely malignant form with a high mortality rate affecting African children between the ages of two and 15, with a male to female predominance of 3:1. This is seldom linked with the otherwise common skin lesions, but rather with pronounced lymph nodes involvement and KS tumors in the visceral organs (Templeton 1976). No causative relation to a particular pathogen was proven; differentiated research has yet to be published (Olweny 1984).

Sarcoma idiopathicum multiplex haemorrhagicum, as KS is known medically, was first described in medical journals in 1872 by the Hungarian dermatologist Moritz Kaposi. Seen were made up of multiple, hyperpigmented, vascular cutaneous nodules on the lower extremities of elderly males (Kaposi 1872). Later on KS, “a fascinating curiosity” (Friedman-Kein 1984 a), was seen in a benign and malignant progression. Publications about most of the KS cases were in Europe and North America. On the one hand the cases concerned white males over fifty of Italian, Jewish or African extraction but on the other occurred in younger patients of differing ethnical backgrounds (Rothman 1962). Two progressions became apparent; multifocal brownish-red to blue nodules, primarily on the lower extremities, and in a later stage systemic or disseminated manifestations above all in the visceral organs and the lungs. Massive disruption to cell-mediated immunity was detected (Dubozy 1973). What was striking was the incidence of particular tissue antigens in KS patients of specific ethnic extraction. Such tissue antigens are found on the cell membranes of all human cells and as they are especially well pronounced on white cells, are termed HLA systems (human leucocyte antigens). The genes for the biosynthesis of these tissue proteins are consolidated in the major histocompatibility complex (MHC). As a result of the extraordinary diversity of expression of these genes an enormous number of HLA antigens are present on cell surfaces. These HLA antigens play an important part in the presentation of irregular proteins (antigens) for activation of T-helper cells. As a consequence it is crucial to ensure before tissue or organ transplantations, that there is as much compatibility of the HLA types as possible between the donor and recipient. Specific illnesses are associated with specific variations of the HLA types. In the HLA gene complex (MHC) four main areas are differentiated (A, B, C, D). The HLA proteins in area D appear, above all, on activated T-lymph cells (specific cell-mediated immunity), T-helper cells (specific humoral immunity) and macrophages (unspecific cell-mediated immunity). KS patients belong, conspicuously often, to the HLA-DR5 group (O’Hara 1982). From these findings it is concluded that people with this HLA variant, after treatment with immunotoxics, react more sensitively to an immune cell dysbalance and could develop AIDS-indicating illnesses. The findings, however, do not exclude the possibility that patients not displaying signs of this HLA variant, but taking high dosages of immunotoxic substances, or over a long time span, also develop an immunity dysbalance and the associated AIDS-indicating illnesses (Levine 1984).

As a result of the findings of organ transplant patients who developed immune cell dysbalances, opportunistic infections, Kaposi’s sarcoma, lymphoma, as well as other cancer types after Azathioprine medication, it became absolutely crucial to search for substances with analogous immunotoxic potency in the medical histories of homosexual AIDS patients. Antibiotics, chemotherapeutics, antiparasitics, fungistatics (fungal suppressive drugs), virustatics (viral suppressive drugs), recreational drugs or combinations thereof, all came into the question. The exceptional strain on a promiscuous minority of homosexuals through long-term medication with antimicrobial substances was clinically sufficiently well documented (overview Root-Bernstein 1993). Firstly, all participating doctors were aware of the principal immunotoxicity of all antimicrobial substances and recreational drugs (Descotes 1988). Azathioprine, as was realized, also acts repressively and antimicrobially on cell-mediated immunity.

The historic conference in March 1983 reflected a completely different realm of interest than its name might imply:

     Of the 44 lectures held over the three days the leading specialists covered the following focal points:

• 12 lectures about Kaposi’s sarcoma (20% of the diagnosed AIDS cases at that time).
• 1 lecture on PCP (80% of the diagnosed AIDS cases at that time).
• 3 lectures on the hypothetical viral cause of AIDS and cancer.
• 9 lectures on immunological problems and cytokine research.
• 2 lectures on lymphadenopathy (swelling of the lymph nodes).
• 5 lectures on clinical specific problems.
• 4 lectures on epidemiological questions.
• 1 lecture on macaque monkeys.
• 1 lecture on changes in the sexual lifestyle of homosexual men since the end of the 1960s.
• 1 lecture on changing patterns of sexually transmitted diseases since the end of the 1960s.
• 1 lecture on the sexual practices of homosexual men and Kaposi’s sarcoma.
• 1 lecture about the challenge to the public of AIDS.
• 1 lecture on the psychosocial support in AIDS.

Not one of the specialists gave a lecture about the immunotoxic and carcinogenic effects of nitrites, nitrosamines, antibiotics etc. The main focus of the conference was clearly concentrated on Kaposi’s sarcoma and viruses as the hypothetical cause of the onset of cancer. The medical professor and cancer researcher Dr. Lewis Thomas, director of the Memorial Sloan-Kettering Cancer Center in New York, one of the most important cancer research centers in the USA, held the opening lecture. He clearly outlined the dominant direction of research, which has prevailed until today: “Whatever we learn about the mechanisms releasing Kaposi’s sarcoma in AIDS will be useful information for the study of cancer in general, and whatever we can discover about the role of immunity in cancer will turn out to be a piece of applied science for the AIDS problem … What is needed, of course, is a series of human experiments, planned and executed in order to answer the sort of question which automatically raises itself: what would happen if you were to remove the putative defense mechanism of cellular immunity in human beings? Would this affect either the incidence or clinical course of cancer? As it happens, unplanned experiments have already been done … It seems to me that there are two alternative explanations for the high incidence of cancer in AIDS patients, and the same alternatives exist for the patients with organ homografts treated with immune suppressive drugs. One is that the impairment of cellular immunity has allowed an oncogenic virus to invade and proliferate, and what we are seeing is a human cancer running wild. This would seem plausible enough for the AIDS patients with Kaposi’s sarcoma if this were the only neoplasm, but these patients are developing other types of neoplasm as well, including the same lymphomas with a special predilection for invading the central nervous system, which are seen in the homograft [tissue transplant] patients. The second possible explanation, which I favor, is that the AIDS agent, whatever its nature, is not a cancer virus, but has as its sole action the suppression of cellular immunity. This action opens the way for a multitude of opportunistic pathogens and at the same time releases any clone of transformed, neoplastic cells that happen to turn up” (Thomas 1984).

Both of the rendered hypotheses about the origins of cancer are inextricably in opposition to the clinical reality:

1. The cellular immunity (T-helper cells) can only recognize intracellular viruses once they have infiltrated the cell, they cannot prevent infiltration. “The impairment of cellular immunity” cannot “allow an oncogenic virus to invade and proliferate” (Thomas 1984).
2. The speaker states that: “AIDS patients are developing other types of neoplasm as well, including the same lymphomas with a special predilection for invading the central nervous system, which are seen in the homograft patients” (Thomas 1984). The same speaker also stated: “The most remarkable feature of the phenomenon, apart from the cancers themselves, has been that a few of these spontaneous tumors have regressed when the immune suppressive drugs were discontinued. On a few occasions, malignant growths the size of a hen’s egg or larger, some with already established lymph node metastases, some of them Kaposi’s, have been reported to melt away after stopping the drugs” (Thomas 1984).

So the speaker ascertains that the tumors of homosexual AIDS patients, identical to those of graft patients, regressed. He diagnosed a clear causative connection between the growth of the tumors after medication and regression after discontinuation of Azathioprine. The “regression when immune suppressive drugs were discontinued” (Thomas 1984) in no way means that the cellular immunity, gathering momentum, had finally discovered the hypothetical viruses in the cancer cells and destroyed them. The immunosuppressive drugs were in actuality not removed, but rather exchanged for corticosteroids and other substances, in order to prevent a potential rejection of the transplanted organs of these patients (Penn 1979, 1981). So the cellular immunity remained suppressed, but still the tumor regressed. The cause of the growth and regression of the tumors was solely the effect and cessation of Azathioprine. The cause of tumors in organ transplant AIDS patients and homosexual AIDS patients could not in any way be “a clone of transformed, neoplastic cells” (Thomas 1984).

3. The second hypothesis, that “it is not itself a cancer virus, but has as its sole action the suppression of cellular immunity … at the same time releasing any clone of transformed neoplastic cells” (Thomas 1984) is incongruous because the cellular immunity does not identify cancer cells as long as firstly, the T-helper cells have not been activated by cells representing the antigens and secondly, the cytotoxic T-cells (including nonspecific macrophages), activated by Th1 helper cells, recognize and attack the presented antigens of the cancer cells. The presentation of cancer cell antigens takes place only after the unprogrammed cell death of cancer cells via necrosis. From this it follows that the primary growth of the cancer cells cannot be caused by immunosuppression, but as in the case of blocked purine metabolism in organ recipients, by Azathioprine. This same substance also negatively affects the immune cells (suppression of the T-helper cells), endothelial cells (Kaposi’s sarcoma), T-helper cells (lymphoma), as well as other cell systems (carcinoma), although under differing circumstances.
        Like most of his colleagues, the oncologist ignored the objective fact that Azathioprine is absorbed not only by T-cells, but also in principle by all human cells. Azathioprine is preferentially absorbed by the immune cells only because the metabolism is especially active in transplant patients and has a special affinity to the substance. Depending on the dosage and duration of the prescription, as well as the disposition of the patient (for instance variance of the HLA type), the purine metabolism of other cells can be critically disrupted; for instance, as a result of a provoked immune cell imbalance, the uptake of Azathioprine by the immune cells decreases, and instead the substance is relatively strongly taken in by the other cell systems, thereby systemically disrupting the purine metabolism.
4. In the same context the prominent cancer researcher spoke, as if it were self-evident, of “an AIDS agent, whatever its nature” obviously with the consensus of his colleagues. Although he had established that the AIDS-indicating diseases of organ recipients were clinically completely identical to those of homosexual AIDS patients and that the former are clearly caused by the immunotoxic drug Azathioprine, he postulated in the same context a possible viral source for the AIDS-indicating illnesses of organ transplant patients both for the suppression of the cellular immunity and for the development of cancer tumors: “There are two alternative explanations for the high incidence of cancer in AIDS patients, and the same alternatives exist for the patients with organ homografts treated with immune suppressive drugs … the second possible explanation, which I favor, is that the AIDS agent, whatever its nature, is not itself a cancer virus, but has as its sole action the suppression of cellular immunity” (Thomas 1984). This speculative premise, including the organ recipients, is inextricably in opposition to the factual assertions made in the same lecture: “Malignancies have been occurring with astonishing frequency in patients receiving grafts of kidneys and hearts in recent years, and the only plausible explanation is the routine, mandatory use of immune suppressive drugs” (Thomas 1984).

It is undeniably evident that the disease hypothesis of an “AIDS agent” and an “immune suppressive virus” was from the outset introduced as a speculative construct lacking any substantial proof. In order to add substance irrefutable medical historical facts were arbitrarily re-evaluated. Urgent and necessary immunotoxicological studies were either not carried out, or their methods were insufficient, as medical interest had been narrowly confined to the construction of the hypothetical “AIDS agent.”

After the above-quoted lecture, two dermatologists and microbiologists from the New York University Medical Center gave a lecture entitled: “An Overview of Classical and Epidemic Kaposi’s Sarcoma.” “Some unexplained, profound, acquired disorders of cell-mediated immunity that predisposes the afflicted host to a variety of unusual and often lethal opportunistic infections as well as a disseminated form of Kaposi’s sarcoma … The cause of this new disease entity remains a mystery. It is most unlikely that Kaposi could have imagined that the neoplasm that bears his name would become linked 100 years later to one of the most devastating epidemics in modern history. The sudden increased occurrence of this rare tumor and its association with specific epidemiologic, immunologic, and clinical findings has focused the attention of the medical community to explore the intriguing puzzle of how these factors may be directly involved in the pathogenesis of AIDS and especially this particular neoplasm” (Friedman-Kein 1984 a).

Nobody in the past had described the fully identical illnesses of organ transplant patients as “a mystery” and “an intriguing puzzle,” as the causative relation between chemotherapeutic immunosuppression and growth and regression of “this particular neoplasm” (namely Kaposi’s sarcoma), was blatantly obvious! Why were these illnesses considered “new disease entities” although identical illnesses were well known in organ transplant patients? Why was there talk of a “sudden increased occurrence of this rare tumor,” although it was documented that practically all KS patients were homosexuals with a preference for anal intercourse, with long-standing use of nitrites, antibiotics, and chemotherapeutic substances?

“Probably the immune deficiency precedes KS. The various drugs, such as amyl nitrite and butyl nitrite, which have been used excessively by many homosexual KS patients, should be tested in animals for their immunosuppressive, mutagenic, and oncogenic potential. Aggressive chemotherapy and persistent infections, such as CMV, Epstein-Barr virus, hepatitis B, pneumocystis, and amebiasis, likely contribute to the final degree of immunologic incompetence” (De Wys 1982). These carefully chosen but explicit formulations were published by, among others, researchers at the American National Institutes of Health and the CDC.

     In 1982 a clinical study by the CDC demonstrated that the amount of T-helper cells in the blood of nitrite users was lower than those in the blood of non-nitrite users (Goedert 1982). In a further study at the Cancer Prevention and Control Research Center of the University of Texas, it was shown in human cell cultures that the quantity of T-helper cells was reduced by nitrite, even at low concentrations that did not kill lymph cells. Nitrite retards the synthesis of type 1 cytokines, such that a two-hour contact of moderate amounts of nitrite with human immune cells is sufficient to induce immunosuppression. “The results suggested that prolonged exposure [to nitrites] may not be necessary [for immunosuppressive and carcinogenic effects] … and their use should be condemned by those physicians who treat patients who use these drugs regularly” (Hersh 1983, Newell 1984, Newell 1988).

The causative connection between nitrate use (Mayer 1983), “aggressive chemotherapy,” (De Wys 1982) and acute, concurrent, and chronic antigenic stress through a variety of infections (overview Root-Bernstein 1993) has been amply covered. The fact that this substance induces immune cell dysbalance, both in organ transplant patients and homosexual AIDS patients, preceding the emergence of KS in most cases, has been conclusively established by researchers from the CDC and other governmental research institutes (Jaffe 1983).

Why did the cancer researchers at the historic conference in March 1983 claim, against better knowledge, that an apparently “new disease” was a “mystery” and a “intriguing puzzle” which in turn led to the arbitrary construction of an “AIDS agent” and an “immunosuppressive virus”?

In 1981, the financial backing for research into retroviruses and cancer, instigated by the republican president Nixon in 1971 as “The War on Cancer,” was withdrawn due to the lack of concrete success. At that time it was, by far, the largest capital investment in medical research. One of those who had profited from the Nixon project was the research scientist Robert Gallo, leader of the Laboratory of Tumor Cell Biology at the National Cancer Institute in the USA. Gallo reported, along with some of his colleagues, at the conference in March 1983, that the team had identified a retrovirus in T-helper cells from blood samples of two homosexual AIDS patients. Gallo and his colleagues had published the first reports about proof of such a retrovirus in human blood cells in 1981. It was concerned with a virus that appeared in an unusual form of leukaemia in Japan and the Caribbean in the leukaemia cells of a small percentage of affected patients. This hypothetical proof of a retrovirus in a few human leukaemia cells, shortly before the termination of the Nixon project with its billions of dollars of investment, was the only meager return from the whole retrovirus cancer research program.

It became later apparent that the Gallo team could by no means produce evidence of the isolation of a retrovirus but only the “fingerprint” of a hypothetical virus, in reality only a partial “fingerprint” of a retrovirus in leukaemia cells. By comparison, it was as if a part of a fingerprint had been discovered and from this a photofit picture was made from which a clear-cut case was being made against the suspect. Likewise, the Gallo team had then apparently located this “photofit” retrovirus in the T-helper cells of two AIDS patients. In doing so there is, however, a trick involved—the T-helper cells from the blood samples of the AIDS patients were incubated together with leukaemia cells to which were added massive amounts of type 1 cytokine as a growth stimulator. Additionally the cell mixture was aggressively treated with highly oxidative maturation stimulators. Often with such cell culture procedures, tiny, virus-like, membrane-encased particles can be observed, which contain cellular debris ejected from the cells. The standard rule in virology is that such particles are only recognized as real viruses once the proteins and nucleic acids have been shown to take on a certain structure, making it possible for the virus to identically copy its RNA/DNA in the DNA strand of a host cell. The Gallo team could not produce such evidence, although it is demanded by routine laboratory practice. It was also unclear whether the particle originated from the T-helper cells or the leukaemia cells. Instead of this, the Gallo team produced the previously mentioned “partial fingerprint.” Such viruses are supposed to be retroviruses, when their genetic make-up is coded by RNA structures, rather than the DNA forms found in most viruses and eukaryotes (single—and multi-celled organisms with nuclei). The RNA make-up of this hypothetical retrovirus is supposed to be transcribed into DNA form in the host cells by means of a virus-specific enzyme. The term retrovirus (from the Latin: retro = reverse), comes from the notion that these tiny particles, contrary to the usual practice, are transcribed from RNA into DNA and then from the DNA matrix back to RNA copies, with the help of the host cell DNA mechanisms. These RNA structures are then encased by membranes, and bud out of the host cell in order to colonize other cells. That is the theoretical concept, anyway; but how exactly these hypothetical retroviruses are thought to trigger cancer during this process is highly speculative. As proof for the existence of these retroviruses, Gallo and his colleagues offered a “partial fingerprint” as supposed evidence of the transcription enzyme of the hypothetical retrovirus (Gelmann 1984).

Such reverse transcription processes, from RNA into DNA rather than the usual way from DNA to mobile messenger RNA, were observed in animal cells since 1970. Instead of the old dogma (DNA to messenger RNA), a new dogma was formulated, namely, that the deviating transcription was exclusively confined to the hypothetical retroviruses (Temin 1970, 1972). By the mid-seventies, researchers reported that reverse transcription had been observed in a variety of cells, not just virus-infected cells, and that this was a repair procedure, principally in embryonic cells and in cancer cells (overview Temin 1975, 1985, Baltimore 1985). The enzyme that supposedly enabled this transcription to take place was termed reverse transcriptase. In laboratory jargon this is shortened to RT. The Gallo team wanted this RT enzyme proven. However, as RTs appear in cancer cells such as leukaemia, and as the lymph culture was incubated together with leukaemia cells to prove the existence of the supposed retrovirus in T-helper cells of AIDS patients, the RT itself was not convincing proof for the existence of a retrovirus in these T-helper cells. Furthermore, evidence in human immune cells, even if the retrovirus had been precisely isolated, in no way means that it had to have a pathological influence. Similar such RNA sequences, termed endogenous retroviruses, have been observed in many animal cells as stowaways and have exercised no pathological influence whatsoever (overview Duesberg 1987, Teng 1996).

The only evidence of a supposed retrovirus in the T-helper cells of AIDS patients that the Gallo team could offer was merely a virus-like particle without documentation of protein and nucleic acid structures within this particle to enable infection, and the RT effects of proteins in a centrifuged culture soup (Gelmann 1984).

Just over a year after the historic conference of March 1983, something unique in the history of medicine took place. The Health and Human Services Secretary of the Reagan Administration, Margaret Heckler, together with Gallo announced at an international press conference in April 1984 that the Gallo team had discovered the “probable cause of AIDS” and had developed a blood test, which could detect evidence of the newly found retrovirus in everyone. Within two years a vaccine would probably be developed. Gallo was hailed by the world’s press as the saviour of mankind from one of the “most devastating epidemics in modern history” (Friedman-Kein 1984 a).

Since then, everyone knows the hysteria in the mass media and medical journals about “Plague! Sex! Sensation!” Without any critical counteranalysis, most doctors throughout the world adopted the construct of the disease theory “HIV causes AIDS.” The State doctrine that the “lethal AIDS agent” could be passed to anyone through sex and blood became the collective obsession that has claimed the lives of countless people.

The prediction of the oncologist Prof. Thomas in the opening paper of the conference of March 1983 served the ideological conversion from “War on Cancer” (President Nixon) to “War against Public Enemy Number One” (namely the “AIDS agent”), as President Reagan declared in the year of his re-election, but this prediction had not met the expectations of the HIV/AIDS researchers. “Whatever we learn about the mechanisms releasing Kaposi’s sarcoma in AIDS will be useful information for the study of cancer in general, and whatever we can discover about the role of immunity in cancer will turn out to be a piece of applied science for the AIDS problem” (Thomas 1984).

The opportunity to learn something from the well-known AIDS illnesses, which had been diagnosed before it was called AIDS, had been lost. “A president of the USA 25 years ago declared a War on Cancer, confident that it was winnable. It has been judged, so far, lost. With the exception of advances in the treatment of haematological cancers, and a few others, 25 years has seen little progress” (editorial in the British medical journal The Lancet on July 6th, 1996). This concise statement documents that retrovirus AIDS research had contributed nothing decisive to the advancement of knowledge about cancer and vice versa. Clinical data merely confirmed what has already been known since 1981: KS as a “particular neoplasm” (Friedman-Kein 1984 a) is not “a new disease entity” and not “one of the most devastating epidemics in modern history.” In Germany, for example, in the 15 years from 1982 to 1997, 2,736 cases of KS had been officially reported. Of those officially diagnosed, 2,505 were men of homosexual preference (92% of all KS cases). There remain, on average, 15 KS cases per year, which in the official reports cannot be labelled as relating to homosexuals or bisexuals (8% of all KS cases) (Harmouda 1997). A 10-year study in Chicago re-checked all male AIDS patients over the age of 18 who had described themselves as non-homosexual. 50% of these AIDS patients turned out to be homosexual after all (Murphy 1997). Correspondingly, with regard to sexual preference, the official annual average of 15 KS cases can be assumed to be a diagnostic contortion and as a result almost all KS AIDS patients could be considered as homosexual. This does not exclude the possibility that on rare occasions, patients other than homosexuals became affected with KS, for instance, from pharmacotoxic sources (excluding organ transplant patients and patients with malignant illnesses who had been treated with immunotoxic substances).

Consequently KS as a “particular neoplasm” and as a toxic/pharmacotoxic illness can be considered to be an illness exclusively confined to homosexual men, at least in Western countries. In sharp contrast to the official announcements KS, even within the male homosexual community, is a rare disease form and in Germany, for example, the annual incidence of KS cases affects one in 10,000 homosexual men.

So what was new about this “new disease entity” manifested by immune dysbalance, opportunistic infections and/or Kaposi’s sarcoma/lymphoma? What was new was the appearance of a combination of diseases in homosexual males, which had previously been confined to organ transplant recipients after treatment with Azathioprine. The conclusion arises that toxic factors which cannot be explained by a retroviral “AIDS agent” must have been originally operative for the complete syndrome of acquired immune deficiency, including the fact that KS practically only appears in homosexual males.

Nitrosamine research had irrefutably proven that nitrosamines are extremely potent carcinogenic substances in the human cell system. It was proven that these carcinogens are intermediate by-products of industrial processes, also present in agricultural products, pesticide residues, in tobacco, in cosmetics and in a diversity of other contamination sources of modern life (Magee 1976, Preussmann 1984). But they have also demonstrated that pharmaceutical products including analgesics, antibiotics, chemotherapeutics, and cancer drugs lead to the development of nitrosamines in human metabolism and are potential carcinogens (Lijinsky 1973, Preussmann 1984, 1986, Loeppky 1994 a). There were also no longer any biochemical doubts that nitrites could be converted to nitrosamines in the human metabolism, and could as a result also have carcinogenic effects (Doyle 1983, Loeppky 1994 a, Lijinsky 1994, Bartsch 1987, Haverkos 1988).

     Why did the clear carcinogenic effect of nitrosamine-forming nitrites and nitrosamine-forming drugs have to be shrouded as a “new disease entity” in the etiological context of toxic AIDS effects? Why did the great minds describe the damage to the cellular immunity and the appearance of KS in habitual nitrite users and long-term consumers of nitrosamine-forming antibiotics and chemotherapeutics as a “particular neoplasm”? Why the “mystery” and the “intriguing puzzle”? Why were “only around 1,200 cases, all told between 1980 and early 1983—not many in a population exceeding 200 million” (Thomas 1984) sold to the mass media at that point in time as “one of the most devastating epidemics in modern history” (Friedman-Kein 1984)?

The financial backing for nitrosamine research, as the American Chemical Association established, had been drastically reduced as a result of pressure from the industry lobby, from 1980 in the US and from 1982 in Germany (Loeppky 1994 a). The competing billion-dollar project of the retrovirus/cancer research of Nixon’s “War on Cancer” ceased to be financed in 1981, due to lack of success (Gallo 1999). The highly tuned laboratory machinery began to falter. It was in this context that the oncologist Thomas, chancellor of the Memorial Sloan-Kettering Cancer Center in New York (which together with the Laboratory of Tumor Cell Biology of the National Cancer Institute under the directorship of the laboratory researcher Gallo, had profited enormously from the billion dollar retrovirus/cancer project), seized the opportunity to reanimate retrovirus research.

Nitrosamine cancer research had a fundamental handicap: research had clearly proven that nitrosamines, formed from both exogenous and endogenous sources, damaged immune cells and triggered cancer. At that time and even today, the prevailing theory is that cancer develops in the nucleus of cells, through a random genetic mutation of the DNA. Nitrosamine researchers could demonstrate displacements and losses in the DNA sequence in the coding mechanisms of the genomes, which is the sum of the 100,000 genes in human nuclei. What could not be conclusively demonstrated, however, was how the random dispersion of defects and mutations in the DNA sequence coding were supposed to alter the transcription (from DNA to messenger RNA) and the subsequent translation (biosynthesis of amino acid proteins from messenger RNA outside of the nucleus), so that the cell mechanisms did not actually stop, but rather switched to an ongoing cancerous cell division program.

     Besides this, some of the cancer cells also developed without any detectable mutation to the DNA of the nucleus of the cells (Lijinsky 1994). The retrovirus cancer researchers tried to solve this problem by postulating that the supposedly isolated retroviruses, after their transcription from RNA to DNA, docked onto a particular location on the DNA strand near the oncogenes of the host cell so that they could activate the oncogenes which up until that point had been inactive, in order to start the ongoing cell division process. But cell division is a highly complex interplay requiring many genes to synthesise the necessary proteins and protein enzymes. This can by no means be considered a “human cancer virus running wild” (Thomas 1984). The cancer cells are highly efficient, active cells, which after a very complex program produce cell energy and organize their proliferation. The difference of normal differentiated cells is, in essence, that cancer cells after transformation no longer attune their activity to neighboring cells and in relation to the organism as a whole become cell parasites. Neither the nitrosamine researchers nor the retrovirus/cancer researcher have managed to convincingly solve the complicated problem of this transformation to cancer cells.

The “particular neoplasm” of Kaposi’s sarcoma in homosexual AIDS patients through “unplanned experiments” (Thomas 1984) now brought Thomas, Gallo and their colleagues the fateful idea of circumventing the unsolved problem of the origin of cancer cell transformation, by relocating the “scene of the crime” of their phantom retroviruses to the T-helper cells. “The second possible explanation, which I favor, is that the AIDS agent, whatever its nature is not a cancer virus, but has as its sole action the suppression of cellular immunity. This action opens the way for a multitude of opportunistic pathogens and at the same time releases any clone of transformed, neoplastic cells that happen to turn up” (Thomas 1984). The critical logical question as to the cause of the initial growth of the “clones of transformed, neoplastic cells” is no longer posed. The original research question of the primary cause for the transformation of the tumor cells, which actually was supposed to be explained by the hypothetical existence of retroviruses in the transformed cells, had suddenly become a secondary issue. The “human cancer virus running wild” (Thomas 1984) had been reinvented as the “AIDS agent” running wild among T-helper cells. The existence of “clones of transformed, neoplastic cells that happen to turn up” (Thomas 1984) is simply presented as a biological fact.

The thought processes of the assistants at the birth of the retrovirus HIV (human immunodeficiency virus), behind this decisive step, have to be made rationally clear in order to understand the implications of this construct and its grave consequences for the whole world.

Gallo who had hitherto localized his hypothetical retrovirus as activator of oncogenes inside the leukaemia cells (as transformed cancer cells), transplanted his retrovirus artefact, in March 1983, for the sake of simplicity into the T-helper cells as an “AIDS agent.” A “cancer virus running wild” (Thomas 1984) becomes with the wave of a hand a “T-helper cell virus” which now, instead of transforming T-helper cells, is supposed to destroy them.

Indeed, Gallo and his colleagues knew since the mid-seventies that in organ recipients and other patients treated with corticosteroids for immune suppression, of whom a certain percentage developed KS, lymphoma and carcinoma, the T-helper cells were not destroyed but under the influence of cortisol moved out of the circulatory system to the bone marrow and other areas (Fauci 1974, 1975, Cupps 1982). The assumption that a destruction of the T-helper cells as the cause of an immune cell dysbalance (a decrease in the T-helper cells circulating in the bloodstream) was by no means compelling. As long as the corticosteroid hormone treated patients developed differing types of cancer then the origin of the cancer could not have been from the T-helper cells as they had drifted out of the bloodstream and so could not be detected in blood samples.

The theory of an “AIDS agent” destroying immune cells and subsequently, as a result of a failure of the immunity surveillance, a “clone of transformed, neoplastic cells” (Thomas 1984) plucked out of thin air, rests solely on the assumption that the number of T-helper cells circulating in the bloodstream is reduced because the T-helper cells have been destroyed beforehand. However, it has been shown that there were homosexual patients with Kaposi’s sarcoma without a reduction of T-helper cells in their blood plasma and without clinical syndromes of opportunistic infections (CDC 1981 b, Haverkos 1982).

Thus the development of Kaposi’s sarcoma does not have to be caused by a reduction in immune cells. In Central Africa, in research on indigenous KS patients, it was also shown that Kaposi’s sarcoma appeared without destroying the immune cells (Kestens 1985). Such cases of KS could, for instance, be triggered by drinking water contaminated by nitrite-forming bacteria. The nitrites are converted to nitrates by hydrochloric acids in the stomach and subsequently enter the bloodstream. Here the nitrates come into close contact with endothelial cells which form NO and its derivatives. These can cause KS, if a long-term NO surplus exhausts the thiol pool and specific counter regulatory measures occur in the endothelial cells.

The postulated pathophysiological sequence—first, suppression of the cellular immunity, and then proliferation of cancer—is the crucial premise for the construction of the “AIDS agent.” “The second possible explanation, which I favor, is that the AIDS agent, whatever its nature is not a cancer virus, but has as its sole action the suppression of cellular immunity. This action opens the way for a multitude of opportunistic pathogens and at the same time releases any clone of transformed, neoplastic cells that happen to turn up” (Thomas 1984).

The assumption of an AIDS agent in the fundamental theory of the immune cell destruction as a prerequisite for the origin of Kaposi’s sarcoma could have objectively been recognized as wrong from the outset. Gallo, in his presentation of a wrong theory deduced from misinterpreted findings, at no point in time actually isolated a retrovirus. The tragedy of this fateful blunder was that the world believed that a high-flying doctor had discovered the right causes, the right theory, at the right time. Gallo had given the world what it wanted, and profited handsomely as a result. In fact the cancer researchers had not solved the problem of transformation to cancer cells, and they had deliberately ignored all available clinical, immunological, biochemical and toxological data about identical AIDS-indicating illnesses, against the better knowledge of researchers in the pre-AIDS era. They sacrificed scientific accuracy and protocol for a timely and “politically correct” theory of a “lethal AIDS agent.” The “mystery” and “intriguing puzzle” is not the supposed “new disease,” but the fact that the so-called “invisible hand of the market” managed to override the fundaments of scientific medical ethics with barely a peep of opposition.

More than 14 years after the historic conference of March 1983, when the idea of the “new agent” came into existence, the most prominent minds in the international community of retrovirus researchers met for another conference. They wanted to take stock of all the knowledge that had in the meantime been gathered as to how the “AIDS agent,” according to the doctrine championed by these researchers that “HIV causes AIDS,” destroyed the T-helper cells. In the meantime more than 200,000 scientific publications about HIV/AIDS had been published and more than 200 billion dollars had been invested. The result of this stocktaking was a remarkable—and remarkably unpublicized—scientific admission of defeat: “The riddle of CD4 cell loss (from the bloodstream) remains unresolved. We are still very confused about the mechanisms that lead to CD4 depletion … but at least we are now confused at a higher level of understanding” (Balter 1997).

In plain language, this meant that the retrovirus-AIDS/cancer theory, elaborated since 1983 from the retrovirus cancer theory, had flopped! The “phantom” retroviruses did not cause cancer directly, by infecting organ cells and creating “human cancer running wild” (Thomas 1983). Nor did they cause cancer indirectly, by destroying the cell-mediated immunity which monitors cancer cells, thereby releasing a “clone of transformed, neoplastic cells” (Thomas 1983).

Furthermore, the depletion of T-helper cells from the bloodstream was not a result of progressive destruction following viral infection. The retrovirus researchers could provide no evidence to support this theory. Rather the stem (progenitor) cells of the T-helper cells undergo a functional shift (Th1-to-Th2 switch) and drift out of the bloodstream to other organ areas where they carry out their special function of supporting the B-cells in the production of antibodies. Just because there is a depletion of T-helper cells in the blood circulation (demonstrated by the so-called T4 or CD4 cell counts) does not necessarily mean that these T-helper cells must have been destroyed by a retrovirus. This conclusion also cannot be reached by the observation of premature extinction of T-helper cells in a test tube after they have been stimulated by certain oxidizing substances. There is a perfectly plausible explanation for this observation, which will be covered later in this text.

The “new disease entity AIDS” had been explicitly defined on the basis of three patterns of findings:

1. Anomalies within the T-helper cells (AID) based on three criteria—depleted counts in the bloodstream, inhibited maturity and division after stimulation in a test-tube, and negative (anergic) reaction in DTH test.
2. Development of opportunistic infections (OI).
3. Development of Kaposi’s sarcoma (KS).

All three patterns lead back to a single hypothetical origin: a progressive infection and destruction of T-helper cells through a “new agent,” a hypothetical retrovirus (see Table 1. Disease Model of the Retrovirus AIDS Theory).

In reality, the immunological, clinical, and epidemiological data showed a considerably different picture of the symptoms (see Table 2. Disease Model of the Non-Retrovirus AIDS Theory).

While all five symptomatic constellations were seen in cases of homosexual patients, the constellations AID+OI+KS, AID+KS and KS applied almost exclusively to this group. The Retrovirus Theory crucially demands that KS cannot appear without a retroviral infection of the T-helper cells. It is contrary to every biological probability, that a retroviral infection of the T-helper cells simultaneously triggers KS in some homosexual patients, but not in others. Conversely, one or more factors must have a direct effect on both the endothelial cells and/or the T-helper cells. This factor cannot be a retrovirus as, according to the Retrovirus Theory, it does not have any effect on endothelial cells. Furthermore, despite all the efforts of research, no hypothetical retroviruses were found in KS cells (Beral 1990).

The alternative explanation accounts for all five constellations in homosexuals who had been diagnosed (AID, AID+OI, AID+OI+KS, AID+KS, KS), in that, dependent on the intensity and duration of the affecting factors and/or the disposition of the patient, the T-helper cells and/or the endothelial cells could be affected to differing degrees.

This is the same situation as with organ recipients, for whom without any reasonable doubt, Azathioprine had a causal effect both on the T-helper cells and the endothelial cells and in a certain percentage induced AID, OI and/or KS.

Azathioprine inhibits the synthesis of the purine bases, which effects a disruption of the DNA and RNA synthesis and thereby the biosynthesis of enzyme proteins. It also affects the synthesis of enzyme proteins in the NO synthase, which produces the immunological defense gas NO. However, the NO-forming enzymes need pyridine nucleotides for NO production. These nucleotides contain the purine base adenine, whose synthesis is inhibited by Azathioprine. This involves NAD⁺ (nicotinamide adenine dinucleotide) as co-enzyme, and both FAD (flavin adenine dinucleotide) and FMN (flavin mononucleotide) as co-factors for NO synthase. These pyridine nucleotides play an essential role as hydrogen donors and acceptors in many biosyntheses, above all in cellular respiration (Bredt 1992, Marletta 1993, Knowles 1994, Richter 1996, Schweizer 1996, Lincoln 1997).

Corticosteroids, frequently deployed for immunosuppression in organ recipients, which also in some cases triggered KS and carcinoma (Hoshaw 1980), also attack the biosynthesis of NO in the T-helper cells in that they penetrate the cells and combine with factors that are important for the transcription (from DNA to mRNA). In this way, the corticosteroids inhibit the biosynthesis of proteins, among others the communication proteins (type 1 and type 2 cytokines), as well as the NO-forming NO synthases. Type 1 cytokines are potent stimulators of NO production (Cupps 1982, Colosanti 1995, Brattsand 1996, Kunz 1996, Lincoln 1997).

Cyclosporine A (CSA) is an important substance introduced in 1983 for the immunosuppression of organ transplant patients. It was isolated from the fungus Tolypocladium inflatum. CSA has an effect on the type 1 cytokine interleukin-2 (IL-2), a growth factor for T-helper cells, in that it indirectly inhibits its synthesis. CSA binds to proteins, the cyclophilins, which are present in many cells and participate in important regulatory processes. CSA medication also inhibits the synthesis and function of NO and its derivatives such as peroxinitrite. CSA medication had also triggered KS, lymphoma and various carcinomas in transplant patients (Kahan 1984, Penn 1991, Schreiber 1992, Richter 1996, Lincoln 1997). The mode of action of the fungitoxin Cyclosporine A, illustrates important aspects of the genesis of cancer, and will be discussed later in this text.

The similarity of the various inhibitory mechanisms on the NO syntheses by immunosuppressive drugs, and the cellular counter-regulation, in high dosage long-term exogenous nitrite usage, endogenous NO stimulation in high and long-term antigen exposure and endogenous nitrosamine formation through long-term consumption of antibiotics, chemotherapeutics and analgesics with a secondary depletion to the thiol pool, has not been discussed by the AIDS researchers. Two illogical arguments are submitted by the nitrosamine researchers, when discussing nitrite inhalation by homosexuals (poppers) as a possible cause factor for AID, OI, and KS:

1. Amyl nitrite and nitroglycerin have been used for many years as treatment for angina pectoris (a narrowing of coronary vessels due to deficiencies in NO synthesis), without carcinogenic effects (Mirvish 1986).
        This argument compares the long-term, high dosage abuse of inhaled nitrites, with the equalization of impaired calcium-dependant NO synthesis in the coronary arteries via short-term treatment with nitrites or nitrates. Nitrite abusers initially have a normal physiological NO production, but simultaneously subject the NO metabolism and the antioxidant thiol pool to other stress factors. In a similar fashion, the risk of lung cancer to a chain smoker could be argued away by equating their habits to those of an occasional smoker. As Paracelsus said, “The poison is the dose.” However nitrites can indeed have a double-edged effect, for instance in cases of dilated cardiomyopathy. The type 1 cytokine, tumor necrosis factor α, is produced in the endothelial cells of the coronary arteries, which suppresses the calcium-dependent NO synthesis and causes the painful symptoms of angina pectoris. However, the induced NO is increased in the cardiomuscular cells, which leads to a slowing down of the heart’s action (negative ionotropic effect) (Habib 1996). An NO balance in the already NO-suppressed endothelial cells cannot trigger KS in the coronary arteries. But the cardiomuscular cells, which cannot develop cancer as they can no longer proliferate, can still be degeneratively damaged.
2. The appearance of KS in heterosexuals in Africa is, in all likelihood, not associated with poppers abuse (Mirvish 1986). Although the researchers confirm that nitrites can be transformed inside the human cell system to become carcinogenic nitrosamines, and that amyl nitrite and isobutyl nitrite both have a high carcinogenic potential in humans, they do not consider the possibility that African KS without AID (Kestens 1985) or with AID (Marquart 1986) could be caused by other nitrite nitrosamine sources—for instance, nitrite-contaminated drinking water and nitrite-preserved foodstuffs stored under the tropical hygienic conditions that are a fact of life in the poorer countries. On account of the frequency of Kaposi’s sarcoma in Africa long before the AIDS era, found in all its various benign and malignant forms with and without AID, the restriction of causal research for KS in Africa to possible poppers consumption is obviously absurd. The association of KS in Africa with leprosy and anti-leprosy therapy, likewise points to a destroyed NO synthesis (Oettle 1962, Olweny 1984). As leprosy medication attacks the folic acid metabolism, the purine synthesis is also affected; additionally the homocysteine production is inhibited, and thus the thiol pool more rapidly expended and the NO synthesis suppressed by counterregulation. In this context, there may exist similar predisposing factors as seen with organ transplant patients, e.g. genetic HLA type of the affected person.

Contrary to the predictions of the Retrovirus AIDS Theory, the fact that there has been no higher incidence of other common cancer forms in homosexuals over the last twenty years (with the exception of lymphoma after AZT treatment) also disproves the assumption that retroviruses indirectly provoke cancer by destroying the immune cells. It was inevitable that this prognosis would be made by the retrovirologists as there was no biological reason to suppose that “a release of clones of transformed, neoplastic cells” (Thomas 1984), and other cancer cell forms such as KS, would occur after depletion of the postulated T-cell surveillance of cancer cells. Incidentally, it had already been demonstrated before the advent of the retrovirus infection theory (supposedly transmitted by sex and blood) that the transformation and growth of cancer cell clones was not dependent on immune surveillance (Kinlen 1982). The fact is, that after the decline of the “poppers craze” among homosexuals, the number of cases of KS in the USA and other Western countries also declined (Haverkos 1990). This clinical finding conforms to the fact that after legal restrictions on nitrite preservation in meat and sausages, together with increased use of refrigeration, the only cancer form to decline was stomach cancer; meanwhile, for instance, the incidence of lung cancer, due among other things to the creation of nitrosamines in tobacco during the drying process, had greatly increased (Hoel 1992, Burton 1994, Djordjevic 1994).

The given data proves that the hypothetical chain of causes—T-helper cell loss leading to provocation of KS cell clones—does not exist biologically. As a result, the “new disease entity” (AID-OI-KS) is not a new syndrome describing a causal disease entity, but rather comprises two separate disease forms in separate cell types: AID (with or without OI) as a disease form of the T-helper cells, and KS as a disease form of the endothelial cells, independent of AID but appearing within the same time-span as AID.

So when we refer to an AID syndrome (AIDS) we must factor out KS as an independent disease form. If we wanted to be more precise we could talk about an Azathioprine syndrome or a nitrite syndrome, in which the term syndrome relates to the appearance of AID and/or KS with the same cause in different cell types. AID can only trigger OI: AID+OI = AID syndrome = AIDS. It is correct that both AID (as anomaly of the T-helper cells) and KS (as anomaly of the endothelial cells) can be triggered by the same causal factor(s), but both disease forms could develop in these cases independently of one another at the same time or at different times in the same patients. There remain pathological changes in two different cell types without the changes in the one cell type being initially responsible for the changes in the other. By analogy, it would mean that if “smoker’s leg” and a lung carcinoma were diagnosed in a single patient, smoking could be seen as the common cause, but the damage to the arteries in the leg could not be blamed on the lung cancer.

On the other hand, AID or AID+OI (= AIDS) can have many different singular causes, or a combination of causes, in that the immune cell network is evolutionary-biologically programmed to react uniformly once a critical threshold has been crossed. The cause of AIDS (without KS), in homosexuals, does not have to be traced back to inhalation of nitrites alone. There has always been AID and AID+OI in homosexuals (overview Root-Bernstein 1993). The most frequent AID+OI disease in homosexuals, PCP, was not diagnosed much before 1980 because the diagnostic techniques were complex and risky. A long needle had to be inserted into the lung tissues and cell material drawn out for analysis (a transbronchial biopsy).

     An improvement in diagnosis was made possible after advances in bronchial lavage techniques, for the purpose of extracting cell material for the microbiological determination of the PCP pathogen (Blumenfeld 1984, Broaddus 1985). PCP, however, was a very well known AID+OI syndrome, seen after multiple applications of chemotherapeutics and immunosuppressives in cancer patients, organ recipients and patients with autoimmune illnesses (Young 1984). Patients without specifically-named illnesses were mostly treated pragmatically and the PCP was not identified: “Young men presenting with interstitial pneumonia without an underlying disorder may not have received a definite diagnosis or specific therapy for P. carinii pneumonia; others may have received empirical therapy with trimethoprim-sulfamethoxazole [Septra or Bactrim]” (Auerbach 1982). The “sudden appearance of PCP in homosexuals” was inevitable as a result of improvements in PCP diagnosis. The sophisticated agent-specific diagnostic process supported the statement of the Canadian pathologist some 20 years ago. “PCP is much more common in this country than we thought, we just have to open our eyes to see it” (Berdnikoff 1959).

Before 1981, there were no medical statistics to show the separate development of atypical non-bacterial lung inflammations specifically in homosexual patients. From the later-published initial diagnosis of KS in a homosexual patient in 1978 until the historic conference of March 1983, a number of important factors acted together to facilitate the (facile) hypothesis of a “new disease entity”:

• 1978: first assignation of a subgroup of T-helper cells (T4 cells) as AID was reported
• Discovery of T4 cell depletion in many other illnesses (Reinherz 1979, 1981 a, 1981 b, Huzzell 1982)
• 1978-1981: first diagnosis in homosexual patients of KS and PCP combined with T4 cell depletion
• After improvements in diagnosis, PCP was now more frequently recognized, while earlier it had often been overlooked
• Homosexual patients report the practice of sexual doping via inhalation of nitrite gases (CDC 1981 a, CDC 1981 b, Gottlieb 1981, Masur 1981, Durack 1981, Haverkos 1982, Auerbach 1982, De Wys 1982, Marmor 1982, Goedert 1982)
• In 1980 the American Chemical Association speaks of a change in the “political philosophy” concerning nitrite and nitrosamines as the toxic causes for cancer and immune disruption—research funding was restricted after conservative government regime change (Loeppky 1994 a)
• 1980-83: First publications from researchers from the National Cancer Institute regarding the so-called retrovirus particle in human cancer cells (leukaemia and lymphoma cells) and of antibodies in blood serum against proteins from these particles—a connection between these particles and the origins of cancer can not be proved—funding for retrovirus cancer research, in existence since 1971, is discontinued in 1981 (Poiesz 1980, Kalyanaraman 1981 a, Kalyanaraman 1981 b, 1982, Gallo 1986, 1991, 1999, Duesberg 1987)
• 1982: The unproven theory that the development and growth of cancer cells is dependent on destroyed immune cells is questioned but supported by most researchers (Spector 1978, Kinlen 1982).

Under the prevailing political circumstances the original explanation of the “new disease entity” in homosexuals as a result of intoxication by industrial products (excessive consumption of nitrites, exogenous nitrosamines, antibiotics, chemotherapeutics) was not considered fashionable. “The only reason for preferring the explanation that an ‘undefined’ infectious factor relating to sexual behaviour appears to be the cause, and not the alternative, appears to be a predisposition to favor a sexually transmitted infection. In fact in homosexuals evidence exists that the variable most strongly associated with KS is the consumption of more than four ‘hits’ of nitrites per night of use” (Papadopulos-Eleopulos 1992).

The obvious intoxication of the patients had somehow now to be turned into an infection by an “unknown agent.” The pathogen must have the capacity to infect T-helper cells in order to explain their depletion in blood serum. However, a new pathogen is not needed to explain the depletion of T-helper cells in many other illnesses. In these cases, the disappearance of T-helper cells can be regarded as a secondary consequence of the primary disease processes. In the case of a “new disease entity,” however, a new rationale had to be found because the toxic damage of the immune and/or endothelial cells was not accepted as the primary cause of the illness and at the same time the appearance of the “intriguing puzzle” of Kaposi’s sarcoma was not allowed to be explained by the use of toxic/pharmacotoxic substances, as it was in the case of KS in graft (transplant) patients.

Type B hepatitis (HBV) was regarded as the model for a viral infection transmitted through sexual intercourse as well as blood and blood products, and urban homosexuals were very often diagnosed as HBV-positive (Schreeder 1981). Acute and chronic HBV infections also cause a depletion of T-helper cells and a decline in cell-mediated immune functions (Klingenstein 1981).

At the end of the seventies, the first vaccine against Hepatitis B was developed in the USA; beginning in November 1978, it was tested on 549 homosexual men in New York, while a further 534 homosexual men were injected with a placebo as a control (Szmuness 1979). The vaccine was licensed in 1981 in the USA and in 1982 in Germany. At the time of the vaccine trials, there were no longer any doubts about the extremely high antigenic stress in urban homosexual men. “Homosexual men have the highest disease load of any North American or European risk group” (Root-Bernstein 1993)

This extreme antigenic stress could indeed adequately explain, as it does in other patient groups, the depletion of T-helper cells, but the rationale of a “new disease entity” demanded a connection between T-helper suppression and the development of Kaposi’s sarcoma. Such a coincidence between immunosuppression and KS was only known among graft patients and others, who had been treated with toxic, immunosuppressive substances. A sexually-transmitted agent was sought as a possible link between immunosuppression and KS—an agent of a new type, which not only suppressed T-helper cells but also destroyed them—because then the disappearance of the T-helper cells from the bloodstream could be attributed to their destruction. A pathogen that was simultaneously an immune cell eradicator and also an indirect KS trigger was unknown. The logical question would have been to ask whether the extremely high antigenic stress along with the disappearance of T-helper cells, was enough to trigger KS, because during this same time, the theory was being promoted that cancer was actually dependent on immunosuppression (Gatti 1971, Waldmann 1972, Spector 1978). It is significant in the light of this theory that children with a congenital malformation of the thymus who suffer from a T-helper cell deficiency, develop fungal, parasitic and viral infections; however, they do not suffer from high-grade bacterial infections, as the function of the B-cells is completely intact. This syndrome matches the symptoms of AIDS patients who can also develop opportunistic infections, but who have an intact or even increased antibody production of B-cells. As a rule AIDS patients do not become ill from bacterial infections, with the exception of mycobacterial infections, as long as toxins do not inhibit the maturation of the B-cells. Even more significant is the fact that children with Di George syndrome (a failure of development of the third and fourth pharyngeal pouches at the embryonic stage) did not have a heightened risk of KS or any other cancer forms (Di George 1968, Lischner 1975). This fact is in opposition to the Retrovirus-AIDS Theory, which states that the depletion of T-helper cells is the causal factor for both Kaposi’s sarcoma and lymphoma.

This evident contradiction was interpreted at the historic conference of 1983 by stating that the Di George children would not grow old enough to develop cancer, and that some factors associated with puberty might be necessary for the development of Kaposi’s sarcoma (Levine 1984). This assumption, however, is in opposition to the development of lymphomas and leukemias in children with combined T and B-lymph cell defects (severe combined immunodeficiency, SCID). These children also develop opportunistic infections and additional high-grade bacterial infections (Gatti 1971, Spector 1978).

The second hypothesis as to why there was no KS in Di George syndrome cases was that the genetic variants of HLA types which are detectable in 50% of classical KS cases, were underrepresented in this group of children (Levine 1984). The discrepancy in this hypothesis is that, particularly in younger patients with classic KS, this HLA variant was also not detected (Rothman 1962).

     The fact remains that neither congenital nor acquired T-helper deficits have been traced as an indirect trigger for cancer.

A “new agent” was not needed in order to explain this “new disease entity;” already present was a massive and diverse blend of microbial and toxic contaminations, which were virtually unknown to medicine before the era of excessive promiscuity. No one in his right mind should assume that an organism, even a young adult, can limitlessly manage industrial and microbial toxins without specific symptoms being manifested. All the evidence summarized thus far, and to be put forth subsequently, suggests that AIDS is the systemic result of such cumulative toxic stress, and not a retrovirus-caused syndrome. This environmental question was, however, treated as a taboo because then the cumulative effect of all toxins in the years preceding the disease (nitrites, antibiotics, chemotherapeutics, recreational drugs, etc.) would have to be included in the diagnostic calculations. As a result of this diagnostic censorship, there came a blanket explanation that all infectious and toxic contaminations of promiscuous homosexual men were insufficient for immunosuppression and the triggering of Kaposi’s sarcoma. At the very most, there was talk of nebulous “co-factors.”

At the historic conference in March 1983, Gallo and his colleagues reported that they had found, in the T-helper cells of two AIDS patients, evidence of an infection of the human T-cell leukaemia virus (HTLV) discovered in his laboratory. The evidence, however, turns out to be rather odd: The Gallo team had mixed human leukaemia cells with T-helper cells and stimulated their growth with oxidizing substances and type 1 cytokine. Finally, the residue of this “culture soup” was placed in a high-speed centrifuge, and the proteins from this amorphous mixture were made to react with antibodies from the blood serum of AIDS patients. The team then claimed this antibody reactivity as evidence of infection with a hypothetical leukaemia virus.

Such procedures cannot be accepted as evidence for real virus isolation, let alone an infection of the patient. The extracted proteins, which reacted to the antibodies in the serum of patients, could have originated from the co-cultivated leukaemia cells and/or the T-helper cells—not necessarily the hypothetical leukaemia virus. First of all, the supposed virus has to be isolated; it must be separated from any other cell material. The core of the selected virus particle would have had to have been examined, the proteins and nucleic acids documented. Only once it had been established that it was a stable virus capable of spreading infections, the proteins from the real isolated virus would be put into contact with human serum.

     Yet even if all the preconditions of proper viral isolation had been followed according to the standard rules of virology, the antibody reaction in the serum of a human being to a precisely identified viral protein would still not be evidence of a prior infection with this virus. In every human’s serum there are millions of antibodies of varying kinds that were originally formed to act against a totally different protein, but are similar enough to react against new, previously unseen viral proteins. Every immunologist knows this process—it is called a “cross-reaction.”

The laboratory stunts of the Gallo team were, however, accepted without any criticism by the gathering of over 500 specialists at the conference. A virologist from the National Institutes of Health also gave a lecture at the conference with the suggestive title: “Viruses, Immune Dysregulation, and Oncogenesis: Inferences Regarding the Cause and Evolution of AIDS.” Among other things he stated: “Retroviruses are also distinctive in that they cause prolonged immune suppression in the presence of neutralizing antibodies, and this has again been found in the case of the recently isolated and characterized human T-cell leukaemia virus (HTLV) … Here, then, is an example of a virus specifically and primarily interacting with the T-helper population” (Levine 1984).

In support of his contentions, the lecturer quoted six publications from the Gallo team and one publication from a Japanese research group (Popvic 1983, Popvic 1982, Poiesz 1980, Manzari 1983, Gallo 1982, Miyoshi 1981 b). The Japanese researchers had incubated leukaemia cells together with leukocytes from a human umbilical cord and used the same laboratory techniques as the Gallo team. None of the studies tested whether the same effects using the same laboratory techniques would be demonstrated without the co-cultivation of T-helper cells with leukaemia/lymphoma cells (or in the case of the Japanese team, umbilical cord leukocytes without co-cultivation with leukaemia cells).

     In his lecture, the virologist Levine had proposed his reasoning of the existence of an exemplary virus, but he did so using an unproven argument that presumably confirmed his rationale. The quoted studies of the Gallo team and the Japanese researchers by no means assume that human retroviruses cause a long-term immunosuppression in the presence of neutralising antibodies. The Gallo team had in 1981 merely demonstrated that a structural protein (p24), extracted from a cell culture and centrifuged with human lymphoma cells, had reacted to antibodies from human serum. Without precisely following the standard isolation procedures (proving whether the proteins actually originated from the studied particle, and whether the particle actually encased structural proteins and RNA of a hypothetical retrovirus), it would be arbitrary to claim that a retroviral protein had reacted to human antibodies, and thus that the person with these antibodies in his serum must have been infected by a retrovirus. As these structural proteins could just as well be structural proteins that were extracted from lymphoma cells during the laboratory process, the reaction with an antibody in human serum proves nothing. Such antibodies are able to react to all proteins from human cells, once the protein is no longer protected by the cell membrane. The biological function of antibodies is such that they react equally to microbial or allergenic proteins, as well as with all the body’s own proteins. These bodily proteins are leaked into the plasma upon cell death if they have not already been dispersed to their individual building blocks. Antibodies only react to proteins above a certain molecular size. Therefore it is also fundamentally absurd to state that retroviruses could cause long-term immunosuppression in immune cells in the presence of neutralising antibodies. Virus particles, whether hidden in immune or other cells, cannot be identified by antibodies. This can only take place in the plasma outside of the cells, once the virus particles bud out of the infected cells, or when viruses have infiltrated an organism but not yet colonized the cells. In order to cause a long-term suppression of immune cells, the retroviruses (if they exist at all) would have had to continuously mature and bud out of the short-lived T-helper cells, in order to colonize newly formed T-helper cells. However, when neutralizing antibodies are already present, they will impede the viruses exiting the immune cells from colonizing new immune cells, thereby neutralizing the infection.

The publications of the Gallo team and the Japanese researchers cited by Levine only demonstrate the following:

• When human cancer cells (leukaemia or lymphoma cells) are treated under certain laboratory conditions with certain biochemicals then particles mature out of these cells that after inspection with an electron microscope could either be viral particles or non-viral particles.
• When leukaemia or lymphoma cells and T-cells which have not transformed to cancer cells are treated in the same way, then particles mature out of the leukaemia or lymphoma cells but likewise out of the T-cells that after studying with an electron microscope could either be viral particles or non-viral particles.
• When the supernatant residue of the co-cultivated cancer and T-cells has been centrifuged a protein mixture is obtained that could contain proteins from cancer cells, T-cells and matured particles. If one were to select a protein from this mixture and put it into contact with antibodies from human serum which displays an antigen-antibody reaction to this protein, then it is not possible to tell from this procedure whether the cause of the reaction was a protein from a cancer cell, lymphoma cell, viral particle, or non-viral particle. This differentiation would only be possible after proper viral isolation following the standard procedures of virology: the viral particles in question—having been cleared of all other cell components, proteins and other molecules—are shown to be composed of specific viral proteins, and contain viral RNA capable of replication.
• When leukaemia cells are co-cultivated with T-cells under the same laboratory conditions and particles mature from both cell types, then the assumption that either viral or non-viral particles from the leukaemia cells have colonized the T-cells is logically inconclusive. Under the same laboratory conditions particles could have matured from either cell types. The counterclaim that lymph cell particles colonized the leukaemia cells is equally inconclusive. Similarly under the same conditions, when lymphoma cells are co-cultivated with T-cells, or leukaemia cells with umbilical cord leukocytes, or umbilical cord cells with T-cells, then the assumption remains inconclusive. The maturation of particles in co-cultivated cell cultures does not prove that the particle will be transferred as an infection from one cell type to another.
• When, under the same laboratory conditions, particles mature in non-transformed T-cells without co-cultivation with cancer cells or other cell types, this does not mean that they are viral particles; proteins in the supernatant which react to human serum does not prove viral origin of the proteins. Such a statement could only be verified if the particle had been truly isolated from other cell components, the contents of said particle had been clearly identified as both structural and enzymatic proteins, the viral RNA was capable of being replicated, and finally that proteins from these pure and proven retroviral particles had reacted to the antibodies in human serum. To this day no one has published these would-be conclusive pieces of evidence (Papadopulos-Eleopulos 2000 a).
• But notwithstanding the grossly inconclusive evidence of the applied laboratory techniques even if the particle had been properly identified as a real retrovirus particle, this finding in itself would not be enough proof to show a pathological infection.

One of the most famous retrovirologists in the USA, the German-American molecular biologist Duesberg, professor at the University of California-Berkeley, (whom Gallo had described in 1985 as the retrovirologist with the sharpest wits) submitted a fundamental analysis of the entire retrovirus species just four years after the memorable birth of the “AIDS agent.” Duesberg came to the conclusion that all retroviral particles were nothing more than benign passengers in the genetic make-up of humans, and by no means were able to cause infections. Duesberg expanded his statement by classifying the cancer genes as unusual re-combinations of DNA instead of activated oncogenes (Duesberg 1987).

“An example of a virus specifically and primarily interacting with the T-helper population” (Levine 1984), which in 1983 was introduced as the prize candidate for the “AIDS agent,” had only attained special scientific attention for a short period of time. In the diagnosis and therapy of cancer diseases it has remained insignificant. A good year later, however, a newer prototype of such a tailor-made retrovirus in the serum of AIDS patients surfaced in publications from the Gallo team. Gallo had created a new variant in his retroviral family with the classification HTLV-III. The product also came from the co-incubation of T-helper cells from the serum of AIDS patients and a leukaemia cell line. Using the same dubious laboratory techniques as with his prototype HTLV, Gallo distilled a protein mixture from the supernatant of co-cultivated hybrid cell culture, which he then used as the substrate for his antibody test.

Again Gallo failed to produce evidence as to whether the proteins in question were the body’s own proteins from the incubated T-helper cells and/or leukaemia cells, or whether they were in fact real retroviral proteins. But this time the “invisible hand of the market” was in play before Gallo introduced the new retrovirus variant and the antibody test to scientific discussion. He patented the test first, and then subsequently announced (together with the then-current US Health Secretary, Margaret Heckler) in front of the international press that he had discovered the “probable” AIDS agent, that he had developed a blood test capable of supplying evidence of HTLV-III, and that in two years a vaccine against this retrovirus would be ready for the market. Since this announcement, the techniques used in producing this HIV test have been protected by patent rights. HTLV-I and HTLV-II, again in the blood serum of AIDS patients, re-emerged in ensuing publications. Later, this supposed leukaemia virus was no longer mentioned, as it had somehow mutated into a phantom-like immune-weakening virus. Evidently the AIDS/leukemia virus was a laboratory artefact, as no AIDS patient ever suffered from it. Rational questioning—why these hypothetical leukaemia viruses suddenly stopped triggering leukaemia and instead (even though only for a short time until it was ousted by its successor), destroyed immune cells and puzzlingly indirectly effected Kaposi’s sarcoma only in the gay community—was thrust aside in the midst of the mass hysteria that the “AIDS agent HIV,” (as the successful laboratory product was termed) has lamentably and scandalously caused until today.

The simple but decisive trick that Gallo used to sell to the world his former leukaemia agent (which had received little acclaim among oncologists), as the AIDS agent similar to the one he had used for HTLV-I and HTLV-II. Gallo now claimed that during co-cultivation of the T-helper cell lines from AIDS patients with the transformed T-cells from leukaemia patients, the retrovirus jumped from the T-helper cells to the leukaemia cells. Correspondingly, Gallo simply repackaged the classification from Human T-cell Leukaemia Virus to Human T-cell Lymphotropic Virus (both HTLV). The jump from the T-cells to the leukaemia cells, according to Gallo, was the proof that the retrovirus had to be the much-sought “AIDS agent.” Thus the cancer agent that transforms lymph cells into uninhibited and growing leukaemia cells became the “AIDS agent” that kills T-cells. Why Gallo had to co-incubate T-helper cells with leukaemia cells in order to elicit the supposed retrovirus from the T-helper cells was explained by stating that the retroviruses develop better in leukaemia cells. In reality, Gallo needed the leukaemia cells to stimulate the repair enzyme, reverse transcriptase (RT). This RT enzyme repairs the last part of the DNA strand in cancer cells (which with every division becomes a little shorter), so that the division frequency of the cancer cells remains stable. Citing as evidence the presence of the RT enzymes (which transcribe RNA sections into the DNA sequence), in his “cell culture soup,” Gallo decisively concluded the existence of a new retrovirus in T-helper immune cells. However, this sequence of reverse transcription (Temin 1985, Baltimore 1985, Greider 1996, Boeke 1996, Teng 1996, Teng 1997, Strahl 1996, Yegorov 1996, Hässig 1998, 1998 a) had long been established in many animal and human cell types (Temin 1970, 1972. 1985, Varmus 1987, 1988), as had the transcription of genetic information from RNA to DNA, which was demonstrated by the American microbiologists Temin and Baltimore (both Nobel prize winners in 1975).

Evidence of reverse transcription after co-cultivation of T-helper immune cells with leukemic cancer cells cannot be considered as proof that the retro-transcription must be due solely to a retrovirus in the T-helper cells. Such an assumption is not only arbitrary, but also contrary to the established biological facts.

Gallo again decanted the cell liquids from his culture mixture, filtered out a mixture of proteins and let them react to the serum of AIDS patients. The expected protein/antibody reaction in these AIDS patients was again proclaimed as a retroviral infection. Gallo had as evidence of a retroviral presence in the T-helper cells of donors with clinical AIDS symptoms, nothing more in his culture than a RT reaction and in the sera of the AIDS patients, nothing more than an antibody reaction to the test proteins from his “cell culture soup.” When Gallo, who also wanted to sell his patented test to the blood donor services, brought his test proteins into contact with the sera of healthy donors, 10% of these healthy sera also reacted! Because a test that turns evidently healthy blood donors into doomed men is unmarketable, Gallo altered the sensitivity of the measuring reaction. This meant that with fewer antibodies in the serum, the test now read negative; correspondingly, with more antibodies there was a positive reading. The arbitrary measuring threshold decides whether a subject will be labelled HIV-positive or HIV-negative (Popovic 1984, Gallo 1984, Schüpbach 1984, Samgadharan 1984, Gallo 1991).

The apparently astounding correlation between those testing HIV-positive and a certain percentage of the target group—antigen-stressed homosexuals, intravenous drug addicts, hemophiliacs with substituted high antigen-contaminated coagulation proteins, multi-transfusion recipients, children of drug-dependent mothers, people from poor countries, etc.—is not surprising (Giraldo 1999 a). Long after the “discovery of the AIDS agent,” a better understanding of the relationship between T4 cell analysis, HIV seropositivity, AIDS-indicating illnesses, cancer, AIDS therapy, etc., is uncovered in light of important newer research findings.

The “predisposition to favor a sexually transmitted infection” (Papadopulos-Eleopulos 1992) set the stage to blindly trust the laboratory stunts of the failed retrovirus cancer researchers who had mutated, so to speak, to retrovirus-AIDS researchers. As there was no other “AIDS agent” in the offing from the laboratory researchers, the phantom-like retroviruses made the grade. With fear of the “lethal virus” infecting the global population, free reign was given to previously muted irrational fantasies. The dictatorially stage-managed fear of a plague became taken as a real plague. US virologists and specialists from varying disciplines had accomplished the task of blaming well-known opportunistic infections and cancer forms on a laboratory construction and then sold it to the mass media as one of the “most devastating epidemics in modern history” (Friedman-Kein 1984 a).

     The most terrifying thing about this fateful failure of modern medicine, was the fact that scientists from around the world, with very few exceptions, swallowed whole this transparent construction without critically analyzing the published data.

     A glance at the relevant medical journals of the sixties would have been enough. At that point in time, over a decade before the “sudden appearance” of a supposedly new retrovirus, the manifestation of the most common AIDS-indicating illness, Pneumocystis carinii pneumonia (PCP), was clearly known as an immunodeficiency disease and the causes given were clearly of an immunotoxic nature. PCP fungal infections were confirmed not only in children, but also in adults after autopsies. Outbreaks of PCP after chemotherapy were demonstrated in animal experiments. After 1964, there were publications about PCP in graft and cancer patients who had been treated with immunotoxins and chemotherapy (Schmid 1964, Hill 1964, Frenkel 1966, Esterly 1967, Robbins 1967, 1968, Harrlin 1968). Opportunistic infections caused either by missing or malfunctioning T-helper immune cells were often classified as immunological deficiency diseases (IDD) (Bergsma 1968). IDD developed into acquired immunodeficiency (AID) so as to distinguish between AID and congenital immunodeficiency (CID). AID then became acquired immunodeficiency syndrome (AIDS) starting in 1982.

Initially there was only the need to state the clinical fact that AID+OI appeared simultaneously in some patients as KS, but by no means stipulate that AID was the cause of KS. At the historic conference of March 1983 the described disease definition became a causal disease definition: it was postulated that the “new agent” was the cause of AID and that AID was the cause of KS. The coincidence of the appearance of two disease phenomena in different cell types became a causal link between two different cell types. From the very beginning, as initiator for the postulated causal link, a virus as a “new agent” was constructed which was supposed to have infected the helper immune cells, triggered AID, and as a result precipitated KS. This construction of a “new disease entity” of a “retrovirus AID syndrome” (HIV/AIDS) facilitated with a greater variability than AID, for whatever reasons, to re-interpret AID plus selected disease symptoms as AIDS. Real symptoms with actual and differing causes were distorted to a virtual disease entity. Mass-psychological stage-managed plague fears were stoked by a laboratory construction. It was the moment of birth of a phantom medicine, which engineered a universal lethal threat from real diseases and by these means created a global market for itself. The “planned experiments on humans” (Thomas 1984) mentioned at the historic conference in 1983 were ready to begin.

It does not take a lot of diagnostic shrewdness to identify the causes of AID indicator diseases, which were diagnosed since 1978 and publicized since 1981, and to see through and rebut the supposed rationale of a “new disease entity” which supposedly could only be caused by a “new agent.” It merely needed a thorough review of the medical facts to avoid millions of people being frightened to death by being “HIV stigmatized” and abandoned to the “clean torture” of AIDS treatment with highly toxic drugs which had been proven to trigger AIDS and cancer.

The published declarations of the University researchers of 1981 that the people suffering from AIDS had been “previously healthy” patients (Gottlieb 1981) can only be taken as unprofessional sophistry, as every patient feels healthy up to the first symptoms of illness. Long-term abuse of prescribed and unprescribed antibiotics and chemotherapeutics, long-term nitrite inhalation, long-term injections of highly contaminated coagulation proteins for hemophiliacs, long-term intravenous drug consumption under the conditions of the street scene, multitransfusions of on average 35 transfusions for grave primary illnesses along with the corresponding medications, extreme antigen stress even in the womb (overview Root-Bernstein 1993)—all of these would provoke any “previously healthy” organisms into counter-regulation without the need to construct a “new agent” for this “intriguing puzzle” (Friedman-Kein 1984 a).

But the engineers of the “AIDS agent,” in addition to the distortion of biological facts, profited from another ominous development. Since 1977 in the USA and in Great Britain discoveries in the laboratory could, like other inventions, be patented. This break in research culture caused a division within the medical research community. Some researchers, whose planned research projects were oriented to marketing possibilities, allowed pharmaceutical companies to finance their research work (either to a large extent or completely), or allowed them options to buy shares in biotechnological companies at below-market prices. Gallo’s “AIDS test” patent was sold to five pharmaceutical concerns, and he is making money to this day from the royalties. For others it is ethically a matter of course to deepen the understanding of healing. These researchers lay open their research work without the using a shroud of secrecy for patents like Gallo and his colleagues. Happily, groups of ethical researchers who are prepared to question and re-evaluate fixed dogmas of medical research have brought fundamental insights that have profoundly changed the concepts of the medical world. But the work of these ethical medics and researchers, although important and welcome, comes tragically too late for the countless victims of the “Virus Hunting” (Gallo 1991).

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The clinicians and immunologists could not explain three decisive findings of the immune response of the T-helper cells of their patients who came down with massive fungal lung infections and other opportunistic infections:

1. The depletion of the T-helper cells in the blood serum of the patients while at the same time an increase in certain classes of antibodies
2. The unsuccessful or unsatisfactory maturing response to stimulation with antigens and/or proliferation factors (concanavalin A, a.k.a. con A phytohaemagglutin, a.k.a. PHA)
3. The anergic response of the immune cells in the skin after provocation with recall antigens in delayed-type hypersensitivity (DTH) tests (Gottlieb 1981, Mazur 1981).

The laboratory construct “retrovirus HIV” also could not be used to explain these immunological anomalies as the cause of opportunistic infections or as an indirect cause of Kaposi’s sarcomas and lymphomas (Balter 1997).

In 1986, the research group of Mosmann and Coffman identified in experimental research on T-helper clone cells (identically duplicated T-cells) two sub-groups of T-helper cells. They varied in the profile of their communication proteins, the cytokines (still in those days termed lymphokines), which were produced after stimulation.

The T-helper cells with a type 1 cytokine profile were termed Th1 and those with a type 2 cytokine profile were termed Th2. A decisive factor that became apparent as the researchers stimulated the T-helper cell culture with different antigens was that there was a shift in the balance between Th1 and Th2 related to the type, dosage and duration of the antigens applied. If the balance tipped towards Th1 then there was an increase in production of the type 1 cytokine profile and the synthesis of type 2 cytokines was inhibited, and vice versa if the balance shifted in the other direction. So it was found that there was a reciprocally inhibiting regulation between the sub-groups Th1 and Th2 and their synthesized cytokines.

The researchers concluded that:

• Th1 cells principally interacted with the nonspecific macrophages, reciprocally to type 2 cytokines.
• Th2 cells principally perform helper functions for the antibody-producing B-cells (with the exception of a sub-group of B-cells which is activated by Th1 and produces antibodies of a sub-group of immunoglobulin class G).
• A shift in balance to Th1 produced a very marked DTH reaction and, vice versa, a dysbalance towards Th2 led to a weak DTH or no response at all (Mosmann 1986, 1988, 1989).

The DTH response was a phenomenon that has been recognized for 200 years and was first described by Jenner in 1798. He observed redness, hardening and blistering at the location where he had injected the vaccine (cow pox) reaching a peak after 24 to 72 hours. In 1890 Robert Koch described a similar reaction to live tubercle bacilli injected into the skin of guinea pigs which had previously been infected with the TBC bacillus, but not in animals that were not infected. In 1942, Chase and Landsteiner demonstrated the interconnection between the DTH reaction and sensitized lymph cells. In addition to cell-mediated immunity the non-specific immune response of the macrophages and the coagulatory systems are chiefly active in the DTH reaction.

Since the mid-1970s, surgeons considered how an improvement could be made in prognosis of the dreaded sepsis after heavy traumata, burns or operations. Sepsis (blood poisoning) is a general infection with constant or periodical dispersion of microbes (bacteria, fungi) spreading from the source of infection into the bloodstream. With this purpose in mind a surgical team in Montreal recorded the DTH reaction of all patients between 1975 and 1985 before and after surgery. Every trained nurse can conduct and record the DTH reaction. The Canadian surgeons categorically stated: “Nearly two centuries following Jenner, and a century following Pasteur, Koch, Lister, Metchnikoff and others, the leading cause of morbidity and mortality after major surgery is sepsis … Despite better surgical techniques, and increased choice of powerful life support systems, sepsis continues to be a major cause of morbidity and mortality in the surgical patient” (Christou 1986).

     The DTH reaction of 202 patients was tested before surgery. 3-5% of all the surgical patients tested developed a sepsis; for patients in post-operative intensive care the proportion was one third. Of the patients with positive skin reactivity, 50% were anergic on the third day after the operation and by the seventh post-operative day most of them had recovered reactivity. Patients who subsequently remained anergic had a higher rate of sepsis in 32% of cases. When the skin test failed to normalize, a subsequent sepsis was associated with a higher level of mortality. Of all the patients that were DTH positive upon hospital admission, 8% developed sepsis and 4% died; of those who were DTH negative (relatively anergic), 21% developed sepsis and 15% died; of those who were DTH negative (anergic), 33% developed sepsis and 31% died.

The surgeons established that many of the immunological parameters of sepsis patients had altered in comparison to the non-sepsis patients. In particular the type 1 cytokine interleukin-2 (IL-2), a growth factor protein for T-helper cells, was heavily inhibited in sepsis patients. Certain antibody classes (IgG and IgA) considerably increased while other antibody classes and the complementary reaction decreased. Additionally, many inhibitors formed in the serum of sepsis patients: “These inhibitors have a profound effect on T-helper lymph cells and polymorphonuclear leukocytes. Teleogically, there is a suggestion that this inhibition postinjury may be a normal response related to the ‘healing processes’ and the prevention of autoimmune reactions to self-denatured proteins. The host is, therefore, caught in a dichotomy between healing and sepsis, in the midst of breached defenses” (Christou 1986).

After severe damage and attacks to the self-regulation of organisms, highly complex and diverse regulations and counterregulations occur, countless mediators and compensating modulators intervene, and cells are thereby activated or suppressed. This total response of the bioenergy, biochemistry and cell biology of the organism to the utmost of stress has until now not been adequately understood, and depends on many predisposing factors (Calvano 1986, Cerami 1992, Jochum 1992, Waydhas 1992, Nast-Kolb 1996). However, the core statement of the Canadian surgeons is worth repeating. They reported that an anergic DTH reaction as an expression of the inhibited cell-mediated immune competence before admission to the hospital was significantly linked to the sepsis results, which, despite massive use of antibiotics, led in a high percentage of cases to the patient’s death. A decade later surgeons at McGill University confirmed that the strong correlation remained between a reduced DTH response and mortality after sepsis of heavily traumatized patients in intensive care, despite a reduction in overall mortality (Christou 1995).

The Canadian surgeons had recognized the evolutionary, biologically programmed dual strategy of the immune response: 50% of the surgical patients responded to the profound stress to the system with a T-helper cell dysbalance up to the seventh post-operative day, and a certain percentage of patients, especially those who had already shown signs of an immune dysbalance before the operation, had a long-standing T-helper cell dysbalance until death or upon overcoming the aftermath of the operation. Whether the surviving anergic patients remained anergic after leaving the hospital was not recorded.

The significant fact still remains that a long-lasting T-helper cell dysbalance under pressure from heavy stress is not altogether uncommon in the population as a whole: anyhow 24% of the surgical patients were anergic on admission, 14% relatively anergic. Conversely, data from the findings also express that not every patient with a T-helper cell dysbalance was threatened by a lethal infection, as 67% of the pre-operative anergic and 79% of the relatively anergic patients did not develop a sepsis. (Christou 1986). This fact is just as significant as the correlation between anergy, sepsis and mortality. It indicates a high variability of the regulation of the immune response between the cell-mediated and humoral immunity manifested either in a stable immune cell balance, a flexible immune balance, or a fixed immune cell dysbalance with or without ensuing sepsis. A long-lasting immune cell dysbalance under profound stress loads (acquired immunodeficiency = AID) with or without infectious syndrome is by no means a rare or “puzzling” occurrence.

The clinical and immunological data from surgical sepsis research before the discovery of type 1 cytokine—type 2 cytokine dysbalance of the T-helper immune cells, concurred with the experimental data of Mosmann and Coffman on T-helper clone cells of infected mice. The researchers could prove a definitive shift to a type 2 cytokine profile with a preponderance of Th2 cells in the spleen lymph cells and lymph node cells of mice that had been infected with the parasite Nippostrongylus brasiliensis. The type 1 cytokines interleukin 2 (IL2) and interferon-γ (IFN-γ) were below normal readings and the amounts of the type 2 cytokines, interleukin-4 (IL-4) and interleukin-5 (IL-5) had greatly increased. As IL-2 was also greatly reduced in surgical sepsis patients and IL-4 and IL-2 inhibit each other reciprocally, it can be assumed that a systemic shift to Th2 dominance had taken place in surgical sepsis patients with an anergic DTH reaction. The clinical and immunological findings were induced by the Th1-Th2 shift.

In a further experiment the researchers infected mice with the parasite Leishmania major (Lm). They chose one strain of mice that was susceptible to an Lm infection and one that was resistant. The susceptible mice developed heavy and advanced infections and died. Like surgical sepsis patients, immunologically they displayed all the features of Th2 activation: anergic DTH skin reaction, high antibody levels, reduced type 1 cytokines and increased type 2 cytokines. The resistant mice on the other hand merely showed signs of a local infection and fully recovered. Their DTH skin reaction was highly developed, the antibody production low and conversely type 1 cytokine syntheses increased and type 2 cytokine syntheses reduced. Lm is an intracellular parasite of the macrophages, so it was clearly demonstrated that an intact Th1 response with type 1 cytokine production is necessary for the elimination of an intracellular pathogen. The reverse was also shown, in that the susceptibility to an intracellular infection leading to a progressive illness and death is dependent on a predominant shift to a Th2 response with type 2 cytokine production; which in fact leads to an increased antibody production and protection from extracellular pathogen attacks but cannot prevent intracellular microorganisms from proliferating (Mosmann 1989).

The fundamental perceptions about the dualistic strategy of the immune response have been substantiated in countless experiments and research on animals and humans. For instance, researchers prepared Th1 and Th2 cell lines and clone cells specifically for Lm antigens. When these cells were re-injected into Lm-infected mice, the Th1 cell lines completely recovered from infection while the Th2 cell lines deteriorated during the course of the infection (Scott 1986). Humans can also become infected by Leishmania parasites with two alternative progressions of the immune response: either a strong DTH reaction leading to a local confinement of the parasitic infection and the elimination of the Leishmania agent, or an increased antibody production with little or no DTH reaction (anergy) and a heavy dispersion of the parasites. In tropical countries like India, this disease is called Kala-azar (Sacks 1987).

The Th1-Th2 switch has been intensively studied in mycobacterial infections like leprosy and tuberculosis. In leprosy, there are two polar disease types, the tuberculoid and the lepromatous forms, with manifestations of a spectrum of transitional forms. The tubercular form is characterized by a strong cell-mediated immunity and few pathogens. A type 1 cytokine profile was found in Th1 clone cells cultivated from the blood serum of tuberculoid leprosy sufferers (Haanen 1991). Th1 helper immune cells are dominant in the damaged skin. Conversely in the lepromatous form, the pathogens are numerous and the cell-mediated immunity of the Th1 helper cells is greatly reduced. A type 2 cytokine profile is dominant in the skin lesion (Modlin 1993).

In cases of human tuberculosis (TBC) the counter-controls primarily come from the type 1 cytokines of the Th1 immune cells although TBC sufferers produce plenty of antibodies against the tubercular bacilli. These antibodies, however, have no protective function against the development of tuberculosis in humans (Des Prez 1990). A strong type 2 cytokine production has been shown in active tuberculosis (Surcel 1994). On the other hand a strong Th1 reaction (DTH reaction) can be responsible for both eliminating the agent and for the tissue damage (Dannenberg 1991). Whether type 1 cytokine plays a beneficial or detrimental role depends on the relative Th1-Th2 balance. In a type 2 cytokine milieu or a mixed type 1/type 2 cytokine milieu, the type 1 cytokines interferon-γ (IFN-γ) and tumor necrosis factor α (TNF-α) are more likely to destroy tissue cells than attack the tubercular agents (Hernandez-Pando 1994).

The third important mycobacterium, M. avium complex, is an opportunistic agent above all in AIDS patients. It appears in a Th1-Th2 switch and type 2 cytokine dominance (Holland 1994, Newman 1994).

Cytokine production and the T-helper cell status in human worm infections are of special interest in that worms played an important role as parasites in the transition from invertebrates to vertebrates, and the humoral antibody immunity developed at the beginning of the evolution of vertebrates. As a consequence, the immune strategy against worm infections should concentrate on the switch to Th2 status with a type 2 cytokine production. With worm infections, there is a pronounced production of antibodies of immunoglobulin class E, and simultaneously a marked increase of a certain type of white blood cells, the eosinophilic leukocytes, known as eosinophilia. The two main groups of worm infections, filariasis and schistosomiasis, which cover numerous sub-groups of human worm infections, are important. With filariasis the Th2 cells in peripheral blood are distinctly increased, the type 2 cytokines boosted with simultaneous increase of antibody production. Among the antibodies the immunoglobulin class E is strongly elevated with a simultaneously strong eosinophilia. The eosinophilic blood cells mainly produce type 2 cytokines. The type 2 cytokines and the antibody production (IgE and IgG) have been experimentally inhibited by type 1 cytokine and interleukin-12, a product of macrophages, which among other things stimulates type 1 cytokine in the Th1 cells (Mahanty 1993, King 1993, 1995). Worms are, however, under certain conditions attacked by Th1 cells, and under other conditions by Th2 controlled antibodies and special eosinophiles. Worm eggs, in contrast, generally provoke a Th2 response. In humans a type 2 cytokine response rather than type 1 cytokine production is associated with immunity against worms from the genus Schistosoma: antibodies of the immunoglobulin class E and type 2 cytokine IL-5 inhibited a re-infection (Capron 1994). A Th2 status generally heals or protects against worm infections (Mosmann 1996).

There are only a handful of studies regarding the cytokine profile in fungal infections in humans. These studies fundamentally support similar research on animals. They show that advanced forms of fungal infections are associated with a type 2 cytokine dominance, for instance in aspergillosis of the lungs and bronchii, candidiasis, cryptococcosis, paracoccidioidomycosis, coccidioidomycosis, blastomycosis and histoplasmosis. Conversely, protection from fungal infections comes principally from Th1 immunity. Also in cases of fungal infections the polarity of the immune response can be beneficial or detrimental: if the cell-mediated immunity was only slightly inhibited then the number of fungal microbes was also small; if the Th1 response was heavily impaired then the number of fungal pathogens was large (Mosmann 1996, Lucey 1996).

In the meantime, of the human protistan infections, only Leishmania infections have been more intensively researched. In all studies the infections with an intact Th1 status and type 1 cytokine production resolved, while an increased type 2 cytokine level was accountable for a lack of protection against these parasitic infections (Bloom 1993). Differing cytokine activities, however, were shown to be dependent on the infestation of the individual organs (Karp 1993). Extracellular bacterial infections (excluding mycobacteria) in humans, with differing cell and organ systems have in relation to the cytokine profile been little researched. There is, however, the tendency in the findings that in acute intracellular infections the Th1 response is decisive, while in cases of chronic infection a Th1-to-Th2 switch with a weak DTH reaction was observed. A comparison between syphilis and leprosy is illuminating. Latent and secondary syphilis is similar in progression to transitional leprosy between the tuberculoid and lepromatous forms. Overcoming syphilis with a strong DTH reaction and an increase in type 1 cytokine profile showed an analogy to the tuberculoid form with few syphilis pathogens. The tertiary stage was analogous to lepromatous leprosy, exhibiting a strong drift towards type Th2, increased type 2 cytokine production and a weak DTH reaction (Sell 1993).

In cases of acute viral infections the stage at which the cytokine readings are taken is decisive. A good example of this is measles: type 1 cytokines increased during and shortly after the appearance of the skin rash. After the acute phase there is an increase in formation of type 2 cytokines, a decrease in type 1 cytokines and a weakened DTH reaction (Griffin 1993). The duration of the Th2 dysbalance or the re-establishment of the Th1-Th2 balance after resolution of the measles infection was not researched.

T-helper cells from liver tissues of patients with chronic active hepatitis B display a type 1 cytokine profile (Barnaba 1994). In test subjects who did not react to the vaccine by forming antibodies (so-called non-responders), the peripheral blood cells after stimulation with the specific antigens HbsAg did not react by cytokine synthesis. The same peripheral blood cells from test subjects who showed a strong reaction to vaccination formed increased amounts of type 1 cytokines. It was concluded that hepatitis B vaccine antigens induced a Th1 response (Vingerhoets 1994).

Experimental and clinical data indicate a clear conclusion:

DTH skin reactivity is an indicator for the competence of the cell-mediated immune response of the Th1 immune cells. If the DTH reaction is positive then a successful defense and elimination of all intracellular microorganisms (bacteria, viruses, fungi, protozoa) can be expected. If the DTH reaction is negative then a successful elimination of intracellular pathogens is less probable. Chronic, opportunistic or highly acute infections could develop.

An anergic DTH reaction indicates a re-arrangement of cytokine synthesis in the stem cells of the T-helper cells mainly towards a type 2 cytokine profile (DTH immune cell status). The type 2 cytokines inhibit the synthesis of type 1 cytokines leading to a diminished capacity to stimulate T-helper cells in the blood serum. Type 2 cytokines activate antibody production. Antibodies, as a preventative barrier to entry, can only attack pathogens outside the cell. During massive bacterial dispersion after heavy traumata, burns, and serious operative invasions, it is possible that the previously existing or incurred Th2 immune cell status is not sufficient for the extracellular inhibition of bacterial or fungal agents. thereby a sepsis develops with a high mortality rate (see Dualistic Strategy of the Immune Response, Table III).

The immunological findings from AIDS clinics in 1981:

• Anergic skin reaction
• Decrease in the number and the capacity for stimulation of T-helper cells in blood serum
• Increased B-cell activity and specific antibody production (Gottlieb 1981, Masur 1981, Mildvan 1982)

The above are clear expressions of a predominant type 2 cytokine synthesis with a Th2 immune cell dominance, the diagnosed opportunistic fungal infections (PCP, candida, etc.), protozoal infections (toxoplasmosis etc.), mycobacteria (M. tuberculosis, M. avium intracellulare) and cytomegaloviral infections are characteristic manifestations of prolonged toxic, medicamentous, and microbial stress. The development of a specific immune cell status and the specific resulting diseases in promiscuous anally receptive homosexual patients was, with the same conclusive certainty, as predictable as the appearance of sepsis in anergic surgical patients.

     The decisive correlation of the DTH reaction as indicator of the dominance of the cell-mediated immunity or the dominance of humoral immunity, were amply documented in medical literature before the laboratory product “HIV” as a “new agent” was imposed, and as a result of groundbreaking work from Mosmann and Coffman the differentiations in type 1/type 2 cytokine functions of the T-helper cells and other immune and non-immune cells were recognized (Zinsser 1921, Landsteiner 1942, Chase 1945, Alexander 1972, Vadas 1976, Hurd 1977, Meakins 1977, Christou 1979, Dvorak 1979, Platt 1982, Poulter 1982, Rode 1982, Van Dijk 1982, Razzaque-Ahmed 1983, Oppenheim 1983, Asano 1983, Van Loveren 1984, Wood 1984).

In contrast to the surgical patients, there was hardly any systematic research carried out on DTH skin reactions in the so-called HIV/AIDS risk groups. Such a study, with very little cost, could have indicated the status of the immune cell deficiency of those affected both in Western and Third World countries, and could have led to a corresponding risk education without the stigma that became associated with a deadly HIV infection. There were, however, numerous studies on patients at risk regarding the T-helper cell status and the antibody status after the introduction of the “anti-HIV antibody tests,” which have clearly proven a significant increase in dysfunctions of cell-mediated immunity in members of the risk groups. After the introduction of the “AIDS test” further cross-sectional and longer-running studies were carried out with HIV-negative and HIV-stigmatized probands from risk groups, which distinctly indicated that both stigmatized and non-stigmatized people from risk groups have a higher frequency of acquired immunodeficiency (AID) than test subjects from non-risk groups (overview Root-Bernstein 1993). In plain language, this means that within comparable risk groups, AID existed before the invention of “HIV-positivity.” Thus “HIV” cannot be the cause of AID, but rather the laboratory result of “HIV-positivity” must be the effect of some other primary cause.

A “positive HIV test” merely discloses whether the test subject has formed, at a particular point in time, enough antibodies in the blood serum to react to the presented protein antigens in the test substrate. As the sensitivity of the HIV tests is set at a certain high level; probands could have the same antibodies in their blood serum but come up either positive or negative. The decisive factor for a negative test result is not the fact that a proband has antibodies in their blood serum that have reacted to the test proteins, but whether the amount of antibodies capable of reacting had reached or exceeded the preset threshold of the “HIV test.” By analogy, a driver who has been drinking is considered capable of driving if during a control the prescribed legal alcohol limits have not been exceeded. A driver who has been drinking can register a positive or a negative result. If the level exceeds the prescribed limits, then the result is positive. In relation to the HIV theory this means that one who has fewer antibodies is negative, and one with more and is positive. In terms of the retrovirus theory, however, both could be “HIV infected”. The test thresholds for “HIV-negative” or “HIV-positive” in the case of an actual “HIV infection” would be totally arbitrary, as the presence of viruses does not depend on an artificially set number of antibodies.

The number of reactive antibodies says very little about the actual capacity of the proband’s T-helper cells to eliminate intracellular agents. The quantity and quality of antibodies play no decisive role in the inhibition and elimination of intracellular agents, as countless studies of cell-mediated immunity have proven. The “HIV test” can, however, give clues about previous events in the immune cell network of test subjects, albeit for different reasons than those claimed by the HIV researchers. Analogous to surgical patients with anergic DTH tests, of whom only a third actually developed a sepsis, a “positive HIV test” does not allow for individual predictions of an unavoidable deadly disease. The “positive HIV test” also reveals nothing about a contagious “retroviral infection.” The “HIV test” can only give general indications of the possible formation of antibodies against cell proteins in test subjects or against certain alloantigens or microbial antigens. Such cell proteins could be released by (among other things) the body’s own cells, for the same reasons as was emulated in the laboratory in the extraction of test proteins from human cell cultures. The antibodies could have been formed against proteins released by an increase in necrosis (unprogrammed cell death), which then reacted after the blood serum of the test subjects made contact with the test proteins derived from human cell cultures.

In this context, it would be of interest to know whether the immunological findings of people at risk detected a type 2 cytokine profile indicating a Th1-Th2 dysbalance (AID). Such an assumption is likely, as the Th1 and Th2 cells are defined after their cytokine synthesis and the immunological findings of the first diagnosed AIDS patients showed characteristic signs of a Th2 dominance. In that case, the basic supposition of the HIV/AIDS theory, namely the destruction of the T-helper cells by a new retrovirus, would no longer be necessary as an explanation for Th2 dominance. Th2 dominance with increased B-cell activity can indeed be activated by a temporary or long-lasting viral infection, but without the necessity of the destruction of T-helper cells. The number of short-living Th1 cells in blood serum automatically decreases in Th2 dominance, in that the stem cells of the T-helper cells are predominantly adapted to the synthesis of type 2 cytokines and the Th2 cells circulate to a lesser degree in the blood serum as their helper function is performed where the B-cells are to be found. The Th2 cells do not produce cytotoxic NO gas with which to target the intracellular pathogens. The Th2 cells do not patrol the bloodstream and the lymph vessels like the Th1 cells—the much quoted “police of the immune system.” By analogy, the situation would be like police officers on the beat being given desk jobs and anyone with a bit of imagination thinking that since the police were no longer to be seen patrolling the streets, they must have all been killed by gangsters.

     As immunologists like to use somewhat graphic terminology (“killer cells”, “killer viruses”) this comparison suits the retrovirus AIDS researchers’ explanation that T-helper cells are terminated en masse by “HIV.” The fact that the Th2 cells are able to survive this supposed immune cell destruction, evident by the intact function of antibody production by the B-cells, like so many other facts, cannot be explained by the HIV theorists. This fact led the surveillance authority, the CDC, to emphatically exclude bacterial diseases from the definition of AIDS-indicating illnesses (CDC 1993). Massive bacterial illnesses only appeared in AIDS patients after highly toxic cell poisons adopted to combat the “HI-viral infection,” had systemically damaged the maturation of the B-cells in the bone marrow of patients.

     The primary problem of AIDS patients then is not the production of antibodies by the B-cells, which in turn were stimulated by the type 2 cytokines of the Th2 cells. What is decisive for the development of intracellular opportunistic pathogens (fungi and parasites), is the lack of cytotoxic NO gas due to the missing synthesis of type 1 cytokines in T-helper cells. As the Th1 and Th2 cells in the blood serum cannot be distinguished by the protein types on their cell membrane, the differentiation between whether a proband had formed mainly Th1 or Th2 cells is only possible by determination of cytokine synthesis in the T-helper cells. Such experiments were carried out on the T-helper cells of asymptomatic “HIV-positive” subjects and on AIDS patients with obvious symptoms. The results showed that the maturation and proliferation of T-helper cells was severely impaired even in the probands of those without symptoms who were “HIV-positive” and who had a nearly average amount of T-helper cells in their blood serum (Shearer 1986, Giorgio 1987, Miedema 1988, Clerici 1989 a, 1989 b).

“It was suggested that cytokine imbalance contributed significantly to AIDS progression and was associated with a switch or shift from a dominant Th1-like to a dominant Th2-like cytokine profile” (Lucey 1996; Salk 1993, Clerici 1993, 1994, Pinto 1995, Shearer 1996). There were, however, no publications about the desperately needed control experiments on the cytokine synthesis in the blood serum of “HIV-negative” risk group test subjects who also had a nearly average or reduced number of T-helper cells and simultaneously an inhibited maturation after stimulation with recall antigens, alloantigens or mitogens. There have been, since the introduction of the “HIV tests” in 1984, numerous experiments that have proven that “HIV-negative” immunosuppressed homosexual patients, drug addicts, hemophiliacs, heterosexuals and children have a reduction and proliferation inhibition of T-helper cells in the blood serum identical to “HIV-positive” patients from the same groups. In comparative clinical studies from 1982 on “HIV-negative” and “HIV-positive” homosexuals, for instance, it transpired that 30% of the “HIV-negative” homosexual men had anergic T-helper cells after stimulation. This anergy has been shown to remain constant (Weber 1986).

This finding conspicuously concurs with the percentage of anergic surgical patients on admission to clinics before operations in the Canadian study (Christou 1986). A comprehensive study in New York showed that almost 75% of homosexual men had an active infection with cytomegalovirus, Epstein-Barr virus, Herpes simplex virus or Hepatitis B infection, fully independent of whether they had reacted positive or negative to the “HIV test.” These findings are in sharp contrast to heterosexual control patients, a mere 6% of whom are actively infected, and then only with a single virus type in semen, saliva or blood. None of the heterosexual control patients had multiple infections whereas 20% of the homosexuals had more than one infection (Buimovici-Klein 1988).

Similar immunological and clinical findings have been made in numerous studies with patients from all risk groups. The criteria for a T-helper switch were apparent in all these patient groups, independent of a negative or positive “HIV status” and the development of opportunistic AIDS-indicating diseases (overview Root-Bernstein 1993). It is then even more astounding that research on cytokine synthesis in the T-helper cells of these patients could apparently only be carried out once the patients had registered positive in the “HIV test” (Lucey 1996, Abbas 1996). This failure must be judged as grave malpractice. Logically an anergy of the T-helper cells (indicator of a switch of the cytokine profile to Th2) of homosexual patients who at first register “HIV-negative” and then a year later “HIV-positive” cannot be retroactively traced to an “HIV retrovirus infection.” A positive reaction to an “HIV test” merely indicates that at a certain point in time there was a gradual shift in the amount of certain antibodies. Whether this increase in antibody production took place at an earlier time or was taking place at the time of the test cannot be determined by the test results, given that antibodies once produced can be detected in blood serum for years, and sometimes for life. The “HIV-positive” test results also cannot give any indication as to whether or not opportunistic illnesses will develop. Such a probabilistic prediction depends on a completely different set of factors including the kind of medical intervention.

It is especially striking that the researchers discovered that the laboratory products, which in the T-helper clone cells were interpreted as indirect evidence of a “retrovirus HIV,” could be found primarily in Th2 clone cells but not in Th1 clone cells (Maggi 1994, Chehimi 1995, Abbas 1996, Lucey 1996). These laboratory findings presented the HIV/AIDS theory with an unsolvable paradox. Since 1981, a causal factor was sought that was supposed to destroy those T-cells that were responsible for the elimination of intracellular opportunistic fungal microbes (Pneumocystis carinii, candida), protoctista (toxoplasma, etc.) and viruses (cytomegalovirus, etc.). But these T-helper effector cells are Th1 cells. If the Th1 cells, according to the laboratory experiments were not colonized by the hypothetical “retrovirus HIV,” then they certainly cannot be destroyed by it. Whoever is not at the scene of the crime, cannot have committed it. On the other hand, the number of Th1 cells depends on how many stem cells of the T-helper cells were trained in the synthesis of type 1 cytokine profile (Mosmann 1996). So HIV must colonize and destroy the stem cells. In that case there would not be any Th2 cells, which are imprinted on the type 2 cytokine profile and stimulate the B-cells to produce antibodies. The patients therefore should have developed massive bacterial infections analogous to those seen with Burton syndrome (lack of gamma globulins) or SCID (combined T—and B-lymph cell destruction). In fact, the contrary was the case: a hypergammaglobulinaemia was observed (Lucey 1996) and in contrast to the imposing opportunistic infections, there were no conspicuous bacterial infections (CDC 1993). The hypothetical colonization of the Th2 cells by a hypothetical “HIV” had zero medical consequences.

However, the type 2 cytokines of the Th2 cells do not inhibit the Th1 cells indirectly with their cytokines, but rather the biosynthesis of the cytokine profile is inhibited or promoted by influencing the genetic expression in the stem cells (Mosmann 1996). The genetic expression of the cytokine proteins is dependent, like all genetic expression, on the redox milieu which inhibits or promotes the transcription factors. The redox milieu is, however, governed by a complex multiplicity of extracellular and intracellular factors. But if particular patterns of the cytokine proteins are expressed, they engage the redox milieu in a regulatory fashion—both in their own expression and in the cytokine proteins and enzyme proteins such as, for instance the NO synthases and many other protein enzymes. If a non-expressed cytokine is added to a culture of peripheral blood cells from “HIV-positives,” the Th2 cells suddenly respond to the recall antigens and exhibit proliferation (Clerici 1993 b). Thus the redox-dependent expression of the cytokine mixture determines the human immune response. A “new agent” is by no means necessary to explain this elementary process. which has functioned in redox-dependent self-organization for millions of years.

The HIV laboratory researchers have tied themselves in a logical knot with their contrived test-tube experiments on T-cell clones, and therefore must continually develop ever more complicated rescue hypotheses in an attempt to justify the existence of HIV (Shearer 1995). Thus they increasingly lose sight of the biological reality, namely the conditions the strategy depends on, which the immune response adopts as partial regulation for the balance as a whole. This question touches on a fundamental dogma of immunology, namely the assumption that immune cells can “recognize” foreign proteins and other foreign molecules and can differentiate between the body’s own 55,000 odd proteins and other molecules, and foreign molecules such as microbial proteins. This perception largely contributed to the seemingly plausible (for the layman) theory that a new sophisticated virus had infiltrated the central recognition base of T-immune cells during sexual intercourse or blood transfusions and had disabled the native defense network of “HIV-positives” and AIDS sufferers.

This immunological dogma has, in the last decade, been severely shaken. The “self/non-self theory” has at no point in time been able to explain certain contradictions, e.g.:

• Why do T-helper cells and antibodies, under certain conditions, attack the body’s own proteins (autoimmune reaction)?
• Why are cancer cells not recognized by immune cells as being foreign?
• During pregnancy, why don’t immune cells attack the embryo, whose cells contain foreign genes and thus synthesize foreign proteins?
• Why are intestinal bacteria not regarded as foreign?

The decisive assessment is that the T-helper cells cannot differentiate between “self” and “non-self” molecules but in principle can inter-react with all molecules. T-cells mature in the thymus. They are produced in the millions by random genetic recombination. Every negatively-charged T-lymph cell is programmed to a suitably charged profile on proteins or other molecules. Most of the T-cells already hook up with the suitable molecule at the location of maturation in the thymus. This contact causes the death of the T-cells. The encounter with the suitable proteins or other molecules, termed antigens, is not enough to activate the T-cells for their ultimate function as effector cells. Only a very small proportion, namely those that cannot find a suitable antigen in the thymus, leave the thymus and move into the bloodstream and lymph vessels (positive selection).

There are essentially three kinds of T-cells:

1. The T-helper cells, which as Th1 cells can activate cytotoxic T-cells and macrophages,
2. The T-suppressor lymph cells,
3. The cytotoxic T-cells, a.k.a. killer cells, which after activation bind directly on cells but do not absorb them like the macrophages do.

The virgin T-helper cells become experienced T-helper cells once they encounter their antigen for the first time. After this initial contact, they either die off or survive as resting cells in a dormant state. Once they have received a specific double signal, the experienced but dormant T-helper cells become effector cells. Signal 1 is offered by special antigen-presenting cells (APCs), which for example present a fragment of a protein molecule. This takes place in the middle of the receptor molecules (MHC II). Signal 2 comes from co-stimulatory molecules of the same APCs, which are mainly termed dendritic cells. The second signal is not only picked up by experienced T-helper cells, but also by macrophages and B-cells; however it cannot be received by virgin T-helper cells.

The basic rule for virgin T-helper cells is as follows:

• If signal 1 is received without signal 2, then die off or wait; but if both signals are received from dendritic cells, B-cells or macrophages, then activate.

The relatively simple, but biologically quite successful principle, of why T-helper cells do not (or very rarely) respond to the presentation of the cell’s native proteins, is a question of statistical proportionality: the few T-helper cells that are programmed to recognize cell native proteins and have not already encountered their protein antigen in the thymus, have an extremely high chance of encountering their molecular partner in the bloodstream, lymph vessels, lymph nodes, or spleen, before they encounter an APC. Relative to the billions of bodily cells and remaining soluble proteins and other molecules, the APCs are quite rare; therefore a virgin T-helper cell, programmed to native antigens, has an extremely low chance of finding its matching molecular partner together with signal 2 on an APC.

The same basic rule also applies to the B-cells, which mature in the bone marrow. Roughly 25% of mature B-cells are sensitive enough to be able to produce antibodies (negative selection). Again the basic rule applies:

• Die if only the antigen signal is received.
• Activate if the second signal comes from activated T-helper cells (Th2 cells).

For the experienced/activated effector T-helper cells and effector B-cells, the basic rule is:

• Perform effector function if signal 1 (antigen contact) has been given irrespective of the presence or absence of signal 2.
• Die or revert to resting state if signal 1 is not received (overview Matzinger 1994).

This simplified representation is enough for a basic understanding of why B—and T-helper lymphocytes, in cooperation with antigen-presenting cells, are able to recognize a viral infection even when a virus particle has colonized some T-helper cells. In the case of the destruction of T-helper cells, these viral proteins will be trapped by APCs and presented along with the necessary additional signals to the T-helper cells (of which only a few would be colonized at the start of such an infection). Therefore, it makes no difference to the T-helper activity whether the virus infected T-helper cells or other cell types.

In the case of the hypothetical “HIV infection,” however, there must be other reasons for a systemic switch from Th1 cell types to mainly Th2 cell types. When followed over a number of years, patients with the same risk factors and identical results of a Th1-Th2 deficiency (AID), but without an “HIV-positive” test result, only experienced seroconversion (a flipping of test results from “HIV-negative” to “HIV-positive”) in a minority of cases (Weber 1986, Root-Bernstein 1993). While both variants exhibit identical anomalies of the immune status (AID with or without “HIV-positivity”), they simply differ in individual proclivity to antibody production.

According to the laws of logic, factor B cannot be the cause of factor A if factor A precedes factor B. As about 2 million new T-cells and 20 million B-cells are formed every day (George 1996, Osmand 1993), the general dominance of type 2 cytokines measured at an early stage of seroconversion in asymptomatic risk-group patients, cannot be traced back to a singular virus, which selectively infects a minority of the T-helper immune cells. Consequently, this means that the impairment of cell-mediated immunity, acquired through a Th1-Th2 switch, is not a reflection of a “retroviral infection” but the expression of a pre-existing long-term prooxidative (oxidative and/or nitrosative) stress.

The T-helper cells do not operate in isolation, but are programmed as particularly redox-sensitive cells with a specialized mission to react to signals of oxidative/nitrosative danger. Such signals are conveyed to them by the change in intracellular redox caused by antigen presentation with its associated co-stimulatory signals, as well as by exposure to toxins. The result of this interaction is the activation of the genetic expression for type 1 cytokine synthesis, which in turn activates the biosynthesis of enzymes which produce cytotoxic NO. With no additional signalling necessary, Th1 cells which have thus been activated to become effector cells will emit an NO gas cloud the next time they encounter the antigen on an infected cell. The gas infiltrates the infected cells and oxidizes essential metalloenzymes of the microbes, leading to the inhibition or death of the pathogen.

Not only T-helper cells, but also countless other immune and non-immune cells are capable of cytokine synthesis and cytotoxic NO gas formation.

The triggers are not only antigens, but also toxic and other oxidative and nitrosative stress factors (Lincoln 1997). After a critical level of NO production has been reached through continuous stimulation, the looming threat of systemic antioxidative depletion gives rise to a dilemma between self-defense and self-preservation. A strategic decision has to be made at a genetic and non-genetic level. In these cases a braking effect happens in T-helper cells by redirecting the genetic expression of the cytokine synthesis and the induced NO syntheses. A Th1-Th2 switch occurs, which leads to an immune dysbalance (AID). The thiol pool is then the critical sensor and modulator of this switching effect; thiol depletion triggers a multidimensional network of regulations and counterregulations. Severe cases of acute infection, serious injuries and burns, operative invasions and poisonings (acute AID) can lead to an emergency polarization between “healing and sepsis” (Christou 1986). Insidious assimilation series with variable intermediary stages can also develop, until the final faulty adjustment of the interconnected regulatory systems to a set level occurs; this happens through protracted fungal, protozoal, viral and mycobacterial infections with a long-term antigenic burden, chronic intoxication (including cytotoxic drugs), malnutrition, starvation, aging processes, and many other prooxidative states of stress (long-term AID). Whether the net effect is primarily a Th1 or Th2 dominance (locally, organ-specifically, or systemically), depends on many internal and external factors. A particularly important external factor is the course of medical intervention, which is influenced by the dominant theories, and supported consciously or subconsciously by non-medical interests.

Since 1990, the paths of cytokine researchers and NO researchers have crossed. Shortly after Furchgott and Ignarro provided fundamental evidence that exogenous nitrate and nitrite in the endothelial cells metabolized into NO (Furchtgott and Ignarro independently of one another in 1986), Marletta reported for the first time about evidence of NO as an oxidation product of arginine in macrophages (Marletta 1988). When Gillespie published in 1989 that NO gas in nerve cells inhibited the transmission of nerve impulses (Gillespie 1989), an unforeseen research boom began. Within a few years it was recognized that NO, from molluscs (Franchini 1995, Johanson 1995, Octaviani 1998) to humans, controlled basic biological functions in all cell systems via oxidation—of metallic compounds such as ferrous proteins and enzymes (e.g. the iron-sulfur centers in the respiratory chain of the mitochondria), and of the sulfur-hydrogen (thiol) groups in the amino acids methionine and cysteine, and the proteins and enzymes which contain them (Moncada 1991). These basic discoveries laid the foundation for a profound change in the understanding of the AIDS and cancer puzzle.

Research on the production and function of cytotoxic NO gases in T-helper cells concentrated on three key areas:

• The significance of cytotoxic NO gases for the inhibition and elimination of microorganisms by the T-helper cells.
• The interplay between the syntheses of the cytokine profile and the inducible NO synthesis in T-helper cells.
• The counterregulation of the cytokine synthesis and the long-term NO synthesis in the context of the Th1-Th2 switch (immune cell dysbalance = AID).

The consequences of the discovery of NO synthesis in the immune cells were recognized at an earlier stage. Had it been apparent that the capacity of the cell-mediated immunity (Th1 cells) and the switching to a mainly humoral immune status (Th2 cell dominance and over-activation of antibody production) were dependent on cytotoxic NO synthesis—then the Th1 immune cell deficiency would not have been a puzzle at all. All factors involved with a long-term functional inhibition of the NO synthesis (nitrite consumption, cell toxic drugs, high and/or long-term antigen and alloantigen loads, oxidizing influences, protein malnutrition, etc.) could potentially trigger immune anomalies and opportunistic infections. An explanation of the Th1-Th2 switch from “HIV-negative” to “HIV-positive” in risk group patients no longer requires a “new agent.” The causes of such diseases could be found in the dysbalance of the cytotoxic NO synthesis. In order to be effective, AIDS therapy would have to treat the causes of the cytotoxic NO blockade.

In 1990, NO production was demonstrated for the first time in the T-lymph cell cultures of rats that had been stimulated with the mitogen, phytohaemaglutinin (PHA). When a substance that inhibits NO production was added to the T-lymph cell cultures, there was a strong increase in the maturation and proliferation of the T-cells (Hoffman 1990). Since then, these findings have been confirmed in numerous T-lymph cell cultures of mice, as well as in living mice. Bacterial infections in mice lead to greatly increased NO levels and a subsequent inhibition of lymphocyte proliferation, resulting in a reduced T-helper cell immune response (Gregory 1993). When the T-cells from the spleen of mice infected with the malaria parasite (Plasmodium) were cultivated with malarial antigens, a significant production of type 1 cytokines (interferon-γ, interleukin-2) was observed. The synthesis of these cytokines was considerably increased when the mice were treated with an NO synthesis-inhibiting substance (Taylor-Robinson 1994). The researchers could also demonstrate these effects when the Th1 clone cells, which specifically had reacted to malaria antigens, were brought into contact with NO synthesis inhibitors; there was a substantial increase in the syntheses of interferon-γ and interleukin-2. Vice versa in the same Th1 clone cells, the same type 1 cytokine synthesis was much reduced when an NO-donating substance was added; above all the synthesis of the growth factors for the proliferation of Th1 cells, interleukin-2, was reduced in proportion to the amount of NO-donating substance added. The inhibition on proliferation of Th1 cells could be reversed by adding interleukin-2 to the cell culture of Th1 clones (Liew 1995). These experiments showed that NO in the Th1 clone cells inhibited the secretion of the type 1 cytokine IL-2. Further experiments with the mitogen concanavalin (Con A) confirmed that the Th1 cells were activated to NO synthesis when stimulated (Kirk 1990). In other experiments with T-helper cells from mammals and humans it was demonstrated that bacteriotoxic lipopolysaccharide (LPS) stimulates type 1 cytokines in Th1 cells, which in turn activate the production of cytotoxic NO gases (Kröncke 1995).

NO gas has two important functions:

• First, NO diffuses from activated Th1 effector cells into infected target cells, in order to inhibit or eliminate intracellular pathogens. This effector function applies in response to all intracellular microorganisms (bacteria, viruses, fungi, parasites). In the same way, cytotoxic NO gas also diffuses into extracellular microorganisms, for instance worms, fungi and parasites. The Th1 cells are supported in this task by the macrophages, which also produce NO gas (van Rooijen 1997, MacMicking 1997). Between macrophages and the Th1 cells, a mutual stimulation occurs through the exchange of type 1 cytokines and interleukin-2.
• Secondly, cytotoxic NO modulates the immune response of the Th1 cells by inhibiting further production of type 1 cytokine synthesis and by doing so, hinders an excessive proliferation of Th1 cells. At the same time, the synthesis of NO gas is inhibited because type 1 cytokines are its strongest stimulators. Hereby a negative feedback loop exists between the NO synthesis and type 1 cytokine synthesis. In cases of acute infection, this braking mechanism can prevent tissue damage from excessive amounts of NO. In cases of chronic infections, this self-inhibition of the NO synthesis can develop into a vicious circle and sustain the infection. NO gas acts simultaneously as a cytotoxin and as an immune regulator (Lincoln 1997).

When the gene for the expression of the protein for the synthesis enzyme of NO was blocked in mice, the inducible NO synthase (iNOS) in these “knock-out” mice displayed exactly this double-edged sword effect. The mice showed a substantially stronger immune response of Th1 cells, as the type 1 cytokines were no longer braked by the NO gas. Simultaneously, they were considerably more susceptible to infections than control mice. They could no longer form NO gas clouds to disable the metabolism and growth of intra—and extracellular agents (Wei 1995). These mice suffered from a special form of AIDS: an acquired immunodeficiency due to lack of effector gas with over-stimulated Th1 cells.

Of special significance was the question of whether the Th2 helper cells can synthesize cytotoxic NO. When the Th2 cell clones were treated in the same way as Th1 clones—with NO synthesis inhibitors, NO donor substances, or type 1 cytokines—they showed no signs of cytotoxic NO production, nor differences in proliferation performance (Taylor-Robinson 1994). Th2 cells differ from Th1 cells in that they do not produce cytotoxic NO (but they do regulate small amounts of calcium-dependent NO for internal modulation of numerous other cell biological processes, as do other cells). Thus, Th2 cells do not participate in the intracellular elimination of intracellular agents (Sher 1992, Kröncke 1995, James 1995, Barnes 1995, Vodovetz 1997 O’Garra 1998, Morel 1998).

A switch to Th2 predominance additionally inhibits the synthesis of cytotoxic NO, as type 2 cytokines are released which suppress the production of cytokines in macrophages. For example, type 2 cytokines inhibit the interleukin-12 of the macrophages, which normally stimulate type 1 cytokines in Th1 cells, and in turn activate the cytotoxic NO synthesis. It is not surprising then, that if a Th2 dominance exists in people with an intact antibody production, irregardless of “HIV status,” opportunistic pathogens (fungi, parasites, mycobacteria, several virus types) will be able to colonize and proliferate within cells—as an effective NO gas attack cannot be mounted against them. This process becomes further complicated due to the fact that fungi and parasites, if they remain unchallenged, can themselves secrete substances that decelerate the NO synthesis in macrophages, and probably also in Th1 cells (Liew 1994, 1997, Green 1994, James 1995, Remick 1996, Lucey 1996, Clark 1996, de Waal 1997, Leit-de-Moraes 1997, Ramshaw 1997, Akaike 1998, Karupiah 1998, Murphy 1998, Cobbold 1998).

Conversely, the danger exists that with a strong NO production for self-defense, localized chronic inflammations could be triggered and/or serious tissue damage could occur (Nussier 1993). Inflammatory processes develop in various organs which are difficult to control (overview Lincoln 1997). Sepsis as a systemic inflammatory process does benefit from a Th2 dominance, however as a result of the massive bacterial dispersion, excessive microbial endotoxins (lipopolysaccharides, a.k.a. LPS, etc.) are formed which stimulate a strengthened NO production in various cell systems, since with the exception of Th1 cells, many other immune and non-immune cells (macrophages, Kupfer cells, mesangial cells, microglial cells, splenic cells, neutrophilic leukocytes, natural killer cells, epithelial cells, endothelial cells, vascular smooth muscle cells, heart muscle cells, liver cells, pancreatic cells, chondrocytes, osteoblasts, fibroblasts, keratinocytes, astrocytes, peripheral nerve cells, etc.) carry the enzymes for inducible NO synthesis, and therefore can produce surplus amounts of cytotoxic NO when under massive provocation from endotoxin. With septic shock, a malignant drop in blood pressure occurs which can lead to impaired circulation in the vital organs. The elevated quantity of NO oxidizes the ferrous enzyme, guanylate cyclase, in the endothelial cells. Through formation of cyclic guanosine monophosphate (cGMP), the vascular smooth muscles become continuously relaxed. The mortality rate of septic shock remains high even today. Promising findings in animal experiments with NO-inhibiting substances are problematic in humans, as it is difficult to attain a selective and organ-specific balance (Petros 1993, Kettler 1998, Kirkeboen 1999).

One of the principal dangers of the inflammatory process, as a result of extreme NO production, is the increase in cell death. The increased type 1 cytokine synthesis leads to an increase in the formation of interferon-γ and tumor necrosis factors, which in turn activates the production of oxygen radicals. These in turn can trigger programmed cell death (apoptosis) or unprogrammed cell death (necrosis), via a cascade of reactions. Unlike programmed cell death, if the cell contents, after the bursting of the cell membrane by necrosis, have not been previously recycled, proteins and other molecules will be released into the extracellular milieu. These are then processed as “foreign substances” by APCs (in this case primarily the dendritic cells and macrophages) and subsequently offered to virgin T-helper cells, as well as being captured by membrane-bound antibodies.

Compatible Th1 cells are similarly activated by a double signal, as with other proteins not originating from native cells, and produce cytotoxic NO clouds once they re-encounter activated cell proteins. The subsequent attacks against cell proteins proceed similarly as with intracellular microbial proteins. The Th2 cells activated by antigen signals from B-cells pass on stimulating signals to the B-cells, which then secrete soluble antibodies. Not only can these antibodies inter-react with the necrotic proteins they were produced against, but just as equally they can cross-react with other native proteins having analogous binding sites on the polymorphic protein structure. Following this model of interaction, autoimmune reactions are thereby geared towards “self” cells (Nicholson 1996, Vergani 1996, Rocken 1997, O’Grady 1997, Heurtier 1997, Weigle 1997. Lafaille 1998, Del Prete 1998, Pearson 1999).

Cancer cells, on the other hand, are tolerated as “self” cells, as long as they do not yield antigens to the APCs. Cancer cell antigens cannot be presented, and therefore T-helper cells and B-cells cannot be activated, until necrotic cell death occurs. In their intact state, the cancer cells are too large for assimilation by macrophages (Matzinger 1994). Cells that are able to divide, shift to enzymatic production of the universal energy carrier adenosine triphosphate (ATP) outside of the specialized cell organelles (mitochondria in which normally 90% of the ATP production is gained by oxidative phosphorylation), and transform into cancer cells. Research up until now suggests that cancer cells are associated with type 2 cytokine synthesis (Lucey 1996).

Intestinal bacteria on the other hand, 99% anaerobes, likewise obtain ATP energy enzymatically instead of with the aid of oxidative phosphorylation of adenosine diphosphate (ADP). Not only do these anaerobes have the task of digesting food remains, but they also line the lower intestines, forming an exosymbiosis with the intestinal mucosa. They are an integral part of the immune defense, in that they supply the organism with sulfurous reducing substances by means of their complex metabolism, and in this way strengthen the reductive powers of the host. Additionally, the anaerobes produce from the amino acid tryptophan the vitamin niacin, essential as the building block of the co-enzyme NAD⁺, which is irreplaceable in many biosyntheses as a carrier and receptor of hydrogen ions. It is striking that in the polymorphic cell composition of the intestinal wall and its mucous membrane, which represents the largest exchange and contact area in the human organism with the outside world and its manifold contaminations, the concentration of T-cells is relatively small, although 85% of all T-cells are found in the intestinal tissue. Clearly the anaerobe colonies, which produce more bacterial cells than the total number of body cells, relieve and strengthen the type 1 / type 2 cytokine balance of the entire organism. There is still too little research into the exact biodiversity and metabolic performance of the anaerobic intestinal flora, but a dyssymbiosis can lead to an increase in Th1 cell activity and the production of cytotoxic NO. Clinically, this reactive local Th1 dominance manifests itself as inflammatory intestinal diseases such as ulcerative colitis, Crohn’s disease, or in both “HIV-negative” and “HIV-positive” homosexuals, the not uncommon inflammatory bowel syndrome (Tomita 1998, Guslandi 1998, Perner 1999, Murad 1999).

The question why during pregnancy the embryonic cells are not recognized as being “foreign” by T-helper cells and then attacked, has been sufficiently explained. During pregnancy the maternal T-helper cells in the region of the placenta (retroplacentary blood lymphocytes) increase the synthesis of type 2 cytokines, most likely governed by elevated progesterone levels. As researchers in animal experiments and with human pregnancies have demonstrated, a Th1 dominance does in fact lead to termination of pregnancy. A successful pregnancy is only possible with the protection of the local synthesis of type 2 cytokines (Lin 1993, Wegmann 1993, Mosmann 1996, Raghupathy 1997, Kasakura 1998).

The questions asked earlier about contradictions in the self/non-self concept dominant in immunology can plausibly be answered in light of the type 1 / type 2 cytokine balance and the related stimulation or inhibition of cytotoxic NO synthesis. But a far-reaching question arises from this knowledge: if the reaction to self and non-self identification is not the special function of the immune cell network, then what is the self-regulatory control for the adjustment of the balance between cell-mediated and humoral immunity? The strongest criticism of the self/non-self paradigm was formulated by the American immunologist Matzinger from the National Institutes of Health (NIH), the highest research authority for health matters in the USA. Matzinger, through analysis of a great many immunological research findings, reached the viewpoint that it is not the recognition of self and non-self molecules, but rather the realization of a danger to the organism in the form of tissue destruction that alerts the immune cell networks:

“Looking from the perspective that the driving force behind immunity is the need to recognize danger, we are led to the notion that the immune system itself does not stand alone. It is not simply a collection of specialized cells that patrol the rest of the body, but an extended and intricately connected family of cell types involving almost every bodily tissue. Tolerance no longer resides solely with deletion vs persistence of single lymphocytes; rather it is seen to be a cooperative endeavor among lymphocytes, APCs, and other tissues. Memory no longer resides with long-lived lymphocytes but in their interactions with antibodies, antigen, and follicular dendritic cells. Immune response modes are governed by interactions between lymphocytes, APCs, basophils, mast cells, and all of their lymphokines (and perhaps themselves, as they try to influence the immune system). By these networks of co-operating cells, the immune system can be alerted to danger and destruction without ever needing to consider the question of self vs non-self. It can contain myriads of auto and foreign reactive lymphocytes, each ready to respond and each ready to be tolerized if necessary. In this way it has the strength to destroy the things it needs to destroy, the tolerance to leave others alone, and the ability to tell the difference” (Matzinger 1994).

The danger theory explains the rules that are followed by the immune cell network when responding to active and passive stress factors. It does not explain the common elements within such apparently heterogeneous conditions as, for instance, protein energy malnutrition, organ transplants, sepses, chronic fungal or parasitic infections, chronic tuberculosis and lepromatous leprosy, AIDS, pregnancy or the aging process. In all of these conditions, the immune cell network switches, partially or systemically, to a type 2 cytokine synthesis and a limitation of cytotoxic NO production. The organism then tries to avert a particular danger, and in doing so takes other risks into account. In dangerous situations the organism has to make decisions as to how it can maintain balance, temporarily or long-term, in the individual compartments of the body, or for the body as a whole. This continuous balancing act can sometimes lead to an overcompensation in one or the other direction, and possibly to self-damage—either through inflammatory processes and autoimmune reactions, as a result of a too high, unchecked cytotoxic NO production (Th1 dominance); or through the deactivation of cytotoxic NO production and the switching of the immune response to an extracellular humoral defense, resulting in an immune cell dysbalance (Th2 dominance). The immune cell network can give too much gas or brake too hard. With acquired immunodeficiency syndrome (AIDS), the organism seems, after a phase of excessive NO activation, to be too exhausted to brake NO production. In the case of pregnancies, for reasons of the physiological cell division frequency, there is no possibility of choice. Not only do the T-helper cells of pregnant women switch to Th2 dominance between mother and embryo in the contact areas of the placenta, but the T-helper cells of the newborn child are imprinted with the Th2 type. After birth, a regulated Th1/Th2 balance has to be trained (Delepesse 1998).

The fact of the type 2 cytokine imprint of foetal T-helper cells in the womb has been linked to other significant clinical phenomena. Worldwide epidemiological studies in many countries have revealed that the prevalence of atopy, including allergic rhinitis, asthma, eczema, and atopic skin diseases have continuously increased since WWII. This increase in susceptibility to allergic reactions is correlated with a Th2 immune cell dominance, an increase in antibody production of immunoglobulin E and certain immunoglobulin G antibodies, an increase in eosinophils and a relatively anergic DTH skin reaction. The immunological findings of atopic patients are analogous to the immune response to worm infections. It can be assumed that there is a cross-reaction between allergy-causing antigens (allergens) and worm antigens, as the immune cell network reacts exactly as it would to a worm infection. That means that the immune cell network, as sensor for internal and external environmental dangers in atopic patients, is adjusted to danger in much the same way as the early developmental stage of vertebrates, when worm parasites made necessary the evolutionary biological innovation of the double strategy of cell-mediated (Th1 cells and cytotoxic NO production) and humoral (Th2 cells and a broad antibody repertoire) immune response (Fedyk 1997, Holt 1997, Romagnani 1998, Paronchi 1999). However, there is an important difference: it has been established that early childhood bacterial infections have a negative correlation with the later development of atopy, so it seems that the lack of childhood infectious incidents encourages atopy and the Th2 dominance promotes susceptibility to atopic reactions. It is hypothesized that the reduction of infections during childhood due to vaccinations and antibiotics contributes to atopic disposition. Also intrauterine conditions, for instance nutritional factors which force the Th2 status and IgE synthesis, have also been discussed as causes (Howarth 1998). What is difficult to understand, is why the exposure of mothers to drugs, foodstuff and drinking water contamination (nitrosamines, pesticides, hormones, antibiotic residues, etc.), cigarette consumption, environmental poisons, exposure to natural and artificial radiation, heavy metals, contraception pills, and so on, have not been discussed.

In this context, it is striking that homosexual AIDS patients who are affected were predominantly born after WWII (average age, mid-30s) although it would be reasonable to assume that precisely older homosexuals could have inhaled nitrite as a means of sustaining erections, comparable to heterosexuals using Viagra for a similar purpose. Nitrites expand the blood vessels in the penis by releasing NO, which in turn activates the ferrous enzyme, guanylyl cyclase, which stimulates cyclic guanosine monophosphate (cGMP), which relaxes the smooth muscle fibers of the blood vessels. Viagra hinders the rapid reduction of cGMP and in this way produces an effect similar to nitrite inhalation. Homosexual AIDS patients, during the progression from asymptomatic AID (anergic DTH skin reaction, Th2 dominance) to opportunistic infections (AID-S), often developed atopic symptoms and allergic reactions to drugs, greatly increased IgE antibody production, and eosinophils with significantly increased amounts of eosinophilic cationic proteins in the blood serum (Parkin 1987, Grieko 1989, Wright 1990, Lucey 1990, Paganelli 1991, Isreal-Biet 1992, Small 1993, Smith 1994, Drabick 1994, Vigano 1995 a, 1995 b, Paganelli 1995).

In general, when compared to younger people, the elderly have a higher prevalence of bacterial, viral and opportunistic infections and cancer. However, this pathology is not associated with AIDS. T-cells of older people exhibit a reduced proliferation after induction with mitogens; and a reduced type 1 cytokine synthesis, while type 2 cytokine synthesis is increased. This Th2 dominance is also typical of healthy elderly people. During stimulation of leukocytes with bacterial endotoxins (LPS), however, records show an increased synthesis of interleukin 1, 6 and 8 as well as tumor necrosis factors in older people as compared to younger people (Rink 1998, Shearer 1997). In T-lymph cell experiments on mice, with increasing age there was a clear shift of the Th1-Th2 profiles, a reduction of natural killer cell activity, and disruption of the B-lymphocyte functions (Doria 1997).

Th2 dominance in newborn children indicates that the T-helper cell activity with cytotoxic NO synthesis cannot be imprinted during foetal development. The increased predisposition in old age for infections and neoplasia demonstrates that the cytokine balance is no longer maintained.

The reasons for these immunological findings at the beginning and end of life, as well as for the symptomatic immune dysbalances due to specific stressors with varying causes are of a profound nature. They are determined by the evolutionary biological fact that all human cells, as with all multi-cellular organisms and most protista, in reality comprise a cell colony formed by intracellular symbiosis. All influences in the course of a lifetime, from embryonic development until death, affect the vital function of this cell symbiosis. The dynamics of acquired immunodeficiency are a special case of regulatory and counterregulatory disruption of this highly complex symbiosis in specific cell systems. This evolutionary medical fact has until now been sparsely contemplated, if at all, in practical medical science; in the HIV/AIDS field it has been repressed by an obsession with a hypothetical retroviral infection.

Recapitulating, the causes of “acquired immune cell deficiency” can be explained: We are dealing with an evolutionary-biologically programmed switching of the immune cell network and other cell systems, acting to protect the cell symbiosis. Dependent on whether the changes to the redox milieu are temporary or long-term, the T-helper cell populations, influenced by the cytokine profile, are imprinted with a Th2 dominance with increased antibody activity. The cytotoxic NO production, reliant on type 1 cytokines, is suffocated, as is the production of reactive oxygen species (ROS), The price of this inflammatory blockade is a weakness in the elimination of intracellular pathogens. This can lead to opportunistic infections (AIDS), as the intracellular opportunistic microbes can only be fought off by an adequate NO synthesis. Very often, the pathophysiological type 2 cytokine dominance follows a short-term and excessive, or a long-term and continual, switching of the NO synthesis and the type 1 cytokine synthesis of the counterregulation to a type 2 cytokine profile. In this sense, the inhalation of nitrites for sex-doping is a special factor in increasing the NO formation in certain cell systems. The results are inflammatory processes, higher local or systemic cell death, necrosis (with antibody formation and tissue damage through autoimmune reaction) and/or apoptosis (without autoantibody formation). Such processes could develop, also in phases and at certain stages of illness, parallel to a Th2 dominance of the immune response.

     In extreme cases, the counterregulations for the protection of cell symbiosis could become overcompensatory and lead to malignant cancer cell transformation; i.e. enzymatic ATP fermentation as an emergency backup plan for cellular survival when mitochondria are malfunctioning. The triggering stressors are of a diverse nature; toxic (including pharmacotoxic), traumatic, nutritional, microbial, alloantigenic (including intake of oxidizing semen during anal intercourse as well as highly contaminated blood products), environmental, psychoemotional, and age-related. Individually or in combination, such stress factors could exert an influence on life expectancy. In relation to dosage, duration, type and combination of the prooxidative stress burden, together with the predisposition of the individual (influenced by genetic, intrauterine, and early childhood imprinting) a latent AID state can shift to manifest AID syndrome (AIDS). This can occur with or without a positive result from an “HIV antibody test.” As a logical consequence, the US surveillance authority (CDC) has since 1987 diagnosed AIDS by the most frequent AIDS-indicating diseases in a catalogue of 29 disease forms, without the laboratory construct of “HIV-positive” (CDC 1987): the laboratory construct “HIV-positive” merely proves the presence of adequate amounts of antibodies and autoantibodies to reach the measuring thresholds of the “anti-HIV antibody test.” Conclusions as to the origins of an acquired immune cell deficiency cannot be drawn from an “HIV test,” because the origin of the proteins used in the testing procedure as evidence of antibodies has not been identified, but merely attributed by virtue of inadequate evidence to a “retrovirus.” A “retroviral” infection of T-helper cells would be neither necessary nor sufficient to explain a Th2 dominance. Only in the context of other clinical and laboratory parameters, can the “HIV test” indirectly give nonspecific clues about the existence of a Th2 dominance and the disintegration of cell symbiosis. There are some 70-odd different conditions in which an “HIV test” comes up positive and even HIV dogmatists recognize that these have nothing to do with having “retroviral” infections (Giraldo 1999).

It is a fact that only 0.1% of the total population of Germany show signs of the quantitative and qualitative antibody and autoantibody combinations that could lead to the laboratory construct of “HIV-positivity.” The majority of these cases are members of the “risk groups”: a minority of anally receptive homosexuals, a minority of intravenous drug addicts, half of the hemophiliacs, and some multi-transfusion recipients. This must be compared to the fact that within a general surgical patient population, roughly 30% featured an anergic Th2 dominance (Christou, 1986).

     Independent of their respective specific causes, all of these AIDS forms comply with the same evolutionary-biological rules. Causal research can only be of use when considering all of the “risky” events in an individual’s life. The actual meaning of Th2 dominance concerning AIDS is dependent on whether the affected patient recognizes and learns to avoid the actual risks, whether the given bioenergetic and biochemical deficit for protecting cell symbiosis can be balanced, and whether medical intervention does not cause more harm than good. Knowledge of the self-organization of cell symbioses, in existence for some 2 billion years, is indispensable in order to reach this curative objective.

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Over the course of the 19th Century, cell biologists discovered a series of living structures in the cells of vertebrates and invertebrates. In 1856 Kolliker discovered rounded forms along the transverse muscle fiber. Later he noticed that these granula became swollen in water and evidently had a membrane. Altmann conducted the first systematic studies of these membrane-coated cell granula. He named these intracellular forms “bioblasts” (from the Greek: bios = life + blastos = grain) or “elementary organisms.” He believed that they were similar to bacteria, and demonstrated that bioblasts could survive as free-living structures when not living in colonies within the cells. Altmann also developed the first methods for the isolation of nucleic acids free from protein, but what he could not have known at the time was that bioblasts themselves also contained small amounts of nucleic acids and genes (Altmann 1894). This discovery was made seventy years later, and confirmed Altmann’s earlier speculation that the cell organelle, known since 1898 as mitochondria (from the Greek: mitos = thread + chondros = granule), originated from former bacteria. By the end of WWI, many cell researchers had described the existence, number, form, and distribution of mitochondria in a multitude of cells: in nuclear protista, fungi, parasites, invertebrates and vertebrates, as well as in human cells (Cowdry 1918). There was much speculation about the function of mitochondria. Altmann had already implied that mitochondria could be a part of the cellular respiration process, but it was not until 1912 that this hypothesis was explicitly established (Ernster 1981). During the first two decades of the 20th Century, there were competing theories as to the process of oxidation in live tissues and cells. The German chemists Wieland and Thunberg had demonstrated that large numbers of organic bonds could be oxidized when brought into contact with small amounts of metal catalysts that could both absorb and emit hydrogen. This reaction supported the hypothesis that biological oxidation was based on previous processes which supply hydrogen, and then release it via substrates as the hydrogen atoms react with the molecular oxide (O₂). Wieland showed that an inhibition of cellular respiration with cyanide led to a blockade of the enzyme, catalase, which neutralizes hydrogen peroxide (H₂O₂). However, no significant increase of H₂O₂ was observed in living cells when treated with cyanide (Tyler 1992).

The German biochemist and later Nobel Prize winner, Warburg, believed that the key process in tissue and cell respiration was the activation of oxygen. He demonstrated that the oxygen was activated by a ferrous enzyme that he termed “atmungsferment,” (breathing enzyme) a term that is used to this day in English medical literature. The ferrous components of an “atmungsferment” are reduced by metabolites to bivalent iron (Fe²⁺, ferrous state) or oxidized by O₂ to trivalent iron (Fe³⁺, ferric state). This reaction could be inhibited by either carbon dioxide or cyanide (Warburg 1949).

Researchers had already recognized that the respiratory process was linked to a special cell structure that served as a catalyzing surface for the reduction/oxidation (redox) process. In 1925, Keilin published a report on the respiratory pigment, cytochrome, in plant cells. He was able to prove that the competing theories about respiratory procedures were two sides of the same coin, and that the activation of hydrogen and oxygen, mediated by cytochromes, interacted as the essential partners in respiration. Cytochrome pigments in muscle fibers had already been discovered 40 years previously, but their function and chemical structure had not been clearly resolved. In the ensuing four decades, the work of Keilin (Keilin 1933) would be the starting point for a gradual clarification of the central function of mitochondria in energy metabolism of all animals, fungi and plants, and nearly all protista (Tyler 1992). In humans, as a general rule, every cell is colonized by approximately several hundred to several thousand mitochondria (with the exception of red blood corpuscles, which have neither cell nucleus nor mitochondria, and obtain their energy enzymatically). If the numbers are extrapolated to the 2 trillion odd body cells, then there are some 2,000 trillion active mitochondria in humans.

     The mitochondria are identifiable as solid bodies in a light-optical microscope with a resolution of 0.2-0.4 microns. Their actual structure could only be clarified by analysis with electron microscopes in the 1950s. Mitochondria possess an outer and inner membrane typical of bacteria. The latter is folded as cristae (from the Latin: crista = crest) into the matrix. A mitochondrion can vary its inner and outer form depending on its functional status. The molecular complexes for the respiratory chain are embedded in the inner membrane and comprised of four complexes: Complex I (NADH-ubiquinone reductase), complex II (succinate-ubiquinone reductase), complex III (ubiquinol-cytochrome-c reductase), complex IV (cytochrome c oxidase). These four complexes are linked by ubiquinone (Q) and cytochrome c, which can diffuse through the membrane. Q acts as a transport molecule for electrons from complexes I and II to complex III. Similarly, cytochrome c transports electrons from complex III to complex IV. This transportation of electrons serves to power the hydrogen pumps in complex I, II and IV with energy. The hydrogen ions are channelled through canals in the inner membrane, and concentrate in the gap between the inner and outer membrane. The hydrogen ion gradients, powered by electrons, activate the coupling of adenosine diphosphate (ADP) with inorganic phosphorus (P_i) to form adenosine triphosphate (ATP) in a fifth complex (F1 ADP-synthase). Complex V is situated in the cristae of the mitochondria. The ATP exits the mitochondria into the cytoplasm, via a special transport protein complex, in exchange for ADP and P_i.

     The electrons are absorbed by molecular oxygen (O₂) at the end of the respiratory chain of complex IV, and subsequently immediately reduced to water. This bioenergetic and biochemical process is termed oxidative phosphorylation (OXPHOS). In human cells almost 90% of the energy-bearing molecule ATP is produced in the mitochondria. ATP serves as a source of energy in countless biosyntheses; as the phosphate bonds of the ATP molecules are split by the absorption of water, and the energy released becomes available for biochemical metabolic processes. As ATP cannot be stored in an organism, it must be continuously produced. In humans, it is estimated that daily 70 kilograms of ATP have to be produced, released and re-produced. Even a short interruption in ATP production can lead to an energetic deficiency. Some 90% of an organism’s absorbed oxygen is used by the OXPHOS system in the mitochondria. Only about 10% of the necessary ATP is produced enzymatically (substrate level phosphorylation) via metabolites from glucose metabolism, occurring in the cytoplasm outside of the mitochondria (Tyler 1992). These data show the immense capacity of the mitochondria, upon whose vital functions all cells, tissues, organs and the entire organism as a whole are dependent for all internal and external activities.

While the OXPHOS system can be fueled by oxidation of a number of different nutrients, it is mainly carbohydrates and fats that are oxidized. Glucose is reduced to pyruvate by a metabolic chain with the participation of a series of enzymes and co-enzymes a number of which are supplied by vitamins, and then infiltrates the mitochondria. The metabolic path from oxidation of the glucose to pyruvate is termed glycolysis. The end product, two molecules of pyruvate, is fed into the citric acid cycle of the mitochondria and completely oxidized to form six molecules of carbon dioxide (CO₂). In this process the co-enzymes NAD⁺ (nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide) are reduced and afterwards deliver their hydrogen ions for the respiratory chain (oxidation). NAD⁺ contains the vitamin niacin from tryptophane and FAD the vitamin riboflavin. There are four metabolic pathways that intermesh during the oxidative process of gaining ATP from glucose: glycolysis in the cytoplasm, the citric acid cycle in the mitochondria, the respiratory chain and the OXPHOS system. Beforehand NAD has to be synthesized in an auxiliary metabolic path of glucose and NADH⁺H⁺ has to be formed by means of a special enzyme reaction. The latter cannot, however, take place in the inner membrane of the mitochondria. For this purpose shuttle molecules act as ferries taking on the hydrogen in reduced form from the NADH⁺H⁺ which they then transport into the mitochondria. The shuttle molecules are converted and return to the cytoplasm to recommence the transport cycle. But the respiratory chain and ATP production are kept going by NADH⁺H⁺ and FADH₂.

This simplified representation serves to demonstrate the tightly regulated import/export system that takes place between the mitochondria and the cytoplasm. If the transport or production pathways are interrupted at any point in the chain then the entire cell is affected. This interrelationship could be compared to the modern just-in-time system between suppliers and a production company, but with the crucial difference that in living cells, the flows of energy and biosyntheses occur according to the principles of self-organization (autopoiesis). The cycle outlined above, however, only describes one of the many functions of the thousands of mitochondria in every cell. Numerous interconnected import and export paths exist between the mitochondria and the cytoplasm, the nucleus, other cell organelles and the cell membrane.

In the 1960s, observations with electron microscopes made it evident mitochondria had their own DNA and a circular, double-stranded genome (Tandler 1972). It turned out that mitochondrial DNA governed, to some extent, the protein synthesis for the respiratory chain complexes and for the ATP synthase complex. The biogenesis (biological manufacture) of mitochondria is a coordinated interplay of different genetic systems—the genome in the nucleus controlling the synthesis of the majority of mitochondrial proteins, and the remaining mitochondrial genomes controlling the synthesis of their own proteins—all of which are crucial for the proper bioenergetic function of mitochondria. Mitochondria, above all, synthesize a proportion of the proteins for the four complexes of the respiratory chain as well as complex V, the ATP synthase. This is the case in all eukaryotic organisms. Despite the considerable contribution of mitochondrial DNA for the biosynthesis of proteins, the majority of genetic information for the formation and function of the mitochondria is encoded in the genome of the cell nucleus (Schatz 1974, Gray 1999, Saraste 1999).

All in all, the mitochondria import over 1,000 proteins that are coded by DNA in the nucleus and synthesized in the cytoplasm. These findings have encouraged discussions about the origin of mitochondria and the role of endosymbiosis (from the Greek: endo = inner + symbiosis = coexist) between a larger unicellular host organism and smaller unicellular cell symbionts, as the forerunners of the evolution of all multicellular organisms, humans included. Today, the fact is generally accepted that all eukaryotic unicellular protista and all multicellular eukaryotic organisms have developed via the integration of various prokaryotic organisms lacking cell nuclei (De Duve 1991). There are, however, different scenarios as to how this endosymbiosis has developed over the course of evolution. These ideas are of crucial importance in understanding human disease processes, including AIDS and cancer.

A popular scenario is the serial endosymbiosis theory enthusiastically propagated by the American microbiologist Lynn Margulis (Margulis 1970, 1988). This theory posits that initially two prokaryotes (from the Latin: pro = before, and Greek: karyon = kernel, meaning before the formation of the nucleus) from the two unicellular domains of cell life—bacteria and archaea—merged and formed a primary cell nucleus. This new cell type—the eukaryon (from the Greek: eu = right + karyon = kernel, meaning with the right nucleus)—developed roughly 2.1 billion years ago.

Margulis deduced this concept in part from the fact that there are primitive protista with nuclei that contain no mitochondria or endosymbionts. The necessity of nuclear formation is explained by the Gaia hypothesis of the British chemist Lovelock (Lovelock 1972, Lenton 1998). In the 1960s, Lovelock contracted with the American space agency, NASA, researching whether life could exist on Mars. Lovelock recognized that the atmosphere on Earth differed from those of the neighboring planets Venus and Mars, due to its high content of oxygen. He postulated that the biosphere of the Earth is a global gas exchange system that had been formed by the bioenergetic activities of prokaryotes, which still today produce 80% of the active biomass in the oceans, on land, and in the air. Lovelock described the biosphere as the outcome of the combined metabolic activities of the prokaryotes, and termed this circulatory, self-regulating, homeostatic system “Gaia.” Together with Margulis, Lovelock further refined this elementary perception by the notion that life on Earth had created its own conditions as massive amounts of oxygen, which had accumulated as the metabolic product of cyanobacteria in the oceans and later in the atmosphere over an immense period of time, created the evolutionary biological conditions for prokaryotes to evolve. Cyanobacteria and other prokaryotes had developed the ability to split water (H₂O) with the help of photonic energy from sunlight, in order to utilize the hydrogen together with carbon dioxide for the composition of energy-stimulated sugar molecules. This photosynthetic process in cyanobacteria, algae and plants to this day forms the basis for the organic substrate of the food chain of the unicellular protista (falsely termed protozoa from the Greek: protos = first + zoon = animal), and the multicellular fungi, animals and humans. According to the serial endosymbiosis theory of Margulis, nucleus formation of the primary endosymbiosis protects the DNA from the corrosive effects of oxygen (Margulis 1988). A further decisive act of integration, according to Margulis and other researchers, was implemented by a targeted attack of proto-mitochondria that could already use molecular oxygen as a source of energy. This predatory parasite is thought to have been domesticated by anaerobic host cells that already had nuclei, with the advantage of the mutual utilization of ATP production of the OXPHOS system of the mitochondria (Margulis 1981). The argument against this scenario was that an aerobic robber and its anaerobic booty could not have met at that point in time as there were hardly any oxygen-free niches in the biological ecosystem and yet the host cell and the proto-mitochondrion must have lived in the same environment. This implies that the host cells could also utilize oxygen, or at least protect themselves from its poisonous effects (De Duve 1991).

In recent years, however, this alternative scenario, together with the serial endosymbiosis theory, have been seriously challenged. In systematic genetic comparative studies in countless cell systems the long-held perception of the endosymbiosis model, that the host cells introduced the already developed nucleus for the integration of proto-mitochondria in the cell combination, has been shaken. It has, however, been confirmed that the nucleus does not originate from a sole unicellular progenitor. The nucleus contains many more DNA components from at least two precursor cells. The eukaryotic genome is thus a chimera: the primary components originate from both an archaeum and a bacterium. The informational genes are mainly archaean, whilst the operational genes are primarily of bacterial origin. The eubacterial portion of the nuclear genome, which until then had been attributed to the gene transfer from the protomitochondria, are not transmitted from the mitochondria, so what we are talking about here are genes that participate in the biogenesis and function of mitochondria.

One surprising finding was the fact that primitive eukaryotes lacking mitochondria also provided evidence of genes coding for typical mitochondrial proteins. In some cases these “mitochondrial proteins” have been found in special cell organelles of these eukaryotes without mitochondria. These cell organelles were called hydrogenosomes, and produce ATP in the absence of molecular oxygen (and are thus anaerobic).

In this process, hydrogen is formed as the reduced end product of the energy metabolism of the cell organelles. This finding posits that the hydrogenosomes and the mitochondria had a common evolutionary-biological source—one that had probably relinquished its genes to the genome of the host cell. The revolutionary conclusion drawn from these genetic analyses was that all eukaryotic cell systems, with or without mitochondria (amitochondrial protista and certain types of animal, plant and fungal cells have lost their mitochondria) owe their existence to a single event. This means that both the eukaryotic formation of the nuclei and the proto-mitochondrial formation took place at the same point in time. The “hydrogenosome hypothesis” explains this primary act of creation in the genealogy of all eukaryotes as a union of eubacteria (α-Proteobacteria) with archaea. The archaebacterium profited from the diffusion of hydrogen through the membrane of the α-Proteobacteria into the cytoplasm of the archaebacterium. They were able to utilize this hydrogen, produced as the end product of the energy metabolism of the eubacterium, as a reductive agent thus increasing their bioenergetic reduction ability. This energetic boost was used to simultaneously merge parts of the genome of the reproducing eubacteria with the genome of the archaea, to form a nucleus with its own membrane (overview Gray 1999). The packaging of genes from both bacterial species into one membrane-coated nucleus, enabled the functional division of transcription within the nucleus (the transcription of DNA information into mobile messenger RNA) and translation outside of the nucleus (translation of the RNA message) onto special structures of ribosomes, which assemble amino acids into proteins according to the coded instructions of the messenger RNA. The result was much improved protein and enzyme syntheses. These “fused” cells were able to increase in size and differentiate (see illustration: model of the fusion of an archaebacterium with proteobacteria for formation of the nucleus and for the development of proto-mitochondria (cell symbiosis) 1.5-2 billion years ago (Gray 1999) (see table IV)).

This interpretation facilitated the notion that the conversion of a part of the eubacterial hydrogen and gene-donating proteobacteria into mitochondria was performed in a second, nearly simultaneous developmental act. The fused cell structure’s opportunity for improved energetic yield was due to the combustion of the end product of the enzymatic ATP synthesis of the archaeal host cell—the still energy-rich pyruvate—by further oxidation stages within the eubacterial symbionts, and to make the gained energy available to increase the ATP production for the entire cell. To achieve this aim, however, the hydrogen from the hydrogenosomes must no longer diffuse through the membrane into the cytoplasm during the ATP production phase in the eubacterial symbionts, but rather concentrate in the intermembrane space so that it can serve as the kindling source for ATP synthesis. In order to achieve this, the membrane potential of the symbionts had to be built in such a way that the diffusion of the hydrogen ions (protons) was no longer possible. An electron transport link had to be developed as energy consolidators for the hydrogen ion pumps which in controlled steps could harness the energy flows in these bioreactors which are now termed mitochondria (Gray 1999, Saraste 1999).

This model—the reversal of the original hydrogen donation processes of the symbionts for optimal energetic yield, by using a respiratory chain with molecular oxygen as the final electron recipient—explains certain phenomena of cell symbiosis much better than the previously held beliefs. Above all, changes and disruptions to the membrane potential of the mitochondria in physiological and pathophysiological conditions become more clearly understood. The workings of the mitochondrial membranes as import and export facilitators for the complicated relationship among the cell symbionts (as well as the cytoplasm, the nucleus, other cell organelles, the cytoskeleton and the cell membrane) still show characteristics of the most successful fusion in the early history of evolution. These processes are also gas-driven and can get out of control in situations of extreme stress, or as a result of certain deficiencies.

Energy metabolism during stimulation of these cell types is of interest in view of the performance of T-helper cells. It was demonstrated that during maturation and proliferation, T-cells exhibited behavioural patterns similar to tumor cells (Wang 1976, McKeehan 1982, Ardawi 1982, Brand 1986, Dröge 1987).

As early as 1924, Warburg described the phenomenon that carcinoma cells predominantly do not produce ATP in the mitochondria, but enzymatically from glucose metabolites in the cytoplasm in the presence of oxygen. The same “Warburg Phenomenon”—aerobic glycolysis with a strong simultaneous increase in the synthesis of the enzymes needed to produce sufficient ATP without the mitochondrial OXPHOS system and in the presence of O₂- was also observed in T-cells during the division phase (Tollefsbol 1985, Marjanovic 1988, 1993). Two crucial questions could not be plausibly answered:

1. How is the transition from predominantly oxidative to mainly glycolytic glucose decomposition switched to lactate and pyruvate in the cells that have not transformed into cancer cells in the division cycle?
2. How could the cells synthesize sufficient ATP in this division phase without an increased ATP production of the mitochondria? In other words, why do the dividing cells maintain a high rate of glycolytic enzyme synthesis, even though the energy yield is considerably smaller than ATP synthesis via the OXPHOS system?

During glycolytic ATP synthesis from the decomposed products of sugar in the cytoplasm, 1-2 ATP molecules are obtained using the energy of 1 molecule of glucose, whilst the oxidative ATP yield in the mitochondria from 1 glucose molecule is a total of 38 ATP molecules. The formidable difference in balance of energy yields exists, thanks to an archaic fusion of two prokaryotes during the evolutionary biological “big bang” of eukaryotes.

The German research team under Brand looked into these questions using the latest laboratory techniques. The researchers studied thymus cells of rats as a model for the changes in the energy metabolism of these cells during the transition from dormant state (quiescence) to division cycle (mitosis, or cell proliferation). A complete division cycle took between 72-84 hours, climaxing with the so-called S-phase (the late cell division phase) after 44-48 hours. This peak is determined by measuring the point of maximum incorporation of labelled thymidines (as the molecular building blocks) in synthesized DNA, the maximum DNA and protein content of the cells, the cellular volume, the number of newly formed cells, and by electron photomicroscopy.

The thymus cells were stimulated with the mitogen concanavalin (Con A). Con A is a glycoprotein of the jack bean and belongs to the phytohemagglutins (PHAs). PHAs are extracts from plants or plant seeds and are used, among other things, for the differentiation of subgroups of blood groups A and AB. Con A and PHA are deployed in laboratories as stimulators (mitogens) for the division of cultivated cells in test tubes. Immunologists in 1981, for example, tried to stimulate the anergic lymph cells, matured in the thymus, of AIDS patients with Con A and PHA. The same mitogens were used by Gallo and his colleagues in 1984 during the supposed isolation of hypothetical retroviruses from thymus-matured T-helper cells from AIDS patients in co-cultivation with leukaemia cells and in the production of the reputedly retroviral proteins as the basis for the “anti HIV antibody test.”

The findings of Brand’s research group and numerous others are important in understanding what really happens in mitogen- and antigen-stimulated cells, as molecules similar to Con A and PHA are also found in the cell membrane of bacteria and all eukaryotic cell membranes (e.g. polysaccharides, glycoproteins, glycolipids). In the case of the mitogen-stimulated thymus cells it transpired that glucose consumption through outright oxidation in the proliferating and in the dormant cells was roughly the same. The total consumption of glucose in proliferating cells, however, was 19 times higher than in the dormant cells. The considerable increase of glucose consumption seen in the proliferating cells is due to the extra-mitochondrial, anaerobic, cytoplasmic synthesis of ATP via glycolytic enzymes. The switch from primarily oxidative glucose reduction to primarily enzymatic glucose reduction took place during the transition from the dormant to the proliferation state. The heightened energy requirement for the increased biosyntheses related to cell division is met exclusively by the aerobic glycolysis, without the involvement of mitochondria. The total consumption of oxygen, however, remains the same in both proliferating and dormant cells. Taking the balance as a whole, it follows that 86% of the total ATP production in proliferating cells was generated by glycolytic enzymes. In this process glucose is reduced to form pyruvate and lactate. 14% of the ATP production continued to be obtained from the mitochondria. In the dormant cells, the proportions are precisely reversed: 86% of the ATP of these non-stimulated dormant cells is obtained through the OXPHOS system in the mitochondria, and 14% through glycolytic glucose reduction in the cytoplasm.

In order to clarify the question of why eukaryotic thymus cells switch to aerobic glycolysis to obtain energy during cell division, the researchers investigated the formation of reactive oxygen species (ROS) in the proliferating and dormant thymus cells, and in other cells. The hydrogen peroxide formation of Con A-stimulated and non-stimulated cells was measured after 46 hours (S-phase). There was a clear-cut difference: practically no hydrogen peroxide (H₂O₂) was found in the mitogenically stimulated cells, whilst the non-stimulated cells produced a clear H₂O₂ reaction. In order to demonstrate that these findings were dependent on mitosis, the non-stimulated cells were, 46 hours after the beginning of cultivation, also stimulated with Con A. 48 to 72 hours after the start of mitogen stimulation, the previously non-stimulated cells also displayed no signs of H₂O₂ formation. Additionally, a similar experiment was carried out regarding the formation of superoxide radicals (O₂-). O₂^- and H₂O₂ are byproducts of molecular oxygen in the respiratory chain. Some 2% of the spent O₂ in the respiratory chain is channelled off for production of O₂^-, H₂O₂ and hydroxyl radicals (HO⁰).

Such ROS are formed when oxygen reacts with ferrous proteins, as for example in the mitochondrial respiratory complexes. If not intercepted at the proper time by antioxidative molecules, ROS can oxidatively damage cellular macromolecules (DNA, proteins) and lipids. Superoxide radicals are neutralized by the enzyme superoxide dismutase (SOD). SOD in the cytoplasm contains copper and zinc, whereas mitochondrial SOD contains manganese. No superoxide radicals were found in the analyzed proliferating thymocytes which consume SOD, however nor were they found in the non-stimulated cells which form H₂O₂.

     The researchers came to the following conclusions: since pyruvate is an effective antioxidant, the ROS were quenched by the pyruvate formed by aerobic glycolysis; at the same time, by minimizing oxidative glucose reduction in the mitochondria (during the critical phase of increased biosynthesis and cell division), the DNA and proteins are protected from damage by radicals and the membrane lipids are protected from peroxidation (Brand 1997 a, 1997 b). The counterargument to this concept was that in T-cells, the expression of genes for the type 1 cytokine, interleukin-2, and its transcription factors, require ROS production for genetic activation; thus the target molecule for T-lymph cell activation needs oxidative signals (Los 1995). However, Brand’s research group demonstrated that the redox status in the gene expression of quiescent and proliferating cells are different: oxidative signals are necessary in the early division phases, whilst reductive signals are needed in the later phases (Schäfer 1996). The researchers concluded that their data showed that the long-known, but until then unexplained, switching of ATP production during cell proliferation—from mitochondrial OXPHOS to a predominant aerobic glycolysis, enzymatically facilitated in the cytoplasm—is an ingeniously simple yet effective strategy to minimize the oxidative stress on proliferating cells (Brand 1997 a, 1997 b).

These research findings demonstrated that the redox-dependent alternating switch of energy production exists as a protective mechanism between the mitochondrial cell symbionts and the dividing host cell during the later stage of cell division. However, it is worth questioning whether this antioxidative protection similarly applies to the mitochondria themselves. If an extended energy requirement for increased biosyntheses during cell division has to be met primarily by escalation of mitochondrial ATP production, the unavoidable increase in ROS formation would damage the macromolecules of the mitochondria. Mitochondrial DNA is ten times more sensitive to oxidative stress than nuclear DNA. Mitochondrial DNA, unlike the DNA in the nucleus, is neither protected by histone proteins nor has any effective repair mechanisms (Tyler 1992, Yakes 1997). Dröge’s research group at the Deutsches Krebsforschungszentrum (The German Cancer Research Center) had shown that in cultures of Con A-stimulated T-cells, the division readiness of these cells was facilitated by the antioxidative sulfur molecules (thiols), cysteine and glutathione, and the addition of H₂O₂ to the Con A-stimulated T-lymph cell cultures inhibited DNA synthesis (Dröge 1994). H₂O₂ formed in the mitochondria is neutralized mainly by the selenium-dependent enzyme, glutathione peroxidase, which receives the necessary hydrogen ions from reduced glutathione. Glutathione is oxidized in the radical quenching process, and must be reduced by the glutathione reductase enzyme, with the help of the hydrogen-donating co-enzyme NADPH. As, according to the findings of Brand et al., pyruvate assumes the role of principal antioxidant in the later division phase, it is worth asking whether the thiol pool is the decisive sensor for initiating the protective switch between the mitochondria and the host cell, in the earlier phases of cell division and redox-dependent DNA biosynthesis.

The alternating relationship between the mitochondria and the host cell, which raises many unanswered questions, has been intensively studied in the liver cells of developing embryos. With the exception of the later division phase, mature liver cells produce their metabolic energy through oxidation of substrates via the mitochondrial OXPHOS system.

Remarkably, however, the embryonic liver cells, and probably all embryonic cells, obtain their ATP energy almost entirely from glycolysis in the cytoplasm. In such cells, the quantity and bioenergetic activity of the mitochondria are quite limited in comparison to the symbiont of mature cells. Correspondingly, the enzymes for the oxidation of pyruvate and fatty acids in the mitochondria are not very active, nor are the regulatory enzymes for the specialized metabolic activities of the liver. In contrast, the glycolytic enzymes in the cytoplasm are more active than in mature liver cells, and therefore more lactate is formed. The necessary amounts of glucose are delivered, without restriction, by the maternal circulation, and the produced lactates are re-processed into glucose by the mother’s liver.

The astonishing thing, however, is the fact that within only an hour of birth, the infant’s mitochondria become fully active, and glycolysis is to a large extent reduced. In a rapid process of transformation the mitochondria of the newborn change, not only in their structure and enzymatic activity, but also in that directly after birth the proton leak for diffusion of H⁺ across the inner membrane is sealed. Adenine nucleotides accumulate which interact with special protein complexes in the inner membrane—the adenine nucleotide translocator. The mitochondrial membrane loses its uniform permeability and instead becomes a controlled export/import channel. Simultaneously, the messenger RNA transcripts (which have already been prefabricated in the fetal cells of the DNA in the nucleus and are “waiting in the wings”, so to speak) are in a concerted action between the nuclear genome and the mitochondria, converted to the synthesis of the necessary proteins for the OXPHOS system. This program of rapid maturation into fully effective mitochondria, recapitulates in fast-forward motion the synergistic events that in the earliest of days made cell symbiosis possible. The H⁺ leak is a clear evolutionary-biological remnant of the hydrogenosomes, as it was the sealing of the mitochondrial membrane which allowed for the build-up of the electron transport chain as a proton-driven power source for the hydrogen ion pumps, and the use of the sealed hydrogen ions as the driving force for ATP synthesis in the mitochondrial OXPHOS system.

The proliferation phase of the mitochondria occurs in parallel to the rapid differentiation program. This longer-lasting phase leads to an increase in mitochondrial population, and a functional homeostasis in relation to the development of the cell as a whole. In this final phase of maturation, the cooperation between the mitochondria and the whole cell is regulated on all levels of genetic expression: the promotion of genes by transcription factors, the transcription of coded DNA sequences into messenger RNA, and the translation of messenger RNA for protein synthesis (overview Cuezva 1997).

The temporary switching of oxidative ATP production in the mitochondria to enzyme-controlled ATP production from glucose in the cytoplasm, is the model for a flexible transition from OXPHOS to glycolysis. The extreme endpoint of this model is illustrated by tumor cells, which are predominantly focused on aerobic glycolysis and remain trapped in the division cycle.

The converse model, of the switch from aerobic glycolysis to OXPHOS, is the fetal cell. The triggering of the OXPHOS machinery remains on hold until the first breath is taken, even though the messenger RNA for the proteins of the four complexes of the respiratory chain (and complex V for ATP synthesis) have already been transcribed in increasing amounts. Tumor cells, which can no longer manage to switch back to OXPHOS, also display this apparently paradoxical phenomenon. That is one reason, although there are others, why the term “re-fetalization” is used in regard to the formation of tumor cells (Cuezva 1997).

The other extreme model is the programmed cell death that can occur in cases of overregulation of OXPHOS activities, as a result of the exhaustion of the thiol pool following a state of extreme prooxidative stress (See illustration: Toggle-switch between OXPHOS and aerobic glycolysis, (Table V)).

The physiological and pathophysiological cell models demonstrate that cell symbiosis, between the mitochondrial cell symbionts and the cell as a whole, is bioenergetically regulated and counterregulated. Calcium balance plays an important role here. Intracellular calcium (Ca²⁺) regulates numerous metabolic processes and energy flows. When T-helper immune cells are stimulated by the appropriate antigen presentation with co-stimulating signals, the calcium levels change. Simultaneously, the synthesis of cytokines and diffusible NO gas is triggered; therefore type 1 cytokines like the tumor necrosis factor (TNF-α), as well as NO⁰ and its metabolites like peroxinitrite (ONOO^-), can exert an influence on Ca²⁺ levels and Ca²⁺ circulation. The mitochondria are an important balancing pool for the Ca²⁺ concentrations in the cytoplasm as they attach Ca²⁺ to proteins that are not membrane-bound. Within the mitochondria, Ca²⁺ regulates the nucleic acid synthesis for DNA assembly, protein synthesis, the indispensable enzymes for dehydrogenation—(dehydrogenases), and the enzymes for ATP synthesis(Ca²⁺-ATPases). In order to protect the cytoplasm from toxic surges of Ca, the mitochondria can absorb large amounts of Ca²⁺ and later release it through various pathways. The releasing and re-absorption of Ca²⁺, termed the “Ca²⁺ cycle,” is crucially relevant to the fate of cells under both physiological and pathophysiological conditions.

In principal, Ca²⁺ can leave the mitochondria in three ways. Ca²⁺ is released non-specifically when the membrane potential (voltage) of the mitochondria drastically falls (for example through disruption to the respiratory chain), and Ca²⁺ leaks out of the inner membrane. Ca²⁺ is also released from the mitochondria by high membrane potentials, assisted by oxidizing co-enzymes like NAD⁺. This occurs on the one hand in a sodium-dependent way, and on the other hand in a sodium-independent way. In the Ca²⁺ exchange, both reactive oxygen species (ROS) and NO and its derivatives can attack. The mitochondria are the richest production source of the physiological metabolites of oxygen (superoxide radicals, hydrogen peroxide, hydroxyl radicals, singlet oxygen), as 90% of oxygen consumption happens in the OXPHOS system. As long as ROS production can be neutralized by the thiol pool and other antioxidants, physiological Ca²⁺ cycling is not threatened. If, however, the ROS production is over-stimulated, perhaps by type 1 cytokines (TNF-α), certain pharmaceutical substances, or oxygen restriction through a sudden deficiency in blood supplies followed by recirculation (hypoxia-reperfusion e.g. cardiac infarction), then excessive Ca²⁺ cycling can be induced. The consequence is a mutual build-up of both Ca²⁺ and ROS. The mitochondrial membrane becomes energetically destabilized, the enzymatic activities of the respiratory chain diminished, and ATP production curbed. A deficiency in the counterregulation will initiate programmed cell death, as a drastic ATP decline leads to the bursting of the cell (overview Richter 1996).

The interactions between NO and Ca²⁺ regulation in mitochondria are complicated, as NO can adopt various redox states (NO radical: NO⁰, NO anion: NO^-, nitrosium: NO⁺); NO⁰ can bind with the ROS superoxide radical (O₂^-) to form peroxinitrite (ONOO^-), and NO can form covalent bonds with metalloproteins, thiols, and thiol-proteins with sulfhydryl groups (R-SH). Research findings indicate that a calcium-dependent enzyme for NO production is also located in the mitochondria. Ca²⁺ absorption in the mitochondria activates the enzyme for NO synthesis. In competition with O₂, NO binds with the respiratory chain enzyme, cytochrome oxidase, and thus inhibits the entire OXPHOS system. In actual fact, the NO concentrations that were measured in a series of biological systems, are similar to those that have been conclusively demonstrated to inhibit the cytochrome oxidase and choke the mitochondrial respiration. Conversely, in many cell systems the experimental inhibition of NO synthesis leads to stimulation of the respiratory chain. From these findings, some researchers have deduced that NO⁰ exercises considerable physiological and pathophysiological effects on the inhibition of cytochrome oxidase in the mitochondrial respiratory chain (overview Richter 1996, Schweizer 1996, Lincoln 1997). NO⁰ could also act as a switch in Ca²⁺ cycling for the toggling between the OXPHOS system and aerobic glycolysis.

Then again NO⁰ promotes Ca²⁺ release and re-absorption reducing the membrane potential of mitochondria by bonding with cytochrome oxidase. The consequence is a loss of energy, which occurs temporarily in low concentrations of NO, but is long-term with higher NO concentrations. In cell cultures, the collapse and re-constitution of the mitochondrial membrane potential relative to NO levels was accompanied by a corresponding rise and fall of cytoplasmic Ca²⁺. From these findings, the researchers drew the following conclusion: “Apparently NO can kill cells by releasing Ca²⁺ from mitochondria and thereby flooding the cytosol with Ca²⁺” (Richter 1996).

The consequence of the oxidative and nitrosative stress from an excess of NO can become aggravated when, for example, type 1 cytokine synthesis is stimulated by simultaneous high and long-term antigen and alloantigen loads. The type 1 cytokine, tumor necrosis factor, can lead to cell death by either apoptosis or necrosis—triggered by increased stimulation of ROS production and subsequent Ca²⁺ cycling. In both cases, the decline in mitochondrial enzymatic activities and ATP production precedes the consequences of prooxidative stress. Both forms of bioenergetic stress are termed prooxidative stress, but as nitrosative stress when NO and its derivatives bind to thiol or to thiol containing proteins. “On the basis of these and other findings, it was suggested that a pro-oxidant-induced Ca²⁺ release from mitochondria, followed by Ca²⁺ cycling and ATP depletion, is a common cause of apoptosis” (Richter 1996).

Under certain conditions, NO can paradoxically perform a protective function, counteracting programmed cell death or necrosis. This occurs when NO interacts with the superoxide radical to form peroxinitrite. However, this requires that equal amounts of NO and superoxide anions are produced simultaneously. Under such conditions, NO can prevent the toxic effects of the superoxide anion; which not only damages the cell membrane via iron-catalyzed lipid oxidation, but also damages the DNA. Conversely, an imbalance in the ratio of NO to superoxide anions causes an inhibition of peroxinitrite, consequently and reciprocally heightening the damaging consequences of prooxidative stress (Mies 1996). Peroxinitrite can redirect the initial phase of programmed cell death (triggered by the radicals NO and O₂^-), as long as enough reduced glutathione is available to compensate for the prooxidative/nitrosative stress (Brüne 1998).

     In contrast to NO, peroxinitrite can stimulate, and even increase, the specific release of Ca²⁺ from mitochondria with an intact membrane potential. This happens when certain mitochondrial thiols, different than glutathione, are oxidized by peroxinitrite. This enables hydrolysis (splitting by water absorption) of the oxidized co-enzyme NAD⁺. The products of the division of NAD⁺—nicotinic acid amide and ADP ribose—regulate specific Ca²⁺ cycling in mitochondria with intact membrane potential (Schweizer 1996). Understanding this process is crucial because peroxinitrite is ineffective for Ca²⁺ cycling in mitochondria with intact membranes when co-enzyme remains reduced as NADH. The inhibition of NADH oxidation plays an important role at the onset of cancer.

Peroxinitrite is a double-edged molecule. When it is synthesized in the presence of free iron, it triggers the formation of ROS hydroxyl radicals (OH^-) which cause mutations in mitochondrial and nuclear DNA. This is the case when the antioxidative thiol pool becomes exhausted through high levels of NO and superoxide radicals. As DNA damage can also lead to programmed cell death or necrosis (Brüne 1996), extreme concentrations of gaseous peroxinitrite can do considerable damage to cells and tissue. Whether this happens depends on a multitude of counterregulations. One such counterregulation is the collective antioxidative capacity, which includes the thiol pool (glutathione, cysteine, and other thiols); antioxidative enzymes (SOD, catalase, glutathione peroxidase, glutathione reductase, transhydrogenase); the co-enzymes NADH, NADPH, FAD and FMN; vitamins C and E; and the polyphenols. When the fluctuating concentrations of the gaseous mixture of NO, O₂^-, peroxinitrite, and other ROS radicals increase in response to prooxidative/nitrosative stress, the redox milieu shifts to an oxidized state (proton deficit). If the antioxidative system can no longer mitigate this redox imbalance which poses a threat to the cell symbiosis, then the proton deficit leads to stimulation of transcription factors that activate the biosynthesis of special protective proteins. To this group belong, among others, the so-called heat shock proteins—ferritin, Bcl-2, and the enzymes hemoxygenase-1 and cyclooxygenase-2 (Kim 1995, Brüne 1998).

The heat shock proteins primarily protect DNA from mutations, whereas ferritin binds iron and stores it in a non-redox form. This release of iron is important in preventing the formation of hydroxyl radicals (Miles 1996).

The inducible enzyme hemoxygenase-1 releases another type of gaseous monoxide: carbon monoxide (CO). The role of CO is still little researched, but there appear to be inverse interactions between NO and CO in various cell systems (Suematsu 1996, Rivier 1998).

Considerably more well-researched are the enzyme cyclooxygenase-2 and the protein Bcl-2, both of which play a crucial role in the toggle switch between the OXPHOS system of the mitochondria and aerobic glycolysis in the cytoplasm.

The enzyme cyclooxygenase converts arachidonic acid into the regulatory substances, prostaglandin and thromboxane (collectively termed “prostanoids”). Decisive in this context, are the prostaglandins (from the Greek: prostatein = protrude + glandula = gland). Though it was initially discovered in the male prostate gland, prostaglandin has a diversity of physiological and pathophysiological functions in all cell systems. Arachidonic acid is an unsaturated fatty acid, and is released by special phospholipid enzymes in the cell membrane. Under pathological stimulation, a heightened and long-term release of arachidonic acid is provoked by the enzyme phospholipase. Arachidonic acid is quickly converted, by the enzyme cyclooxygenase (COX) via intermediary products, into prostaglandin and thromboxane. There are two variations of the COX enzymes: COX-1 is widespread in a multitude of cell types and physiologically regulates the prostanoid levels; the second variation, COX-2, is induced by growth factors, cytokines and molecules that appear in inflammations. The decisive feature is that COX-2 synthesis is stimulated by the exact same factors as the inducible NOS enzyme (which synthesizes cytotoxic NO gas): microbial endotoxin lipopolysaccharide (LPS), type 1 cytokines, and platelet-activating factor (PAF).

     High levels of prostaglandins are not only formed in acutely or chronically infected cells, but also in activated T-helper immune cells. All of these factors stimulate the activation of inducible NO synthase, but also interact with a series of receptors releasing a flood of communication signals, activating transcription factors and increasing the genetic expression for the biosynthesis of COX enzyme proteins (Goppelt-Struebe 1995, Appleton 1996, Herschman 1996, Minghetti 1998).

The connection between the common stimulation of the enzyme for cytotoxic NO production and the COX-2 enzyme for prostaglandins is key, as the prostaglandins are involved with the redisposition of T-helper cells from a type 1 (Th1 cells) to a type 2 (Th2 cells) cytokine profile (Betz 1991, Gold 1994, Hilkins 1995, Katamura 1995, Lucey 1996).

In fact, the genes for the isoforms of NOS, at least for mammals and humans (Knowles 1994, Nathan 1994, Lincoln 1997), and the isoforms for COX-2 enzyme synthesis in various animals and humans (Fletcher 1992, Kosaka 1994, Bauer 1997, Minghetti 1998), are evolutionarily conserved and show a high degree of homology. Large increases in prostaglandin levels in activated T-helper immune cells suppress type 1 cytokine synthesis but not type 2 cytokine synthesis. A synergy takes place between the type 2 cytokines and high levels of prostaglandins, suppressing the synthesis of cytotoxic NO, as well as tumor necrosis factors which activate the superoxide anions (Milano 1995, overview Minghetti 1998). The depletion of the oxidative/nitrosative gases NO and O₂^- further inhibits peroxinitrite formation, thereby preventing the danger of programmed cell death or necrosis as a result of loss to the mitochondrial membrane potential. The upregulation of COX-2 enzymes and prostaglandins by acute and chronic pathological stimulation (microbial and non-microbial toxins, microbial and non-microbial antigens and alloantigens, immunotoxic pharmaceutical substances and drugs, etc.) serves to protect the cell symbiosis and is evolutionarily programmed.

Prostaglandins (PG E2) intervene in a further protective manner in the restriction of NO synthesis. PG E2 operates in the same way as a regulating factor related to type 2 cytokines (Abbas 1996): the transforming growth factor TGF-β (Vodovotz 1997, Minghetti 1998). TGF is a versatile cytokine that among other things increases the synthesis of prostaglandin and in conjunction with PG E2 suppresses large amounts of the cytotoxic NO production. PG E2 and TGF also activate in stimulated cells the genetic expression for the biosynthesis of the enzyme arginase. This converts arginine to ornithine in the first phase of the metabolic pathway of the synthesis of polyamines. The latter likewise inhibit the enzyme for the synthesis of cytotoxic NO (Szabó 1994). Since both NO synthase and arginase compete for the same amino acid, arginine, in the case of the simultaneous biosynthesis of both enzymes in stimulated cells, the amount of arginine available for NO synthesis diminishes (Modolell 1995). Additionally, there is the important fact that polyamines promote the proliferation and repair of various cell types; PG E2 and TGF-β thus lower the cytotoxic effects of NO, encourage the repair processes for damaged cells, and stimulate the formation of new cells. However, this also means an increase in aerobic glycolysis. It is striking that both cancer cells and parasitic cells show high concentrations of polyamines. This factor serves as a measure of success in chemotherapeutic treatment in oncology (Papadopulos-Eleopulos 1992 b).

Also impeding programmed cell death, is the simultaneous counterregulatory synthesis of Bcl-2 during excessive prooxidative stress (by NO and its derivatives, as well as ROS). Bcl-2 prevents disruption to the cellular Ca²⁺ equilibrium and thus inhibits ROS production. It is presumed that Bcl-2 shifts the ratio of oxidized NAD⁺ to reduced NADH in favor of the latter. Thereby the release of Ca²⁺ from the endoplasmic reticulum (membrane structures in the cytoplasm) is inhibited. This release requires the hydrolysis of oxidized NAD⁺ (Richter 1996). Bcl-2 is, furthermore, located in the membrane of the nucleus and in the outer mitochondrial membrane. It is here that Bcl-2 performs its crucial function: it is, so to say, the gatekeeper of the mitochondrial import/export lock-gates. Bcl-2 stabilizes the mitochondrial membrane potential, preventing energy loss, thereby modulating the flow of Ca²⁺ into and out of the mitochondria. The effect is controlled by interaction with protein complexes that keep the mitochondrial membrane permeable to Ca²⁺ ions and protein molecules. In the first phase of programmed cell death, which could ensue as a result of prooxidative stressors, the Bcl-2 proteins close the lock-gates thus preventing the “infection” of the host cell by the mitochondrial endosymbionts.

     Bcl-2 belongs to a wide-ranging family of proteins that continue to be discovered. This assembly of proteins includes some that prevent programmed cell death (apoptosis, from the Greek: apo = from + ptosis = falling) as well as some that promote apoptosis. An imbalance in the genetic expression of these protein products has been established in roughly half of all human cancer forms (overview Zamzami 1997). Therefore it can be assumed that Bcl proteins also play an important role in the toggle switching of ATP production between the OXPHOS system of the mitochondria and aerobic glycolysis (Warburg Phenomenon), for the prevention or mitigation of NO and ROS stress in the closing mechanisms of the mitochondrial membrane. On one hand, this assumption is related to the transitory physiological barrier against the interaction between the cell symbionts and the maturing cells, during the embryonic development phase, during the S-phase of cell division, and in the transitional phases of heightened stress loads. On the other hand, under the substantial and long-term influence of pathological factors and their combinations, a hyperexpression of Bcl-2 proteins can be enforced which in synergy with other counterregulations blocks the switch from Warburg Phenomenon back to the mitochondrial OXPHOS system—at least for as long as it takes the redox milieu to re-establish self-organizing homeostasis. Dependent on cell type, the cells “re-fetalize” and, trapped in the cell division cycle, uncoordinatedly found a new cell colony as a tumor. Other cell types, which are no longer active in division, such as mature muscle and nerve cells, degenerate in specific ways to a state of cell dyssymbiosis (myopathy, encephalopathy, neurodegeneration) (Johns 1996, Wallace 1999).

Yet NO can also produce other important molecular bonds. Besides the binding with metalloenzymes (such as the ferrous enzyme guanylyl cyclase, which catalyzes the production of cyclic guanosine monophosphate, a secondary messenger which initiates growth processes and a multitude of biosyntheses), the redox status of many other enzymes can be altered by NO, thereby modulating the information profile in the cells. Such procedures control, for instance, the relaxation of blood vessels, the transfer or inhibition of impulses in the central and peripheral nervous system, intestinal peristalsis, and so on. For the understanding of cell-mediated immune deficiency and carcinogenesis, however, the tendency of NO in various redox states (NO⁰, NO^-, NO⁺) to bond with sulfurous molecules is very important. These molecular bonds are termed S-nitrosothiols (RSNO), and when the RSNO bond is made with a thiol-containing protein, the term is S-nitrosylation. Many of the reactions associated with NO synthesis, of which NO alone is incapable, are stimulated by nitrosation or S-nitrosylation. Stimulation of T-cells, for instance, is triggered by S-nitrosylation of the protein molecule p21ras (Lander 1995). Also the efficiency of cytotoxic NO gases (and other NO derived molecular species) against microbes depends on the S-nitrosylation of microbial proteins (Stamler 1992, 1995, De Groote 1995). The nitrosothiols are produced in high concentrations in infectious and inflammatory conditions. Under normal physiological conditions, the S-nitrosylation of proteins serves as a reciprocal functional regulator in a variety of cellular control mechanisms, including: ion channels in both the cell and organelle membranes, signal-transmitting proteins (e.g. proteins that transfer or split phosphorus), various enzymatic proteins (e.g. controlling the glucose breakup for glycolysis and the OXPHOS system, for prostaglandin synthesis, and for the glutathione system), and many others (Han 1995, overview Stamler 1994, 1995).

Nitrosation and S-nitrosylation also intervene in the activation of transcription proteins that activate the transcription of certain genes to messenger RNA for the biosynthesis of enzyme proteins of the antioxidative counterregulation. Stamler’s research group in the USA introduced the term “nitrosative stress” to describe the interaction of S-nitrosothiols (Hausladen 1996). Nitrosative stress, parallel to oxidative stress situations, depletes the intracellular thiol pool in the cytoplasm as well as in mitochondria and activates certain transcription factors. The redox-dependent expression for the biosynthesis of antioxidative and antinitrosative genes is increased via the altered redox-dependent transcription. This gene activity leads to an increased biosynthesis of thiols and enzymes which neutralize and metabolize the reactive O₂ species (ROS) and S-nitrosothiols (RSNO) (see illustration: Compensated/decompensated oxidative and nitrosative cell stress (see table VI)).

But if the antinitrosative thiol capacity is exhausted, the S-nitrosothiols search for other thiol-containing target molecules. One such target is an important enzyme that ferries hydrogen ions from the co-enzyme NADH⁺H⁺ into the mitochondria. ADP ribosylation follows that irreversibly inhibits enzyme activities. The result is a disruption of the electron transfer in the respiratory chain of the mitochondria. At the same time, NO radicals can attack the iron-sulfur centers in the enzymes of the respiratory chain (oxidoreductase, cytochrome oxidase), enzymes of the carbon metabolic pathway from the breakup of glucose (cis-aconitase), enzymes from DNA synthesis (ribonucleotidase), and others. ATP production in the OXPHOS system begins to wane and the mitochondrial membrane is energetically destabilized (Brüne 1994, Richter 1996). Ca²⁺ cycling between the mitochondria and the cytoplasm gets out of control. If the loss of energy happens rapidly, then the cell dies through necrosis. Intracellular protein, DNA, and other molecules pass into the extracellular space and increasing numbers of autoantibodies are formed. If the energy loss is at a slower pace, so that there is still enough ATP for an energy-dependent dismantling of the nucleus and the remaining cell contents via programmed cell death when the cell membrane is still intact, then apoptosis takes place; without alloantigenic stimulation, no autoantibodies will form. If the cell switches on the “emergency power unit” (glycolytic ATP production in the cytoplasm) in time, and reacts to this state of cell dyssymbiosis with a coordinated counterregulation (the type 2 cytokine profile shuts down cytotoxic NO synthesis, dampening the calcium-dependent NO synthesis, upregulation of heat shock proteins, ferritin proteins, COX-2 enzymes, prostaglandin, Bcl protein family, etc.) then the cell symbiosis can be restored and the cell will survive. If the thiol pool and antioxidative/antinitrosative capacity remains depleted over the long-term (or intermittently, given that the causes continue to afflict, become more serious, or cannot be neutralized), then the cells—could simultaneously or successively suffer from cell dyssymbiosis, the outcome of which varies depending on cell, tissue and organ type.

The cytoplasm can accomplish its functions only in a highly reductive state. Under extensive oxidative and nitrosative stress, whether acute or chronic, the endosymbiotic eukaryote cells have a strategic dilemma: the cells must either seal the import/export lock-gates of the mitochondrial membrane (to calcium, proteins and other molecules), or keep them open. In the latter case, the cells are sacrificed to necrosis—or if it is still possible, to apoptosis. In the case of lock-down, the cells remain in the counterregulated state of cellular dyssymbiosis, at the expense of the number and vitality of the mitochondria. Cells that are no longer able to divide will degenerate, and those that are still capable of division may transform to cancer cells.

Programmed cell death is an evolutionarily conserved program that has already been proven in unicellular eukaryotes such as the trypanosomes. This is a sign that apoptosis is triggered by cell symbionts in these archaic eukaryotes, as well as in multicellular animals, and probably in fungi as well (Kroemer 1997).

The proliferation of tumor cells, within which the mitochondrial population is extremely reduced and inactive, apoptosis by NO and its derivatives cannot be easily induced experimentally but merely a cell inhibition (cytostasis) is attained; this fact supports the assumption that programmed cell death is dependent on the destabilization of the mitochondrial membrane (Hibbs 1987, Nussler 1993, MacMicking 1995, Wei 1995, Lincoln 1997).

Apoptosis is an important component of immune defense against intracellular agents, including viruses, as the dispersal of microbes within cells and to a certain extent in extracellular areas can be prevented by sacrificing the affected cells. A well placed fully-dosed gas cloud from NO and oxygen radicals of the Th1 immune cells, macrophages, microglia cells, natural killer cells, neutrophilic leukocytes, and many other immune and non-immune cells, is for all multicellular organisms, including humans, the most effective weapon of choice. The most primal of cell types of the nonspecific gas defense—the macrophages—are classified as the most evolutionarily ancient cells of natural immunity and stress defense. They synthesize a common pool of peptides (derived from proopiomelanocortin, which is also synthesized in brain cells), cytokines, biogenic amines (dopamine, adrenaline, noradrenalin [USA: epinephrine, norepinephrine]), glucocorticoids, as well as NO and its derivatives, and reactive oxygen species. Macrophages are deemed to be the evolutionary progenitors of both the immune network and the neuroendocrine systems (Ottaviani 1998). Like T-cells, macrophages can trigger apoptosis or necrosis by producing oxidative and nitrosative stress in microbial or bodily cells, but can for the same reasons also die by apoptosis or necrosis.

It is, however a gross oversimplification of the given physiological facts to attribute the immune cell network solely to the defense against foreign protein. Rather, the immune cell network is comprised of particularly redox-sensitive cells, whose diverse function it is to ensure a balance in the energy flows. If this can no longer be maintained on a cellular or intracellular level (i.e. too many immune cells and non-immune cells become apoptotic or necrotic), then in compliance with the rules of cell protection, the immune cells switch from intracellular home defense of the bioenergetic balance (based on redox equilibrium) to an extracellular shield; this is done mainly by increasing antibody production as an emergency measure. The active strategy is determined by the health of the cell symbiosis. The immune cell network is thus an early warning system for the organism as a whole. The immune cells are feelers and executors, sensors and effectors, that continuously measure and modulate the redox milieu as control variables for the continual perfusion of energy and substance flows.

The regulators of this process, however, are the gas-driven cell symbionts. An intensive exchange takes place between the immune cell network and the neuroendocrine system, as both cell systems synthesize, to all intents and purposes, the same signaling molecules (neurotransmitters)—biogenic amines, cytokines, NO, CO, prostaglandin hormones, etc. (Ader 1980, Spector 1985, 1988, Rivier 1998, McCann 1998 a, 1998 b). In this respect, the immune cells process all stress factors found in the blood or lymph pathways, in the extracellular liquids, or those mediated by cell-to-cell contact. It makes no difference to the cell symbionts of the helper lymph cells whether, for instance, the disruption is caused by microbial antigens or alloantigens, psychic traumata and pain, protein deficiency syndrome or antioxidant impairment as a result of faulty nutrition, nitrites and nitrosamines, bacterial toxins or pharmatoxic substances, serious injuries or burns, operations or organ transplants, radiation damage or environment toxins, drug abuse or doping agents, contaminated coagulating proteins or multi-transfusions, vaccines or antibiotics, congenital or acquired factors. The T-helper immune cells and other cell systems will always react, modulate, and adapt, following the same evolutionary biological laws.

Cellular life happens from the outset almost four billion years ago, quantum dynamically speaking, in the marginal phase between solids (macromolecules) and fluids (liquids and gases), between order and chaos (Langton 1990). Macromolecules (proteins, nucleic acids) alone are not living materials. They require quantum dynamic oscillation by fluid molecules. An over-rigorous order is just as hostile as overstepping the boundaries to chaos. A fortnight before death, the heartbeat is completely regular. On the other hand, gaseous molecules have the highest degree of freedom for quantum dynamic fluctuations, and can quickly construct, alter, and destroy information patterns and energy flows. However, they must be constantly counterregulated in order to maintain the bio-energetic self-organization of the cellular “island of order in the middle of thermodynamic chaos” (Schrödinger 1967). In accord with the standard model of the development of life, the first storage of photonic energy from sunlight took place in the “thioester-iron world” (De Duve 1991). When the first macromolecules which could store information organized energy flows and metabolism in a membrane, away from thermodynamic equilibrium, the sulfur-iron centers in the substrates were already existent as were NO and its derivatives as terminal electron receivers instead of molecular oxygen. Anaerobic prokaryotes to this day use nitrite and NO for respiration and cell growth (Kucera 1983, Satoh 1983, Barton 1983, Papadopulos-Eleopulos 1988). So life began with nitrosative stress and still overcomes it with the help of reduced sulfur and selenium. Both elements, together with oxygen, belong in the same column of the periodic table and can exchange electrons with one another (Hässig 1999, Kremer 1999).

The global gas exchange of the prokaryotes in the autopoietic biosphere of the Gaian world (Lovelock 1974) was to become the driving force for the evolutionary quantum leap of cell symbioses (Margulis 1997). The micro-Gaian environment (endosymbiotic, gas-controlled hybrid cells) enabled a deeper thermodynamic oscillation to occur in the marginal zone between the solid and fluid matter phases, which allowed the evolution of the ever-increasing complexity of the human mind, intellect, and spirituality.

It has taken modern medicine 150 years to understand the meaning and function of the laws of the most successful fusion in the history of evolution. The mitochondrial genome holds only 37 informational and operative genes all of which are indispensable. In all sexually-reproducing eukaryotes, humans included, the cell symbionts are exclusively passed down by maternal inheritance (Wallace 1999). There are huge amounts of mitochondria found in the ovarian cells. Within the last 30 years, an ever-increasing number of systemic diseases, serious myopathies and encephalopathies, Alzheimer’s-like and Parkinson’s-like diseases, diabetes and cardiac defects, multiple sclerosis and cancer as well as geriatric diseases have been recognized as resulting from maternally inherited mutations of the mitochondrial DNA, or as a result of oxidative/nitrosative stress of the OXPHOS system and an inability to repair the mitochondrial genome. The list is growing and already includes 200 defined diseases. It is remarkable that such mitochondrial diseases are not known in mammals living in the wild, and can only be found after being provoked by experimental tests in clinical studies (Wallace 1999). The clinical picture becomes complex and puzzling in congenital mitochondrial diseases through mutation of individual genes (genotypes) which cause a plethora of different disease symptoms (phenotype) and vice versa several mutations (genotype) causing a single symptom (phenotype). This phenomenon is deemed to be puzzling, despite the manageably small number of remaining genomes, as the interplay between the two genomes—the nuclear genome with roughly 25,000 genes and more than 3 billion base pairs and the mitochondrial genome with 37 genes and more than 16,000 base pairs, make the multitude of combination possibilities of both genomes difficult to determine.

     These complicated interactions make a “gene therapy” on the mitochondrial genome of maternal ovarian cells at present utopian, although such “repairs” may become possible in the future (Johns 1996). Then again, acquired non-inherited mutations in Alzheimer’s-like and Parkinson’s-like diseases, primarily caused by oxidative free radicals, glutamates and NO, has been discussed (Johns 1969).

     Somatic, non-inherited mutations have been identified in various tumors and tumor cell lines: “In principle, these mutations could contribute to neoplastic transformation by changing cellular energy capacities, increasing mitochondrial oxidative stress, and/or modulating apoptosis” (Wallace 1999).

To modern humans, the evolutionary-biologically programmed protection of cellular symbioses becomes a disadvantage, in that the immune and non-immune cells answer to every form of prooxidative (oxidative and/or nitrosative) stress with counterregulations, and have the potential for overreaction in today’s toxic industrialized world. To counter the enormous quantity and diversity of synthetic and physically generated oxidative and/or nitrosative sources of stress, evolution could predispose no other strategy for achieving its aims than the capacity for social intelligence. The opportunity to exercise this, however, is left to the free will of individuals. Even the simplest bacteria have intelligence, in the spiritual sense of perception to environmental dangers and autopoietic adaptive response (Maturana 1987). As a rule, microbes are outgunned by the higher reduction powers of cellular symbioses in the human organism, as long as the micro-Gaian milieu is functional. The genetic make-up of human mitochondria has been under threat since the introduction of sulfonamide chemotherapy in 1935, and the ensuing prevalence of antibiotic therapy; as these pharmaceutical substances not only attack intracellular microbes, but also the cell symbionts in human cells. As the mitochondria are former bacteria, they are just as vulnerable to targeted attacks as actual bacteria.

     To this day, nobody knows whether ever-increasing inherited mitochondrial DNA mutations and the associated degenerative and tumorous diseases (Johns 1996, Wallace 1999) are caused by such pharmatoxic damage to the genetic make-up of human cell symbionts. For obvious reasons, up to now these problems have not been well investigated, although it has to be assumed that antimicrobial substances which can penetrate the cell membrane, also damage the cell symbionts. This has already been demonstrated with chloramphenicol, tetracycline and some macrolides like erythromycin and carbomycin: “The treatment of animals or man with antibacterial drugs can have harmful effects on mitochondrial function, especially in tissues that have a high proliferation rate” (Tyler 1992). As health diseases, ageing, and death of humans are dependent on the vitality of the micro-Gaian milieu, more precedence should be given to the study of acquired energy dyssymbiosis syndrome (AEDS) (Kremer 1998 b) for understanding AIDS and specific cancer diseases, than to the “Invent[ed] … AIDS virus” (Duesberg 1996).

The precious legacy of the human symbionts should have long ago been declared a protected species. In all primitive societies, cancer was practically unknown (with a few exceptions like Kaposi’s sarcoma) before they came into contact with civilization (Goldsmith 1998). Recently, the WHO prognosticated that in 50 years, every second person will die of cancer; 100 years ago the figure was one in ten. In no way does this affect only the elderly, as cancer in children is increasing annually by 1% (Epstein 1998, White 1998). The growth of systemic human illnesses still reflects the strategic dilemma of the cell-symbiotic fusion of an archaeum and a protobacterium, some two billion years ago. Chronic systemic diseases are the answer in an energetic/spiritual sense to the cumulative burden of excessive stressors in an extremely different inner and outer environment which has not been previously experienced in the course of evolution (Kremer 1997 a).

The evolutionary-biologically programmed limits on how far the human cell symbioses can be stretched from equilibrium, within the border zones between solid and fluid matter phases (Langdon 1990) has, however, remained unchanged. 50 years ago, a doctor’s practice would treat nine out of ten patients for acute complaints; today, nine out of ten patients need treatment for chronic illnesses. Taken as a whole, the spectrum of diseases reflects a clear shift towards cell dyssymbiosis. AIDS and cancer are in no way puzzling phenomena, but simply overcompensated Type-II counterregulations of the micro-Gaian milieu (see illustration: cell symbiosis and cell dyssymbiosis in dependence on NO and ROS production (plate VII) and illustration: Clinical examples of cell dyssymbioses resulting from Type-I overregulation or Type-II counterregulation (table VIII)).

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The Nobel Prize winner for Chemistry in 1993, American research scientist Kary Mullis, gave an account of his experiences while searching for scientific references for the disease theory that “HIV is the probable cause of AIDS”. His account is a astonishing document of contemporary history, and highlights the mass psychological staging of “the most devastating epidemic of the 20th Century” (Gallo 1991).

“In 1988 I was working as a consultant at Specialty Labs in Santa Monica, setting up analytic routines for the Human Immunodeficiency Virus (HIV). I knew a lot about setting up analytic routines for anything with nucleic acids in it because I had invented the Polymerase Chain Reaction. That’s why they had hired me.”

The Polymerase Chain Reaction (PCR) is a laboratory process in which the tiniest DNA fragments can be amplified. The prerequisite is that the DNA sequences that flank both ends of a given region of interest are known, and that a short fragment of the corresponding start sequence is available to bootstrap the amplification process. Today, PCR is one of the most important methods in every medical and molecular biological laboratory (Wirthmüller 1997). In his 1993 Nobel Prize acceptance speech, Mullis addressed the problem of lacking evidence for the hypothetical retrovirus HIV as the supposed cause of AIDS. In over 100 years of the Nobel Prize, his speech is the only one that was not published.

“Acquired Immune Deficiency Syndrome (AIDS), on the other hand, was something I did not know a lot about. Thus, when I found myself writing a report on our progress and goals for the project, sponsored by the National Institutes of Health, I recognized that I did not know the scientific reference to support a statement I had just written: “HIV is the probable cause of AIDS”. So I turned to the virologist at the next desk, a reliable and competent fellow, and asked him for the reference. He said I didn’t need one. I disagreed. While it’s true that certain scientific discoveries or techniques are so well established that their sources are no longer referenced in the contemporary literature, that didn’t seem to be the case with the HIV/AIDS connection. It was totally remarkable to me that the individual who had discovered the cause of a deadly and as-yet-uncured disease would not be continually referenced in the scientific papers until that disease was cured and forgotten. But as I would soon learn, the name of that individual—who would surely be Nobel material—was on the tip of no one’s tongue. Of course, this simple reference had to be out there somewhere. Otherwise tens of thousands of public servants and esteemed scientists of many callings, trying to solve the tragic deaths of a large number of homosexual and/or intravenous (IV) drug-using men between the ages of twenty-five and forty, would not have allowed their research to settle into one narrow channel of investigation. Everyone wouldn’t fish in the same pond unless it was well established that all the other ponds were empty. There had to be a published paper, or perhaps several of them, which taken together indicated that HIV was the probable cause of AIDS. There just had to be. I did computer searches, but came up with nothing. Of course, you can miss something important in computer searches by not putting in just the right key words. To be certain about a scientific issue, it’s best to ask other scientists directly. That’s one thing that scientific conferences in faraway places with nice beaches are for. I was going to a lot of meetings and conferences as part of my job. I got in the habit of approaching anyone who gave a talk about AIDS and asking him or her what reference I should quote for that increasingly problematic statement, “HIV is the probable cause of AIDS”. After ten or fifteen meetings over a couple years, I was getting pretty upset when no one could cite the reference. I didn’t like the ugly conclusion that was forming in my mind: The entire campaign against a disease increasingly regarded as a twentieth century Black Plague was based on a hypothesis whose origins no one could recall. That defied both scientific and common sense.

Finally, I had an opportunity to question one of the giants in HIV and AIDS research, Dr. Luc Montagnier of the Pasteur Institute, when he gave a talk in San Diego. It would be the last time I would be able to ask my little question without showing anger, and I figured Montagnier would know the answer. So I asked him. With a look of condescending puzzlement, Montagnier said, “Why don’t you quote the report from the Centers for Disease Control?” I replied, “It doesn’t really address the issue of whether or not HIV is the probable cause of AIDS, does it?” “No,” he admitted, no doubt wondering when I would just go away. He looked for support to the little circle of people around him, but they were all awaiting a more definitive response, like I was. “Why don’t you quote the work on SIV [Simian Immunodeficiency Virus]?” the good doctor offered.

     “I read that too, Dr. Montagnier,” I responded. “What happened to those monkeys didn’t remind me of AIDS. Besides, that paper was just published only a couple of months ago. I’m looking for the original paper where somebody showed that HIV caused AIDS”. This time, Dr. Montagnier’s response was to walk quickly away to greet an acquaintance across the room” (Mullis 1996).

Beside Dr. Gallo, the former director of the Laboratory for Tumor Biology of the National Cancer Institutes in the USA, Dr. Montagnier is a worldwide authority on HIV. Since 1983 he is considered to be the discoverer of the “retrovirus HIV”. Together with Gallo he is the patent holder for the “HIV test” and earns a certain share on every “HIV test”. Montagnier has led the research team for viral cancer research at the world-famous Pasteur Institute in Paris since 1972 and has been the leader of the AIDS and retroviral department at the same institute since 1991. Dr. Montagnier has also been President of the World Foundation for Aids Research and Prevention since 1993.

In 1997 Dr. Montagnier gave a detailed scientific interview in which in answer to the final question about his belief in the existence of “HIV” he stated: “Oh, it is clear. I have seen it and I have encountered it.” In the same interview Montagnier explains why the electron microscopic photographs of the supposed “new agent” produced and publicized by his research team were made only from cells in the cell culture and not, in accordance with the standard rules of virology, after the purification of the supposed virus particle from the remaining cell debris: “There was so little production of virus it was impossible to see what might be in a concentrate of virus from a gradient” (density gradient: the separation of the tested material in a sucrose solution after ultracentrifugation of the cell fluids of the stimulated cell culture. This process is one of the standard rules of isolation of a retrovirus).

“There was not enough virus to do that. Of course one looked for it, one looked for it in the tissues at the start, likewise in the biopsy. We saw some particles but they did not have the morphology typical of retroviruses. They were very different. Relatively different. So with the culture it took many hours to find the first pictures. It was a Roman effort! It’s easy to criticise after the event. What we did not have, and I have always recognized it, was that it was truly the cause of AIDS” (Tahi 1997).

Montagnier was referring in his interview in 1997 to findings in cell cultures of T-helper immune cells. These experiments were carried out by Montagnier’s viral cancer research group at the Pasteur Institute in 1982/1983 and publicized in the leading scientific journal Science in March 1983, the same month as the historic conference in New York postulated a “new agent” as the cause of AIDS. The findings of the Montagnier team were not presented at the historic conference, but only the discovery by the Gallo team of a supposed retrovirus HTLV-1 in T-cells of two American AIDS patients. The T-cells analyzed by the Montagnier team originated from the blood serum of patients who had shown clinical and immunological signs of a Th1-Th2 switch. The cells were treated in a culture with a growth factor (type 1 cytokine interleukin-2) and heavily oxidized substances like PHA as mitogens. After a few days physical and biochemical analyses were carried out both on the surface of some of these cells and in the cell fluids. These resulted in unspecific findings. In 1972 researchers at a symposium at the Pasteur Institute—Montagnier has led the research team for viral cancer there since 1972—established the standard practice for the isolation of retroviruses from cell cultures, which were supposed to exclude the possibility that unspecific findings from cell cultures and cell fluids of human cells could be confused with specific characteristics of retroviruses (Sinoussi 1973, Toplin 1973, Bader 1975, Papadopulos-Eleopulos 1993 a). In the publication of the Montagnier team in Science of March 1983, which later was deemed to be the first publication about the discovery of the “human immune deficiency virus HIV”, the authors emphatically refer to the standard rules of isolation of retroviruses in human cell cultures from 1972, as proof for the isolation of a “new retrovirus” in human T-helper immune cells (Barré-Sinoussi 1983, Montagnier 1985).

The most important standard rule for isolation of a retrovirus in human cell cultures is the separation of the cell material gained in the cell culture from all cell debris other than the cell particles thought to be retroviral, which after stimulation of the cell culture have budded out of the cell membrane. The cell particles that are considered retroviral particles have to be separated from the cell culture fluids by ultracentrifugation and absorbed in a sucrose solution. From experimental analysis it is known that during this process retroviruses band at a certain level known as the density gradient. 1.16 gm/ml is the accepted level. Molecules, cell debris, virus particles and non-virus particles from the centrifuged cell fluids of different cell cultures all band at this density gradient as the components separate not according to molecular weight but according to the density of the components in the sucrose solution. In order to be sure that, as far as possible, only the supposed virus particles have banded at the 1.16 gm/ml density gradient, purification and concentration procedures have to be carried out, as only the particles at the density gradient may be tested as to whether they correspond in diameter and volume to the supposed retroviral particles that were ascertained by studying electron-microscopic (EM) photographs during maturation from the cell membrane. As there are many non-viral particles in stimulated cell cultures whose shape, structure and appearance cannot with absolute certainty be distinguished from actual retroviruses, the contents of the particles have to be biochemically processed after isolation by purification. The proteins of the particle’s membrane together with proteins from the inner particle membrane, including the characteristic enzyme proteins of retroviruses and nucleic acids, have to be exactly identified by a routine molecular biological process.

Only if structurally completely identical proteins and nucleic acids are present in the isolated and purified particles, and only if the nucleic acids in these particles form RNA instead of DNA molecules, can it be assumed as a probability that they are retrovirus particles. The findings can only be considered to be sure proof of the existence of a retrovirus in human cells when the RNA molecules in these particles construct genes which present the coded instruction for the biosynthesis of proteins within this particle and if these proteins can actually be identically synthesized. Once these findings have been verified it is still not possible to say whether these retroviral particles are exogenous, transmittable and infectious retroviruses as they could be endogenous retroviruses that have often been identified in the center of the genotype of many human cell types and are not infectious. In order to enable a differentiation between exogenous and endogenous retroviruses in human cells the properly isolated and biochemically characterized retroviruses would have to be transferred to human cell cultures, mature out of the cell again, it has to be separated again from any cell material by means of proper isolation and purification, successful isolation would have to be confirmed by EM photographs, the biochemical identity of the proteins and nucleic acids have to be substantiated and the RNA of the particle as coded genotype for the specific protein synthesis of the retrovirus particle would have to be verified.

In an interview in 1997 Montagnier admitted that he and his colleagues did not carry out purification of the cell particle. “I repeat, we did not purify” (Tahi 1997). Montagnier also conceded that only an “assemblage of properties” of the cell particle was detected by his team on the cell membrane and only components were found in the density gradient. No EM photographs were published to show which cell material had banded at the density gradients. Nevertheless, non-identified proteins from the density gradients were used as substrate for the “HIV test” patented by Montagnier in 1983 with the claim that they were retrovirus proteins of the “newly isolated HIV”.

The Pasteur Institute receives half its finance from the state and the other half through the production of vaccines, test diagnostics etc. The Pasteur Institute, in competition with the Gallo team from the National Cancer Institute in the US, very definitely had commercial interests in capturing the worldwide market for test substrates against the “new AIDS agent”. What in fact happened was that in 1983, three months after the first publication of the Montagnier team’s “isolation” of a new retrovirus in T-helper cells from the blood serum of risk-group AIDS patients, the license for the Pasteur Institute’s vaccine against hepatitis B was cancelled, for example, in Germany and Switzerland. Instead the use of hepatitis B vaccines from the US was recommended. This hepatitis B vaccine was approved in the US in October 1981 and in Germany and Switzerland in October 1982. The justification for the international ban on the Pasteur Institute’s substrate was, according to a confidential official memo: “suspicion of AIDS contamination of the French vaccine”. Although the American and French vaccines were extracted from comparable human cell cultures the National Health Authority’s suspicion of “AIDS contamination” only fell on the Pasteur vaccine. In the same issue of Science in which the Montagnier team reported about the “isolation” of a “new human retrovirus”, the Gallo team published about the “isolated retrovirus HTLV” in T-helper cells of homosexual patients, allegedly carried out in 1980 (Marx 1983, Barré-Sinoussi 1983). By mid-1983 the irrational notion of a “lethal AIDS/sex plague” was psychologically programmed on the basis of a few hundred cases of “infection” among anal receptive homosexuals with a long-standing abuse of nitrite inhalants and antibiotics. By mid-1983 an interaction between retroviral and cancer laboratory specialists, national health authorities and the mass media had long established that AIDS diseases were the consequence of a “new agent” and a “lethal new plague of sex and blood”. It was only a question of who would control the “invisible hand of the market” for the marketing of the worldwide test substances. The Gallo team evidently needed to win time to come up with the decisive laboratory trick of how to isolate enough “HIV” in order to produce enough “HIV proteins” for mass testing. “HIV production” in a test tube was not sufficient for this purpose. In September 1983, Gallo announced that the Montagnier team could not have discovered a “new retrovirus” as they could not provide evidence of continuous “HIV production”. In an interview in 1997 Montagnier stated: “For example Gallo said: “They have not isolated the virus … and we (Gallo et al.), we have made it emerge in abundance in an immortal cell line.” But before making it emerge in immortal cell lines, we made it emerge in cultures of normal lymphocytes from a blood donor. That is the principal criterion” (Tahi 1997).

Gallo and Montagnier’s statements are both objectively misleading and are based on deliberate acts of deception.

     But in the economic war between the French and the Americans the Americans initially retained the upper hand. The denunciation of the Pasteur Institute’s hepatitis B vaccine as “AIDS contaminated” had its effect. Montagnier’s patent application for an “anti-HIV antibody test” was rejected in the USA, the patent application of the National Cancer Institute for Gallo’s “anti-HIV antibody test” was authorized in record time even before Gallo had published one line in scientific journals about the “isolation of HIV” and the development of an “anti-HIV antibody test” on the basis of proteins from his “isolated HIV”. Only after year-long litigation between the USA and France were the patent charges for the “anti-HIV antibody test” awarded equally to Gallo and Montagnier at a conference between President Reagan and the then Mayor of Paris, Chirac and then given in an apparently noble gesture to the World Foundation for AIDS whose president Montagnier was to become. In reality this absurd dispute over the patent rights served as a distraction from the real problem—namely the fact that neither Gallo nor Montagnier had “isolated” a human retrovirus and that the source of the proteins for “HIV tests” had by no means been established as having a retroviral origin. The worldwide public was led to believe that when two specialists from such renowned research institutes like the Pasteur Institute and the National Cancer Institute quarrel about the honor of discovery, then “Public Enemy No.1” (President Reagan 1984) must really exist and be the cause of the “most devastating epidemic of the 20th Century” (Gallo 1991), and also that the “AIDS test” would protect the world population from this “deadly mass plague”.

Nobel Prize winner Mullis’ “little question” as to the original references that demonstrated that “HIV is the probable cause of AIDS”, which neither Montagnier nor any other specialists would or could answer, answered itself by virtue of scientific historical facts. Fear of plagues is deeply anchored in the archaic subconscious of mankind as a legacy of evolutionary experience. It is very easy to trigger especially in association with sex and blood. When non-stop images are shown on television and in other mass media of condemned, relatively young people in connection with a “puzzling plague” and it is suggested that this “deadly incurable mass plague from the malicious depths of Nature” affects homosexuals today and tomorrow every man, woman and child, then people are scared. Then the question of whether the causes of the disease are correct will already have been answered, before a rational analysis could even be initiated. The all-or-nothing approach is adopted when confronted with archaic fears. You are either frightened of not. Reason confirms with hindsight what apparently the emotions already had known. With the continuous barrage of horrific images in the media and the statements of medical authorities, apparently in the know, terms like “HIV” and “AIDS” become provisory triggers whose objective truths can no longer be queried.

The majority of people surrender helplessly to suggestive manipulation. There are plenty of object lessons in the history of the 20th Century in totalitarian systems and also in the world of modern media. Psychologists name this process “operant conditioning”. When a non-specific, diffuse prospect of fear is associated contemporaneously with enough concrete stimuli or projections, the appearance of the stimulus without a concrete reason for fear is sufficient in the future, to search for and find a collective consensual protective mechanism for fear. There is no need to seek out original scientific references to prove whether the statements associated with these fears are justified. They are secure as they have been collectively internalized as a “healthy strategy”. The people who are considered dangerous are those who reject the apparent dangers through rational analysis. The standard answer, since the “outbreak of AIDS epidemic” among uninformed doctors remains to this day “Do you want send millions of people to a certain death?” or “You should be happy that the young are frightened of something during sex and are more careful”. When reasons are given as to why the false disease theory “HIV causes AIDS” is a danger to millions of people and that making the sex life of young people neurotic by means of HIV/AIDS propaganda detracts from the real dangers, you get at most a look of “condescending puzzlement” just as Nobel Prize winner Mullis did from Dr. Montagnier in reply to his “little question” (Mullis 1998). After verifying that there were no scientific references to show that “HIV is the probable cause of AIDS”, Mullis publicly described this fact as one of the greatest scientific scandals of the 20th Century (Mullis 1998).

In the first publication about the “isolation of a human retrovirus” in the T-helper immune cells of AID and AIDS patients in 1983 the Montagnier team claimed to have followed all the procedural steps according to the standard rules of isolation of a retrovirus with the exception of electron-microscopic photographs of the density gradients. Such photographs are, however, of crucial importance to verify which proteins are present in the band of the density gradient. An arbitrary choice of these proteins may not be used as antigen substrate for the “HIV test”. If decay proteins from the stimulated human cells in the cell culture have banded in the density gradient, then “HIV positive” will register as increased quantities of antibodies are found in the blood serum of test subjects which formed naturally against decay proteins inside the organism, against alloantigens (e.g. foreign semen after anal intercourse) or against microbial antigens. These antibodies in “HIV positive tests” then also react against decay proteins from the foreign human cells of the cell culture. This means, however, that millions of patients have received the medical death sentence of a “lethal retroviral infection” as a consequence of a natural antibody reaction and in countless cases the patients have been treated with highly toxic drug cocktails which have been proven to trigger AIDS and cancer. The electron-microscopic control of the protein components at the density gradient in the “isolation of HIV” and the construction of the “HIV test” is of immense importance to a large number of people and their dependents.

Yet, between 1983 and 1997, the EM photographs of the protein components of the density gradient were not published either by Montagnier, Gallo, or any other retro-virologist. The very first EM photographs of the density gradient of “HIV isolation” were published in March 1997 by two research groups, fourteen years after the first apparent “HIV isolation” by Montagnier and Gallo. These EM images showed “disastrous results”, as judged by Professor De Harven, one of the pioneers of the use of electron-microscopy for the control of the isolation of retroviruses in mammalian cells (De Harven 1998 a). The first EM photographs, as truth test for the cell material of the density gradient after “HIV isolation” from human cells showed “practically only cell material” from human cells of the cell culture (Papadopulos-Eleopulos 1998 a). So, fourteen years after the alleged “first isolation of HIV” and thirteen years after the introduction of “HIV tests” it transpired that the retrovirus cancer researchers Montagnier and Gallo feigned the “isolation of HIV” and that the cell proteins for the protein antigens of the “HIV test” were nothing more than decay proteins from human cell cultures. The test result “HIV positive” meant the reaction of natural, if increased, antibody levels in the blood serum of test subjects.

Whatever else the retrovirus cancer researchers fabricated by laboratory trickery, the omission of EM photographs of the test proteins for the “HIV test” objectively amounted to grievous bodily harm, in uncounted cases leading to death, as patients as a rule were treated with highly toxic pharmaceutics, which could trigger AIDS and cancer. The explanation of Montagnier in an interview in 1997 is significant in understanding the grave charge that is based on firm scientific documents. Montagnier suddenly denies that he and his research team adopted the standard rules of isolation of retroviruses during the “first isolation of HIV”. This statement is a direct contradiction to the claims in several publications by Montagnier and his colleagues in which it is explicitly reported, with reference to the rules determined by the Pasteur Institute in 1972, that these procedures were carried out for the “isolation of HIV”, excluding the crucial EM cell material images at the density gradient after centrifuging the cell fluids of the suspected retrovirus cell culture of lymph cells from the AID and AIDS patient’s blood serum (Barré-Sinoussi 1983, Brun-Vezinet 1984, Vilmar1984, Rey 1984, Klatzmann 1984, Montagnier 1985). As to the question of whether the standard rules for the isolation of retroviruses (Sinoussi 1973), defined at a symposium at the Pasteur Institute in 1972 and which he and his colleagues referred to in the initial publication of the “Isolation of HIV” were respected—namely:

• “culture [the suspected T-cells], purification of the material by ultracentrifugation, Electron Microscopic (EM) photographs of the material which bands at the retrovirus density, characterisation of these particles, proof of the infectivity of the particles”

Montagnier answered unequivocally in an interview in 1997: “No, that is not isolation” (Tahi 1997).

There are only two possible explanations for this response from one of the leading HIV specialists in the world:

• Either Montagnier and his team, contrary to the claims in their publications, did not follow the standard rules of retrovirus isolation during the “isolation of HIV”, in which case these publications are scientific falsifications
• Or they did follow standard procedures and realized that the required results—the existence of human retroviruses in the T-immune cells of AID and AIDS patients—were not to be proven, in which case we are dealing again with a serious case of scientific falsification.

The fact that Gallo and his team published the same procedure as the Montagnier team for “HIV isolation” and that the Pasteur team sent the cell fluids from its cell cultures to the Gallo laboratories in 1983, speaks against the first possibility (Popovic 1984). In an interview in 1997 Montagnier admits that in 1983 he had seen only unspecific factors for the existence of retroviruses, but that through an assemblage of unspecific factors his mind’s eye perceived the retrovirus “HIV” and this speaks for the latter possibility: “It is not one property but the assemblage of the properties which made us say it was a retrovirus of the family of lentiviruses. Taken in isolation, each of the properties isn’t truly specific. It is the assemblage of them. So we had: the density, RT, pictures of budding and the analogy with the visna virus. Those are the four characteristics” (Tahi 1997).

All four characteristics are absolutely unspecific, they are found in many human cells, normal cells and cancer cells in cell cultures (overview Papadopulos-Eleopulos 1998 a). For fifteen years (1982-1997), both Montagnier and Gallo and all other retrovirologists dispensed with the only specific characteristic, a highly specific characteristic, namely the EM control of the density gradient after purification by ultracentrifugation, in order to be able to determine whether human cell proteins or retrovirus proteins were to be found in the density gradient for the “HIV test” construction. This is a routine matter in laboratories. “Dangerously enough, EM was progressively dismissed in retrovirus research after 1970. Molecular biologists started to rely exclusively on various “markers”, and what was sedimenting in sucrose gradient at density 1.16 gm/ml was regarded as “pure virus”. It is only in 1997, after fifteen years of intensive HIV research, that elementary EM controls were performed, with the disastrous results recently reviewed in Continuum. How many wasted efforts, how many billions of research dollars gone in smoke … Horrible. Errare humanum est sed diabolicum perseverare … [To err is human. To repeat error is of the Devil]” (De Harven 1998 a).

So Montagnier and Gallo must have blindly fished out of their “cell soup” protein antigens for the test substrate of the “HIV test”, a test which in positive cases meant horrific suffering and death for millions of people, for the healthy and ill “HIV positives”, for those with symptoms and those without. “How sad it is to think that a simple EM control of such “bands” (which takes about two days, and costs a few hundred dollars, but has never been done before 1997) could have prevented these highly misleading interpretations of “markers” (De Harven 1998 a).

It is, however, very difficult to imagine that of the thousands of highly specialized laboratory scientists in countless retrovirus research laboratories all of which have an electron-microscope on hand, with a budget of over 200 billion dollars in research funds, nobody in 15 years thought of running an EM control of the sucrose gradient in the “cell culture soup”. The acceptance of such a syndrome, in light of the alleged threat to mankind of a “deadly mass HIV plague”, required a devout deference to authority. Gallo, Montagnier and a few of their colleagues were proclaimed as “HIV discoverers”, consultants in chief and lords of the greatest capital investment in modern medical history. The majority of retrovirologists profited knowingly and silently from the funding. “It was like having a money-printing machine in the basement, when you based a funding application on HIV, irrespective of what you wanted to research, the funds flowed. Without HIV every funding application was a lottery” (anonymous laboratory researcher about research practices in the AIDS era).

The most absurd thing about the statements from Montagnier and his co-workers is the fact that every interpretation of the observed phenomena in the cell cultures, the cell fluids, the density gradients and the interaction of cell cultures had to be objectively false. In the 1980s there was still a lack of knowledge among laboratory researchers and clinicians about the fundamental processes in human cell systems. The less they definitely knew, the more dictatorial the assertions that the research findings had been properly rendered (Epstein 1996, Lang 1996).

The first trailblazing insights of NO research, cytokine research, mitochondrial research and many other research fields have heralded a radical change in the understanding of many apparently puzzling phenomena. For the first time it is possible to recognize all phenomena in the context of “HIV isolation”, “HIV test construction” and “HIV test findings” as being within the bounds of evolutionary biological laws. The insights suggest a more than strong suspicion that Montagnier, Gallo and their colleagues had not only examined the four unspecific standard characteristics for the isolation of retroviruses in human cells, named by Montagnier in an interview in 1997, but had also made up the standard characteristic—the EM control of the material in the sucrose solution in the density gradient. The logical reason for this assumption is the fact that the Montagnier and Gallo teams had made publications of EM photos of budding particles from the cell membrane of human cell cultures that they had stimulated with strong oxidizing substances. Why, then, would they not be interested in checking these EM findings with a control of the purified materials in the density gradient. Both teams have, to this day, sold these unspecific EM photos of budding from the cell membrane as evidence for the existence of “HIV”. The budding of particles from stimulated cells is not specific evidence for retrovirus particles, not even if this particle arouses unspecific initial suspicions that it could be a retrovirus particle. Presenting the unsuspecting public with budding EM photos as evidence of the “existence and isolation of HIV” is a premeditated act of deception and a deliberate scientific falsification. Noted virologists have clearly proven that: “budding virus-like particles from the cell membrane can be ascertained in numerous non-infected normal cell lines and transformed cell lines, in T-cell lines, in transformed B-cell lines; and in cultures of primary human lymphoid cells from cord blood, which were either PHA stimulated or not and grown with or without serum and in cord lymphocytes directly after Ficoll separation”. (Dourmashkin 1991, overview Papadopulos-Eleopulos 1993 a, 1993 b, 1996, 1998 a, 1998 b). Such budding particles have been demonstrated in the cell membranes of cells in enlarged lymph nodes in 90% of cases of “HIV associated” AID and AIDS patients as well as in the cell membranes of cells in enlarged lymph nodes in 87% of cases of non-“HIV associated” AID and AIDS patients (O’Hara 1988). In the same way as the embryonic umbilical cells and the transformed cells, all cases were concerned with cells after a Th1-Th2 switch and a type 2 cytokine dominance. Montagnier and Gallo knew nothing at the beginning of the 1980s about the existence of the two T-helper lymph cell populations, Th1 and Th2. They also did not know that these cells synthesize different cytokine profiles and that this was the reason why they showed differing patterns in the regulation of cellular symbiosis. They also did not know that T-helper cells produce or do not produce NO depending on the redox status. They also did not know that, depending on the redox status and the stimulation by oxidizing substances, T-helper cells activate counterregulations that either accelerate or inhibit apoptosis/necrosis and activate glycolitic energy production from outside the mitochondria.

     The latter, however, meant an increase in lactate formation and the export of cell debris, accrued by proteolytic enzymes activated by the lactate. The budding of virus-like particles from the cell membrane is the garbage collection of the type 2 cytokine cells. The proof is the findings in typical Th2 cells: transformed T- and B-cell lines, embryonic lymphoid cells in umbilical tissue, productive lymph nodes independent from antibody levels obtained in the “HIV test” (Dourmashkin 1991, O’Hara 1988).

But Montagnier and Gallo definitely had a dire need to confirm, by means of EM photos of the materials in the sucrose solution, their initial suspicion, on the basis of the budding EM photos, of being on the trail of a “new retrovirus”. If, after ultracentrifugation, there was a banding at the density gradient of predominantly retrovirus-like particles, then it could be possible by biochemical identification of the proteins and amino acids of this particle to prove that it was a new retrovirus. The disappointment must have been immense when, exactly like the first EM photos from 1997, practically only cell debris from the human cells of the stimulated cell culture was represented (Bess 1997, Gluschankof 1997). Such EM photos were the counter-evidence of the “isolation of a new agent”. Proteins from human cell debris are not suitable to be sold as protein antigens for a worldwide antibody test. So Montagnier and Gallo declared the four unspecific characteristics for “HIV” for specific by a generous interpretation of the set theory—four times minus equals plus (Montagnier in interview 1997, Tahi 1997). They expounded the unspecific budding EM photos as specific evidence of a “new agent HIV”. The specific EM photos of the sucrose gradient were not published; the unspecific budding EM photos were sufficient to quench the thirst of the mass media craving for images of the plague. Photofit images of “HIV” were later supplied together with computer designed monster-like excrescences, so-called knobs and spikes, to stimulate the collective plague fantasies, how the “new agent of the deadly mass plague” enters the immune cells and how it goes about its deadly deeds (see illustration: HIV photofit [table IX]). In reality the best-known electron microscopist for “HIV” EM photos had published that the “HIV particle” on average only exhibited 0.5 knobs per particle. These protein complexes on the cell membrane of the “HIV particle” are supposed to be decisive for the infectiousness of “HIV”. This protein with a molecular weight of gp 120 is one of the proteins—the alleged “HIV protein” in the “HIV test”—that reacted to the antibodies in the human serum and can produce positive results in the test. The EM researchers established that knob-like structures could be observed, even when gp 120 proteins were not present, the EM results could then be falsely positive (Layne 1992). But how is “HIV” without the gp 120 configuration supposed to dock onto the immune cells, if, according to the unanimous view of the “HIV” researchers it could not possibly be infectious without it? The act of deception with the budding EM photos and the gp 120 protein complex for the “HIV test” is of crucial importance to the virus hunters for the optical staging of the trick series. As the human sensory organs receive some 11 million bits per second, of which roughly 10 million are optical bits, pictorial presentation is the best means to generate fear or fancy. From a mass psychological viewpoint it is not to be assumed that Montagnier and Gallo had forgone the opportunity to produce considerably more specific EM photos of the sucrose gradient as there were very convincing EM photos of retrovirus particles in the sucrose gradient after purification by ultracentrifugation even in the 1960s. Such EM photos were published by, among others, the Pasteur Institute under Montagnier and by the National Institute of Cancer in the USA under Gallo. These EM photos were taken of cell cultures of mice suffering from leukaemia. EM photos of particles from human cancer cells and other cell types after purification could, however, never be demonstrated. The scientific contemporary witness, De Harven, who as one of the pioneers of retrovirus research had already shown in the 1950s convincing EM photos of purified retrovirus particles from animal cancer cells at the most famous American cancer research center—the Sloan-Kettering Institute in New York—stated: “In the 1950s and 1960s many EM cancer research centers [in the USA and Europe], were spending a considerable amount of time in attempts to demonstrate virus particles associated with human cancer cells. “Virus-like particles” were occasionally reported but convinced nobody. Typical viruses were never conclusively demonstrated. This was in sharp contrast with the highly reproducible demonstration, by EM, of viruses in a variety of murine and avian leukemias and tumors. Very few papers were published to report on these negative findings in human cancers and leukemias. However, Haguenau, in 1959, reported on the difficulty of identifying any typical virus particles in a large series of human mammary carcinomas. Bernhard and Leplus, in 1964 in an EM survey of cases of Hodgkin’s disease, lymphosarcomes, lymphoid leukemias and metastatic diseases failed to recognize virus particles associated with these malignant conditions. At Sloan Kettering in New York, I decided, in 1965, to stop surveying cases of leukemias and lymphomas by EM for the presence of viruses in view of our entirely negative results. This was reported at a conference on Methodological Approaches to the Study of Leukemias held at the Wistar Institute, in 1965 (Haguenau 1959, Bernhard 1964, De Harven 1965). Publication of these negative findings failed to discourage fanatical virus hunters! An explanation for these negative results had to be found somewhere! Perhaps the technique of EM by the thin section method was not the best approach? (although it worked perfectly for mice!). Preparing thin sections was time-consuming and skill-demanding! Who had time for that, when research funding was getting difficult, and when major pharmaceutical corporations were starting to finance “crash programs” for speedy answers? … It became acceptable to postulate that when viruses cannot be seen by EM in cancer cells, biochemical or immunological methods supposedly identifying viral “markers” were enough to demonstrate viral infection of the cells under scrutiny. Such markers can be an enzyme (RT), an antigen, various proteins, or some RNA sequences. “Never seeing the viral particles was conveniently explained by the integration of the viral genome into the chromosomes of the alleged infected cells. To accommodate such interpretations implied complete oblivion of all we knew from previous research on cancer of experimental animals …” (De Harven 1998 b).

The fact that the leading lights of “HIV isolation” and the patentees of the “HIV antibody test”, Montagnier and Gallo, were not in the position to produce a specific EM photo of purified cell debris and instead of this were able to feign for 17 years the unspecific budding EM photos as the official “wanted” poster for “HIV” just goes to show that counter controls no longer work in medical research: “As far as scientific policy is concerned, research on potentially oncogenic viruses was dominated by the retrovirus hypothesis. Federal funding took the same direction, amplified by the incredibly naive idea that success was primarily a matter of money! Unusually large levels of federal support resulted in the creation of a retrovirus research establishment. Large numbers of research jobs were created in this venture. The intellectual freedom to think along other avenues of cancer research was rapidly dwindling, especially when major pharmaceutical companies started to offer tantalizing contracts to support polarized retrovirus research … The top priority was to demonstrate, at any cost, that retroviruses had something to do with human cancer, a hypothesis, however, which didn’t receive the slightest support throughout the 1970s. Such a misdirected research effort would have been relatively inconsequential as long as public health was not involved. Unfortunately, the emergence of acquired immunodeficiency syndromes (AIDS) in 1981 gave the retrovirus establishment an opportunity to transform what could have been only an academic flop into a public health tragedy” (De Harven 1998 b).

The remaining unspecific characteristics can also be explained by the concept of cell dyssymbiosis. The Montagnier team and the Gallo team specified as second characteristic, besides the budding of cell particles from the stimulated human T-helper cells, evidence of the repair enzyme reverse transcriptase (Barré—Sinoussi 1963, Popovic 1984). Such enzymes transcribe the RNA sequences to DNA sequences. From an evolutionary-biological viewpoint, information storage began in living cells, with less stable RNA codings, as “RNA world” (overview De Duve 1991). DNA coding is, however, more stable and in all living cells the carrier of information for protein synthesis in the cytoplasm. Mobile messenger RNA, after redox dependent activation, is transcribed to the DNA form. Up until 1970 the biological dogma was that flows of genetic information always ran from DNA to RNA. As Temin and Baltimore discovered in 1970 that there is also a counter-flow of information from the RNA form to DNA form, they termed the enzyme involved reverse transcriptase (RT). At first it was thought that this enzyme was present exclusively in animal cell identified RNA tumor viruses (retroviruses). This assumption was soon recognized as a mistake. RT is active in all eukaryotic cells and in bacterial cells (Temin 1972, 1974, 1985, Baltimore 1985, Varmus 1987, 1988).

The claim by Montagnier and Gallo that RT was fished out of the density gradient 1.16 gm/ml, which was shown to contain Montagnier’s impure cell debris from the cell fluid (Tahi 1997), and that this find is exclusive proof of the presence of “HIV” and so the proteins from the same density gradient are exclusively “HIV proteins” is a grave scientific deceit. As Montagnier and Gallo did not purify the material from the banding by ultracentrifugation and also did not wish to verify the presence of retrovirus particles with EM photos, in order to disguise the absence of retrovirus particles (!) the whole process becomes a dreadful game with concealed cards. Montagnier said in an interview in 1997, after the 1997 EM photos (Bess 1997, Gluschankof 1997) had exposed the non-existence of the retrovirus particle in the sucrose gradient which had been intimated since 1983: “I repeat, we did not purify … Gallo? … I don’t know if he really purified. I don’t believe so” (Tahi 1997).

The safest and clearest procedures for the isolation of retroviruses from stimulated human cells was not employed and substituted by the objectively false statement that evidence of RT is exclusive proof of the “isolation of HIV”. As the discoverer of RT, the Nobel Prize winners Temin and Baltimore and Nobel Prize winner Varmus (Temin and Baltimore 1972, Varmus 1987, 1988) had unequivocally shown that RT features in all cells, the presence of RT in the cell debris of cell fluid from human cell cultures, which were stimulated with strong oxidizing substances, was to be expected.

Montagnier and Gallo as well as all the other HIV researchers were only able to demonstrate “HIV characteristics” in stimulated cells (Klatzmann 1986, Papadopulos-Eleopulos 1993, 1998 a). The stimulation of the cell cultures took place as a result of the addition of strong oxidizing mitogens (PHA, Con A etc.) and type 1 cytokine interleukin-2 (IL-2). IL-2 activates, however, Type 1 cytokine interferon-γ (IFN-γ). IFN-γ stimulates cytotoxic NO production. As the Montagnier team and the Gallo team stimulated T-helper cells (TH cells) from homosexual AID and AIDS patients and it has been demonstrated that such patients show a TH-2 dominance (overview Lucey 1996), these cells have mostly been counterregulated, this means on activation of NO synthesis by interferon-γ these cells either die by apoptosis or necrosis, as IL-2 also stimulates tumor necrosis factors and as a consequence increasingly ROS. Or the cells increase the counterregulation to protect against apoptosis/necrosis which means that by activating the type 2 cytokine profile (IL-4, IL-5, IL-10 etc.) the formation of the enzyme COX-2, prostaglandin (PGE) and the repair enzyme, transforming growth factor (TGF) is increased. PGE and TGF suppress the NO synthesis and activate from arginine the metabolic path for the synthesis of polyamines that stimulate the proliferation and repair mechanisms. The synthesis of reverse transcriptase, the enzyme for the neosynthesis of DNA from RNA, also belongs to the repair sequence.

“HIV positive” tested people have a conspicuously low thiol pool in T-helper cells. Both the cysteine levels in the blood plasma are lower as well as the intracellular glutathione levels in the T-helper cells that are on average 30% lower (Dröge 1988, Eck 1989, Buhl 1989, Gmünder 1991, Roederer 1991 a, 1991 b, Harakeh 1991, Kinscherf 1994, Dröge 1997 a, 1997 b, Herzenberg 1997). Thiol depletion is to be expected in long-term stress in which a number of factors are involved and is a specific expression of a profound cell dyssymbiosis in AID and AIDS patients. The antioxidative and antinitrosative emergency status of the T-helper immune cells can only be remedied by massive counterregulation or apoptosis/necrosis. The stimulation by IL-2 and heavily oxidized mitogens and antigens of these thiol depleted immune cells in the cell culture triggers oxidative and nitrosative stress. Considerable cell damage can be expected through this provocation of the synthesis of cytotoxic NO gases, which in the cell culture also diffuse to the neighboring cells. The net effect is that the RT levels also increase in counterregulated cells.

In plain language the procedures of the virus hunters meant that they placed the immune cells that were already dyssymbiotic under artificial prooxidative/nitrosative stress, inevitably provoking apoptosis/necrosis and /or increased counterregulation. Finally the released cell products, including RT and other cell specific proteins, RNA and DNA molecules as well as the export particles of the stressed cells (budding) are interpreted by chicanery as unspecific, but then again apparently in toto specific, characteristics of a “new retrovirus”. The “HIV test” is assembled using disintegrating proteins with the full awareness that people with an increased antibody count (Th2 status with increased antibody production) and/or cross-reacting antibodies and autoantibodies according to the natural laws could show an antigen antibody reaction on contact with human foreign protein. The selection of the “HIV positive” stigmatized is governed by an arbitrary specification of the measuring threshold of the test, this means at which point of sensitivity the antigen antibody reaction counts as “positive”. With this technique of measuring a targeted haul can be made within the population as a whole as it is already known which particular subgroups will be stigmatized. Subsequently the necessity was suggested to those who had been scared to death at being stigmatized, for a long-term therapy with highly toxic pharmaceutical combinations to combat the phantom retrovirus that a few thousand laboratory specialists with a simple EM photo costing “a few hundred dollars” were apparently unable to conceive for 17 years. Then again the extremely expensive pharmaceutical cocktails, the unfailing implementation of the “planned experiments on human beings” promoted at the historic conference of the manqué retrovirus cancer researchers in March 1983, have been shown to cause prooxidative/nitrosative stress and compound cell dyssymbiosis. The circle closes, the pharmatoxic consequences, to the point of fatal organ failure, are interpreted as “specific characteristics” of the “lethal HIV infection”.

Countless experimental studies with all kinds of cell types have proven that the “four HIV-specific characteristics” (Montagnier) observed in cell cultures can equally arise in “HIV negative” cell cultures under stimulation stress. When HIV researchers say that they have infected previously “non-infected cell cultures” with “HIV” it always means that they have stimulated oxidative/nitrosative stress (without stimulation stress there are no “HIV characteristics”!) and that these cells, dependent on cell type or the state of cell symbiosis, have reacted with counterregulations. The subsequent diagnosis of “HIV positive” in the cell culture is reached in that budding was observed, a portion of RNA (or DNA!) was re-modelled to DNA in an artificial initial sample, and that this is regarded as evidence for the presence of the enzyme RT, that the one or the other protein is proven by molecular weight, as occurs in every cell, but that this one is defined as an “HIV protein” in advance and that possibly these proteins will react to antibodies in animal or human blood serum. In the last case it is claimed, from a scientific viewpoint incorrectly, that these antibody reactions are specific and exclusively a reaction to “HIV proteins”.

In reality there are no “specific” antibodies. Rather there are special protein molecules that are formed by the million each day by B-cells in every human being. They are positively charged whereas T-cells are negatively charged. Antibodies have varying charging centers on the molecular surface. When they come into contact with an antigen, mostly proteins but also other molecules, then one or more of the positively charged centers on the antibody react to one or more negatively charged centers on the antigen. The antibodies are, so to say, the molecules with the positive plug that fit into the antigens’ negative socket. If you have a negatively charged antigen many different antibodies with roughly the same positive “plug” can fit the negative “socket” of the same antigen. Conversely many different antigens with the same negatively charged “sockets” can couple with positive “plugs” of the same type of antibody. This process is called cross-reaction. The logic is that the more different antibodies a person has formed in the blood serum in increasing amounts, the higher the statistical probability is that they will react on contact with antigens. It is not known, however, whether these antibodies were originally produced “specifically” against these particular antigens or against other antigens. As antibodies remain a long time in blood serum, sometimes lifelong, it cannot be stated for certain whether the antibody activating incidents are backdated or persist from the time of the test (Guilbert 1985, 1986, Pontes de Carvalho 1986, Chassagne 1986, Termynck 1986, Matsiota 1987, Parravicini 1988, Gonzalez-Quintial 1990, Berzofsky 1993, Fauci 1994, Owen 1996, Papadopulos-Eleopulos 1998 a).

The claim of the retrovirologists that a positive “HIV test” signifies a “specific” antibody reaction against “HIV proteins” is thus consciously misleading. As Montagnier admitted in an interview in 1997, originally he and Gallo brought the “unpurified” protein mixture from their “real cell culture soup”, as Montagnier described it in the same interview (Tahi 1997), into contact with the serum from AID and AIDS patients. If there was shown to be an antigen antibody reaction in the serum, which was by no means the case in all the serums, then the reaction as such would be published as evidence that “HIV” must exist and that the patients must be suffering from AID and AIDS because they had become infected with “HIV”. This meant that T-helper immune cells extracted from the serum of immune-stressed AID and AIDS patients were exposed to a further immune stress through oxidizing substances in a cell culture. The highly oxidized proteins, released by the overstrained immune cells by cell disintegration or cell particle export were ultracentrifuged and then banded in a sugar solution, but not purified and identified. Finally a sample was taken from the material that had banded at a particular density (a level at which according to procedures in earlier experiments with animal cancer cells, retrovirus particles, among other things, had concentrated)—blindly and without identification of the material. Taking the protein as antigen from the sample it was allowed to react with antibodies from the blood serum of likewise immune-stressed AID and AIDS patients. Nobody, not even the most imaginative retrovirologist, could even with the remotest semblance of certainty say which proteins from the cell culture had reacted to which antibodies from the serum of AID and AIDS patients. It could only be said that if the proteins from the immune cells of immune-stressed patients were treated prooxidatively/nitrosatively in a laboratory and the released proteins were made to react with antibodies from the serum of equally immune-stressed AID and AIDS patients, then an antigen antibody reaction can be seen. This arcane process and the alleged evidence that unspecific repair enzyme RT is released in immune-stressed immune cells after immune stress in a cell culture is up until now the only evidence for the “existence and isolation of HIV” as well as for the “infection with the immune cell killing HIV”.

The first “HIV test” process was called the ELISA test. It was said later that the ELISA test was wrongly positive in 90% of the positive results. In reality all ELISA tests are wrongly positive as without proper isolation of a retrovirus no test can be constructed that can display the antibody formation against a retrovirus. Later the proteins from the blind sample from the cell culture soup were run through an electric field and defined as “HIV proteins” a handful of proteins that stood out distinctively according to particular molecular weights. In laboratory jargon this process is called Western Blot. The ELISA test becomes the screening test and Western Blot the confirmatory test. If the ELISA test is positive twice then a subsequent Western Blot test is carried out. If this is also positive then the patient is considered to be “HIV positive”. In reality the Western Blot test also does not measure antibody formation against a “retrovirus HIV”. It measures an antibody reaction against what was put into the test substrate: undefined proteins, released by repeatedly stressed human immune cells.

The screening test also cannot find what it is looking for, namely the human antibodies against a “retrovirus HIV” that Dr. Gallo and Dr. Montagnier also failed to find. The confirmatory test also cannot confirm the antibody formation against “retrovirus HIV”, as Dr. Gallo and Dr. Montagnier only saw “unspecific characteristics” and for the only specific characteristic that could confirm the existence of a “retrovirus HIV”, namely EM control after purification of the cell fluids, they evidently did not want to expend “two days time and a few hundred dollars” (De Harven 1998 b).

Nevertheless, can the “HIV test” give information about the condition of a human’s immune system? As the test substrate contains human proteins it can only indicate the degree of sensitivity that a test subject reacts to human proteins. From this alone it cannot be deduced why a proband reacted to a particular protein with antibodies of a particular intensity. There might be, for instance, a cross-reaction between antibodies against tubercular bacteria, leprosy bacteria, pneumocystis carinii fungi, candida fungi and the proteins of the “HIV test”. There are many other cross-reactions that have still been little researched (Mathews 1998, Calabrese 1989, Müller 1990, 1991, Ezekowitz 1991, Tumijama 1991, Kion 1991, Kashala 1994, O’Riordan 1995, Fraziano 1996, Papadopulos-Eleopulos 1997 c). The test cannot provide information about the concrete significance of an antibody reaction against the proteins of the “HIV test” for the past, present or future of test subjects. At the very most a test can indicate that the proband could have Th2 dominance with an increased antibody production. The “HIV test” has no more informational value than the simple DTH test that measures the reaction of the skin lymphocytes to antigen stimulation. As was demonstrated with surgical patients (Christou 1986) the DTH skin reaction could give significant indications about which patients could develop sepsis after severe traumata, burns and operative intrusions. In this respect the DTH skin reaction is superior to the “HIV test” as it indicates the readiness of stimulation of the Th1 immune cells. As the “HIV test” merely shows an increased antibody sensitivity, which can have a lot of different or evident causes in excessive immune stress, and as antibodies are not decisive for the development of opportunistic infections and certain cancer forms but for the elimination capability of Th1 immune cells for an intracellular agent and the antioxidative capacity for the efficiency of cell symbiosis, the “HIV test” is unsuited as an aid to diagnosis and prognosis. But as the construction of the “HIV test” is based on sham particles this test should be banned internationally as quickly as possible and the groundbreaking work of NO research, cytokine research, mitochondria research and other seminal research fields should be implemented into medical practice.

From the numerous experiments with different cell cultures, two experiments from Gallo and Montagnier should demonstrate how they themselves have shaken their “HIV causes AIDS” theory (Zagury 1986, Laurent-Crawford 1991). At the time of the cell experiments the fact of the existence in humans of different cytokine profiles (type 1 and type 2) of the T-helper cells, Th1 cells and Th2 cells, were not yet published. Likewise the fact that during excessive or long-term immune stress of the redox milieu a re-programming of the cytokine profile of the T-cells can take place. These facts were finally verified in 1991 (Romagnani 1991). The additional fact that Th1 cells and Th2 cells can be differentiated as Th1 cells produce cytotoxic NO gas after stimulation with interleukin-2, while Th2 cells suppress the formation of cytotoxic NO gas was only demonstrated in 1995 (Barnes 1995). In this respect the consequence of a Th1-Th2 switch to Th2 dominance was also not known then, namely the fact that after severe immune stress Th2 dominance impairs or totally prevents the elimination of intracellular agents. The further consequence that with a Th2 dominance massive counterregulations are triggered resulting in a cell dyssymbiosis in mitochondria and that these cells export highly oxidized proteins by transporting particles from the cells as well as producing an increase in repair enzymes instead of NO gas production was also at that time not understood.

The Montagnier team (Laurent-Crawford 1991) provoked by mitogen and cytokine stimulation (PHA, interleukin-2) in three human cell lines the appearance of “unspecific characteristics”.

The experiments of the Montagnier team (Laurent-Crawford 1991) show that the four “HIV characteristics” cited by Montagnier as evidence supply the counter-evidence; that we are dealing with cell products under prooxidative and nitrosative stress (see illustration: Experimental findings of the Montagnier team as counter-evidence against the disease theory “HIV is the cause of AID and AIDS” (see table X)).

The results demonstrate the following findings:

1. In T-helper immune cells and other human blood cells that have been acutely stimulated in cell cultures with highly oxidized mitogens (PHA) and the type 1 cytokine interleukin-2 (IL-2) cell disintegration always occurs (cell culture A, C, D).
2. Those cells in the cell culture showing no signs of cell disintegration are those that have reacted with counterregulations to stress provocation by PHA and IL-2 or those that were already counterregulated (cell cultures A, B, C). The counterregulations lead to a shutting down of cytotoxic NO production and to the choking of ROS production in the OXPHOS system of the mitochondria (cell dyssymbiosis).
3. The maximum cell disintegration appears a few days before the maximum appearance of “HIV characteristics” (cell culture A).
4. Cell disintegration occurs after stimulation by PHA and IL-2 even when there are no cells in the cell culture that had previously been provoked for the formation of “HIV characteristics” by stimulation with PHA and IL-2 (cell culture D).

Explanation: In case A, the cell culture was stimulated with mitogens and IL-2 for as long as it took some cells from the cell culture to show signs of “HIV characteristics” (in a cell culture it is always only individual cells that are “HIV positive”). This cell culture is then declared as “HIV infected”. After further stimulation the cells that are not counterregulated (or have not been counterregulated through the additional stimulation) die (apoptosis/necrosis). These are mainly the Th1 cells. If these Th1 cells are thiol-depleted, as has been proven in numerous studies on AID and AIDS patients (Herzenberg 1997 et al.), they die even more quickly as the provoked NO gas and the ROS in the Th1 cells can no longer be neutralized quickly enough. Thiol-depleted Th2 cells have a better chance of survival as with a type 2 cytokine profile they can shut down the enzyme for cytotoxic NO synthesis and slow down calcium-dependent NO synthesis in the cytoplasm. In doing this the level of the powering gases for the mitochondrial channels in the mitochondrial membrane sinks. The import and export facilities of the mitochondria are reduced, the mitochondrial membrane relatively or totally closed, the Ca²⁺ level in the cytoplasm is lowered, apoptosis or necrosis (depending on the diminished ATP level) is prevented. In the cell culture there remain, in essence, the cells that already before stimulation (“HIV characteristics”) or during stimulation (“HIV characteristics”) were no longer capable of apoptosis or necrosis (cases A and B). The cell culture is “chronically HIV infected” and shows no apoptosis/necrosis. Logically the maximum apoptosis/necrosis has to precede the maximum “HIV production” as is the case in cell culture A. The length of time for maximum apoptosis/necrosis after prooxidative/nitrosative stimulation (case A) is well known: an attack of flu in immune healthy people lasts a week, with or without treatment. The Th1 cells react to the intracellular agents. For people with a Th2 dominance, for instance the elderly, a flu infection can be lethal because hitherto compensated cell dyssymbiosis can decompensate which could lead to organ failures ending in death. The same critical period of time was also apparent in the surgical sepsis patients. If the anergic DTH skin reaction as expression of Th2 dominance failed to improve after seven days a significant sepsis developed (Christou 1986). In cases C and D apoptosis/necrosis occurred in Montagnier’s experiment, independent of whether the T-helper cells for the provocation of “HIV characteristics” had been placed under immune stress. In case D without previous “HIV stimulation” apoptosis/necrosis occurred somewhat later than in case C. That is easily explained by the thiol usage of the preceding prooxidative/nitrosative stimulated cells of cell culture C some of which, although not the majority, had developed “HIV characteristics”. Subsequently through further stimulation with PHA/IL-2 even more cells died even more quickly. As can be seen in all four cases it is the stimulation by PHA/IL-2 that is decisive in cell disintegration and not the formation of “HIV characteristics”. These are in fact the results of counterregulation and not the cause of cell disintegration (see especially cases A and B).

As the “HIV researchers” measured the cell effects after stress stimulation only as a net effect of the total amount of cells in the cell culture, the differentiated reaction and regulation (or as the case may be the counterregulation of individual cells) remained concealed. Up until now there have been no publications from the “HIV researchers” about NO-induced effects on an individual cell level. Mitochondria researchers, however, have carried out such studies with the fluorescence-activate cell sorter. In human myelomonocytes from bone marrow after a direct dose of an NO-donating substance at 2mM some 30% of the cells showed necrosis and 30% apoptosis depending on time and dose. The loss of the electric membrane potential of the cell symbionts (mitochondria) preceeded in each case cell disintegration (Richter 1996).

The findings of the experimental studies of Gallo and his assistants confirmed, in principle, the results of the Montagnier team (see illustration: Experimental findings of the Gallo team as counterevidence of the disease theory “HIV causes AID and AIDS”, table XI).

The Gallo team stimulated three T-lymph cell cultures with oxidizing mitogens (PHA) and type 1 cytokine IL-2. Previously cell culture A showed signs of “HIV characteristics” in some cells after stimulation with PHA and IL-2 but the majority of the cells in cell culture A showed no “HIV characteristics”. Cell cultures B and C were not previously stimulated with PHA and IL-2 and had no signs of “HIV characteristics. The Gallo team then exposed the two cell cultures, the “HIV infected” cell culture and one of the two “HIV negative” cell cultures, to the same amounts of immune-stress-triggering PHA and IL-2. The third “HIV negative” lymph cell culture was not stimulated as a control. All three T-lymph cell cultures had a 34% proportion of T-helper cells (Zagury 1986). The AEDS concept (acquired energetic cell dyssymbiosis syndrome = acquired cell dyssymbiosis) now predicts that:

1. Cell cultures A and B will feature a cell loss of T-helper cells after stimulation with PHA and I-2,
2. Cell culture C will show no loss of T-helper cells,
3. Cell culture A will show a greater loss of T-helper cells than cell culture B as the cells from cell culture A were previously treated with oxidizing substances (PHA, IL-2) and some cells had shown signs of “HIV characteristics”.

The latter is a sign of a relative thiol deficiency. These cells will respond to stress stimulation with a stronger apoptosis/necrosis as the previously damaged cell symbioses will react more sensitively to the induction of cytotoxic NO gas and oxygen radicals with cell disintegration (as they had not previously responded with counterregulation). Their cell receptors alter in such a way that they respond to PHA and IL-2 in a reduced way. This would mean that a proportion of the Th1 cells do not die but can no longer be measured as Th1 cells due to monoclonal antibodies. The results must have been as follows:

• T-helper cell loss in cell culture A > cell culture B > cell culture C
• T-helper cell loss in cell culture C = 0

The data of the Gallo team were unequivocal (Zagury 1986). The findings confirmed the later results of the Montagnier team that apoptosis/necrosis in T-helper immune cells is dependent on stress stimulation. The strength and duration of the reaction of the T-helper immune cells, either as a type 1 reaction (apoptosis, necrosis) or a type 2 reaction (counterregulation with loss of Th1 characteristics) is dependent, among other things, on the thiol pool. In the Gallo team’s experiment there were probably among the 3% of T-helper cells, those that could be traced a few days after cultivation through stress stimulation, cells that featured signs of “HIV characteristics” (the publications, however, do not mention this). These cells on further cultivation will “continuously produce HIV” (Laurent-Crawford 1991) as in case B of the Montagnier team’s T-lymph cell cultures, and show no signs of apoptosis or necrosis. This process of counterregulation has been demonstrated by NO researchers. When liver cells were pretreated with low, tolerable amounts of NO gas (NO-donating substances) then a resistance to apoptosis/necrosis was subsequently induced by the addition of higher amounts of NO gas. This resistance was linked to an increased counterregulation through the synthesis of heat shock proteins, the enzyme hemoxygenase and ferritin proteins that can store iron in a non-redox active form (Kim 1995).

As already documented the system of genetic and supragenetic counterregulations is much more comprehensive and complex. A crucial point is that a part of the counterregulation for the stabilization of the redox milieu is the export of highly oxidized proteins by “retrovirus-like” particles and an increased synthesis of the repair enzyme RT. Montagnier identified both of these factors as being “unspecific HIV characteristics” (Tahi 1997). They actually occur in AID and AIDS patients not as causes, but on the contrary as consequences of a severe or long-term immune stress status and have nothing to do with an “HIV infection”. This evolutionary-biological switching from a Type I reaction to a Type II reaction in states of highly acute or long-term immune stress has been demonstrated in all animals from microbes to human beings. As the cell symbionts in human cells were former bacteria they are also confronted, under severe and/or long-term stress, with the strategic dichotomy, literally, of “gas pedal” or “brakes”. The net result of the counterregulation of the gas-driven micro-Gaian milieu are subject to intricately networked, non-linear adherence to the rules that have only recently, at least in principal, been recognized. The knowledge that all plant cells also react to stress stimuli by producing NO as a protective gas is helpful here. What is remarkable is the fact that plant cells using the unique messenger substance NO and its capacity to diffuse, can relay alarm signals to distant plant cells within its cell system. These primarily unaffected plant cells become subsequently and in increasing numbers resistant to the same initial stress stimulus, as the warning signal triggered an adequate counterregulation in good time. Plants have also developed a dual strategy although they do not have a specific immune cell network. They react by closing down NO production and the formation of ROS (superoxide anion, hydrogen peroxide) when confronted with microbial toxins that trigger a physical/chemical reaction, with a too strong UV irradiation or with heat stress. The affected plant cells respond to acute stress attacks with a hypersensitive Type I reaction and programmed cell death or necrosis. Simultaneously a series of transcription factors are stimulated via a highly networked alternating cooperation between NO and ROS that activate, on a genetic level, a multitude of expressions for the biosynthesis of enzymes. These effect a Type II protective reaction that inhibits NO/ROS/ONOO production and lowers the increased calcium level (Delledonne 1998, Dangl 1998, Hachtel 1998). The ratio of cyclic guanosine monophosphate (cGMP) to cyclic adenosine monophosphate (cAMP) plays an important role in this process. The cGMP, activated by NO, participates in many productive metabolic processes, while the cAMP, as opponent, brakes overreactions. The ratio of cGMP to cAMP is regulated in human cells by corticosteroid hormones (glucocortico steroids) from adrenal glands in favor of cAMP. Practically all stress influences provoke in T-cells as net effect a strong increase of cAMP. The result is a loss of function and the dwindling of T-helper cells (AID) (Fauci 1974, 1975, Hadden 1977, Haynes 1978, Cupps 1982, Coffey 1985, Calvano 1986). Glucocorticoids infiltrate the T-helper cells, bond with transcription factors and inhibit via a chain reaction the synthesis of all cytokines, type 1 cytokines and type 2 cytokines. The only exception is the synthesis of certain repair phase cytokines, like transforming growth factor (TGF) and platelet derived growth factor (PDGF) (Brattsand 1996). Every doctor knows this fact, including the laboratory specialists Gallo and Montagnier.

Polyamines are synthesized by TGF and prostaglandin PGE2 from arginine in competition with the NO synthesis via the enzyme arginase. These inhibit the production of cytotoxic NO and activate repair mechanisms. Included in this process is an increased production of the repair enzyme reverse transcriptase (RT) (overview Lincoln 1997).

Gallo left a lead as evidence for his ploy. In 1984 the Gallo team had used T-helper cells from homosexual AID and AIDS patients “as evidence of the isolation and continuous production of cytopathic retroviruses” as well as for the production of the “anti-HIV antibody test” (Popovic 1984, Gallo 1984, Schüpbach 1984, Sarngadharan 1984). External colleagues participated in the laboratory work. Two of these assistants worked for Litton Bionetics, Kensington, MD, USA. In 1987 they reported on the way the Gallo team had treated the T-helper cells of the AID and AIDS patients. Among other things they disclosed: “Stimulation in vitro [in cell cultures] could be provided by mitogen or added cells (allogenic antigens) … Certain manipulations of culture conditions were found to improve the outcome, e.g., cocultivation of patient cells with mitogen stimulated peripheral blood leukocytes from uninfected donors. Isolation of virus from cultured cells also was substantially facilitated by inclusion of hydrocortisone in the culture media” (Sarngadharan 1987). The statement by scientists participating in the “HIV isolation” in Gallo’s laboratory confirmed the simulated “HIV isolation” and the use of released proteins from human cells from the cell culture as protein antigens for the “anti-HIV antibody test” (Kremer 1998 a, 1998 c):

1. Hydrocortisone is a glucocorticoid.
2. Glucocorticoids inhibit the increase and proliferation of human T-helper cells. They effect in all physiological, psychological and pathophysiological states of stress an effective immune suppression (Gabrielsen 1967, Machinodan 1970).
3. Real existing retroviruses in human T-helper cells can only proliferate when the enzymes for the duplication and division of the DNA strand of the T-helper cells—the DNA polymerases—are present and active (Levine 1991).
4. Glucocorticoids inhibit the synthesis and activities of the DNA polymerases of the T-helper cells (Gillis 1979 a, 1979 b).
5. Glucocorticoids inhibit the genetic expression of the enzyme NO synthase for the production of cytotoxic NO on the genetic transcription level and at the translation stage of RNA transcripts in the biosynthesis of proteins (Kunz 1996).
6. Glucocorticoids promote the synthesis of repair enzymes and the repair processes in T-helper cells (Brattsand 1996, Lincoln 1997).
7. The indispensable prerequisites for the production of “HIV” in T-helper cells are stimulation by the type 1 cytokine IL-2 (Gallo 1984, Montagnier 1985) and mitogens. Glucocorticoids block the effects of IL-2 and mitogens (Gillis 1979 a, 1979 b).
8. The production of type 1 cytokines in the human organism is subject to a day/night rhythm. When the glucocorticoid (cortisol) level in the blood serum is at its lowest during the night and in the early morning, the production of inflammatory type 1 cytokines is at its peak (Petrovsky 1998).
9. Glucocorticoids are employed clinically for the treatment of type 1 cytokine overreactions in countless inflammatory and autoimmune diseases, leukaemia, and tumors as well as for organ transplant patients to prevent rejection of the transplant (Cupps 1982).

The statement: “Isolation of virus from cultured cells also was substantially facilitated by inclusion of hydrocortisone in the culture media” (Sarngadharan 1987) is objectively misleading. All specialists are agreed that the indispensable prerequisite for the cultivation of retroviruses from human T-helper cells is blocked by the glucocortico steroid hydrocortisone. In order to be scientifically correct the quoted passage should read: “The production of the repair enzyme reverse transcriptase (RT) in human cells, which were cultivated by stimulation with mitogens and type 1 cytokine IL-2, was substantially facilitated by the inclusion of hydrocortisone in the culture media”.

In his original publication in 1984 Gallo kept quiet about the manipulation of the cell culture of T-helper cells of AID and AIDS patients with hydrocortisone for “isolation of HIV” (Gallo 1984). After publication of these facts (Kremer 1998 a, 1998 c) Gallo was asked at an international press conference at the World AIDS Congress in Geneva in 1998 whether it was the case that: 1. He and his assistants had added hydrocortisone to the culture media “for proof of isolation and the continuous production of HIV” in T-helper lymph cell cultures of homosexual AID and AIDS patients. 2. Whether the “HIV isolation” from cells that had been previously activated by stress stimulation with mitogens and interleukin-2 had been substantially facilitated by the addition of hydrocortisone.

Gallo countered with the question: “What are you implying?” After persistent questioning by journalists Gallo admitted that it was correct and that during the first experiments for “isolation of HIV”, hydrocortisone was added to the “HIV infected” culture media. All other comments as to how the “retrovirus isolation” had been substantially facilitated when he and his team had blocked the proliferation of “retroviruses” with hydrocortisone, were declined by Gallo. The questions to Gallo, Montagnier and their colleagues, posed by representatives of the German Research Group for Investigative Medicine and Journalism (regimed) have remained unanswered to this day. A few weeks after the World AIDS Congress it was prematurely announced in the press that Gallo was to be awarded the most prestigious medical research prize in Germany. The HIV/AIDS establishment was alarmed, the award ceremony was planned for a number of months later in 1999. A statement from the president of the Paul-Ehrlich-Stiftung, which awards this research prize, declared: “This prize is not being awarded for the discovery of HIV” (Paul-Ehrlich-Stiftung 1998). An absurd statement as bar the “isolation of HTLV-I, HTLV-II and HTLV-III (HIV)” by Gallo there is no “discovery of human exogenous retroviruses” (the reason for the prize). HTLV-I and HTLV-II were produced by Gallo with the same laboratory techniques as the “retrovirus characteristics” in leukaemia cell cultures and in contrast to “HIV” play no role clinically. “HIV”, however, was supposed to be threatening all of mankind, why then should the most prestigious German research prize be awarded to Gallo “for not discovering HIV”? In his acceptance speech for this special honour Gallo does not mention a single word explaining whether “HIV isolation” had been substantially facilitated by hydrocortisone. He also did not waste a single word about concrete isolation techniques for “retroviruses”, the “discovery” of which, under his auspices, he described in detail. In the listing of “retroviruses” that he had discovered, Gallo remained silent about the “very first human retrovirus”, HL23V, propagated by Gallo in 1976. This oversight is interesting because for the “isolation” of that particular “human retrovirus” Gallo was still using the standard rules that he ignored for the “isolation of HIV”.

The absurdity of this “first human retrovirus” is, however, that this particle of “HL23V” did not constitute a “retrovirus” and also that Gallo no longer tried to maintain this assertion (Papadopulos-Eleopulos 1996, 1998 a).

Also, it has also to be said that it is an irresolvable logical contradiction to claim that retroviruses find it considerably easier to propagate in human T-helper cells with the addition of hydrocortisone.

The assumption that evidence of the repair enzyme RT under the influence of hydrocortisone, is the result of the activation of TGF and prostaglandins as a Type II counterregulation of cell dyssymbiosis against oxidative and nitrosative stress stimulation, has been supported by an overwhelming amount of clinical and experimental research data. The fact that Gallo remained quiet about the inclusion of hydrocortisone and to this day is not prepared to give an explanation proves that he has systematically suppressed all evidence that contradicts this claim of “HIV isolation” and all evidence that the protein antigens used for the “HIV test” could be exposed as human cell proteins. The only possible explanation is that Gallo had sold the products of evolutionary-biological counterregulation of human T-helper cells under oxidative and nitrosative stimulation stress as “retrovirus HIV” and as “anti-HIV antibody test” to the scientific community and the population of the world as a whole.

But how could Gallo “cultivate the virus en masse” (Montagnier in an interview 1997, Tahi 1997) in order to gain enough “HIV proteins” as protein antigens for the “HIV test”?

T-helper cells only have a limited lifespan. As Gallo had made his “retrovirus HTLV-I and HTLV-II” appear in leukemic lymph cell lines, it seemed appropriate to establish the mass production of “HIV proteins” by having the “HIV particles” mature out of unlimitedly cultivatable, transformed leukaemia cancer cells via prooxidative and nitrosative stress stimulation. For this purpose Gallo chose cell line H9 (HUT78) that came from patients with T-helper cell leukaemia. Gallo cultivated this H9 cell line together with T-helper cells from AID and AIDS patients and claimed that the observed “unspecific characteristics” were proof that “HIV” had relocated from the T-helper cells to the T-helper cells leukaemia cells (Gallo 1984). This process is called co-cultivation. As the cancer cells are highly counterregulated cells in a state of decompensated cell dyssymbiosis we can say according to the AEDS concept that these leukaemia cells in a co-cultivated cell culture will respond to the NO gas production in the T-helper immune cells by increasing counterregulation. The NO gas produced after oxidative and nitrosative stress stimulation also diffuses between the two cell types. The “immortal” T-leukaemia cells that as a consequence of the decompensated cell dyssymbiosis (heavily reduced vitality and number of mitochondria) no longer show signs of programmed cell death, behave in the mixed stimulated cell culture similarly, but even more distinctly, to cell culture B in the Montagnier team’s experiment in 1991. The leukaemia cells increase the already running counterregulations and display chronic “HIV characteristics” (increased RT production, increased budding of export particles for oxidized cell proteins). And exactly that was the case. Cancer cells respond to NO exposure, depending on the dosage, with cell inhibition (cytostasis), subsequently with a heightened counterregulation (Brüne 1996, Lincoln 1997). Up until now nobody has been able to demonstrate actual “HIV production” in the H9 leukaemia cells, as was also the case of the T-helper cells of AIDS patients. Also the H9 cells were by no means destroyed by “HIV” as they should have been according to the “HIV/AIDS theory”. Again in these limitlessly cultivatable leukaemia cells unspecific “HIV characteristics” remained, nobody has demonstrated the actual presence of “HIV retroviruses” in these cells. Though in this way any old cell debris from the cell fluid from this “immortal” cell culture can be centrifuged out and some of these scrap proteins can be used as antigens to assemble the “HIV test” (Sarngadharan 1984). In “HIV tests” these proteins from the special refuse of co-cultivation (foreign proteins from human cells) could react with increased amounts of antibodies in the blood serum of probands. An absurd vicious circle with tragic consequences.

Unspecific pseudo evidence was published for the “isolation of HIV” and the “existence of HIV”—unspecific “HIV characteristics” and unspecific “molecular markers”—but never challenged in scientific discourse. The scientific contemporary witness, Professor De Harven, after decades of laboratory experience and as an internationally renowned expert in the field of detection and isolation of retroviruses categorically stated:

     “When around 1980, R. Gallo and his followers attempted to demonstrate that certain retroviruses can be suspected of representing; human pathogens, to the best of my bibliographical recollection, electron microscopy was never used to demonstrate directly viremia in the studied patients. Why? Most probably, EM results were negative and swiftly ignored! But over-enthusiastic retrovirologists continued to rely on the identification of “viral markers”, attempting to salvage their hypothesis. When retrovirus particles are legion, the study of molecular markers can be useful, and provide an approach to quantification probably better than direct particle counting under the EM (which I always found very difficult). But when, using EM, retrovirus particles are absent relying exclusively on ‘markers’ is a methodological nonsense. ‘Markers’ of what? … In conclusion, and after extensive reviewing of the current AIDS research literature, the following statement appears inescapable: neither electron microscopy nor molecular markers have so far permitted a scientifically sound demonstration of retrovirus isolation directly from AIDS patients” (De Harven 1998 c).

The “invisible hand of the market” that had produced the conditions for heavy and long-term immune stress (AID) (nitrite gases, the raw materials of recreational drugs, pharmaceutical substances for antibiotic, chemotherapeutic and analgesic abuse, highly contaminated coagulating protein preparations and blood products etc. etc., conditions for poverty), then arranged the patented marketing of “unspecific HIV characteristics”—the subsequent symptoms not the causes of acquired immune stress syndrome: “anti-HIV antibody tests”, “anti-retroviral” substances for “anti-HIV prevention” and “HIV synthesis inhibition”.

The agencies of the “invisible hand of the market” (Centers for Disease Control, CDC, National institutes for Health, NIH, Food and Drug Administration, FDA) had already issued warnings about the “human immunodeficiency virus” (CDC and NIH 1982, CDC, FDA, and NIH 1983) before the desired product design was developed and marketable (Popovic 1984, Gallo 1984, Sarngadharan 1984, Schüpbach 1984).

“Unfortunately, the emergence of acquired immunodeficiency syndromes (AIDS) in 1981 gave the retrovirus establishment an opportunity to transform what could have been only an academic flop into a public health tragedy … Soon after the first cases of “Gay related immune deficiency” were described by Gottlieb it was obvious for all observers that Gallo and his associates were going to jump on the new syndrome as a Godsent opportunity to attempt to justify the lavish federal budgets they had consumed on retroviruses over the past 10 years. In 1980, the scientific community was getting more and more concerned about the absence of results in “The War against Cancer” based on retrovirus hunting. The minor episode of HTLV 1 was not enough, by far, to calm the fears of grossly misdirected federal research funds. The fact that the syndrome, soon tactically renamed “AIDS”, had nothing to do with cancer was apparently of little embarrassment for Gallo. Frequent association with Kaposi sarcoma helped to blur the difference in the eyes of the public. Dominated by the media, by special pressure groups and by the interests of several pharmaceutical companies, the AIDS establishment in his efforts to control the disease lost contact with open-minded, peer-reviewed medical science since the unproven HIV/AIDS hypothesis received 100% of the research funds while all other hypotheses were ignored. The general public and the medical community were made to believe that the presence of circulating antibodies is diagnostic of this disease … And to ensure that the AIDS establishment could profitably continue to flourish, research on any dissenting (i.e. non-HIV) hypothesis was carefully prevented by tight control of research funding and by the extreme difficulty of publishing anywhere any dissenting views … In the late 1980s, I was considering adding to my research program in Toronto more EM observations on samples from AIDS patients. Unfortunately, by that time the media and the CDC had so perfectly orchestrated the panic of a plague-like epidemic that I was quickly made to understand that my assistants would all transfer out of the lab if I had insisted to activate such a program … The HIV seropositivity test was still at that time regarded as providing reliable diagnostic data. Since then, Papadopulos and the Australian team have demonstrated that this is very far from the truth” (De Harven 1998 b, Papadopulos-Eleopulos 1993 a).

In comprehensive scientific analyses the internationally renowned research group of Eleni Papadopulos-Eleopulos and her colleagues at the Royal Perth Hospital and the University of Western Australia have published numerous critical publications about the “isolation of HIV”, the construction of the “anti-HIV antibody test”, AIDS-indicating diseases, their causes and proliferation as well as about HIV/AIDS therapy (Papadopulos-Eleopulos 1988, 1992 a, 1992 b, 1993 a, 1993 b, 1995 a, 1995 b, 1995 c, 1996, 1997 a, 1997 b, 1997 c, 1998 a, 1998 b, 1999, 2000 a, 2000 b, Turner 1998).

In German-speaking countries the most important critical studies on the same questions about “HIV isolation”, “HIV test”, AIDS diseases, AIDS therapy and AIDS politics have been published by the study group Ernährung und Immunität (Nutrition and Immunity) in Bern and the research group regimed (Research Group for Investigative Medicine and Journalism) in Stuttgart as well as the Zentrum zur Dokumentation für Naturheilverfahren (ZDN) (Center for the Documentation of Natural Healing Processes) in Essen (Hässig 1993, 1994 a, 1994 b, 1996 a, 1996 b, 1997 a, 1997 b, 1998 a 1998 b, Kremer 1990, 1994, 1996 a, 1996 b, 1998 a, 1998 b, 1998 c, 2000 b, 2000 c, Lanka 1994, 1995, 1997, ZDN 1995, 1998).

Three quarters of a century ago the German biochemist Otto Warburg made a crucial discovery: He had recognized that unlike normal differentiated cells, cancer cells could produce the universal energy-bearing molecule adenosine triphosphate (ATP) mostly without the assistance of molecular oxygen from the cell symbionts—the mitochondria. Warburg was the first to demonstrate “Atmungsferment” in mitochondria. This German term for one of the indispensable enzymes of the mitochondrial respiratory chain has remained in use to this day in English scientific terminology. The astonishing thing about Warburg’s discovery was that the cancer cells that he studied synthesized ATP, to a large extent outside of the mitochondria in the cytoplasm, from the degradation products of glucose with the aid of enzymes, even when oxygen was available (Warburg 1924). This finding contradicted the Pasteur effect of the 19th Century French chemist and discoverer of microbes, Louis Pasteur, who stated that enzymatic glucose degradation is inhibited by microbes in the presence of oxygen (Pasteur 1876).

     As the ATP production of the cancer cells occurred directly from the degradation products of glucose in the metabolic chain up to pyruvate, before entry of pyruvate in the mitochondria, Warburg called this process aerobic glycolysis (in the presence of oxygen, while the fermentative glucose degradation observed by Pasteur in the absence of oxygen is termed anaerobic glycolysis).

Warburg and his colleagues at the Kaiser Wilhelm Institute in Berlin deduced from the anomaly in the Pasteur effect in cancer cells that the oxygen in the respiratory chain could no longer be used due to a defect of the Atmungsferment (Warburg 1949, 1956). This original substantiation of the “Warburg phenomenon” prompted controversy and bitter scientific feuds for decades with no satisfactory explanation for cancer metabolism. Some years before his death there was a final historic confrontation at the annual meeting of Nobelists at Lindau on Lake Constance. Warburg was awarded the Nobel Prize in 1931 for his discovery of Atmungsferment as well as for the evidence of aerobic glycolysis in cancer metabolism, and a second Nobel Prize in 1944, but was prevented from receiving the award. Warburg gave a lecture at Lindau in 1966 on “The Prime Cause and Prevention of Cancer” that triggered fierce criticism among his colleagues:

“Oxygen gas, the donor of energy in plants and animals, is dethroned in the cancer cells and replaced by an energy yielding reaction of the lowest living forms, namely, a fermentation of glucose … Nobody today can say that one does not know what cancer is or what the prime cause of cancer is. On the contrary, there is no disease whose prime cause is better known, so that today ignorance is no longer an excuse that one cannot do more about prevention. That prevention of cancer will come there is no doubt, for man wishes to survive. But how long prevention will be avoided depends on how long the prophets of agnosticism will succeed in inhibiting the application of scientific knowledge in the field of cancer research. In the meantime, millions of men must die of cancer unnecessarily” (Warburg 1967, Werner 1996).

There are a number of objective objections to the assumption that the “Warburg phenomenon” is caused by a primary structural defect in the respiratory chain of mitochondrial cell symbionts. But in 1966 due to the research techniques at that time Warburg’s hypothesis on the structural blockade of the OXPHOS system could neither be definitively refuted nor confirmed. Instead, Warburg was confronted with criticism that he had not made sufficient allowances for the tumorigenic role of the retroviruses that in those days were still termed RNA tumor viruses (Racker 1981).

The postulate of RNA retroviruses originated in 1911. The cancer researcher Peyton Rous filtered a cell-free extract from a muscle tumor though gauze with extremely fine pores (diameter under 120 nanometers). He injected the filtrate into chickens and was able to induce malignant sarcomas (cancer of the connective tissues). From then on it was referred to as Rous sarcoma virus (from the Latin: virus = poison). Rous himself had misgivings in viewing his filtrate as infectious cells: “The first tendency will be to regard the self-perpetuating agent active in this sarcoma of the fowl as a minute parasitic organism. Analogy with several infectious diseases of man and the lower animals, caused by ultramicroscopic organisms, gives support to this view of the findings, and at present work is being directed to its experimental verification. But an agency of another sort is not out of the question. It is conceivable that a chemical stimulant, elaborated by neoplastic cells, might cause the tumor in another host and bring about in consequence a further production of the same stimulant” (Rous 1911).

Rous’ discovery was confirmed in countless experiments on birds and mice. In the ensuing development of electron microscopes in the 1930s the possibility of making such virus particles visible played an important role. As Claude, after the WWII demonstrated via electron microscopic photographs of the Rous sarcoma virus particles in chickens, “the direct observation of virus particles in these experimental tumors gave an enormous [today, we would perhaps say excessive!] impetus to virus research in oncology” (Claude 1947, De Harven 1998 b, 1998 c). But intensive and elaborate experiments to demonstrate virus particles in human cancer cells met a complete lack of success:

“Virus-like particles were occasionally reported but convinced nobody. Typical viruses were never conclusively demonstrated. This was in sharp contrast with the highly reproducible demonstration, by EM, of viruses in a variety of murine and avian leukemias and tumors” (De Harven 1998 b, De Harven 1965).

And while Warburg was confronted by colleagues with the notion that RNA tumor viruses were the probable cause of human cancer cells, the retrovirus cancer research scene had decisively changed:

“Publication of these negative findings [about the lack of EM evidence of retroviruses in human tumor cells] failed to discourage fanatical virus hunters! … Unfortunately many cell debris and vesicular fragments, when air-dried for negative staining, form similar ‘tailed’ structures. Interpreting ‘tailed’ particles as RNA tumor viruses was therefore a bonanza for virus hunters! Still, we had demonstrated that ‘tailed’ virions were preparation artifacts which can be avoided by proper control of the osmolarity and by osmium fixation prior to negative staining, or by critical-point drying. The chaos created by reports on ‘tailed’ particles damaged the credibility of EM in the search for cancer related viruses. Cow’s milk and human milk were being screened for ‘tailed’ particles and Sol Spiegelman (then a well-known retrovirus researcher) was eloquent on the possible risks of breast feeding …” (De Harven 1998 b).

From this point in time onwards the combined electron microscopic and biochemical identification of retroviruses, precisely following the predetermined standard rules, became gradually displaced to be replaced by “molecular markers” (De Harven 1998 c) for “proof, isolation and identification” (Popovic 1984) of retroviruses in human tumor, leukaemia and, finally, lymph cells. According to the latest figures from the German Krebsforschungszentrum (Cancer Research Center) of “viruses responsible for tumors” in humans there are about 220 different viruses that “promote the growth of human cells” (Kohlstädt 2000), almost double the number of human cancer types. Decisive insights for understanding the cancer puzzle were gained, roughly thirty years after the introduction of “molecular markers” as a substitute for proper retrovirus isolation, through the groundbreaking findings of NO and cell symbiosis research which were able to integrate research data from many other fields of research into a unified understanding.

Warburg’s hypothesis that the primary cause of the transformation of differentiated cancer cells to undifferentiated cancer cells is brought about by a primary structural defect in the complexes of the oxidative respiratory chain of mitochondria was logical as the cancer cells, despite the normal oxygen tension in the cells, use it only in greatly reduced amounts for the production of ATP. Warburg’s assumption, however, turned out to be incorrect:

“In contradiction to the assumption of Warburg those cell lines that are defective in respiration are less tumorigenic than cell lines with active respiration” (Mazurek 1997).

This statement is of fundamental importance, as the earlier research findings confirmed that human cells without traceable structural defects of the mitochondrial DNA (overview Cuezva 1997) or rather without structural defects of the DNA in the nucleus (Lijinsky 1973, 1992), transform to cancer cells. These findings, however, shake the doctrine prevailing to this day—that the transformation to cancer cells is triggered by structural defects of the DNA sequences in the nucleus (chance mutations, viral infections, toxic DNA damage, radiation injury etc.).

Warburg’s original discovery in the 1920s that cancer cells gain their operational energy mostly from glucose degradation in the cytoplasm without using the available oxygen, thus through aerobic glycolysis, was time and again confirmed in many experiments on cancer cell cultures and in animal experiments (Warburg 1929, Crabtree 1929, Burk 1967, Krebs 1972, Racker 1976, Weinhouse 1976, Eigenbrodt 1980, Racker 1981, Argiles 1990, Bagetto 1992, Mathupala 1997, Mazurek 1997, Bannasch 1997, Brand 1997 a, Capuano 1997).

Aerobic glycolysis as a source of energy for transformed cells, however, is not the only energy source. In cases of glucose deficiency cancer cells also use other nourishing substrates, for instance by oxidizing glutamine or degrading galactose (McKeehan 1982, Mazurek 1997). However, the seperation and migration of tumor cells as metastases requires aerobic glycolysis as a driving force and for biosyntheses (Mazurek 1997).

     The considerably increased rate of aerobic glucose degradation, around 18- to 38-fold, up to the pyruvate and lactate stage in the citric acid cycle of mitochondria (Golshani-Hebroni 1997, Brand 1997 a, 1997 b) balances out the low energy yield of aerobic glycolysis, a mere 5% of the energy available in glucose (Mazurek 1997). The increased glucose turnover and the resulting 19-fold lactate production compared to normal cells in a quiescent state was considered from the time of Warburg’s discovery until a few years ago a “metabolic enigma” (Mathupala 1997, Brand 1997 a).

Crucial to the solution of the cancer puzzle is the fact that in liver cancer cells, as well as in other tumor cells, exactly the opposite of the differentiation and proliferation of mitochondria could be demonstrated. The number of mitochondria and activity of the mitochondria in liver cancer cells drastically declines. An apparent paradox appeared (exactly as in the case of the fetal cells shortly before birth) in that the transcripts of RNA messages for the syntheses of the protein complexes of the respiratory chain and for complex V for ATP production (OXPHOS) in comparison to adult liver cells were synthesized in increasing numbers without being converted to protein synthesis. This finding equally applied to the RNA messages of the corresponding nuclear genes and the RNA transcripts of the mitochondrial genes.

By contrast the synthesis of the enzymes for glycolytic ATP production in the cytoplasm is considerably higher in comparison to the adult liver cells. These enzymes are, however, identical in cancer cells to isoforms of the fetal enzymes for glycolysis (above all hexokinase II, whose genetic expression increases 5-fold). As is the case in fetal cells, the synthesis of nucleic acids, enzymes and co-enzymes together with other molecules for enforced DNA synthesis for an increase of cell division is considerably boosted. These molecules are synthesized from components of glucose degradation via a special metabolic pathway (pentose phosphate pathway). Inversely, the influx of glucose degradation products for oxidation in the citric acid cycle of the mitochondria remained moderate, analogous to the fetal cells in liver cancer cells. Also similar to the fetal cells, the transport of hydrogen ions for the mitochondrial OXPHOS system by means of molecular ferries (glycerol 3-phosphate shuttle and malate aspartate shuttle) is restricted or blocked. The hydrogen in normal differentiated cells with an active OXPHOS system is transferred onto shuttles by NADH⁺H⁺ formed in the glycolytic metabolic chain, and then is ferried into the mitochondria.

On a genetic level an equally astonishing similarity occurs between fetal and cancer cells. In both cell types redox-dependent altered transcription factors are stimulated. These switch on promoters (promoters define which gene sequences are expressed for the biosynthesis of proteins and enzyme proteins) and gene sequences that are sensitive to glucose, hypoxia, pseudohypoxia, insulin and glucagon in differentiated adult cells. As a result of the amount of genetic, metabolic and bioenergetic harmony between fetal and cancer cells, “re-fetalization” of tumor cells was coined as the appropriate terminology (overview Cuezva 1997, Capuano 1997, Brand 1997 b, Mathupala 1997, Mazurek 1997, Bagetto 1997, Bannasch 1997, Dorwand 1997, Dang 1997, Golshani-Hebroni 1997).

The bioenergetic cooperation of mitochondrial symbionts with the fetal cells (Cuezva 1997), the replicating cells in the late S-phase of division (Brand 1997 b), the regenerating cells during the wound healing process (Capuano 1997), and tumor cells with varyingly quick rates of reproduction (Cuezva 1997) evidently obey the same rules. The elementary difference between the activity states of the cell types arises from the fact that the fetal cells and the cell symbionts up until birth have not yet been regulated by the OXPHOS system, the replicating cells in the S-phase of division and cells in the early regeneration stage of healing have temporarily not been regulated and the tumor cells are no longer regulated.

To understand re-fetalization and the Warburg Phenomenon, the following assumptions must be established:

• Like all eukaryotic cells, the human genome developed from the integration of two genome cultures—the archaeal genome and proteobacterial genome. The informational genes originate mostly from archaeal genes, while the operational genes are primarily from proteobacterial genes (Gray 1999).
• The energy-gaining system of the archaeal stem cells in archaic cell symbiosis is glycolysis for enzymatic ATP production. The reduction product is lactate. The genetic equipment for the glycolytic enzymes is evolutionarily conserved. The original energy gain system of the proteobacteria, the precursor cells of the mitochondria (before installation of the respiratory chain) is the energy provision of hydrogen as the reduced end product (by means of hydrogenosomes). In addition, oxidation from glutamine (glutaminolysis) in the citric acid cycle of proteobacteria, that metabolically and evolutionarily is pre-switched to the respiratory chain and the OXPHOS system, could be used as energy source. The oxidation product is glutamate.
• The glycolytic replication system (cell division) is dominated by the archaeal genome portion, the biogenesis of the mitochondria, probably, is dominated by the proteobacterial genome portion (in an interplay between archaeal and proteobacterial genes in the nucleus and the proteobacterial genes in the mitochondria). During the activity phase of cell division (S-phase in physiological cell division, early wound healing phase, fetal cell division, tumor cell division) an effectual production of glycolytic enzymes and phosphometabolites is provided for cell division. The primary stimulation for glycolytic enzymes (hexokinase II etc.) is hydrogen ion diffusion through the mitochondrial membrane. The “quantum dynamic depth” of photon oscillation is less than during the active OXPHOS phase of respiratory cell symbiosis. These reduced quantum dynamic states in tumor cells are interpreted as “dedifferentiated.”
• The quantum dynamic states are not, however, linear on/off switches but are subject in their marginal phases to non-linear quasi-deterministic rules that are modulated by complex cellular and cell-spanning influencing variables (Waliszewski 1998).
• The increased “quantum dynamic depths” of the activated cell symbioses enable a greater fluidity via the production of increased amounts of liquid oxides (nitrogen oxide, superoxide, peroxides). Peroxinitrite as product of equal amounts of NO and superoxide anion (O₂^-) seems to play a vital role in the maintenance and variability of the bioenergetic potential of the mitochondrial membrane. The latter serves as a checkpoint for Ca²⁺ cycling. Too high amounts of oxides lead to a sinking of the membrane potential and to an increased membranal permeability (as trigger for apoptosis and necrosis), too small amounts of oxides lead to a stabilization of the membrane potential and a reduced permeability of the membrane (as trigger for degeneration and transformation). As information-bearing genes, the archaeal components of the genome are more sensitive to increased oxide production than the proteobacterial components. In oxidative and nitrosative stress on a genetic level the expression for the biosynthesis of counterregulators is activated via redox-dependent transcription factors. Part of the system of counterregulation is the biosynthesis of type 2 cytokine proteins that inhibit the synthesis of NO as well as the superoxide anion and peroxides and trigger a further cascade of counterregulations (here compactly termed Type-II counterregulations of cell dyssymbiosis).
• The Type-II counterregulation that is modulated beforehand via steroid hormones, insulin hormone, thyroid hormone and other hormones, restricts the OXPHOS activities, increases the membrane potential and diminishes the mitochondrial membrane’s permeability as well as weakening the sensitivity of immune and non-immune cells to external stress stimuli. This redox-dependent switch to Type-II status is among other things determined by the strength, duration and type of external and internal stress stimulation, as well as by the cell type, the previous damage to cell symbiosis and the depletion of the antioxidative thiol pool and other enzymatic and non-enzymatic antioxidants.
• Phases of excessive nitrosative stress as a consequence of the bonding of NO and its derivatives to non-protein thiols (nitrosation of glutathione (GHS) to GSNO, cysteine to SNO-Cys etc.) lead to the formation of nitrosothiols. After depletion of the thiol pool, NO and its derivatives bond on thiol-containing proteins (nitrosylation of R-SH to RSNO). As a result, the function-regulating characteristics of the cellular control of membrane receptor proteins and ion channels, signal-carrying protein substances, transcription proteins, and enzyme proteins are altered (overview Stamler 1995).

Considering the well-founded conclusion that there are varying thresholds of sensitivity in the archaeal and proteobacterial genome elements against states of nitrosative stress, a dissociation of the interplay between the differently structured genome elements is to be expected. On the one hand under these conditions a massive Type-II counterregulation is triggered by archaeal gene activities to minimize nitrosative stress. On the other hand the proteobacterial gene activities continue synthesizing transcripts for the biosynthesis of the protein complex of the respiratory chain and the OXPHOS system. Because of the continuing blockade of the mitochondrial membrane channels to proteins and ions (especially calcium ions) as a result of the increased membrane potential (Golshani-Hebroni 1997), the proteins for the complexes of the respiratory chain and the OXPHOS system can no longer be optimally supplied.

This networked function model explains the apparent paradox of the provision of transcripts for mitochondrial proteins without a sufficient conversion to protein synthesis, as well as the dwindling number and activities of mitochondria in the transitional activity phases of cell division (fetal cells, late phase of physiological cell division, early wound healing phase) and the permanent cell division phases of tumor cells.

Regarding the tumor cells, they are prevented from executing programmed cell death (apoptosis) or sudden cell death (necrosis) as they require a lowering of the mitochondrial membrane potential and the opening of the mitochondrial channels. Instead of this there is a forced aerobic glycolysis for enzymatic ATP production in the cytoplasm. The driving element is hydrogen diffused from the mitochondria. The glucose degradation products of glycolysis are invested in nucleic acid and DNA syntheses for cell division via the pentose phosphate metabolic path. An increased number of phosphorus metabolites from the pentose phosphate metabolic path keep mitosis running. The glycolytic cells transform to tumor cells and remain trapped in the cell division cycle.

So the tumor cell is a permanent regression of oxidative cellular symbiosis to the early evolutionary stage of cell symbiosis between archaea and proteobacteria, the phase of the first eukaryotes that are termed protista (Kremer 1997 b, 1998 d, 1999). In this symbiotic stage (proto-cell symbiosis of the protista) the eukaryotes profited from the hydrogen diffusion of the proteobacteria (overview Gray 1999). Only the later development of a respiratory chain, as electron transport pathway for the electromotive powering of the hydrogen ion compression pumps, enabled the reversion of the hydrogen driving of hydrogenosomes for the oxidative phosphor coupling (OXPHOS) to increase ATP synthesis in mitochondria drastically.

Under pathophysiological conditions the “hybrid impulse” of cell symbiosis can be overdriven or underdriven: on the one hand, under the influence of versatile acute stressors the production of oxidative/nitrogen oxides, superoxides and peroxides can be too strongly increased and lead to a breakdown in the counterregulation of the thiol pool and other antioxidative systems. The consequence is a too high fluidity and “acute infection” by the cell symbionts. The membrane potential of the mitochondria sinks below a critical threshold, the permeability of the lock-gates of the mitochondrial membrane, the permeabiity transition (PT), increases leading to too many Ca²⁺ ions and induced proteins being released from the cell symbionts, the cell nuclear DNA and other cell structures are degraded by a cascade of protein-splitting enzymes. Programmed cell death or necrosis occurs dependent on the speed of the decline of oxidative ATP production (overview Richter 1996, Kroemer 1997, Zamzami 1997). The mitochondrially triggered apoptosis and necrosis are the expression of a decompensated dysregulation of cell symbiosis that is dependent on a dominance of the type 1 cytokine profile. That is why this form of reaction of cell symbiosis will be termed here as a Type-I overregulation of cell dyssymbiosis (Type-I AEDS). Clinical manifestations are acute infections, inflammatory processes and, after necrotic cell death, autoimmune reactions and autoimmune illnesses (overview Mosmann 1996, Abbas 1996, Lucey 1996).

On the other hand, under the influence of versatile chronic stressors a too-high nitrosation of non-protein thiols and secondary nitrosylation of thiol proteins can severely inhibit the production of nitrogen oxides, superoxides and peroxides. The consequence is too little fluidity and “chronic infection” by the cell symbionts: The PT channels are severely restricted, and the impaired Ca²⁺ cycling leads to inhibition of the biogenesis of the number and activities of the mitochondria. The bioenergetic “hybrid impulse” reverses, the supply of hydrogen ions by the glycerol 3-phosphate and malate aspartate shuttling from the cytoplasm to the mitochondria is disturbed, and the compression of hydrogen ions by electron transfer in the respiratory chain for the OXPHOS system of the mitochondria is impeded.

The cell symbionts produce smaller amounts of ATP for their own needs. Surplus hydrogen ions diffuse into the cytoplasm and increase the “antioxidative stress” of transforming cells resulting from the critical shifting of the phase of the negative redox potential. The consequence is the continued genetic expression of the fetal isoform of the glycolytic enzyme hexokinase II, which switches on the metabolic chain for a predominant ATP production through aerobic glycolysis.

The degradation products of sugar metabolism are invested in forced cell division via the pentose phosphate metabolic pathway. The cells are re-fetalized, the alternate switch of the previously intact cell symbiosis no longer functions, and the transformed cells remain trapped in the division cycle (overview Cuezva 1997, Capuano 1997, Brand 1997 b). Without the compensation of the thiol pools and the phase reversal to an adequate negative redox potential aerobic glycolysis can no longer be switched off. The primary preventative and therapeutic consequence can only be the biological compensation therapy of the thiol pool.

According to this model of an overdriven Type-II cell dyssymbiosis (identical to the archaic cell symbiosis of the hydrogen-donating proto-mitochondria) it is to be expected that highly glycolytic tumor cells are most strongly counterregulated and feature only minor NO synthesis. For this reason NO-insensitive daughter cells of highly glycolytic tumor cells should have the best chances of survival on their metastatic wanderings as, due to their high lactate production, they secrete increased proteolytic (protein-splitting) enzymes, metalloproteinases and other proteinases which pave the way through the extracellular matrix, and they gain access to the capillary blood vessels. On the other hand chemotherapeutics, which activate the synthesis of cytotoxic NO gas, for instance cisplatin (Kröncke 1995, Son 1995) or taxol (Jun 1995), increase the risk of selectively further increasing a Type-II counterregulation and favoring the formation of resistant metastases.

From the very beginning a constant fine tuning is required via the thiol pool and other enzymatic and non-enzymatic antioxidants, in order to be sure of the best gas mixture from NO, ROS, and peroxinitrite for the micro-Gaian milieu of an intact cell symbiosis. Under these conditions peroxinitrite subsequently oxidizes neighboring sulfhydryl groups (SH groups) in proteins in the inner mitochondrial membrane and short-circuits the SH groups. In this way the opening of the mitochondrial membrane is facilitated without loss of the membrane potential. Analogously peroxinitrite oxidizes SH groups from mitochondrial proteins and enables the enzymatic division of oxidized NAD⁺ by hydrolysis. The split product of NAD⁺, ADP ribose, activates the specific release of Ca²⁺ from the mitochondria into the cytoplasm. The enzyme Cyclophilin (peptidyl-prolyl cis/trans isomerase) participates in the hydrolysis of NAD⁺ (in ADP ribose and nicotine acid amid) that also opens the PT channels for the Ca²⁺ metabolic pathway (Richter 1996, Zamzami 1997, Kroemer 1997).

The blockade of Cyclophilin enzymes through long-term medication with Cyclosporine A is an illuminating model for the onset of cancer resulting from the reversal of the bioenergetic and metabolic differentiation and maturation of the cell symbionts and the related re-fetalization of tumor cells (Type-II counterregulation of cell dyssymbiosis). This substance isolated from fungi (an undecapeptide) has been used since 1983 on organ transplant patients to inhibit rejection reactions, but is also employed on patients with autoimmune illnesses. This drug has induced the development of lymphomas (cancer of the B-cells) and other lymphoproliferative disorders, as well as carcinomas and opportunistic infections in a not inconsiderable proportion of transplant patients (Penn 1991). This clinical manifestation equates in a fatal way to the appearance of Kaposi’s sarcomas, lymphomas, carcinomas and opportunistic infections since the 1960s in organ transplant patients (Krikorian 1978, Penn 1979, 1981).

Cyclosporin A forms a complex with Cyclophilin that is termed immunophilin in immune cells. This complex bonds to calcineurin (serine-threonine phosphatase) and inhibits its activities. Calcineurin is activated in type 1 T-helper cells when they react with their receptors to the signal of a suitable antigen MHC complex of antigen-presenting cells. In this case the calcium level in the Th1 immune cells is raised and calcineurin splits a phosphoric ester off a particular transcription factor in the cytoplasm. This then moves into the nucleus and triggers the transcription for the biosynthesis of type 1 cytokines, interleukin-2 (IL-2). IL-2 induces the synthesis of interferon-γ, which in turn triggers the synthesis of cytotoxic NO gas as antigen defense.

The bonding of CSA Cyclophilin complexes to calcineurin does not make the latter active and the synthesis of IL-2 does not take place (Clipstone 1992, Schreiber 1992, Bierer 1993). The deficient production of cytotoxic NO in organ transplant patients treated with CSA, provoked by IL-2 inhibition, explains the acquired immune deficiency (i.e. transplantation AIDS) of these patients against intracellular opportunistic agents (fungi, parasites, and mycobacteria).

The operating mechanism of CSA attacks on two different levels:

• The first CSA effect is the inhibited synthesis of type 1 cytokine profiles that favor a Th1-Th2 switch. Subsequently CSA promotes the counterregulation of Type-II cell dyssymbiosis. Increased numbers of type 2 cytokines become effective when the mutual balance between type 1 and type 2 cytokines is disrupted (overview Del Prete 1998, London 1998, D’Elios 1998, O’Gara 1998, Murphy 1998, Carter 1998, Morel 1998, Muraille 1998, Viola 1999, Coffman 1999). Type 2 cytokine stimulates the formation of prostaglandin (PGE 2) that in turn inhibits NO synthesis and causes the peroxinitrite level to sink (overview Lincoln 1997). The peroxinitrite function for the opening of the PT channels is impeded. The result is a limitation of the central function of the mitochondria as balancing pool for the modulation and maintenance of cellular Ca²⁺ homeostasis (overview Richter 1996). The surplus calcium ions are bonded to membranes of cell structures by the over-expression of proteins from the Bcl-2 family. This takes place on the outermost membrane of the mitochondria, the effect being an increased impermeability of the mitochondrial membrane. Bcl-2 acts in this way to impede apoptosis/necrosis in the presence of too large amounts of oxides. The over-expression of Bcl-2 proteins has also been demonstrated in many tumor cells (Mazurek 1997). The expression of the Bcl-2 genes as oncogenes has been traced back to a mutation effect but their biological function can only be grasped once the evolutionary history of cell symbiosis has been sufficiently understood. The increased formation of TGF and PGE triggers simultaneously the production of polyamines that are present in tumor cells in increasing numbers. Polyamines force cell division processes and repair mechanisms of DNA (overview Lincoln 1997).
• The second CSA effect takes place within the mitochondria and combines with the first CSA effect. Cyclophilin D is found in the mitochondrial matrix. It activates a protein complex in the inner mitochondrial membrane (adenosine nucleotide translocator, = ANT) that facilitates the opening of the PT channels. If CSA bonds with Cyclophilin D, ANT is not activated. At the same time CSA blocks the hydrolysis of oxidized NAD⁺ so that the specific Ca²⁺ cycling between the mitochondria and the cytoplasm is disrupted. In combination with the depleted peroxinitrite level resulting from the CSA effect in the cytoplasm the CSA effect in the mitochondria builds up. The PT channels of the mitochondria open inadequately or not at all. As the energy potential of the mitochondria can be maintained or even increased programmed cell death or necrosis can no longer be triggered (overview Richter 1996, Kroemer 1997, Zamzami 1997). (See table XII: Model of the mitochondrial channels—open with Cyclophilin and peroxinitrite—close with CSA and peroxinitrite deficiency and Table XIII: The channel rhythm in mitochondrion).

The CSA effects are in no way only selectively operative in T-helper immune cells but also in other immune cells and non-immune cells. Besides the toxic damage to the kidneys and other organs, the appearance of tumors in CSA-treated transplant patients could also be explained by the provocation of a Type-II cell dyssymbiosis (proto-cell symbiosis).

The fact is that there are striking similarities in the immune cells and tumor cells of organ transplant patients (Kaposi’s sarcoma, lymphoma, carcinoma) and AIDS patients (Kaposi’s sarcoma, lymphoma):

• Type 1 to type 2 cytokine switch
• Inhibition of cytotoxic and calcium-dependent NO synthesis as well as the formation of peroxinitrite by the type 2 cytokine profile
• Closing of the PT pores of the mitochondria due to the absence of oxidation by peroxinitrite of the sulfhydryl groups of the ANT protein complexes (or other protein complexes) in the inner membrane of the mitochondria
• Deficient NAD⁺ hydrolysis in the mitochondria because of too little peroxinitrite formation, resulting in no release of Ca²⁺ with maintenance of the energy potential of the mitochondrial membrane
• Inadequate permeability of the mitochondrial membrane for calcium ions and for the proteins coded in the nuclear DNA for the complexes of the respiratory chain and the OXPHOS complexes
• Increased readiness of the RNA transcripts for the biosynthesis of proteins of respiratory chain complexes and the OXPHOS complexes (inhibition of the conversion of fetal cells up until the first breath and in tumor cells a permanent inhibition)
• Missing balancing pool of the mitochondria for the calcium ions of the cytoplasm due to increased impermeability of the mitochondrial pores
• Inhibition of apoptosis/necrosis in the mitochondria normally triggered by increased amounts of NO⁰, ROS, and peroxinitrites, simultaneous maintenance or increase in the energy potential of the mitochondrial membrane
• Inhibition of the biogenesis of mitochondria, strong reduction in numbers and activities, loss of differentiation and maturation of cell symbionts
• Hydrogen ion diffusion from the mitochondria into the cytoplasm
• Forced aerobic glycolysis for enzymatic ATP production, stimulated by the expression of the fetal isoenzyme, hexokinase II, located on the outermost mitochondrial membrane, in tumor cells always the expression of hexokinase II, irrespective of the hexokinase type of the differentiated original cells (hexokinase type I to IV)
• Enzymatic ATP synthesis mainly by aerobic glycolysis and investment of the glucose metabolic products, via the pentose phosphate metabolic pathway, in an increased rate of division
• Production of higher amounts of lactate and higher amounts of fetal metalloproteinases and other proteinases

Cuezva and his colleagues have demonstrated the processes of re-fetalization of tumor cells at the transcription level (transcription of the DNA sequences in the nucleus and in the mitochondrial genome resulting from the signals by transcription factors into messenger RNA) and at the translation level (the translation of messenger RNA in protein synthesis for the biogenesis of mitochondria). As a consequence of the striking similarities between the genetic processes in the fetal cells shortly before birth and in tumor cells they conclude: “The million dollar question here is who orchestrates this cellular response?”

And after debating the role of genetic factors for the expression of tumor cells they summarize: “We are still far from reaching the expected answer that could explain the altered energetic metabolism of tumor cells, a challenge of the scientific community set out more than 60 years ago” (Cuezva 1997).

In the article by Cuezva and his co-workers there is no mention of the studies of NO research. The question about the orchestrator of the transformation processes of tumor genesis, on a genetic or non-genetic level, was wrongly posed. The answer is:

There are no orchestrators. The popular dogma that genes have stored and can retrieve the program of life is a biological myth. The network of energy flows is the program and it is self-organizing. The information pattern of living cells and cell systems is modulated and dependent on fluidity and “quantum dynamic depths.” The macromolecular components (genes, proteins, transcription factors, enzyme proteins and many others) perform a “semiconductor” function for the upping and downing of regulations of the complex supragenetic network of cellular symbiosis. Physically the electron flows do not alter in proportion to the voltage as with metals but in “tailback stages.” The electrons have to physically overcome the energy gaps in order to be able to move from the valance band to the conduction band in which they can move freely. Biophysically the macromolecules feature a relatively large energy gap of several millivolts that enable a corresponding modulation range.

The macromolecular protein complex of the PT lock-gates of the mitochondrial pores is one such “tailback stage.” There are variable physiological and pathophysiological states of the opening and closing of the PT lock-gates. These determine the fate of cell symbiosis and are governed by the proportions of fluid NO and superoxide anions (O₂^-), respectively, and the diffusion product of both oxides—fluid peroxinitrite (micro-Gaian milieu). Extreme, intolerable amounts of the components of the oxide mixture (overoxidation) lead to programmed or unprogrammed cell death (apoptosis/necrosis) (Richter 1996) via an energy loss of the membrane potential of the cell symbionts. The result is an uncontrollable opening of the PT lock-gates and an outflux and influx (Ca²⁺ cycling) of large amounts of calcium ions inducing a cascade of energetic and metabolic chain reactions ending in cell death. Too small amounts of the diffusion product peroxinitrite can trigger a transformation to tumor cells (permanent regression to the state of proto-cell symbiosis before the development of the respiratory chain in mitochondria) in cells that are actively dividing. Analogous degradation states are provoked in cells that are no longer actively dividing (mature nerve and muscle cells and the retina). The synthesis and regulatory tasks of the fluid oxides are interlaced in a highly complex manner with all energetic, metabolic and informational procedures of the complete cell and the organism as a whole.

In cellular terms it is more important that Cyclophilins are isomerases. They are enzymes that catalyze the isomery (from the Greek: isos = same + meron = part) of the molecules. Isomery is the phenomenon that molecular substances with the same configurations with diverse atoms (sum formula) can assume a different structural composition of the atoms. For instance, lactic acid has the same sum formula as glycerine aldehyde and dihydroxy acetone but a different structural formula. In addition the spacial composition of the same molecules with the same sum and structural formula can be different. The biochemical and biophysical characteristics, including the semiconductor functions of the macromolecule, can considerably change through isomery. Isomerase enzymes such as Cyclophilin can influence the energy flows and informational patterns dramatically by activating or inhibiting. The evident interaction of Cyclophilin isomerases with calcium cycling, NO synthesis, oxide synthesis, peroxinitrite formation as well as NAD⁺ hydrolysis for the regulation of intact cell symbiosis and the pathologic inhibition of these regulating processes by CSA manipulation of Cyclophilin isomerases demonstrate the basic model of tumor genesis.

The explanation of Brand’s research group of the archaic regression of energetic and metabolic processes during fetal development, the late phase of the cell division cycle and the early wound healing phase and the necessity of protection from oxidative stress at the expense of energy exploitation is not alone convincing as the mitochondrial genes have, as a general rule, survived without defects for around 2 billion years in an oxidative milieu without the presence of protective proteins. In contrast, during fetal development and also in tumor cells they are particularly inactive despite having their own energy supplies through glutaminolysis and oxidative remnant ATP production. It is more likely that during the increasing cell division phases the cooperation of the archaeal and proteobacterial genome elements in the nucleus is altered and the symbiotic competition-free cooperation with the proteobacterial genes in the mitochondria in this phase is not assured. In these cell division phases, a regulated function of the archaeal genomes is only possible on low fluid levels with a simultaneous choking of the synthesis of nitrogen and oxidative oxides at the expense of mitochondrial activity.

This assumption is also supported by the fact that the cell division apparatus had to have functioned after symbiotic fusion, before the OXPHOS system was installed in mitochondria, and later could not be accommodated to the OXPHOS system. Instead of this the toggle switch between aerobic glycolysis in the late division phase and the OXPHOS system in the active operational phase was the successful solution. This splitting of responsibility has, after all, been able to function for about 2 billion years.

In the case of the transplantation of a foreign organ the massive provocation by alloantigens is answered by excessive nitrosative and oxidative stress. This is suppressed medicamentally by the complex formation of Cyclosporin A with Cyclophilin isomerase. The effect is the inhibition of the synthesis of type 1 cytokines and the compensatory increase in type 2 cytokine profiles. These trigger a cascade of Type-II counterregulations. The result is a choking of NO synthesis, the synthesis of ROS as well as the formation of peroxinitrite, the inhibition of calcium cycling, a strong reduction of mitochondrial activity and the closing of the mitochondrial membrane with a maintained or increased energy potential. Dependent on dosage and duration of the medication and the disposition of the patient, the redox milieu concerning particularly sensitive cells is manipulated according to the physiologically based functional phases of the increased cell division cycle. In the end the same bioenergetic state is signalled in the supragenetic network that also precedes the active cell division cycle. The state corresponds to a pseudohypoxia (an apparent oxygen deficiency from failure to exploit oxygen) and can be termed as such because the OXPHOS machinery of the mitochondria merely performs as if it were dormant (Brand 1997 b) despite sufficient quantities of oxygen being available—almost as if the cell symbionts were suffering from a real oxygen shortage.

If it is assumed from the well-founded supposition that the original archaea were facultative anaerobes with a capacity for non-oxidative energy extraction and that the respiratory chain with oxidative phosphorus bonding for ATP production was composed at a later stage, after the act of symbiosis (Gray 1999), then it is to be expected that in a state of pseudohypoxia the evolutionary-biologically conserved programs for survival could be reactivated without oxygen.

Pedersen’s research group was able to demonstrate that the promoter for hexokinase II genes in tumor cells is regulated by various signal transmission pathways including, among others, glucose, insulin and glucagon. Although insulin and glucagon are hormones that have opposite actions, surprisingly they stimulate the same genes. The response element of the promoters for the hexokinase II gene in tumor cells overlaps the element that corresponds to hypoxia. Pseudohypoxia in diabetes with a simultaneous NO inhibition (overview Lincoln 1997) can be associated with a higher incidence of cancer in those suffering from diabetes (overview Bannasch 1997). The hexokinase II enzyme, located on the outer mitochondrial membrane, catalyzes glucose degradation to the first phosphorus metabolic product and in fast growing tumor cells there is a 5-fold amplification compared to normal differentiated cells. Furthermore genetic studies showed that the promoter for the hexokinase II gene in tumor cells resembles the promoter of hexokinase II genes in normal differentiated cells by up to 99%. From this and other findings the researchers concluded that the hexokinase gene normally remains mute and is not activated by mutation but by the type of combination of transcription factors on a different level: “Therefore, altered DNA sequences within respective promoters cannot be involved in the changes observed during reporter gene expression studies” (Mathupala 1997).

This statement fundamentally opposes the prevailing theories of carcinogenesis by random mutation. The findings support the concept stated here that cancer originated from a primary comprehensive switch in the micro-Gaian milieu to a level of early proto-cell symbiosis (Type-II cell dyssymbiosis) and followed by the activation of evolution-biologically conserved gene programs. Pedersen and his colleagues confirm indirectly this pathogenesis model of tumors by finally stating about the genetic findings:

“The studies indicate a strategy used by highly malignant tumors to survive as well as thrive within a host using a remarkable set of coordinated molecular mechanisms. These mechanisms, which are very similar to those utilized by some highly successful parasites, indicate a “sophisticated strategy devised by tumors to survive even the most inhospitable microenvironments within the host” (Mathupala 1997).

In other words: “Highly successful parasites” (protozoa and fungal microbes) are those which under permanent conditions of hypoxia/pseudohypoxia, analogous to re-fetalized cancer cells, can switch to a Type-II counterregulation of cell dyssymbiosis (regression to the early protista stage, Kremer 1999). That is how they can survive the body’s own immune defense (inhibition of cytotoxic NO gas synthesis in the neighboring immune and non-immune cells by type 2 cytokine associated cancer cells similar to parasitic cells) in “the most inhospitable microenvironments within the host” almost as if they were counterregulated cancer parasites with an increased proliferation rate and even survive targeted chemotherapeutic attacks as “resistant agents” (similar to fungal and parasitic microbes in full-blown AIDS).

The term strategy is misleading, as all eukaryotic cells have the evolutionary-biological capacity to switch back to archaic proto-cell symbiosis as the physiological reproduction phases demonstrate. The micro-Gaian milieu conditions both within cells and, in multicellular organisms, between the cells—with respect to the organism as a whole and its environment—which promote or inhibit assimilations in the self-organized network, are highly complex. We should rather speak of an evolutionary-biological option as the bioenergetic processes are nonlinear and can only be realized with a high degree of selection. This does not mean that every individual parasite or cancer cell can choose arbitrarily a “sophisticated strategy” to “survive even the most inhospitable microenvironments within the host” (Mathupala 1997). From colonized daughter cells of a primary tumor, for instance, roughly one in 10,000 survive in the bloodstream with the potential to colonize another organ (metastatic cells, from the Greek: meta = other + histanai = place). As most cancer patients do not die from their primary tumor, but of cachexy and metastatic formation, this fact is of great importance. However, cancer cells do not survive or die by accident. Metastatic cells are clone cells, meaning that they originate from a single cancer cell that has formed a tumor cell cluster. These contain heterogenic subpopulations of cells. In order to discover where the difference lies between metastatic and non-metastatic daughter cells, the capacity for stimulation of the enzymes for the synthesis of cytotoxic NO (iNOS) was studied in these cancer cells (Xie 1996).

Metastatic melanoma cancer cells from mice that had lung metastases were treated with different type 1 cytokines and bacterial lipopolysaccharides (LPS) for the stimulation of iNOS. There were no signs of iNOS activity and no cytotoxic NO production. The same procedure with non-metastatic cells from the same tumor, however, activated a high iNOS level and high amounts of cytotoxic NO. In the cell culture it was shown that after stimulation, cytotoxic NO-producing cancer cells died by apoptosis.

This experiment demonstrates that cancer cells differ energetically and metabolically from normal differentiated cells by a limited production of NO and O₂^-, or rather the product of both—peroxinitrite. This deficiency led to the closing of the PT pores of the mitochondria and impeded the normal toggle switch between aerobic glycolysis and OXPHOS, thereby blocking programmed cell death. In contrast stimulation of the non-metastatic cancer cells with type 1 cytokines, or as the case may be, LPS, stimulated iNOS synthesis and O₂- synthesis and in doing this also peroxinitrite formation. The sudden opening of the PT channels starts Ca²⁺ cycling and triggers apoptosis. In order to discover why the metastatic cancer cells did not react to the stimulation with iNOS, the same research group manipulated metastatic melanomas by genetic transfection in three ways:

The first cell group was equipped with functioning iNOS genes, the second with non-functioning iNOS genes, the third with neomycin resistance genes. A fourth non-manipulated metastatic cell group served as control.

All cell groups remained highly metastatic, except the first group with the functioning iNOS genes. After implanting the four cell groups in nude mice, which are especially sensitive to tumor cells, the first cell group developed slow growing tumors under the skin and the metastatic cell groups fast growing tumors.

In a further experiment the researchers demonstrated with sarcoma cancer cells in the lungs of other strains of mice that after a repeated injection of synthetic lipopeptides (similar to stimulation with bacterial lipopolysaccharides) the genetic expression of the enzyme proteins of iNOS was switched on in the metastatic cells and cytotoxic NO was produced. The metastases completely regressed. The scientists concluded: “These data demonstrate that the expression of iNOS in tumor cells is associated with apoptosis, suppression of tumorigenicity, abrogation of metastasis, and regression of established metastases” (Xie 1996).

(See illustration: Programmed cell death in metastatic cancer cells after transfer of a functioning iNOS gene (see table XIV) and after repeated injection of synthetic lipopeptides (see table XV))

The fact that initially metastatic cells on repeated and strong stimulation display iNOS activities and die off, indicates that in metastatic cells the sensitivity of the transcription barrier of the expression of the iNOS genes is altered. Such changes in the behavior of transcription of the iNOS genes in tumor cells can appear selectively because of the nonlinearity (Waliszewski 1998) of the highly complex Type-II counterregulations. They can also be selectively triggered by chemotherapy and are then termed as “resistance” of tumor cells. Of the counterregulations the increased expression of type 2 cytokine transforming growth factor (TFG-β) for the control of NO production in tumor cells (Vodovotz 1997) as well as for the spreading of metastatic cancer cells via proteinases (Zvibel 1993) seems to have gained a special importance. The role of NO gases in tumor cells in relation to the inhibition of the tumor’s growth and the new formation of capillaries through the deployment of NO-donating and NO-inhibiting substances has been examined in many experimental and clinical studies. The results are contradictory. The findings showed that tumor cells require a low calcium-dependent NO synthesis for the sprouting of new capillaries and a higher NO synthesis that inhibits tumor growth (Chinje 1997). In the systemic treatment of cancer patients with interleukin-2, leaks in the capillary vessels occurred that were traced back to an increased cytotoxic NO stimulation and that could be retarded by the simultaneous dosage of NO inhibitors. On the other hand, NO-blocking substances alone could reduce tumor growth and metastatic formation so that it can be assumed that cancer cells require a fine balance of low calcium-dependent NO levels (Orucevic 1998) that are no longer sufficient to maintain an intact cell symbiosis. Then again this assumption corresponds to the very low lipid peroxidation in cancer cells (Horrobin 1990).

The explanation of the old clinical observation that fungal and parasitic infections often precede a cancer disease can be found in the fact that chronic infections lead to an increase in cytotoxic production, which in turn leads to the inhibition of the type 1 cytokine profile, while the type 2 cytokine profile is more vigorously synthesized. The cross-regulation between type 1 cytokines and cytotoxic NO evidently impedes overreactions of Th1 immune cells and inflammatory processes (overview Lincoln 1997). On the other hand chronic overproduction of NO after the exhaustion of the thiol pool and S-nitrosylation (NO formation on sulfhydryl groups in function proteins and enzyme proteins (overview Stamler 1995) leads to considerable counterregulations (Type II cell dyssymbiosis).

Chronic parasite infections (and probably fungal infections) can trigger secretion of substances on the part of the agents (e.g. glyco-inositol phospholipids), which can inhibit NO synthesis (Liew 1994). This effect is comparable to the effect of the fungal extract Cyclosporin A on the Cyclophilin isomerases and the thereby triggered inhibition of interleukin-2 resulting in inhibition of cytotoxic NO synthesis as well as the blockade of NAD⁺ hydrolysis and the closing of the mitochondrial lock-gates.

The causal link between chronic infections and chronic inflammatory processes has been proven in many studies and been associated with the nitrosamine formation from endogenous NO (overview Tannenbaum 1994, Oshima 1994, Kerwin 1995). Nitrosamine research, furthermore, has shown with absolute certainty, in wide-ranging experimental and clinical analyses, an immense number of exogenous sources, e.g. in nutrition, in drinking water, in tobacco, at industrial places of work, but also through antibiotics, chemotherapeutics, analgesics, cosmetics etc. A large number of N-nitroso compounds as well as similarly operating alkyl hydrazine, alkyl azoxy, alkyl triazine, compounds have been demonstrated as being highly carcinogenic substances in a large variety of animals including apes. Carcinogenic nitroso compounds are formed by N-nitrosation reactions between different secondary and tertiary amines and nitrites and other substances capable of nitrosation. These reactions can take place in the environment and within an organism (overview Lijinsky 1992, Loeppky 1994 a).

The “fingerprints” of these chemicals in DNA are discussed as evidence of the carcinogenic effect of nitrosamines and related substances in humans. It concerns changes in the bases, the building blocks of DNA, which have been established in the DNA in the formation of tumors by UV light on the skin and by the fungal toxin, aflatoxin in liver and other tumors. They are changes to the tumor suppressor gene p53, that expresses a protein that promotes programmed cell death and is considered to be the opposite number of oncogene Bcl-2, whose protein product bonds Ca²⁺ ion to membranes forcing the closure of the PT lock-gates of mitochondria (Vogelstein 1992, Oshima 1994). The American pharmacologist Magee, a pioneer of nitrosamine research of the Thomas Jefferson University Cancer Research Institute in Philadelphia, after 40 years of research into the links between nitrosamines and cancer observed:

“N-nitroso compounds (NNOC) are toxic in human beings, causing acute and subacute pathological changes that are closely similar to those found in experimental animals. There is convincing epidemiological evidence that the cancer chemotherapeutic drug semustine, an N-nitrosourea derivative, is a human carcinogen. On the plausible assumption that all the NNOCs, including N-nitrosamines, act as carcinogens through the formation of the same active intermediates, probably alkyldiazionum ions, it seems reasonable to conclude that all the carcinogenic nitroso compounds are human carcinogens. Whether the compounds play any significant part in the causation of human cancers remains problematical. The proposal is attractive because of their ubiquitous occurrence in the environment, albeit in very small amounts, and the potential for their formation within the body from amine precursors and nitrite or other nitrosating agents. Definitive evidence might be obtained by the demonstration of mutations in oncogens specific for nitroso carcinogens, as has been shown with aflatoxins and UV light. So far this has not been achieved and further research in this area could be rewarding. Even though conclusive proof has not been obtained that the NNOCs are important causes of human cancer, it is clearly desirable that their occurrence in the environment and their formation in the body are reduced to the lowest practicable levels” (Magee 1996).

The ambivalence conveyed by these words after 40 years of nitrosamine research underlines the bewilderment of a whole generation of cancer researchers, who in countless experiments with more than 300 nitrosamine links in a wide range of animals and in all kinds of human cell cultures time and again observed the transformation to tumor cells. The researchers, consistent with the prevailing school of thought in cancer research as a whole, had manifestly sought the primary cause of cancer in the wrong place. The fixation with gene mutations, based on the dogma that the nuclear genome was the command center of the living cell, had clouded their judgement that the bioenergetic network is a self-organizing (autopoietic) program. The cancer researchers could not have realized without the fundamental knowledge from NO research, cytokine research and cell symbiosis research the possibility that cancer cells could represent a permanent regression to an archaic status of protosymbiosis, as executed for a limited time span in fetal cells and in certain cell division phases.

     Now these findings have been available for over 10 years and the observations of respected nitrosamine researchers even for 30 years are again highly topical. Gene mutations are neither sufficient nor necessary to trigger transformation of cancer cells as cancer also develops without traceable gene changes (Lijinsky 1973, 1992). Mitochondria researchers, too, for a long time have confirmed that cancer, if anything, is more likely to develop with intact mitochondrial DNA than after gene toxic mutations (overview Mazurek 1997).

The assumed “fingerprint” of the nitrosamine effect, the altered p53 gene in tumor cells (Vogelstein 1992), on the basis of the concept of Type-II dyssymbiosis—a long-term or overly strong activation of NO and its derivatives that force a continual counterregulation to evolutionary-biologically programmed protosymbiosis (state of pseudohypoxia = seemingly deficient oxygen state)—can be explained in another way, without “altered DNA sequences within the respective promoters” (Mathupala 1997) having to be involved:

“Recent studies have shown another interesting observation for the Type II hexokinase promoter within tumor cells, where functional p53 elements were identified within the same promoter region that harbors the glucose and hypoxia responsive elements. This correlated with the presence of a p53 protein with an enhanced half-life expressed in the same tumor. Co-expression of this protein with the Type II hexokinase promoter during reporter gene analysis resulted in enhanced transcription. The proximity of the p53 elements to the hypoxia and glucose response elements, as well as the recent observation that tumors within hypoxic regions promote p53 mutations at a high rate, implicate an important relationship between hexokinase expression, the expression of mutated p53, hypoxia, enhanced glucose catabolism, and cell-cycle progression or proliferative capacity of highly glycolytic, rapidly growing tumors” (Mathupala 1997).

In other words the altered gene expressions are not the cause but the response to the loss of fluidity and the “quantum dynamic depths” resulting from the forced choking of the synthesis of nitric and oxygenic oxides (NO, O₂^-, peroxinitrite) and the closing of the PT lock-gates of the mitochondria.

The Bcl-2 gene, the p53 gene and their protein products are components of an ever increasing ensemble of genes and proteins that are involved in the opening and closing of the PT lock-gates of the mitochondria (Richter 1996, Zamzami 1997). Protein patterns are synthesized dependent on the sensitivity of the expression of genes that inversely either force the opening or the closing of the PT lock-gates. The kind and variability of the gene expression and the following synthesis of the protein pattern is dependent on the fluidity of the redox milieu. In this way the semiconductor characteristics of the macromolecular DNA, namely the thresholds of the electron flows which define the transcription profile, can be variably modulated. Redox-dependent modulation of the genes thus govern whether and which RNA messages for the biosynthesis of function, structural, signal and enzyme proteins are mediated. So the genes do not have to be altered by mutations in the sense of a biochemical structural defect.

The “Warburg Phenomenon” of aerobic glycolysis, not understood for more than 80 years, is switched on as a strategy for survival in states of pseudohypoxia based on the scenario of archaic protosymbiosis. The pseudohypoxia is based on a secondary NO/peroxinitrite deficiency that leads to a Type-II cell dyssymbiosis.

“These mechanisms, which are very similar to those utilized by some highly successful parasites” (Mathupala 1997) are not only very similar, but the tumor cells are actually trapped in the division cycle by facultative anaerobic parasites (protista) and after every cell division cycle try in vain to offer their atrophying cell symbionts (mitochondria) the transcripts for proteins for the respiratory chain and the OXPHOS system (Cuezva 1997) in order to re-animate mitochondrial respiration.

As the unaltered p53 protein is involved in the opening of the mitochondrial lock-gates, the altered p53 gene through co-expression in the hypoxic region, which can be assigned to the archaeal genome part, is jointly responsible for the blockade of the switch back to the OXPHOS system. On the other hand, the transcripts for the synthesis of proteins for the respiratory chain and the OXPHOS complex could be coded on the proteobacterial portion of the nuclear genome. This assumption would explain the paradox that these transcripts continue to be supplied. In contrast the behavior of the transcripts makes sense in fetal cells because immediately after the first breath the necessary proteins for the respiratory chain and OXPHOS system can be implemented. The variable for this evolutionary-biologically programmed switch of the bioenergetic and metabolic network is the thiol pool (glutathione, cysteine etc.) and the nitrosylation of vital enzymes and signal proteins (overview Stamler 1995).

This causal link explains the fact of tumorigenesis through nitrosamines and other nitroso compound considerably more plausibly than any mutation theories and fictitious retrovirus theories. But it also explains the relative lack of success in the elimination of tumor cells by operations, radiation and chemotherapy. Without a balance to the excessive nitrosation and nitrosylation, enforced Type-II dyssymbiosis counterregulations will intensify, in the long run in even more cell systems, and as a result of the increased nitrosative and oxidative stress, selective subpopulations of metastatic tumor cells will proliferate. The epidemiological result is that the life expectancy of conventionally treated cancer patients is considerably shorter than that of untreated patients (Abel 1990), which reflects the short-sightedness in prevailing tumor research and cancer treatment.

Certainly the excessive stress of nitrogen compounds only demonstrates one section of the wide-ranging causal spectrum of cancer origins as, theoretically, longer-term disruptions can occur at every junction in the self-organizing bioenergetic network in the grey areas between solid and fluid phase. In general, however, the response to extreme stress will follow the same archaic evolutionary-biological rules. In this respect, the development of Kaposi’s sarcoma as Type-II dyssymbiosis (regression to protosymbiosis) resulting from a primary NO overload and secondary NO^-/O₂^-/peroxinitrite choking, is a plausible model for understanding tumorigenesis.

During the long process of evolution the human organism was primarily confronted with biological sources to stress with nitrogen oxides. The main factor probably was endogenous NO stimulation by microbial toxins and antigens (acute and chronic infectious and inflammatory processes). Additionally, nitrite-bonding bacteria in contaminated drinking water and nitrite-contaminated foodstuffs (in later cultural history through preserved meat and sausage products) could play a role. The increased bonding of sulfur-containing thiols and thiol proteins through the formation of nitrosothiols could, however, be dramatically intensified by famine and malnutrition. These involve an accelerated utilization of the thiol pool and antioxidative capacities through a depletion of thiol-containing amino acids (cysteine, methionine), folic acid deficiency, deficits in antioxidative vitamins, essential fatty acids, polyphenols, polyanions, minerals and trace elements.

In industrialized countries acute and chronic infectious and inflammatory processes were continuously minimized as causes of disease and death from the middle of the 19th to the middle of the 20th Century by improved nutrition, hygiene, living conditions, drinking water purification, sewage, pest management, education as well as progress in modern medicine and the natural sciences (Sagan 1987, 1992). This drastic decline in the rates of infection and mortality was reached before the introduction of vaccines, chemotherapeutics and antibiotics (see illustration: Examples of the continuous decline of disease and mortality rates by infectious illnesses from the mid 19th Century to the mid 20th Century (see table XVI)).

In the poorer countries malnutrition and deficient nutrition, in combination with higher exposure to microbes, favored by contaminated drinking water, hygiene problems, unfavorable living conditions, marginal education, lack of medical infrastructure etc., continue to be the dominating factors for the origins of acute and chronic infectious and inflammatory processes including opportunistic diseases (nutritional AIDS, Beisel 1992, 1996). In the industrial countries, however, completely new load profiles of insidious chronic nitrosative and oxidative states of stress are developing as a result of the products of civilization. This chronic nitrosative and oxidative load, unique in this combination in the history of evolution, can be answered by the archaic cellular symbiosis no differently than by using the same counterregulations used for chronic nitrosative and oxidative stimulation from parasites and worms. The result is a type 2 dominance and under the described conditions a fixed switching to Type-II dyssymbiosis. This evolutionary, biologically programmed, unchangeable option to the disruption of the micro-Gaian milieu as a result of chronic nitrosation, which in extreme cases can only be answered by the choking of the cells’ own synthesis of nitrogen and oxygen oxides, is the cause of the reversion of ratios of acute to chronic diseases in the last fifty years, manifested by degenerative and cancer illnesses as the major cause of deaths. This view is supported by the evidence of many research groups, which shows that malign tumors are associated with type 2 cytokine dominance (Clerici 1998).

Unique in history of mankind, however, is the sum-total prooxidative burden of a minority of promiscuous homosexual men, engaging in unprotected anally-receptive intercourse, combined with long-term sex doping through inhalation of nitrite gases (“poppers”); excessive abuse of nitrosative antibiotics, antiparasitics, antimycotics, virustatics, numerous “recreational drugs,” etc.; chronic multiinfections; and massive exposure to oxidative/nitrosative alloantigens via intake of foreign semen (overview Root-Bernstein 1993).

In 1985, animal experiments demonstrated that the simultaneous administration of nitrites and antibiotics provoked the formation of tumors (Brambilla 1985). The American pharmacologist Ignarro, who at the same time as his American research colleague Furchgott first proved the existence of gaseous NO molecules and their physiological functions in human cell systems, had demonstrated that NO is formed from nitrite in the endothelial cells of blood vessel walls. NO gas molecules that do not directly bond to iron in the enzyme guanylate cyclase for regulating blood pressure are stored as nitrosothiols via nitrosation from molecules from the thiol pool, and via nitrosylation as nitrosoproteins in special cell organelles—the lysosomes (Ignarro 1992).

     If the thiol pool is exhausted by exogenous nitrite supply, the same regulations will be triggered by the thiol sensor as those by sustained and strong NO synthesis by stimulation through microbial toxins, microbial antigen loads or non-microbial alloantigen loads. The thiol pool becomes even more quickly depleted when NO from exogenous nitrite and other NO syntheses (through microbial stimulation, alloantigen load and the degradation of nitrosative drugs) have to be metabolized synchronously. Under such conditions, the cells’ own NO^-/O₂^-/peroxinitrite production is choked, the altered redox milieu effects a switch from a type 1 to type 2 cytokine profile, and the OXPHOS system of the cell symbionts switches off in favor of aerobic glycolysis. The sensitivity of the signal-transferring proteins, transcription factors, and transcription genes become altered. If the bioenergetic and metabolic network remains decompensated and cannot regain an equilibrium on a non-genetic and genetic level, then the endothelial cells transform into Kaposi’s sarcoma (Type-II counterregulation of cell dyssymbiosis).

Numerous studies have confirmed that “HIV positive” patients in the earliest stage of seroconversion display a drastic depletion of the thiol pool. Both the cysteine and glutathione levels are severely diminished in the blood plasma and within the cells (overview Herzenberg 1997, Dröge 1997 a).

Also clearly demonstrated in many studies is the switch of the intracellular cytokine pattern from a type 1 to a type 2 profile in the earliest stage of seroconversion in “HIV positive” patients as well as an immune status identical to worm infections, chronic parasitic and fungal infections and chronic mycobacterial and spirochete infections (overview Lucey 1996).

In Western countries, the appearance of Kaposi’s sarcoma is clinically diagnosed almost exclusively in anal receptive homosexuals with a history of nitrite inhalation. Since the decline in nitrite consumption among homosexuals, a decline in the incidence of Kaposi’s sarcoma has also been observed, in contrast to the increased incidence predicted by the HIV/AIDS theory (overview Levine 1982, Marmor 1982, Lauritsen 1986, Haverkos 1988, 1990, Papadopulos-Eleopulos 1992 b, Duesberg 1996, Kremer 1998 a, 1998 c).

     Clinical HIV/AIDS research also published disparate cases of Kaposi’s sarcoma: patients were diagnosed as KS cases who did not register “HIV positive” and whose immune status was not characteristically altered. This observation corresponds to the fact that endothelial cells, in isolated cases, can transform after counterregulation against nitrite abuse without the frequently synchronous Th1-to-Th2 switch. As a result of this and other clinical and laboratory data, orthodox HIV/AIDS researchers have come to the conclusion that HIV is not the cause of Kaposi’s sarcoma and that KS cannot be the result of a sexually transmitted retroviral infection (Beral 1990).

On the whole, the clinical, anamnestic, epidemiological and laboratory data confirm, after 20 years of KS research, the bioenergetic, metabolic and genetic concept of tumorigenesis as a result of the decompensated regression of cell symbiosis to the archaic stage of proto-cell symbiosis due to excessive nitrosation and exhaustion of the thiol pool.

The prediction made at the historic conference of retrovirus researchers in March 1983—that by researching the “intriguing puzzle” (Friedman-Kein 1984 a) of Kaposi’s sarcoma, useful information could be gained for the study of cancer in general (Thomas 1984)—has proven to be correct. However, the concepts of retrovirus-AIDS and retrovirus-cancer research have led to a dead end, even though the dogma of the disease theory “HIV causes AIDS” is stoutly defended with all available means, and kept alive by massive research grants and the ubiquitous media dictatorship. The crucial knowledge, which nobody had during the propagation of the HIV/AIDS theory in 1983/84, was gathered from outside of retrovirus-AIDS and—cancer research by, most notably, bioenergetic cell symbiosis research.

The evolutionary-medical concept of the Type-II cell dyssymbiosis of tumorigenesis based on bioenergetic investigation of the micro-Gaian milieu can integrate, without any contradiction, all pivotal research data gained since the quiet revolution in fundamental medical research in the 1980s.

Two statements from two of the most prominent, internationally acclaimed retrovirus cancer researchers promptly throws the spotlight on how they evaluate their theory—that retroviruses are the cause of cancer—as a contribution for the solution of the cancer puzzle.

Baltimore, who together with Temin in 1970 discovered the reverse transcription of RNA in DNA, a discovery which gave the crucial impulse for the retrovirus/cancer research within the framework of President Nixon’s 1971 “War on Cancer,” and who was awarded the Nobel Prize in 1975 for retrovirus/cancer research, stated in 1988 as president of the Rockefeller University in New York:

“I have no idea when we’ll know enough to develop anything [for oncology] that’s clinically applicable, and I don’t know who’s going to do it … It’s not a high priority in my thinking” (Angier 1988).

Varmus, 1989 Nobel prize winner for retrovirus/cancer research, and director of the National Institutes of Health in the USA, the most prestigious research authority for all the US health authorities, including the National Cancer Research Institute stated, in 1988: “You can’t do experiments to see what causes cancer. It’s not the sort of thing scientists can afford to do” (Angier 1988).

In actual fact the retrovirus/cancer researchers, mutating to retrovirus/AIDS researchers at the historic conference in March 1983 in New York, had suggested just such experiments on AIDS patients with immune weaknesses, some of whom had developed Kaposi’s sarcoma. The ensuing million-fold treatments on AIDS patients stigmatized as “HIV positive” with immunotoxic and cytotoxic antibiotics and chemotherapeutics could not finally solve the “cancer puzzle.” However, the clarification of fatal mistakes and deceitful practices have contributed to a profound change in opinion about the nature of cancer cells and accordingly the effective therapy and prevention.

Warburg was basically right: The unplanned and planned pharmatoxic experiments on humans had proven that cancer is caused by a primary functional and secondary structural inactivation of mitochondrial symbionts. The functional blockade of cell respiration activates, in the case of prevented cell death, the evolutionary-biologically programmed survival competition of the archaeal genome and inactivates the cooperation with the proteobacterial genome elements inside the nucleus and in mitochondria. The result is a permanent Type-II counterregulation of cell dyssymbiosis.

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The products of laboratory research initiated more than 50 years ago whose target was to plant analog transformed bases in the biosynthesis of the building blocks of nucleic acid of the DNA—the purine bases, adenine and guanosine as well as the pyrimidine bases thymine and cytosine—were supposed to inhibit the biosynthesis in microbe, immune and cancer cells. Hitchings’ laboratory team from Burroughs Wellcome synthesized three substance groups, which in their molecular composition contain nitro structure groups as a common characteristic. These substances produce both antimicrobial effects in microbe cells and immune suppressive and carcinogenic effects in immune and non-immune human cells on top of degenerative DNA damage.

• The first substance was Azathioprine, adopted as an immune suppressive drug for organ transplant patients since the 1960s (Chen 1987). Azathioprine triggered clinically opportunistic infections, Kaposi’s sarcoma and lymphomas (transplantation AIDS) (overview Penn 1979, 1981).
• The second substance was Azidothymidine (AZT), from 1986 until today the most frequently prescribed drug for the prophylaxis of AIDS. AZT is supposed to inhibit the proliferation of the hypothetical “HIV retrovirus” in “HIV positive” and AIDS patients. AZT is highly toxic has antimicrobial, immune suppressive and carcinogenic effects and causes degenerative DNA damage in numerous human cell systems (overview Duesberg 1996, Giraldo 1999, Brink 2000).
• The third substance was Trimethoprim (TMP). TMP as a combination preparation with sulfamethoxazole, a sulfonamide derivative, was authorized as co-trimoxazole in 1969 in the USA and Europe as an antimicrobial drug (DTB 1969). Trimethoprim as sole medication or in combination with sulfamethoxazole (co-trimoxazole) produced in addition to its antimicrobial mechanisms, immunosuppressive and carcinogenic effects and degenerative DNA damage in numerous human cell systems.

All three substances, Azathioprine, Azidothymidine (AZT) and Trimethoprim respectively co-trimoxazole (T+S) possess the chemical attributes to realize the clinical research program postulated by the retrovirus cancer researchers at the historic conference in New York in March 1983 in “a series of human experiments, planned and executed in order to answer the sort of question which automatically raises itself: what would happen if you were to remove the putative defense mechanism of cellular immunity in human beings? Would this affect either the incidence or clinical course of cancer?” (Thomas 1984).

The assumption that T-helper immune cells are destroyed by a hypothetical retrovirus was extremely helpful in leading to proof of whether the loss of the function of T-helper immune cells could cause the development of tumor cells. This hypothesis allowed for the deployment of a substance group that was known to have immunosuppressive effects and to cause the formation of tumor cells. Using the excuse of retrovirus inhibition in order allegedly to prolong the life of, according to medical opinion, the inevitably moribund AIDS patients it was possible to prescribe such experimental substances without ethical scruples to willing patients.

There was one such substance. It was first isolated in 1961 from herring sperm cells and in 1964 was synthesized as 3'-azido-3'-deoxythymidine by Horwitz from the Michigan Cancer Foundation (Horwitz 1964). Animal experiment trials in mice and rats with leukaemia showed the development of lymphomas (Yarchoan 1987, Adams 1989). As a result of its tumor-causing effects and the lack of inhibition of leukaemia cells this substance was not authorized for clinical human trials (Duesberg 1996). In 1985, shortly after the worldwide introduction on the market of the “anti HIV antibody tests,” developed according to the patented production procedures of Gallo at the National Cancer Institute in the USA, publications appeared from the same institute in which it was reported that Azidothymidine (AZT), a chemotherapeutic from nucleoside analog substances, inhibited the proliferation of “retrovirus HIV” in cell cultures (Mitsuya 1985).

Since 1984 it had been acknowledged that nucleoside analog substances not only cause lymphomas but also exercise massive immunosuppressive effects on the T-helper immune cells and provoke opportunistic infections.

“Each of the nucleoside analogs is associated with a profound lymphocytopenia [loss of T-helper immune cells], with a reversal of the CD4/CD8 [the ratio of T-helper immune cells to T8 lymph cells] and opportunistic infections” (Cheson 1997).

So nucleoside analog substances cause AIDS and cancer. AZT is consequently the suitable propagated substance for the “removal of cellular immunity” (Thomas 1984) and tumorigenesis.

After only a 17-week trial in a multi-center study in a number of US clinics in 1986/87 AZT was authorized in record time as a medication for AIDS patients. Clinical trials of a new medicament in the USA usually take on average 8 to 10 years. Burroughs Wellcome, the same US pharmaceutical firm that produced Azathioprine, undertook the marketing of AZT. The global British/American pharmaceutical giant Burroughs Wellcome, which in the 1990s merged to become the largest pharmaceutical company in the world—Glaxo Wellcome (now GlaxoSmithKline)—had an unusual historical company policy: a large portion of the profits were directed to research foundations and donated to biochemical research institutes and clinical studies. As a result of this financial flow a close financial dependency developed between the researchers in laboratories and university clinics and the national health authorities and pharmaceutical companies. Burroughs Wellcome financed many experimental and clinical studies on chemotherapeutic treatment. The head of research there, Barry, had previously worked as a virologist for the American authority responsible for the admission and surveillance of food and drugs—the FDA. He was, conveniently, the right man at the right place at the right time to organize the mass human experiments of the cancer therapeutic, AZT on AIDS patients, and to use the right channels of cooperation for the very rapid approval of AZT by the FDA. The National Cancer Institute had transferred the data and technology for the synthesis of AZT to Burroughs Wellcome. In July 1985 Burroughs Wellcome was accorded “orphan drug status” for AZT by the FDA, even before the first scientific publications from researchers of the National Cancer Institutes on the “anti HIV effect” of AZT in October 1985.

     “Orphan drugs” are medications that are required by fewer than 200,000 patients annually in the USA, so production by pharmaceutical companies is not financially lucrative. The respective US law provides for seven years of exclusive marketing rights and tax relief for the production of such “orphan drugs.” In the case of AZT, which is extremely expensive, the FDA did not assign a price limit for Burroughs Wellcome. In February 1986 Burroughs Wellcome transformed from a non-commercial organization into a corporation. In November 1986 Barry, together with his colleagues from the National Cancer Institute, published research data on “anti HIV inhibition” in T-helper immune cells of AIDS patients after AZT treatment. This caused a furor. Burroughs Wellcome stock almost quadrupled within a year (Adams 1989). The “invisible hand of the market” had ensured, as in the case of the patenting of Gallo’s “anti-HIV test” before the first publication of data that could be analyzed, that strategic decisions for the global marketing of “planned human experiments” for the “removal of cellular immunity” by medication with immunosuppressive and carcinogenic chemotherapeutic AZT had already taken place before the research data of the first experimental study (October 1985) as well as the second experimental and first clinical study (November 1986) were published.

     At the time of publication of the latter, clinical tests were already under way in a multi-center study in the USA. AZT was authorized by the FDA and was already being deployed for all AIDS patients in the early summer of 1987. Barry’s co-workers were the then leader of the research and development department and later director of the National Cancer Institute (1989-95), Broder, and the clinical retrovirologist Bolognesi from Duke University in North Carolina (Duesberg 1996). As authors they were responsible for the key publication in the proceedings of the National Academy of Science in 1986, in which it was claimed that AZT was 100 times more effective at inhibiting DNA synthesis in “HIV infected” cells than in “non-HIV infected” cells in cell cultures. The same non-specific “molecular markers” were cited as proof of the presence of the “retrovirus HIV” that Gallo and Montagnier had deliberately misinterpreted as “evidence of the isolation and continuous production of cytopathic retroviruses” by virus-like particles (Popovic 1984). At the same time the allied experimental scientists from the pharmaceutical company Burroughs Wellcome, The National Cancer Institute and Duke University, claimed after intake of AZT in the first clinical studies on AIDS patients that the substance was 2,000 to 20,000 times more effective at inhibiting the replication of “HIV DNA” (measured by means of unspecific markers) than the nuclear DNA of “HIV infected” T-helper immune cells (Furman 1986).

     These claims have since been refuted in numerous experiments of orthodox HIV/AIDS researchers who had followed the same assumptions about the existence of “retrovirus HIV” on the basis of molecular markers and the workings of AZT (overview Chui 1995). The supposition of a higher affinity for the integration of AZT in “retroviral DNA” in comparison to nuclear DNA of human cells has to this day not been corrected by the researchers of the producers, Burroughs Wellcome (now GlaxoSmithKline), the National Cancer Institute or Duke University. On the basis of this false assumption and these false claims countless doctors all over the world have prescribed AZT to AIDS patients since 1987. They have also prescribed the proven dangerous drug to healthy, asymptomatic “HIV positive” patients since 1990 (Volberding 1990).

Before the global marketing of AZT for “life-prolonging treatment of AIDS patients through inhibition of retroviral replication” in 1987 and the “preventative inhibition of HIV replication in T-helper immune cells of asymptomatic HIV patients” neither the researchers from the company producing AZT, nor the researchers from the NCI or any other researchers had tested the actual functioning mechanisms of AZT. Without exception all researchers and prescribing physicians, independent of the respective assumptions about the affinity of AZT to “retroviral DNA” or to nuclear DNA, took for granted, without checking, that AZT as a transformed molecular building block is integrated into the DNA chain in place of the natural building block, thymidine, either by the “HIV enzyme RT” or by the natural nuclear enzymes of the DNA polymerases.

In the long drawn-out chain of about 25,000 human genes, spread out on 23 paired chromosomes, several billion building blocks are strung together. These nucleotides (from the Greek: nucleos = core) are molecular, composed from a sugar, a base and three phosphate group atoms. Nucleotides contain one of four bases (adenosine, cytosine, guanosine or thymidine). These bases have an OH molecule group to which the respective proximate nucleotide is attached. The sequence of the bases in each case with three bonded sets of paired nucleotides form the coding pattern for the building instructions for the synthesis of proteins from amino acids in the cytoplasm. This DNA coding profile is transcribed, after redox-dependent stimulation by transcription factors, to a messenger RNA and translated into the biosynthesis of proteins. This process is called expression and one talks of genes being expressed.

According to the dogmatic doctrine of HIV/AIDS medicine it is this process that the transformed building block AZT affects. In the thymidine base of this molecule the OH group is replaced by an azido group. Should the false building block AZT be integrated into a DNA copy of the “HIV RNA” via the RT enzyme of the supposed “retrovirus HIV,” then on this location of the short DNA string of “HIV” (termed provirus) no further nucleotides could align as the integrated AZT has the wrong pairing. The provirus genome of “HIV” would remain incomplete and could no longer be reproduced, with the aid of the cell division apparatus of the host cell, as new infectious “retrovirus HIV.”

That is the theory anyway by which the “invisible hand of the market”-manipulated HIV/AIDS doctors suggest, to this day, to their asymptomatic “HIV-positive” patients and AIDS patients, that the intake of AZT for life, alone or in combination with other substances, will prolong their lives through the inhibition of the sooner or later “deadly retrovirus infection with HIV.” This doctrine is spread by an immense propaganda input throughout all countries in the world. Unfortunately it has nothing to do with the biological realities and those responsible know this full well.

AZT is a synthetic nucleotide, the precursor of a nucleoside triphophate that merely docks one phosphate atom. In order to be integrated into DNA, regardless of whether it is “HIV provirus DNA” or nuclear DNA, the nucleoside monophosphate AZT in the nucleus must have three phosphate atoms and could only then be incorporated at the growing end of the DNA as a nucleotide by an “HIV RT” or the nuclear enzyme DNA polymerase. In this case the synthetic nucleoside monophosphate AZT would become the DNA nucleotide Azidothymidine triphosphate (AZT TP) that is capable of integration. Countless studies over the last decade, however, have clearly shown that only about 1% of AZT is transformed to AZT TP—thus, at prescribed AZT doses of between 500 and 1,500 mg per day, much too little to be able to cause any kind of inhibition of “HIV provirus DNA” or nuclear DNA as a “DNA terminator” as the claimed effects of AZT state (overview Papadopulos-Eleopulos 1999).

When in 1961 Azidothymidine was isolated from the sperm cells of herrings and subsequently synthetically produced in 1964 (Adams 1989) the obvious question that nobody asked should have been: What was the natural function of Azidothymidine in the sperm cells of vertebrates? Two reasons are conceivable: the fertilization of the ova and the development of the embryo. Firstly, all eukaryotic organisms that propagate sexually, inherit their mitochondria only through the maternal hereditary line (Wallace 1999). The mitochondria of the sperm cells thus have to be somehow inactivated before penetration of the egg cell, yet nobody has subsequently studied how this happens. Secondly, the sperm cells must not introduce intracellular agents to the egg cells as the embryonal cells, as a result of their type 2 cytokine dominance, are not able to adequately eliminate intracellular agents (Coffman 1986, Mosmann 1996). Azidothymidine, as a nitrosative substance, serves both purposes. The azido groups of Azidothymidine inhibit the mitochondrial enzyme cytochrome oxidase (Tyler 1992). The biological logic is that the inhibition of cytochrome oxidase in sperm cells takes place shortly before they penetrate the egg cell, and the sperm cell mitochondria are inactivated by azidothymidine. Azidothymidine is thought to have the same effect on cytochrome oxidase in microbes.

After the worldwide licensing of AZT as an AIDS drug for the supposed blockade of the “retrovirus HIV,” a number of research groups reported that the administration of AZT caused damage to DNA and mitochondria (overview Lewis 1995). These findings did not concur with the claims of the HIV/AIDS researchers that AZT is exclusively incorporated into “HIV proviral DNA,” as a selective DNA chain terminator.

     In order to test the causes of AZT damage to mitochondria and to study whether the observed DNA damage was responsible for the subsequent growth inhibition of the cells after AZT treatment, researchers from the State University in New York carried out experiments of the effect of AZT on mitochondria. They allowed mitochondria to grow in a medium for five days with a pharmacotherapeutic AZT dose (5 micromoles for five days). As soon as three hours after the addition of AZT, the mitochondria showed signs of characteristic changes: reduced number of mitochondria, a reduction in the intake of oxygen, reduced ATP synthesis and an increased lactate synthesis. As the new formation of DNA takes considerably longer than three hours, the change in mitochondrial quantity and energy production, and the glycolytic formation of lactates, could not be based primarily on the inhibition of mitochondrial DNA (Hobbs 1995).

Research teams from a number of French research institutes studied the effects of AZT and two other AIDS drugs (the nucleoside analogs ddI and ddC) in human muscle cells. All three substances cause a dose-dependent reduction in the proliferation and differentiation of cells, a reduction in enzyme activity in the mitochondrial respiratory chain (cytochrome c-oxidase in complex IV and succinate dehydrogenase in complex II of mitochondria as well as an increase in glycolytic lactate synthesis). The researchers concluded that AZT, ddI and ddC exercise a cytotoxic effect on human muscle cells and cause functional changes through the blockade of mitochondrial respiratory enzymes.

A number of fundamental consequences arose from the research findings that were not explicitly discussed by researchers:

Warburg discovered the “Atmungsferment” cytochrome in the 1920s. This molecule transports electrons in the respiratory chain from complex III to complex IV, where the electrons are transferred to molecular oxygen O₂ by the enzyme cytochrome c oxidase. Through the reaction O₂ is reduced to water. 90% of oxygen used worldwide, in algae, plants, fungi, parasites, animals and humans is converted by this reaction. The transferred electron energy in the mitochondrial respiratory chain compresses the hydrogen ions in the mitochondria, the hydrogen generator activates the synthesis of the energy-carrying molecule ATP, and the whole cell is then provided with energy for biosyntheses. Azidothymidine inhibits the enzyme cytochrome c oxidase and thus interrupts the ATP synthesis. This effect is easy to follow: The azido group of azidothymidine is made up of N₃. This triple nitrogen atom configuration is just as reactive as nitrosative molecules, such as NO and its derivatives. The azido group analogous to NO and its derivatives, can oxidize metal ions such as those found in cytochrome oxidase; and likewise oxidizes sulfhydryl groups in thiols (glutathione, cysteine) and thiol proteins (R-SH).

In fact, this characteristic of azide (N₃) has long been used by mitochondria researchers to inhibit the electron transfer from complex IV to molecular O₂ in the respiratory chain of the mitochondria (overview Tyler 1992).

This is why it is incomprehensible why the HIV/AIDS researchers did not want to know about this function of azidothymidine, and instead claim to this day that AZT is incorporated in “HIV provirus DNA” as a selective DNA chain terminator, although AZT is only marginally transformed into AZT triphosphate.

The blockade of cell respiration in mitochondria can be short and it can be reversible. Depending on the dosage AZT can cause, however, with a sudden reduction of ATP through the blockade of cytochrome c oxidase, programmed cell death due to the loss of tension of the electric mitochondrial membrane potential and massive Ca²⁺ cycling. Adenosine triphosphate (ATP) is formed in mitochondria from adenosine diphosphate (ADP) and inorganic phosphate (P_i). If the ratio of ADP to ATP sinks below the critical level of 0.2, necrosis begins (Richter 1996).

However, a multitude of Type-II counterregulations can be triggered by longer-term exposure to AZT. These are dependent on the depletion of the thiol pool through nitrosative stress. The type 1-type 2 balance shifts to a type 2 cytokine dominance (overview Lucey 1996). The type 2 cytokine profile effects an increased expression of the cyclooxygenase-2 enzyme (COX 2) and transforming growth factor (TGF-β). COX 2 controls the increased formation of prostaglandine E2 (PEG2) from arachidon acid, which is formed from essential fatty acids (overview Minghetti 1998). TGF-β and PEG2 suppress the inducible enzyme of cytotoxic NO synthesis and activate the enzyme arginase, which transforms arginine to ornithine. The diminished concentration of arginine in the cytoplasm leads to a diminished production of NO and peroxinitrite, that contributes to a closing of the mitochondrial membrane. The resulting Type-II cell dyssymbiosis (proto symbiosis) triggers an increased expression of heat shock proteins, Bcl-2 proteins (calcium bonding on membranes) and transformed p53 proteins, ferritin protein (bonding on free irons) and the enzyme protein hemoxygenase (overview Lincoln 1997).

The latter leads to the excessive formation of carbon monoxide (CO), which as well as NO regulates many processes (Suematsu 1996, Rivier 1998). CO can likewise block the enzyme cytochrome c oxidase of the mitochondrial respiratory chain. Under the influence of CO increased polyamines are formed from ornithine via the decarboxylase reaction. Polyamines activate repair processes and increase the cell division cycles (McCann 1987, Bachrach 1989, Lincoln 1997). The ornithine decarboxylase reaction induces simultaneously via the putrescine product, enzymes for ATP synthesis via aerobic glycolysis (Brand 1997 b). So the result is the “Warburg Phenomenon”, a puzzle for more than seventy years, as a consequence of a nitrosative and/or oxidative provoked pseudohypoxia (an apparent oxygen deficiency). The genetic and non-genetic programmes in response to pseudohypoxia are evolutionary biologically conserved and are regulated by the autopoietic micro-Gaian milieu.

So the effects of azidothymidine inactivate mitochondria by blocking the enzyme cytochrome oxidase, which contains iron and copper ions, inhibit ATP synthesis and depending on the dosage and the duration of administration, together with the disposition of the antioxidative capacity of the cells, trigger a Type-I cell dyssymbiosis (apoptosis /necrosis) or a Type-II cell dyssymbiosis (immune deficiency, degradation or the formation of tumors). Clinically all forms of compensated and decompensated cell dyssymbiosis have been more than abundantly documented (overview Giraldo 1999, Brink 2000).

The observed changes of mitochondrial DNA by nitrosative or oxidative effects analogous to the DNA transformations by NO, peroxinitrite, nitrosamine and ROS are viewed as secondary effects (overview Lijinsky 1994, Loeppky 1994, Lincoln 1997, Wallace 1999).

By inactivating cell respiration enzymes, azidothymidine not only has immunosuppressive and carcinogenic effects, but also antimicrobial ones. The enzyme cytochrome c oxidase and other enzymes able to be oxidized by AZT, are also present in bacteria, fungi and protozoa. The clinically apparently beneficial effects of AZT, which for the stated reasons can by no means be traced back to the inhibition of any “HIV provirus DNA”, are based on a different absorption of the substance both in the body’s cells and in microbial cells. This effect of AZT can lessen microbial stress over a limited period of time if as a consequence of the type 2 cytokine dominance the T-helper immune cells of the patient no longer produce cytotoxic NO and can no longer eliminate intracellular microbes. At the same time, however, the cell dyssymbiosis of immune and non-immune cells of the patient deteriorate depending on the remaining thiol pool. As surviving microbes can also respond to nitrosative stress from AZT with a Type-II counterregulation, the question is who will win the competition for the best possible assimilation to the targeted attack by AZT and a whole battery of other cytotoxins, man or microbe. On the one hand counterregulated intracellular microbes find in counterregulated human cells a favorable environment as they can no longer be eliminated due to the lack of cytotoxic NO gas. On the other hand AZT can only inhibit fungi and parasites that have not been counterregulated.

When confronted with AZT drugs, microbes capable of survival switch to glycolysis and glutaminolysis and can profit even better in cell systems whose defense is weakened by the lack of cytotoxic NO gas as the formation of lactate enables the acidification of the neighboring tissue as well as the penetration of the blood vessels and the possibility of movement through cell areas with an undersupply of oxygen by means of the activation of proteinase enzymes like heparanase (Liew 1994, Brand 1997 b). The fact that highly malignant tumors behave in a very similar manner to some highly successful parasites (Mathupala 1997) proves that the cell types are conforming to the same archaic evolutionary-biological rules.

Whether azidothymidine or similar substances are formed in human sperm cells and other cells has not been studied, but there are indications that this could be the case. Human sperm cells, like highly malignant cancer cells or quickly proliferating microbes, contain high amounts of polyamines that are formed by the ornithine cycle. Lethal protozoa infections as well as the fungal agents of Pneumocystis carinii pneumonia (PCP), the most frequently diagnosed AIDS-indicating disease, can be effectively treated by ornithine decarboxylase inhibitors (alpha difluoromethylornithine) (Sjoerdsma 1984). This form of treatment for analog cancer cells has not been tested as apparently it was not taken into consideration that:

• The inactivation of the mitochondrial respiratory chain through nitrosative and/or oxidative nucleosides (for instance through the change in reaction of nucleosides in nitrosamines)
• The counteractivation of CO synthesis through hemoxygenase I

In 1991 a Japanese research team stated: “Oxidative damage of mtDNA can be accumulated during even short period of AZT administration … For AIDS patients, it is urgently necessary to develop a remedy substituting this toxic substance, AZT” (Hayakawa 1991).

This appeal did not particularly impress the retrovirus cancer hunters or their hunting companions on the HIV/AIDS front. AZT is still the most frequently prescribed AIDS drug (Papadopulos-Eleopulos 1999).

Before the approval of AZT by the FDA in spring 1987 their toxicologist had internally issued an urgent warning about AZT as a possible carcinogenic rat poison. The study of AZT using the toxicological standard method of “cell transformation assay” and other processes produced the following results:

“This behavior is characteristic of tumor cells and suggests that AZT may be a potential carcinogen. It appears to be at least as active as the positive control material, methylcholanthrene [an extremely potent carcinogen] … Dose-related chromosome damage was observed in an in vitro cytogenetic assay using human lymphocytes … Although the dose varied, anemia [maturation inhibition of red blood cells] was noted in all species (including man) in which the drug was tested” (Chernov 1986, overview Lauritsen 1987, 1988 a, 1988 b, 1990 b, Young 1988).

The FDA on the licensing of AZT ignored this unequivocal toxicological report by one of their own staff, violating their own guidelines. The producers Burroughs Wellcome (now GlaxoSmithKline) falsified toxicological findings with the directions on the information leaflet for AZT stating: “The significance of these in vitro results is not known.”

The FDA’s toxicologist criticized this claim and unmistakably stated:

“The sentence: ‘The significance of these in vitro results is not known.’ is not accurate. A test chemical which induces a positive response in the cell transformation assay is presumed to be a potential carcinogen” (Chernov 1986).

In the USA the therapeutic use of potential carcinogens on humans is forbidden by law (Nussbaum 1990). The FDA’s internal toxicological reports about the AIDS and cancer-causing effects of AZT first became public knowledge when the FDA was forced to release them under the US “Freedom of Information Act” (Lauritsen 1987, 1990 a). Nevertheless, the majority of doctors and media expressed no doubts about its use for symptom-free “HIV positive” and AIDS patients. The toxicological test results before the authorization of AZT were very quickly confirmed in the clinical use of AZT on AIDS patients both regarding its AIDS-causing and carcinogenic effects.

After a more or less short phase of prooxidative mobilization of the reserve capacities of the immune cells, depending on dosage, AIDS patients developed a massive inactivation of mitochondria and DNA effects, profound damage to the immune cell functions and the maturation of red blood cells as well as tumorigenesis, degeneration of nerve and muscle cells, liver failure and wasting syndrome and other toxic syndromes (Richman 1987, 1990, Pizzo 1988, Lauritsen 1988 a, 1989, 1990, 1990 b, 1990 c, Young 1988, Ostrom 1989, Bach 1989, Marx 1989, Cherfas 1989, Pluda 1990, Dalakas 1990).

In 1989, on the recommendation of the National Institute of Allergies and Infectious Diseases, under the directorship of the most senior assessor of research funding for HIV/AIDS medicine in the USA, Dr. Fauci, the FDA’s approval of azidothymidine (AZT—biochemically termed zidovudine, trade name Retrovir) for the unlimited treatment of symptom-free “HIV positives” was forced through under massive political pressure (Farber 1989, Larhoven 1990, Lauritsen 1989 a, 1989 b, 1990 a, 1990 b, 1990 c, 1990 d, 1993, Cotton 1990, Friedland 1990, Volberding 1990, Fischl 1990, Duesberg 1996, Lang 1998). From 1990, all the health authorities in Western countries, as already was the case in 1987 in accepting the FDA’s decision to approve AZT for the treatment of manifest AIDS patients, sanctioned AZT for unlimited treatment of symptom-free “HIV positives,” newly born babies, children, adolescents, pregnant and non-pregnant women, and men with and without recognizable risks.

As might have been expected with the chemical characteristics of such a substance, clinical studies in numerous human immune and non-immune cells revealed toxic damage through AZT medication that were not in accordance with the preservation of life. Not even the crushing abundance of scientific evidence published on the state-sanctioned poisoning excess through administration of AZT to pregnant women, newly born babies and children could end this medically irrational and therapeutically useless worldwide mass poisoning (Gill 1987, Richman 1987, Bessen 1988, Gorard 1988, Helbert 1988, Yarchoan 1989, 1991, Pluda 1990, Till 1990, Dalakas 1990, Smothers 1991, McLeod 1992, Bacellar 1994, Parker 1994, Kumar 1994, Rosenthal 1994, Chiu 1995, Zaretsky 1995, Moye 1996, Giraldo 1999 b, Brink 2000).

Even the manufacturers, the pharmaceutical company Glaxo Wellcome (now GlaxoSmithKline), who marketed AZT under the chemical name of Zidovudine and the trade name Retrovir, felt compelled to state, as a legal safeguard against the right of recourse: “Retrovir (Zidovudine [= AZT]) may be associated with severe hematologic toxicity including granulocytopenia and severe anemia particularly in patients with advanced HIV disease … Prolonged use of Retrovir has also been associated with symptomatic myopathy similar to that produced by human immunodeficiency virus” (Glaxo Wellcome 1998).

Nothing can more clearly demonstrate the callous loss of medical ethics than the admission of a global pharmaceutical concern, that a substance, which on the basis of numerous indubitable experimental findings cannot objectively accomplish its claimed effect, namely the integration of AZT allegedly selectively in the DNA chain of a “provirus DNA of retrovirus DNA,” but instead causes severe toxic damage to blood and muscle cells. This statement by the manufacturer justifies the criminal charge of grievous bodily harm with fatal consequences. Nobody had in actual fact isolated a “provirus DNA of retrovirus DNA” (Papadopulos-Eleopulos 1993 a, 1998 a) and nobody had been able to prove the pathogenetic mechanism of the “provirus DNA of retrovirus DNA,” despite the largest capital investment and the most intensive research efforts in medical history (Balter 1997).

     On the contrary, severe maturation disruptions of immune and non-immune cells were diagnosed with absolute regularity in the million-fold AZT prescriptions all over the world. The statement by Glaxo Wellcome that the associated severe cell damage in quick maturing white blood cells “particularly in patients with advanced HIV” appear after AZT medication means no more than AZT aggravates the shift to type 2 cytokine dominance, as shown in numerous studies of the earliest stages of “HIV positive” (overview Lucey 1996), resulting from the chemical characteristics of the substance. “Advanced HIV disease” means that the detoxication capacity of the immune and non-immune cells fails due to a permanent nitrosative and/or oxidative stress status. To administer a highly nitrosative and oxidative substance to a patient in this diagnostic situation, instead of improving the detoxicative performance of the cell systems, is in a legal sense wilful poisoning that sooner or later must result in death for already poisoned patients. The admission by Glaxo Wellcome that “symptomatic myopathy similar to that produced by human immunodeficiency virus” (Glaxo Wellcome 1998) proves that the symptoms of the “HIV disease” cannot be differentiated, diagnostically or pathologically, from a medicamentous intoxication by AZT. AZT causes an “HIV disease” in exactly the same way as an “AZT disease” is caused by excessive and permanent nitrosative and oxidative stress.

The fact that the “antiviral” AIDS drugs (nucleoside analog and non-nucleoside analog substances as well as protease inhibitors for the supposed inhibition of the replication of “HI viruses”) due to the given biochemical attributes could not inhibit the reproduction of “HI viruses,” whatever the immunotoxic, carcinogenic and degenerative effect they had on immune and non-immune cells, raises a further decisive question, and that is to what degree the antimicrobial substances that are deployed for the prophylaxis and therapy of opportunistic infections in “HIV positives,” AIDS patients and other groups of patients can also provoke immunotoxic, carcinogenic and degenerative effects.

The first AIDS patients were, from 1980, routinely treated with Trimethoprim/Sulfamethoxazole (co-trimoxazole, T+S, trade name Bactrim, Septra, Eusaprim, Cotrim Forte etc.) against the agent of Pneumocystis carinii pneumonia (PCP), which is still the most frequent AIDS-indicating disease in Western countries (CDC 1981 a, Gottlieb 1981, Masur 1981). When T+S failed the medication was changed to drugs with pentamidine, an antiparasitic substance in use since 1939, Pyrimethamine, Dapsone and others as well as combinations of these substances. The exact working mechanisms of most of these substances were not known but were employed on a trial-and-error basis both as long-term prophylaxis and in acute treatment as chemotherapeutic inhibitors of fungi and parasites.

Trimethoprim bonds to an enzyme whose function is indispensable in all cell systems from microbe to man. The enzyme converts essential folic acid to the biologically active form tetrahydrofolate (THF). The enzyme is named dihydrofolate reductase (DHFR). THF supplies, among other things, carbon building blocks for the construction of the purine bases, the building blocks for nucleic acid for the synthesis of DNA and the co-enzymes NAD(P)H, FAD, and FMN. THF also participates in the synthesis of the pyrimidine base thymine, which as the phosphate-coupled DNA molecule thymidine triphosphate (TTP) is supposedly suppressed by azidothymidine (AZT). The blockade of THF through inhibition of the enzyme DHFR leads to major disruptions to DNA synthesis, co-enzyme synthesis and the metabolism of certain amino acids. That is why the effects of this disruption affect a multitude of central biosyntheses. At the end of the 1940s, Methotrexate was developed as one of the substances acting as a DHFR inhibitor. This substance effectively bonds to the human DHFR enzyme and is deployed as a blocker of the biologically active forms of folic acid in leukaemia cells and carcinogenic cells. Methotrexate bonds relatively solidly to the DHFR enzyme in cancer cells and healthy cells; nevertheless folic acid turnover, dependent on cell type, is also inhibited in the latter. The results are the side effects of this chemotherapy, which dependent on cell type and the redox conditions proceed both as biochemical target effects and as the target effects against cancer cells.

Soon further DHFR blockers were developed and it was recognized that the DHFR enzymes in bacterial, parasitic, fungal and mammalian cells, including humans, feature minor structural differences. This fact was used to synthesize DHFR enzyme blockers that could selectively bond to the respective microbe enzymes more solidly than to the human DHFR enzymes. This expectation proved to be a dangerous illusion in clinical practice.

One of these substances is Trimethoprim (TMP) whose selective bonding to DHFR enzymes was recognized in 1965. Selective always means merely a relatively strong bond to the enzyme of microbe species as they are dependent on the presence of the co-enzyme NAD and a multitude of bioenergetic conditions. Depending on the preferred bonding to the DHFR enzyme it was possible for the DHFR inhibitors to inhibit folic acid metabolism in bacteria with Trimetoprim, in parasites like the malaria agent with Pyrimethamine, and in tumor cells with Methotrexate and other substances. Trials on Trimethoprim for the inhibition of bacterial growth gave the researchers the idea of combining TMP with other chemotherapeutics containing folic acid inhibiting sulfonamides introduced since 1935. The active principal of sulfonamides was based on the fact that most bacteria, many parasites but also fungi like Pneumocystis carinii (the PCP agent) cannot transport available folic acid through the cell membrane but must assemble it from three molecules within the cells. The middle molecule is para amino benzoic acid whose integration to folic acid is regulated by an enzyme that is inhibited by sulfonamide so that insufficient amounts of active folic acid can be synthesized.

Decisive was the consideration that bacterial inhibiting effects of the individual substances could strengthen TMP and sulfonamides in such a way that the combination of substances had a bacteria-killing effect. At the same time it was hoped that through this combination preparation the unpleasant “resistance capacity” of the microbes against the individual substances might be prevented (Bushby 1968). This double folic acid blocker, appearing on the market in the USA and Europe in 1969 (DTB 1969), was going to have an exemplary career as “one of the most successful agents ever developed” (Then 1993). In 1972 Trimethoprim was introduced as a single substance and since then TMP as a stand-alone preparation is annually prescribed to between four and five percent of the population (Steen 1985). The amounts of T+S prescribed in Western countries is considerably higher:

“Co-trimoxazole, Bactrim etc., the fixed combination of sulfamethoxazole and Trimethoprim, constituted until recently the best option for many mundane infections in outpatient practices” (Gysling 1995).

The introduction on the market of T+S as the then unique chemotherapeutic strategy of inhibiting the colonization of human organisms by bacteria, parasites and fungi through the simultaneous inhibition of two essential enzymes of folic acid metabolism in microbes, occurred at the same point in time as the beginning of the decade of sexual liberation for homosexuals. The minority of multi-infectious promiscuous homosexuals and the doctors in the cities specializing in this clientele had the illusory feeling that there was in Bactrim etc. a prophylactic and therapeutic safeguard from infection. The list of infections with agents from all kinds of species, above all in homosexuals with a preference for unprotected anal receptive intercourse, is long and without precedent (Jaffe 1983, Callen 1990, Root-Bernstein 1993).

“Gay men were aware of their disease susceptibility long before AIDS emerged as a problem … They made chronic use of antibiotics, some prophylactically and some to treat recurrent venereal and other infections. I have been told by a number of gay men that it was not uncommon to take a few antibiotics and sniff an ampule or two of amyl nitrite on the way to the baths or bars for a round of anonymous sex … Over 40% of the men surveyed responded that they ‘routinely’ treated themselves with prescription antibiotics. Chronic and high-dose antibiotic abuse can lead to significant immune suppression” (Pifer 1987, Root-Bernstein 1993).

One of the chemoantibiotics most frequently consumed by homosexuals in Western countries, whether prescribed or not, was T+S (co-trimoxazole). However, there was a lack of studies about long-term consumption of T+S both in AIDS risk groups and in the population as a whole. One of the few studies, which at least covered a time span of 45 days after the beginning of the administration, came from the General Practice Research Database. The data were gathered from 420 general practitioners in Great Britain after prescription of T+S and other chemoantibiotics between 1988 and 1993. A treatment time of 45 days is insufficient for an assessment of the long-term consequences as folic acid can be stored in human cell systems for roughly 45 days. Serious long-term damage through lack of folic acid became manifest after months-long T+S medication, for instance in urinary passage infections or in unlimited prophylaxis in “HIV positives” and AIDS patients usually up to six weeks after the beginning of treatment, and was not at that time associated with a folic acid deficiency. Unwanted acute effects were relatively unusual in the studies of the British general practitioners, but dependent on the disposition of the patients they could be serious. Already in 1985 cases of mortalities after T+S medication were published. After a series of deaths heavy restrictions on the indications for T+S were issued in Great Britain (Jick 1995, Committee on the Safety of Medicines 1985, 1995). Also in the USA indications for T+S were stringently revoked and a maximum medication time of no longer than one week recommended.

The remaining European countries have up until now drawn no consequences from the resulting data (overview Lacey 1985, DTB 1995). However, it is rationally incomprehensible that in the terms of the pseudo-logic of the state doctrine that “HIV causes AIDS” T+S medication for unlimited long-term prophylaxis of PCP in “HIV positives” was excluded from this restrictive administration as the only exception, even in Anglo-Saxon countries. The admission of the unlimited indication for T+S medication for immune cell-damaged HIV-stigmatized patients is a blatant contradiction as the restrictions were recommended principally because of serious damage to the blood formation systems resulting from T+S medication (overview Gysling 1995, DTB 1995). This recommendation to prescribe co-trimoxazole, above all in patients who had been diagnosed as being in danger of opportunistic infections as a result of a functional disruption of cells in the immune cell network, for an unlimited long-term prophylaxis, defies all medical logic. “They must have been out of their minds,” was the stunned diagnosis of one pharmaceutically independent therapist. However, there was method in the madness.

A crucial problem arose from these findings: A decade before the “sudden” appearance of opportunistic fungal infections as AIDS-indicating diseases in homosexual men, it was already recognized that long-term medication with folic acid inhibitors could provoke neutropenia and systemic fungal infections. At the same time it was known that long-term inhalation of nitrite gases had an intoxicating effect, which also favored fungal infections. It was known that homosexual men with opportunistic fungal infections (AIDS) were habitual T+S abusers and chronic nitrite gas consumers (CDC 1981 a, Gottlieb 1981, Masur 1981). What was the rationale that found the appearance of opportunistic fungal infections in homosexuals puzzling and declared that long-term prophylaxis with T+S was the chosen therapy method for these patients, if indeed they had survived acute treatment with T+S (Gottlieb 1981, Masur 1981)? How could the medical logic be rationally understood when it had been emphatically stated that in the same homosexual patients with fungal infections (AIDS) “Aggressive chemotherapy … contributes to the final degree of immunologic incompetence” (De Wys 1982)? Why instead did they seek recourse in the “new agent” (Haverkos 1982) which was eventually created as a fictitious “retrovirus HIV” in test tubes in the Pasteur Institute in Paris and in the National Cancer Institute in the USA?

There is only one rational explanation for the most calamitous failure of modern medicine: The collective repression of the fact that the would-be “miracle weapons” of the 1970s like co-trimoxazole (Bactrim, Septra, Eusaprim etc.) had led to a disaster. The admission of these facts, namely that microbial enemies and malign cancer cells had to be eliminated by aggressive chemotherapy, had so shaken the leading minds and business interests of modern medicine at such a time that the fundamental knowledge of the fluidity principle of the micro-Gaian milieu as archaic laws of the co-evolution of man and microbe had yet to be gained. As a result of this there was a collective stampede and much trumpeting on the virus hunt and new chemo-cocktails that were inevitably to make the disaster even worse. 20 years after the first diagnosis of opportunistic fungal infections in homosexual patients, the dreadful consequence of this obsession is to this day blindly being executed using all the instruments of power as the events before and during the World AIDS Congress in South Africa in July of 2000 demonstrated.

In 1970, shortly before the launch of Bactrim, Septra etc. a research team at St. Mary’s Medical School in London carried out a revealing study on animals. The clinical researchers were interested in whether the Trimethoprim analog to Azathioprine caused immunotoxic effects. The study was based on three facts:

• The substances Azathioprine and Trimethoprim have similar biochemical structural characteristics and attack the nucleic acid synthesis of DNA as well as the synthesis of nucleotides of the co-enzymes NAD⁺, FAD and FMN.
• Azathioprine had suppressed as an immunosuppressive substance the cellular immunity in organ transplant patients and other patients with systemic illnesses and caused opportunistic infections, Kaposi sarcomas, lymphomas and degenerative cell transformations.
• Azathioprine had, like Trimethoprim, inhibited the proliferation of microbial cells.

From these facts the researchers produced the hypothesis that the immunosuppressive substance Azathioprine (producer Burroughs Wellcome) via the same functional mechanism caused antimicrobial effects and vice versa the antimicrobial substance Trimethoprim (producer Burroughs Wellcome) via the same functional mechanism caused immunosuppressive effects.

The researchers transplanted from a strain of brown mice a same-sized piece of skin to four groups of white mice from the same strain. The first group were injected with Trimethoprim, the second group with Azathioprine, the third group with Trimethoprim + Tetrahydrofolate (THF). The fourth group, not injected, served as control.

During the experiment the concentration of hemoglobin, hematocrit, white blood cells and their differential number, the weight of the mice and other readings were measured. The dosage of the substances was so chosen as to be the equivalent of that used in oral therapy in humans (on the basis of comparative weight). The weight of the mice in all groups was comparable for the duration of the experiment, and there were no signs of either suppression of bone marrow cells or a general toxicity. In order to differentiate the non-specific toxic effects from the immunosuppressive effects, the blood concentration of Trimethoprim was measured in the mice blood. Up to the end of the experiment it did not overshoot the relative concentration in humans after oral Trimethoprim medication.

The findings were clear:

The immunosuppressive inhibition of rejection of the transplanted skin in the mice treated with Trimethoprim took exactly as long as the mice treated with immunosuppressive Azathioprine.

The rejection of the skin transplant in mice treated with Trimethoprim + Tetrahydrofolate (THF) took place just as quickly as the non-immonusuppressed control group (Ghilchick 1970).

According to today’s knowledge Trimethoprim, just like Azathioprine and later azidothymidine (AZT) (producer Burroughs Wellcome, today GlaxoSmithKline), suppressed the function of NO gas-producing Th1 immune cells and caused, after a few days, a Th1-Th2 switch of cellular immunity. In the third group of mice the immunosuppressive effects of the folic acid blockade by Trimethoprim were compensated for by the simultaneous dose of THF. So the assumption was justified that a medicamentous folic acid blockade with long-term medication with Trimethoprim could, similarly to Azathioprine, induce opportunistic infections, Kaposi’s sarcomas, lymphomas, carcinomas and degeneration of muscle and nerve cells (AIDS). Kaposi’s sarcomas appeared in organ transplant patients treated with Azathioprine within a few weeks or up to 12 years later and on average after 36 months (Penn 1979).

The London research team subsequently stated:

     “The site of the immunosuppressive action of Trimethoprim is the same as that of its antibacterial action—at the conversion of folates to folinates” (Ghilchick 1970).

The study was funded by Burroughs Wellcome, the findings of the study failed to prompt the producers of the T+S preparation to issue a warning about long-term immunotoxic effects of Trimethoprim (Bactrim, Septra, Eusaprim etc.) or about even a warning to people with an immunosuppressive disposition about the short-term effects.

To understand rationally why a whole generation of doctors since the 1970s is unwilling to give up the antimicrobial “miracle weapons” and to consciously realize their immunotoxic manifestations in “HIV positive” and AIDS patients as substance-induced effects one has to look at why the fact that immunotoxicity of “one of the most successful antimicrobial agents ever developed” (according to the Research Department of the Bactrim, Septra producer Hoffmann-LaRoche, in 1993) is still being denied. The blinkered adoption of the fictitious HIV/AIDS theory had system supporting advantages and stabilized the complex network of give and take between the offering pharmaceutical industry and a reluctant generation of doctors understandably averse to considering its own activities as a major contributor to systemic diseases. The advantage of this system is thus precisely substantiated, to view severe damage to immune cells and non-immune cells as the cause of an apparently unavoidable deadly “retrovirus infection,” which requires a battery of chemotactic substances as “life-prolonging therapy”; the toxic consequences of its own activities are explained and exculpated from the outset as the destructive consequences of this “deadly retrovirus infection” (Glaxo Wellcome 1998).

The analogy to chemotherapy in oncology and other fields of clinical medicine is blatant. This system of thought and trade conceals the fact that the half-life of medical theory is becoming ever shorter, thus the practicing doctor unavoidably acts erroneously, a correction to medical malpractice is as a rule only possible once those responsible have lost their influence. The price of the constraints of the system is paid by those affected, for whom medicine is the last bastion of credibility in which they have to confide.

     This tragedy, intrinsic to the system, more than clearly demonstrated by Dr. Montagnier, Dr. Gallo and their adherents before and during World AIDS Conferences, poses the question by which right they withheld the knowledge, for example from the people of the Third World, that folic acid deficiency due to undernutrition or malnutrition (nutritional AIDS, Beisel 1992, 1996) and/or chemotherapy against tuberculosis (Davis 1986) and/or Bactrim, Septra etc. and/or other antibiotics can cause exactly the same opportunistic infections and other AIDS-indicating diseases which have been, according to the disease theory “HIV causes AIDS,” accredited exclusively to exactly these “HI viruses” that are detected by extremely questionable “HIV Tests.”

     Instead of offering the required discourse they gathered roughly 5,000 signatures of doctors and scientists in the leading scientific journal Nature to keep up appearances. A medical science that is no longer prepared to continue what it does or does not do on the basis of data and facts, which are available for all to verify, deserves no confidence and disqualifies itself as a guarantor of credibility. Scientifically based questions on production procedures of the “HIV tests” remained unanswered by the patent holders Dr. Gallo and Dr. Montagnier and those responsible from the national authorizing institute, stereotypically referring to the relevant secrecy clauses of the producing companies. The control processes demanded by law in all Western countries on the simple suspicion of damaging aftereffects of already authorized medications were not carried out on the “anti-HIV” and anti-AIDS drugs with the claim that it was a lethal infection to which there were no alternatives to the “life prolonging” substances. Referring to the dominant doctrine of HIV/AIDS medicine, the charges of failure to adhere to the control processes demanded by law were rejected. The impression that the established HIV/AIDS group operate above the law can only be counteracted by free discourse within established medical science without being dictated by business personalities like Dr. Montagnier and Dr. Gallo.

The causal link between folic acid deficiency and chronic and/or opportunistic infections as well as the incidence of tumors has been demonstrated by numerous studies. It has been observed, for instance, that people with a sufficient supply of folic acid have a 35% decrease in the incidence of colon carcinomas compared to those with a smaller provision of folic acid. Comparable findings apply to other tumors (Tönz 1996). Equally, there is no doubt that “persistent infections” (De Wys 1982), for instance in “HIV positive” homosexuals, require an increased demand of folic acid (Davis 1982). Folic acid deficiency inhibits a diversity of biosyntheses and metabolic processes. The blocking effect of Trimethoprim is accordingly complex for the availability of biologically active folate. Trimethoprim disrupts the metabolism of amino acids, for instance the transformation of the amino acid serine to glycine, which supplies one of the three building blocks essential to the sulfurous antioxidant, glutathione. Glycine also participates in the recovery of the essential sulfurous amino acid methionine from homocysteine. The sulfurous amino acids homocysteine and cysteine, which are essential to the organism, can be synthesized from methionine. Homocysteine levels play a important role in all systemic diseases (De Groote 1996). Cysteine is the central building block for glutathione and vital for the detoxification processes of all cell systems. Active folic acid is in turn necessary for the enzyme that can equip methionine in such a way that it can act as indispensable donor for methyl groups in mammalian metabolism.

Activated folic acid is closely related to vitamin B12 and the degradation path of histidine. Additionally, activated folic acid plays an important role for enzymes that are involved in the synthesis and transformation of biogenic amines (dopamine, adrenaline, noradrenaline, serotonin, melatonin) (Lambie 1985).This incomplete list shows that it is misleading to restrict chemotherapeutic substances like Azathioprine, Trimethoprim or Azidothymine (AZT) to either their “immunosuppressive” or “antimicrobial” or even their “anti-retroviral” effects. Chemical substances with or without the decorative epithet “therapeutic” have to be judged on which biochemical compounds they can respond to on the basis of their structural attributes and which metabolic reactions they can indirectly disrupt on the basis of their bonding characteristics. Trimethoprim attacks in a diversity of ways the maturation, function and detoxification of immune cells but at the same time disrupts the synthesis of the co-enzymes which are indispensable for the synthesis of defensive NO gases in immune cells and non-immune cells. The impairment of the co-enzymes through the blocking of activated folic acid resulting from Trimethoprim medication applies, besides many other biosyntheses, also to the co-enzymes of the respiratory chain in cell symbionts, the mitochondria. There is an interaction, a cycling between enzymes and co-enzymes. Trimethoprim attacks this cycling in mitochondria in an incalculable way.

The question of how the doubled folic acid inhibitor in combination of Trimethoprim/Sulfamethoxazole (Bactrim, Septra, Eusaprim etc.) is metabolized is of vital interest. The well-founded assumption is that the already synthesized folic acid, on account of its molecular size, is unable to penetrate the mitochondrial membrane. Mitochondria in all human cells originate from proteobacteria (Gray 1999). All bacteria, just as fungi and parasites, which in contrast to bacteria contain mitochondria, have to assemble folic acid from the three single building blocks within the cytoplasm or as the case may be in the mitochondria. The consequence is that T+S medication attacks a diversity of the functions of mitochondria leading to the following assumptions:

• Sulfamethoxazole blocks the synthesis of folic acid in human mitochondria as well as in microbes.
• Human mitochondria are just as vulnerable to Sulfamethoxazole as bacteria cells.
• Trimethoprim blocks the activation of folic acid in mitochondria as well as in intracellular microbes, the bonding affinity of Trimethoprim to the enzyme DHFR is an analog to the bonding affinity of the substance in bacteria cells.
• Human mitochondria are just as vulnerable to Trimethoprim as bacteria cells.
• The metabolic product of Sulfamethoxazole, above all the toxic hydroxylamine, has to be detoxified by glutathione. Toxic nitroso compounds form in cases of increased glutathione use an ensuing deficit of the forming glutathione. This leads through nitrosative and oxidative stress to inhibition of cytochrome oxidase in the respiratory chain, to a decreased ATP production, to DNA damage and disruption to protein synthesis, to increased cell disintegration (Type-I overregulation of cell dyssymbiosis) or to cell transformation as glycolytic tumor cells (Type-II counterregulation of cell dyssymbiosis).
• The metabolic product of Trimethoprim, especially the nitro groups, caused nitrosative and oxidative stress effects in mitochondria analogous to those in bacteria cells, and the mitochondrial stress effects are analogous to the effects of NO radicals as well as the nitro groups of Azathioprine and azidothymidine (AZT).
• The bacterial stem cells of the human mitochondria can, during the course of a glutathione deficit (through increased use and disturbance of the new syntheses) and deficits of other antioxidants under prolonged medication with T+S, react more vulnerably than opportunistic agents that are able to switch facultatively and selectively to a Type-II counterregulation: T+S provokes T-helper immune cells (NO gas-producing Th1 cells) to die at a faster rate (Type-I overregulation) and/or newly maturing T-helper stem cells from the thymus to switch to a type 2 cytokine profile (Th2 cell dominance, Type-II counterregulation) and stimulate increased antibody production. Other T+S provoked immune cells can also die at a faster rate (neutrophile granulocytes, neutropenia, Type-I overregulation) or be increasingly activated (eosinophile granulocytes, eosinophilia, Type-II counterregulation). T+S-provoked non-immune cells can also die at a faster rate (apoptosis/necrosis, Type-I overregulation) or degenerate (myopathies and encephalopathies through a Type-II counterregulation in muscle and nerve cells no longer active in division).
• Trimethoprim respectively Trimethoprim/Sulfamethoxazole (and pentamidine, pyrimethamine, dapsone analogs) alone or synergetically with other immune stressors and immunotoxic/cytotoxic substances can provoke “HIV positive” test reactions, opportunistic infections (AIDS), cancer cell transformations and degeneration in muscle and nerve cells no longer active in division.
• Trimethoprim or as the case may be, Cotrimethazole induced damage of human mitochondrial DNA is passed on over generations from mother to child via the exclusive inheritance of the mitochondrial DNA of the egg cells and can trigger a diversity of systemic diseases like AIDS, cancer and degenerative muscle and nerve illnesses in progeny. These are dependent on the ratio of still intact to already defective mitochondria in the specific cell systems (heteroplasmy). In the course of the load from lifetime stressors the mitochondrial functions which have until that time been compensated could decompensate and congenital mitochondrial damage strengthened through acquired mitochondrial diseases which exponentiate to systemic deficits (Johns 1996, Wallace 1999).

Nobody knows how the mitochondria status in the population as a whole is obtained as the appropriate survey has not been carried out yet. It is to be feared that after 65 years of chemoantibiotic treatment (the introduction of sulfonamide was in 1935) lasting mitochondrial effects have accumulated and exponentiated both transmitted from mother to child and a brought on by an insidious disposition for Type-II cell dyssymbioses. This founded assumption also applies to AIDS and cancer dispositions by the corresponding exposure to prooxidative stress (Kremer 1997 a).

The pathogenetic causal link of mitochondrial damage through the combined inhibition of folic acid metabolism in human cell systems and the enforced appearance of acquired immunodeficiency syndrome (AIDS) dependent on dose and duration of medication and the disposition of the patients was first broached for discussion as a research concept for an experimental study in 1996 (Kremer 1996 c, 1996 a, 1996 b, 1997 a).

An inquiry about experimental and clinical studies of the effects of combined TMP/SMX (T+S, co-trimoxazole) on the functions of human mitochondrial cell symbionts at the pharmaceutical company Hoffmann LaRoche in Basel, producer of Bactrim and Septra with the highest global turnover, produced a clear disclosure from the “pre-clinical research” department:

“Over the years I have time and again been dealing with different aspects of the TMP/SMX combination, but with regret have to inform you that I know of no studies on the questions you addressed. Also my other colleagues involved with co-trimoxazole are unable to help … A colleague with extensive knowledge is on holiday at the moment. I will contact you again on his return should he have information on the themes addressed” (Then 1996).

The “colleague with extensive knowledge” was also unable to name one single publicized study on the effects on the ultrastructure and function of human mitochondria resulting from medication with Bactrim, Septra etc., “one of the most successful agents ever developed” (Then 1993). Additional questions to the research departments of the pharmaceutical companies Glaxo Wellcome (now GlaxoSmithKline) and Bayer confirmed the negative results: There were no experimental or clinical studies about the mitochondriotoxic effects of the single substance Trimethoprim or the combination substance co-trimoxazole. Extensive research in medical literature confirmed the statement from the producers of T+S. The discussion among specialists on, “Thoughts about an experimental study on the effects of folic acid inhibitors on the ultrastructure and function of mitochondria in human lymphocytes and in human microbial opportunists” (Kremer 1996 c) made the community aware of the deficit of experimental and clinical mitochondrial research and the rationally incomprehensible lack of knowledge of doctors, about whether and which effects chemoantibiotics like Trimethoprim and Sulfonamide or the combined chemoantibiotic co-trimoxazole and other antibiotics actually cause in mitochondrial immune and non-immune cells.

The internationally respected mitochondria researcher Professor Richter from the Laboratory for Biochemistry at the Federal Technical University in Zürich stated in a proposal for the research project “Antibiotic-induced damage to mitochondria”:

“The survival of mitochondria and thus the cell as a whole crucially depends both on an intact mitochondrial DNA and protein synthesis. Studies of diseases associated with mDNA, show that a large number of degenerative processes and cell death are caused by defects of mitochondrial oxidative phosphorylation [the supply of energy]. Antibiotics are compounds that are aimed against microorganisms that cause diseases. They operate by destroying the cell wall structure, changing the membrane permeability, transforming DNA, inhibiting protein syntheses or altering energy metabolisms. As former bacteria, mitochondria still possess many attributes that are otherwise only found in microorganisms. Thus it is possible that antibiotics also lead to changes in mitochondria … Up until now there have been no studies on antibiotic-induced mitochondrial damage in higher organisms. It seems urgently necessary to study the effects of antibiotics on the hereditary structure and functionality of mitochondria … In contrast to nuclear DNA, damage to mDNA, according to the present state of knowledge, is either not or only partially repaired … In the suggested study we expect to find evidence of medication-induced damage to the mitochondria. Of particular importance is the possibility, which has not been tested up until now, that antibiotics can provoke congenital mutations of mitochondrial DNA, which could be passed down via the germline from mother to the following generation. Evidence of antibiotic-induced damage to mitochondria obviously has far-reaching political, social and economic consequences” (Richter 1997).

Richter’s intended research project failed to attract funding, the fact that the world’s largest pharmaceutical concern, the Eusaprim producer Glaxo Wellcome demanded to have a say in the research publication as a condition of funding throws a bad light on the practices in present-day medical research when concerned with controlling the research findings that have obvious “far-reaching political, social and economic consequences” (Richter 1997).

There are, however, a few studies on damage to mitochondria by chemoantibiotics. It was first demonstrated in 1973 that chloramphenicol inhibited protein synthesis in mitochondria. Protein synthesis was blocked in isolated mitochondria by lincomycin and antibiotics from the macrolide classes (erythromycin, oleandomycin, spiramycin, tylosin and carbomycin). Possible mitochondrial damage in human cells is dependent on whether the antibiotics can pass the cell membrane.

“The treatment of animals or man with antibacterial drugs can have harmful effects on mitochondrial function, especially in tissues that have a high proliferation rate, such as bone marrow, intestinal epithelium, and tumor cells. Chloramphenicol causes a dose-dependent depression of bone-marrow function during treatment, probably by inhibiting mitochondrial protein synthesis. It can also cause a lethal late-onset toxicity (aplastic anemia) long after treatment has ceased … In the rat, inhibition of mitochondrial protein synthesis by prolonged tetracycline treatment causes a substantial decrease in the content of respiratory-chain-phosphorylation complexes in intestinal and in skeletal muscle. Fortunately, the apparent overcapacity in the catalytic activity of these complexes can provide protection against these effects, so that an 80% decrease in intestinal cytochromic c oxidase activity is tolerated without adverse effects” (Tyler 1992).

The research findings on the reduction of the oxygen respiration of mitochondria after prolonged administration of tetracycline were already published in 1981 (Busch 1981), but the consequences of the research data were not understood at that time. The fact that an 80% decline in the performance of the respiratory chain was still tolerated shows the necessity, according to the laws of nature, for all cell systems that are dependent on the supply of oxygen and its conversion, to still be able to tolerate a broad spectrum of fluctuations in performance.

But the research findings also demonstrate that at 20% remaining capacity of the complexes of the mitochondrial respiratory chain the critical threshold is reached beyond which the energy supply of ATP for the whole cell is endangered. This performance parameter corresponds very well to the stable levels of the alternate switch under physiological conditions from oxygen-dependent cell respiration for ATP production in cell symbionts to oxygen-free enzymatic ATP production in the cytoplasm.

The sudden loss of more than 80% of the cytochromic c oxidase activity of the respiratory chain can be caused by nitrosative stress through chemotherapeutics and antibiotics (for instance Azathioprine, azidothymidine (AZT), co-trimoxazole) and/or oxidative stress and/or structural damage of the DNA and protein syntheses after too high usage of antioxidants and/or too little absorption or neosynthesis of antioxidants (thiol pool, enzymatic and non-enzymatic antioxidative molecules). The result is a too weak transmission of electron flows to molecular oxygen (O₂) at the end of the respiratory chain, a quick degradation of mitochondrial ATP production, a sudden sinking in the membrane potential, increased Ca²⁺ cycling and increased formation of reactive oxygen species (ROS) and NO and its derivatives (Richter 1996, Kroemer 1997, Zamzami 1997).

The above-mentioned processes cause “infectious” cell death for the whole cell through the additional release of “apoptosis-inducing factors” from the mitochondria. The procedure here corresponds to a Type-I regulation of cell dyssymbiosis and can also be understood to be a hypercatabolic reaction.

Richter’s statement follows the laws of nature:

“The survival of mitochondria and thus the cell as a whole is crucially dependent both on an intact mitochondrial DNA and protein synthesis” (Richter 1996), however, has to be amended on one decisive point:

Mitochondria and thus the cell as a whole can survive a more than 80% loss of the performance capacity of the respiratory chain, if the bioenergetic membrane potential of the mitochondria can be stabilized or overstabilized by a Type-II counterregulation and the energy supply for the whole cell can be safeguarded mostly independently of the OXPHOS system of the mitochondria (Type-II counterregulation of cell dyssymbiosis).

Under these conditions the number and activities of the mitochondrial cell symbionts are substantially reduced to a fifth of their norms (Mathupala 1997). The bioenergetic, metabolic and proliferative prolonged transformation of the cells active in division, which happens largely on the performance level of archaic protista (Kremer 1999) are termed undifferentiated tumor cells. However, it is misleading to view, as does mainstream oncology, the formation of tumor cells primarily as the result of degradative mutations of nuclear DNA. The prime cause of transformation to tumor cells is to be understood as a bioenergetic process which, under a strong and prolonged nitrosative and oxidative stress, triggers survival strategies in the cells active in division after persistent inhibition of the OXPHOS system.

DNA damage can be caused after depletion of the antioxidizing capacities synchronously or sequentially and in a vicious circle aggravating the stable switch of the supragenetic network to a quantitatively and qualitatively lower fluidity level.

Degradation mutations alone in nuclear DNA and mitochondrial DNA involve deficient cell performance and the corresponding clinical syndromes. The fact that tumor cells can also develop without DNA mutations in the nucleus and in mitochondria confirms this consequence of the concept of Type-II counterregulation of cell dyssymbiosis that is represented here. Awareness of this obviously has a far-reaching significance for prevention and therapy.

“Tumor cells divide more frequently than normal cells and often have a low reserve capacity for respiratory-chain phosphorylation. The deliberate inhibition of mitochondrial protein synthesis in vivo by antibiotic treatment could be used to block the growth of malignant tumor cells, and it might offer some clinical advantage when used in conjunction with other therapeutic methods” (Tyler 1992).

Chemotherapeutics and antibiotics can indeed block, under certain circumstances, tumor cells from the reserve capacity of the OXPHOS system, which not only often but regularly is lower than the critical thresholds (Mathupala 1997), but this is a cause and not a result of tumor formation (Kremer 1999). Chemotactic attacks, however, can eliminate cancer cells not only by blocking the reserve capacities of the cell symbionts but also selectively strengthen the Type-II counterregulation in cancer cells. This is demonstrated in cancer cells that are characterized by higher sensitivity thresholds of the genetic expression of calcium-dependent NO synthesis and very low NO gas productions; they grow and divide especially quickly (Chinje 1997). But there could be other cells in the critical areas of performance capacity of the mitochondrial respiratory chain that are forced to a Type-II counterregulation by chemotherapeutic and antibiotic treatment and then secondarily transform to cancer cells. Equally there is the danger that after chemotherapy and/or radiation treatment a few metastatic cells form selectively, as through forced counterregulation the sensitivity barriers for the genetic expression of inducible calcium-independent NO synthesis in these cancer cells is seriously increased. Metastatic cells are characterized by a very low capacity for the stimulation of inducible cytotoxic NO gas and can thus prevent the cytokine stimulation of the cytotoxic NO gas synthesis in the metastatic tumor cells that have been induced by immune cells and non-immune cells (Xie 1996). Apart from cachexy the majority of cancer patients die from metastases. The fact that in the Deutsches Krebsforschungszentrum (German Cancer Research Center) after evaluation of the results of chemotherapeutic treatment on cancer patients over many years it was observed that:

“ … Even after decades of clinical use the cytostatics have proved to be a failure in broad areas of oncology” (Abel 1990). This reflects the effects of a Type-II counterregulation of cell dyssymbiosis and the forced switch through chemotherapeutics and antibiotics.

The same observations apply to nerve cells no longer active in division as well as heart and skeletal muscle cells, whose oxygen-dependent performance can degenerate as a result of chemotactic influences through a Type-I overregulation or a Type-II counterregulation.

However, in the age of chemotherapeutics and antibiotics the evolutionary-biological programmed counterregulation can be disastrous. As a rule, chemotactic acute treatment of intra- and extracellular agents in humans is successful if the patients still have sufficient thiol reserves and other protective antioxidizing molecules as well as a reasonably well functioning cytotoxic NO gas defense of T-helper immune cells, as the performance, antioxidizing capacity, and the reduction power of the complex human cell symbiosis is superior to the comparable capacity of single and multicellular microbes. If, however, the human immune and non-immune cells are exposed to a continuous pharmacotoxic bombardment and manifold immune stressors over a long period of time, then even in “previously healthy patients” (Gottlieb 1981) after the loss of critical reserve capacities the cell symbiosis in immune and non-immune cells responds to previously tolerable chemotherapeutics, antibiotics and immune stressors with “acquired immune deficiencies” in the form of clinically manifest opportunistic infections (AIDS) and/or specific tumors.

However, there is another factor in play. As a few especially successful opportunists, which just like successful cancer cells (Mathupala 1997) could survive chemotactic attacks in human organisms by counterregulating, these selected opportunistic agents could be relatively more tolerable to these chemotactic weapons than human immune and non-immune cells which have become dyssymbiotic.

The same process could take place when people with “acquired immune deficiencies” in symptom-free intervals are given long-term prophylaxis with immunotoxic antimicrobial substances such as co-trimoxazole, Trimethoprim, Sulfonamides, Trimetraxate, Pentamidine, Pyrimethamines, Dapsone and many other pharmacotoxins (antiparasitics, antifungals, antibacterial and antiviral substances), singularly or in combination, or with “antiretroviral” nucleoside analogs or non-nucleoside analogs or protease inhibitors, alone or combined. Or when various immunotoxic and cytotoxic preparations are temporarily allotted, combined and exchanged as “life prolonging cocktail or combitherapy” in a colourful mixture and sequence, on a trial and error basis, until a respective “incompatibility” is reached, as usual without an antioxidative compensation therapy.

That alone the doubled folic acid inhibitor co-trimoxazole achieved the basic condition of a toxic chemo-antibiotic, not only to penetrate the membrane barriers of single-celled and multi-celled microbes but also the cell membranes and mitochondrial membranes of human cells, is demonstrated by a choice from a long list of serious cell damage following short-term medication with Bactrim, Septra, Eusaprim, Cotrim Forte etc.:

• “Hematologic toxicity [toxic damage to blood formation]: Leukopenia/Neutropenia, various forms of anemia, thrombocytopenia [deficiency of blood platelets], hypoprothrombinaemia [deficiency of coagulation factor II]
• Vascular changes: Vasculitis, periarteriitis nodosa (seldom)
• Central nervous system: Ataxy [inability to coordinate muscles], tremors, convulsions, aseptic meningitis, psychoses with hallucinations, depressions
• Metabolic problems: hypercalcemia [elevated calcium levels], hyponatremia [reduced sodium levels], hypoglycemia [reduced sugar levels],
• Stomach/intestinal problems: Vomiting, inappetence, diarrhea, pseudomembranous colitis [inflammation of the mucous membrane of the colon]
• Liver and pancreas: Transaminase elevation [increase in liver enzymes], hepatitis, intrahepatic cholestasis [biliary stasis], liver necrosis [liver cell degradation], pancreatitis
• Nephrotoxicity [toxic damage to the kidneys]: Creatinine increase, interstitial nephritis [kidney infection], crystalluria [excretion of crystals in urine], urolithiasis [kidney stones]
• Skin reactions: exanthema, exfoliative dermatitis, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis [degradation of the skin cells], urticaria [nettle rash]
• Further allergic/toxic phenomena: Fever, angioedemas” (Gysling 1995).

Already in 1981 a research team published the proof by means of a micronucleus test that pathological transformations of nuclear DNA appeared in patients who had been treated to customary doses and durations of co-trimoxazole for urinary tract infections:

“The present study shows that trimethoprim-sulfamethoxazole [co-trimoxazole], like other folic antagonists [for instance, methotrexate for the treatment of leukaemia], damage the human genetic material” (Sørensen 1981).

This clear research finding was published in the same year that AIDS specialists were recommending unlimited medication with co-trimoxazole as a long-term prophylaxis for patients who had already been seriously immunotoxically and cytotoxically impaired (CDC 1981 a, Gottlieb 1981, Masur 1981, De Wys 1982).

The fact of DNA damage due to co-trimoxazole medication established the compelling logic that such DNA transformations would also be apparent in the mitochondrial DNA that was decoded for the first time in 1981 (Tyler 1992). Nuclear DNA is protected by special histone proteins and repair mechanisms while mDNA can either not be repaired or only partially (Richter 1997) and the damage rate is ten times higher than nuclear DNA (Yakes 1997). The working mechanisms of the doubled folic acid inhibition of nucleic acid synthesis of nuclear and mitochondrial DNA as well as the inhibition of co-enzymes essential for all biosyntheses change in many ways, indirectly and directly, the redox milieu of human cell systems. These redox transformations in turn influence the whole pharmacokinetics and pharmacodynamics of folic acid inhibitors and their bonding to enzymes and co-enzymes, which via the biological activation of folic acid drive other enzymes that regulate the nucleic acid metabolism, the synthesis of amino acids and biogenetic amines (Mathews 1985, Stone 1986, Zimmermann 1987, Oefner 1988, Hitchings 1989, Gilli 1990, Margosiak 1993, Sasso 1994).

The toxic effects of medication with folic acid antagonists like co-trimoxazole become aggravated when various chemoantibiotics influence the bioenergetic and biochemical patterns of absorption, bioavailability, distribution of the metabolic reactions and detoxification. Even small changes to the distribution of substances in organisms (pharmacokinetics) and actions and interactions in organisms (pharmacodynamics) can induce severe unwanted and inestimable consequences (Van Meerten 1995).

The degradation products of Sulfamethoxazole, in particular, play an important role in the toxic short-term effects of co-trimoxazole on immune and non-immune cells. Sulfonamides are converted to highly reactive metabolic products in an enzyme-driven process. The first stage of this biological activation is the oxidative metabolism of sulfonamides to hydroxylamine. This degradation product can under physiological conditions be oxidized quickly and spontaneously to nitroso compounds. These are even more highly reactive and even more toxic than hydroxamines (Uetrecht 1985, Shear 1985, 1986, Rieder 1988, Spielberg 1989, Cribb 1990, 1992).

Nitroso compounds (initially N-nitrosodimethylamine, Magee 1956) have been recognized as carcinogenic substances in hundreds of variations since 1956 (Loeppky 1984 a). They have to be detoxified, particularly by sulfurous reduced glutathione, which in all cells and above all in mitochondrial cell symbionts as reduction equivalent breaks down oxidized metabolic products (Siliprandi 1978, Meister 1983, Beutler 1985). The toxic sulfonamide product, hydroxylamine from co-trimoxazole is reduced by glutathione and prevented from transforming to potential carcinogenic nitroso compounds (Shear 1985, Rieder 1988, Spielberg 1989).

Asymptomatic “HIV positives,” however, already showed signs of a systemic glutathione deficit in immune and non-immune cells before and after the laboratory reaction “HIV positive” (Buhl 1989, overview Herzenberg 1997).

In addition to high glutathione usage through enforced detoxification actions in excessive chemoantibiotic medication and exposure to other immune stressors, glutathione deficiency was encouraged in promiscuous homosexuals for other reasons by the deficit of biologically active folic acid: As a result of chemoantibiotic abuse, frequently intermittent intestinal infections lead to resorption dysfunctions in the small intestine. This impedes the absorption of important nutrients including folic acid and the glutathione building blocks of the sulfurous amino acid cysteine or respectively sulfurous methionine which can be metabolized to cysteine in the liver (Lambie 1985, Davis 1986).

Methionine on the other hand requires methyl groups for the formation of cysteine, which is supplied by active folic acid (tetrahydrofolate, THF). Trimethoprim in turn intervenes in the formation of THF from folic acid and thus depletes the provision of cysteine from methionine as a building block for the neosynthesis of glutathione. A too high usage of glutathione and the inhibition of the neosynthesis of glutathione lead to a systemic glutathione deficit.

This in its turn then favors nitrosative and oxidative stress under specific risk loads, which in acute cases leads to an increased cell death (apoptosis/necrosis: Type-I overregulation of cell dyssymbiosis) in immune and non-immune cells and/or with a time lag to exhaustion of the long-term effects of the performance of cell respiration in immune and non-immune cells (asymptomatic acquired immune deficiencies with NO inhibition, Th2 cell domination and increased humoral immunity [AID], symptomatic acquired immune deficiencies with clinically manifest opportunistic infections [AIDS, and/or specific tumors in endothelial and lymph cells], cancerous disposition in the cells active in division/degeneration in the nerve, cardiac muscle and skeletal cells inactive in division) (Type-II counterregulation of cell dyssymbiosis).

There is no need to possess a particularly medical imagination to picture what actually happened in the 1970s on the proclamation of “sexual liberation” in the homosexual scene in Western cities before the first Kaposi’s sarcoma in 1978 and the first PCP fungal infection in 1980 were diagnosed in homosexual patients. How could these patients be termed “previously healthy” (Gottlieb 1981) although it had been ascertained that “Aggressive chemotherapy … contributes to the final degree of immunologic incompetence” (De Wys 1982)? How could it be stated that these diseases developed “without a clinically apparent underlying immunodeficiency” (CDC 1981 a) although it was recognized that the immunotoxic co-trimoxazole promoted systemic fungal diseases through neutropenia (Lehrer 1971 a, 1971 b) and chronic inhalation of organic nitrites (poppers) caused very serious damage to cellular immunity (overview Haverkos 1988) and 95% of the homosexuals from Washington, New York, San Francisco and Los Angeles examined in a study on nitrite usage by the US surveillance authority reported use of nitrites, often regularly (Jaffe 1983)? How was it possible to assume that “a speculative new virus” (Haverkos 1982) was the cause of the disease although the long list of infections with all kinds of agents, particularly in promiscuous homosexuals with a preference for unprotected anal receptive intercourse, was unprecedented (Jaffe 1983, Callen 1990, Root-Bernstein 1993)?

Doctors and patients knew full well the causes of AIDS-indicating diseases but still the specialists spoke in unison at the historic conference of March 1983 in New York (the first World AIDS Conference) of a “new agent” and the “intriguing puzzle” of Kaposi’s sarcoma (Friedman-Kein 1984 a) although animal experiments had clearly demonstrated the carcinogenic effects of simultaneous administration of chemoantibiotics and organic nitrites (Bambilla 1985). How could the international medical fraternity tacitly and almost without objection accept in the light of the accumulated knowledge that patients who had already been severely immunotoxically and cytotoxically damaged or even immune healthy patients who through a more than obscure antibody reaction test had been stigmatized as death candidates, were treated with chemotherapeutics and antibiotics in open-ended “planned experiments” (Thomas 1984) “practically like guinea pigs in one of the largest and most expensive experiments of our time” as the Wall Street Journal reported in 1996? Every informed person in the medical profession has known for more than 30 years that these drugs trigger AIDS and cancer as well as nerve and muscle degradation and that patients on long-term medication with these substances die of internal poisoning of the cellular respiration in immune and non-immune cells. Who is responsible for the deadly consequences of HIV/AIDS medicine run amok? Was it incomprehensible incompetence, twisted obsession or indifferent professional routine, which allowed a host of international doctors to become accomplices, lackeys or bystanders in one of the most disastrous tragedies of modern medicine? There is only one explanation: The dictates of the “invisible hand of the market” has since the approval of patents of medical laboratory findings, techniques and products at the end of the 1970s, polluted modern medicine and used the unscrupulous international media and professional media reliant on sponsorship in order to create an atmosphere of plague panic and mortal fear and to exploit helpless victims in all corners of the world.

At an international press conference at the World AIDS Conference in Geneva in 1998 Dr. Fauci, director of the National Institute for Allergy and Infectious Diseases in the USA, was asked by a specialized journalist:

“The American surveillance authority, the CDC, has explicitly excluded bacterial infections from the catalog of AIDS-indicating diseases (CDC 1993). Why do AIDS patients in Western countries develop almost exclusively systemic fungal infections?”

The immune specialist Dr. Fauci answered amicably:

     “Oh yes, I have many AIDS patients with bacterial infections.”

The journalist, in the presence of many colleagues, countered:

     “Yes, and these HIV positives and AIDS patients were treated with AZT.”

To the astonishment of the journalists instead of answering Dr. Fauci stormed out without uttering a word. Most of the journalists were unclear about why Dr. Fauci was in such a hurry. The journalist had exposed the pivotal question of HIV/AIDS medicine: Why were patients with an acquired immune deficiency being treated with a “cocktail therapy” of substances which trigger acquired immune deficiencies?

Dr Fauci, a long-standing coordinator for HIV/AIDS research, had endorsed in 1989, as chief medical evaluator, the approval of AZT as the “retroviral” prophylaxis for the medication of asymptomatic HIV positives. For this endorsement AZT was approved by the FDA, the American authority for the licensing of drugs, without having to wait a number of years for the mandatory clinical studies on the effects and side effects of the substance. AZT suppressed the maturation of blood cells in the bone marrow and inhibited the formation of antibodies against bacterial agents (Rosenthal 1994). At the beginning of the 1990s suddenly an increase in massive bacterial pneumonias appeared in previously asymptomatic HIV positives who had been treated with AZT; until that point in time these pneumonias had not been diagnosed to this serious degree in HIV positives.

The pneumonias, more over, were often fatal: “Bacterial pneumonias account for up to 40-50% of hospital admissions for lower respiratory tract infections among people with HIV” (Arzuaga 1994, Marco 1998).

The sudden increase in the appearance of bacterial infections, which by a characteristic “HIV positive” Th1 immune cell deficiency is usually inhibited by a compensatory increase in antibody production and an increase in other cells of the immune cell network, was explicitly traced back to medication with AZT:

“Neutropenia [loss of neutrophile white blood cells which mature in the bone marrow] is becoming more common because of the use of myelotoxic [those which damage bone marrow cells] drugs such as AZT, ganciclovir and other bone marrow suppressive agents” (Wilder 1998).

Dr Fauci, Dr. Montagnier and all their colleagues know precisely why they have to decline open discourse: They had tried to drive out the Devil “retrovirus HIV” with Beelzebub “AZT etc.” and fear the cross-complaints of the victims and their family and friends, as HIV/AIDS therapy is not rationally sustainable. An Australian doctor sums up the swashbuckling virus hunt, the poisoning of the already poisoned by a blind dogmatic “cocktail therapy,” which responds to one medically induced symptom with the induction of ever increasing symptoms by means of pseudo-rationally combined pharmacotoxins:

“It is therapeutic chaos. Doctors are prescribing what patients ask for, or they’re guessing, adding different drugs when they feel like it. I’ve never seen anything in Medicine quite like it” (Christie 1997).

The “HIV positive” patients, who through an unrestrained publicly staged campaign of hysteria were metaphorically scared to death, in turn believed that they could be saved from the phantom-like deadly virus by an almost masochistic belief in the promises of the pharmaceutical industry of the healing powers of a multitude of immunotoxic, mitochondriotoxic, glutathione-consuming mixture of substances—substances of which they should perhaps have been more scared. In this mutually delusional world the only real puzzle is why patients and doctors still believed in the fiction that AIDS drugs would solely target the microbes so that without progressive cell destruction by the “HI viruses” the diversity of toxic symptoms up to fatal organ failure would not be able to develop. This fiction was based on a fundamental error: Every toxic antimicrobial substance also attacks human cells, as all human cells are descended from archaic cells that have developed from the cellular symbiosis of single-celled microbes. Human cells differ from microbial cells, in principal, through a relatively better capacity for detoxification—as long as cell symbiosis is intact. But precisely this fundamental prerequisite has been endangered by the rapid change in external and internal toxic load patterns of the development of civilization over the last 150 years. AIDS and cancer diseases in Western countries are only a symptomatic reflection of overstepping the load limits. Modern medicine will have to find a more intelligent response to the challenge than a collective mobilization of deep-rooted fears of plague and uninformed “shotgun” virus hunting. Without the strict observance of the laws of co-evolution within human cells, between human cells and microbes as well as between human transformed and non-transformed cells the vital heritage of the micro-Gaian milieu will be irreparably squandered by a medicine governed by totalitarian commerce and ignoring evolutionary developments not only for the limited number of individuals of today’s generation but via the hereditary transmission of the maternal germline as the basis for the “Health of the Nations” (Sagan 1987) as well as for those in future generations (Sören 1981, Richter 1997, Yakes 1997, Kremer 1997, Wallace 1999).

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The prevailing AIDS and cancer medicine has mostly been unsuccessful through ignorance, or failing to take notice, of the evolutionarily conserved bioenergetic, genetic and metabolic fundamental principles of the intact or disrupted alternating switch of cellular symbioses. The one-sided medical intervention of attempting to eliminate the “HI viruses” and the eradication of cancer cells and metastases through prooxidative chemotherapy has by its nature caused more harm than good.

The disease theory “HIV causes AIDS,” as the resulting construction of retrovirus cancer research, has more than clearly demonstrated the meanderings of modern hi-tech laboratory research. Experimental and clinical research data since the historical statement by Warburg that the causes of no other disease are better known than the causes of cancer, however, show a way out of this diagnostic, preventative and therapeutic dead-end.

The diagnosis of HIV-positive from a laboratory reading—the identification of a positive test result in the “anti-HIV antibody test”—cannot be the guideline, as there is no such thing as an HIV test that contains proteins of a “retrovirus HIV” as test antigen, either in the ELISA test process or in the Western blot process (overview Papadopulos-Eleopulos 1993 a). The test contains proteins from a human cell culture and is adjusted in such a way that it displays the availability of higher than average amounts of antibodies. Such antibodies are not specific and in a Th2 cell dominance could have been generated against all sorts of innate or microbial antigen proteins (Hässig 1996 c, 1998 a, 1998 b, 1998 c, Papadopulos-Eleopulos 1997 c, Wang 1999). The “HIV test” also tells us nothing about the point in time of increased antibody formation. Since antibodies survive for a long time in blood serum, the increase of antibody levels could have happened at some time in the past or the cause for this rise in antibodies could still be given at the time of the test.

The easily conducted delayed-type hypersensitivity (DTH) skin test with recall antigens is suitable for measuring the T-cell reactivity (Christie 1986, 1995). Weak or anergic reactions permit the supposition of Th2 immune cell dominance.

Measuring the Th immune cells (T4 cells or CD4+ cells) in the blood does not reveal the relation between Th1 and Th2 cells, as no reliable surface markers were shown in order to routinely differentiate the proportions of the Th1 and Th2 cells subgroups. This is only possible via special measurements of type 1 and type 2 cytokine profiles in T-helper immune cells. A Th2 immune cell dominance can be expected with a high degree of certainty if the numbers of T-helper cells and the ratio of the numbers of T4 to T8 cells clearly drop with a simultaneously decrease in natural killer cells (NK), neutropenia (a decrease below the norm of neutrophile granulocytes) and simultaneous eosinophilia (an increase in eosinophilic granulocytes) and an increase in antibody levels (especially immune globuline G and E).

The measuring of glutathione (GSH) values in plasma and the intracellular GSH values in T4 cells are crucial for preventative and therapeutic intervention in “HIV-positives” as indicators of the status of the redox balance and thus the performance capacities of the whole immune cell network. “HIV positives” with normal GSH values in the plasma and in T4 cells and other peripheral blood cells, and normal cysteine, glutamine, arginine and glutamate values in plasma as well as other balanced readings of T4 cells, NK cells, neutrophiles and eosinophiles within normal fluctuations are not threatened by opportunistic infections. They require a detailed clarification about the clinical insignificance of an isolated “HIV positive” test result. Even orthodox HIV/AIDS medicine admits that 5% of the “HIV positive” test results are “false positive,” and thus 5% of the “HIV positives,” even within the bounds of the HIV/AIDS theory, are confronted with a medical death sentence for no reason. The disability to differentiate between a “false positive” and a “real positive” is a tragedy on top of a tragedy. It shows, too, how irrational the approach of HIV/AIDS physicians is in diagnosing and predicting the possible dangers to a symptom-free patient on the basis of a more-than-arcane antibody test, the measuring of the T4 cell status and the non-standardized unspecific measurements of “HIV RNA” as viral load by means of the error-prone PCR method.

If you stand back from the obsession with an “HIV infection” as the cause of AIDS and assume from the firm facts that in all immune and non immune cells glutathione levels, conforming to the norm, are of central importance to the vitality and performance of intact cellular symbiosis as well as a stable redox balance, then it should be mandatory to treat a proven glutathione deficiency. This medical principle applies completely independently of any “HIV characteristics” for symptom-free and symptomatic patients with known or unknown prooxidative stress risks (Ohlenschläger 1991, 1992, 1994, Scandalios 1992, Meister 1995).

The causal chain of a Type-II counterregulation of cellular dyssymbiosis in immune cells or non-immune cells in risk patients with a recognized excessive prooxidative burden has clearly shown:

• Strong or long-standing prooxidative stress ⟶ glutathione depletion ⟶ loss of the redox balance ⟶ type 1 to type 2 cytokine switch (Th1-Th2 switch) ⟶ inhibition of the synthesis of cytotoxic NO ⟶ opportunistic infections ⟶ organ failure (AIDS)
• Strong or long-standing prooxidative stress ⟶ glutathione depletion ⟶ loss of redox balance ⟶ type 1 to type 2 cytokine switch ⟶ mitochondrial inactivation ⟶ aerobic glycolysis ⟶ re-fetalization ⟶ wasting syndrome ⟶ organ failure (AIDS, cancer, nerve and muscle degeneration among other systemic diseases).

If the suppositions of glutathione depletion and cysteine deficits are confirmed through laboratory diagnoses and Th1 to Th2 dysbalances are confirmed immunologically, non-toxic balancing measures are always necessary and effective to even up the redox performance:

• Minimization of prooxidative loads
• Balancing of the thiol deficit
• Balancing of the amino acid dysregulation
• Liver protection to relieve the systemic thiol deficiency
• Modulation of Type-II counterregulation
• Balance of the micronutrients
• Strengthening of the extracellular matrix
• Mitochondrial activation
• Curbing of hormonal stress state
• Reduction of fear and ‘psychagogic’ aid

The military metaphor of an “ongoing titanic struggle between HI viruses and the immune system” (Ho 1995 a, 1995 b) used by HIV/AIDS medicine has obstructed the view of what the time-delayed prooxidative stress in general and specifically for the glutathione-protected cellular symbioses in immune and non-immune cells really means. The human organism is exposed, in daily life, to the effects of almost 60,000 chemical compounds, of which 4,000-6,000 display carcinogenic characteristics. Alone the skin macrophages and the T immune cells of the outer skin in dealing with the immune cell network as a whole have to perform enormous glutathione-consuming detoxification activities to stabilize the redox status. A vast number of preservatives (lindane, pentachlorophenol, halogenated fungicide), 8,000 dyes, of which roughly 2,000 are nitrosative azodyes and 6,000 textile additives (halogenated hydrocarbons, phosphoric acid esters, formaldehyde, ammonia etc), penetrate mostly through the skin and continuously have to be prevented from triggering uncontrollable chain reactions that would overtax the reserve capacities of cellular symbiosis either directly via reduced glutathione (GSH) in immune and non-immune cells or enzymatically with support from the enzymes of the multifunctional oxygenases of the cytochrome system.

Additionally, there is the increased inhalation of aerosols (nitrogen oxides, nitrosamines, ozone, aromatic hydrocarbons like benzopyrenes, benzanthracenes etc., metallic dusts, organic solvents, plutonium, radon etc.). These nitrosative and oxidative stressors also have to be neutralized by GSH to prevent damage to bronchial and lung epithelial cells as well as lung macrophages and T-helper cells and the especially vulnerable surfactant factors. GSH consumption is at the same time strained by a diversity of more than 1,000 toxins in conventional agricultural and industrial foodstuffs (heavy metals, insecticides, pesticides, nitrates, nitrosamines, aliphatic and aromatic hydrocarbons, monomers and oligomers as well as softening agents of plastics, dyes, preservatives, aldehydes etc.). These nutrition toxins contaminate not only intestinal, hepatic and pancreatic cells, but also directly burden the T-helper immune cells in the lining of the intestines and in the spleen, which form the largest proportion of the T-cell reservoir in the organism (overview Ohlenschläger 1992).

The total of electrophile (electron-receiving) toxins have to be decontaminated in a number of stages by nucleophile (electron-donating) GSH via conjugation with the aid of special enzymes (glutathione S-tranferase). After conjugation of the foreign matter with GSH, enzymes separate the amino acids glutamine and glycine from the glutathione tripeptides, a cysteine conjugate is produced that is acetylated and releases water. The stable end-product mercapturic acid is produced, which is readily soluble in water and can be excreted by the kidneys and liver (overview Ohlenschläger 1992).

This outline of the fundamental workings of the decontamination of prooxidative foreign matter by the unique and most important nucleophilic molecule in all cell systems and cell symbionts in the human organism—glutathione—is of vital importance for understanding therapy. It demonstrates that on top of the continuing task of glutathione to balance out countless redox oscillations with nitrogen oxides and radical oxygen species, to limit radical chain reactions and to regenerate radical intermediate stages of ascorbic acid (vitamin C) and ß-carotene, vitamin E etc., cysteine is permanently withdrawn through the forced conjugation of toxic foreign molecules to GSH. The consequence is that the increased demand for the balancing neosynthesis of glutathione can no longer be covered when additional excessive prooxidative pressures overtax the capacity for the biosyntheses of GSH. The redox balance is in danger of tipping when the critical reserve capacities of the mitochondrial OXPHOS system become exhausted and an optimum gas mixture from NO/O₂- for regulating cellular symbioses can no longer maintain the fluidity of the micro-Gaian milieu. Depending on how quickly and how steeply the exponential increase in the gas components takes place, inflammatory cytokine profiles are synthesized, which trigger apoptosis or necrosis, or immune cell weakening cytokine profiles are synthesized, which could lead to pre-AIDS and AIDS, cancer and nerve and muscle cell degeneration.

It is rationally incomprehensible why, ever since the proof of the systemic and intracellular glutathione depletion in immune and non-immune cells of “HIV positives” at an early point in time of the “HIV seroconversion” (Buhl 1989, Eck 1989, Roederer 1991), HIV/AIDS physicians did not obligatorily treat the glutathione deficit of “HIV” infected individuals, despite very detailed and differentiated knowledge about the essential importance of the glutathione system for the vitality of all cell systems (Ohlenschläger 1991). Already in 1985, the research team at the Royal Hospital in Perth, Australia, had discussed the obvious hypothesis that the oxidative stress of the risk factors was the primary cause of AIDS and could be counteracted by glutathione and N-acetyl cysteine (Papadopulos-Eleopulos 1998). One of the Perth Group posed the adjuratory question:

“Reducing agents and AIDS—why are we waiting? … There is now abundant evidence that HIV-positive individuals as well as AIDS patients have an altered redox state and that this may be an important factor in their disease process. For example, in February 1989 Eck and his colleagues showed that plasma levels of acid-soluble thiols (cysteine) and glutathione levels in peripheral blood mononuclear cells and monocytes [precursor cells of macrophages] are significantly decreased in the various AIDS groups (Eck 1989). Their in vitro studies also showed a strong dependence of intracellular glutathione concentration on extracellular cysteine with an accompanying strong correlation between the glutathione concentration and the viability and functional activities of T cells. In December 1989, Buhl et al. described systemic and lung epithelial lining fluid glutathione deficiency in symptom-free HIV-positive individuals (Buhl 1989). The levels reported were respectively 30% and 60% of the levels in healthy controls. These authors also pointed out that, although unexplained, the glutathione deficiency might be a direct causative factor in the reduced immune function observed in patients with HIV infection. Glutathione is the major transport system in plasma for the sulphydryl-containing amino acid cysteine which itself is a major antioxidant. Oxidants cause breaks in the DNA strands of lymphocytes and damage many of their innate functions. Sulphydryl compounds also augment a number of lymphocyte functions in vitro, including mitogenic T cell proliferation and T and B cell differentiation. The fact that glutathione deficiency is clearly demonstrated in the lungs of HIV-positive patients may be of importance in understanding the genesis of opportunistic pulmonary infection that characterises AIDS [pneumonia caused by the Pneumocystis carinii fungal pathogens = PCP, the most frequent AIDS-indicating illness up until now] … There are at least two reducing substances that are cheap, readily available and virtually devoid of any serious side effects. These are glutathione and N-acetyl cysteine. The latter is familiar to clinicians as an agent originally used in the treatment of chronic bronchitis and probably more recently used as an antidote for paracetamol poisoning. Herzenberg from Stanford University has recently documented reversal of low systemic glutathione levels in HIV-positive individuals by use of N-acetyl cysteine (Roederer 1990); experiments in vitro indicate that N-acetyl cysteine can produce highly desirable effects on HIV replication including a reduction in the appearance of p24 antigen (Clayton 1990). An Italian company, Zambon, will be assigned a patent on this drug for the purposes of treating AIDS when the United States Food and Drug Authority approves the first clinical trials. Oxidative stress as an important mechanism in AIDS and its possible reversal by reducing agents was hypothesized as long ago as 1985 by another Australian researcher (Papadopulos-Eleopulos 1988, 1989). Surely it is time someone carries out trials of therapy with reducing agents.” (Turner 1990).

The research data were clear. In addition to the presence of the repair enzyme reverse transcriptase (RT), Montagnier and Gallo had misinterpreted the presence of the protein molecule p24 as the second “molecular marker” of “HI viruses”. Proof of the inhibition of these cellular prooxidative stress products, p24 and RT, in glutathione-depleted immune cell cultures by the application of reducing substance that are “cheap, readily available and virtually devoid of any serious side effects—glutathione and N-acetyl cysteine” (Turner 1990) endangered, however, the interests of the pharmaceutical industry and the industry-dependent laboratory researchers and clinicians, whose research budgets were financed and re-financed by the revenues from sales of expensive chemotherapeutics. The reducing substances glutathione and cysteine are unpatentable. From a background of knowledge established since the end of the 1980s of the evolutionary biologically programmed laws of the interactions between the essential redox balance provided by the central cysteine/glutathione system, in addition to the mitochondrial vitality, NO/ROS production and the balance of cytokine profiles loomed the fiasco of the aggressive therapy strategies of AIDS and cancer treatment. The confession of the fateful scientific errors and the clear role of toxic and pharmacotoxic industrial products in the development of AIDS, cancer and other systemic diseases as well as the lethal failure of AIDS and cancer therapy via toxic chemotherapeutics could have triggered incalculable political, social, economic, scientific and medical consequences (Epstein 1998).

The response of the AIDS establishment dominated by retrovirus cancer researchers was clear: the revolutionary findings of the more recent cellular symbiosis research were ignored and the world public and the media were deliberately misled with the infinitely variable claims about the supposed effectiveness of “anti-retroviral” AIDS therapy. The clear-cut question of the Australian research team: “As AIDS has a 100% fatality rate and 60% of HIV-positive individuals are said to develop AIDS in five years, would it not be reasonable to give urgent consideration to trials of therapy and prevention with reducing agents?” (Turner 1990), was answered by the US drug approval authority, the FDA, by fast-tracking authorization for glutathione-consuming AZT for asymptomatic HIV positives (Friedland 1990).

Compensation therapy with cysteine/glutathione, proven to be non-toxic, was not promoted.

Generally, cysteine demands in systemic disruptions of the redox balance are considerably underestimated, for instance, the increased proton consumption in oxygen-independent sugar degradation for ATP energy acquisition for the reprocessing of the dropping amounts of lactate is calculated to a respective proton contribution of 23 g cysteine per day in patients with Crohn’s disease or ulcerative colitis (Erikson 1983, Dröge 1997 a). These patients have a dysregulation of non-protein thiols and amino acids, cellular weaknesses and wasting syndromes similar to “HIV positives,” cancer sufferers, sepsis and trauma patients, overtrained athletes and ill elderly people (Dröge 1997 a). The Birmingham study of 1998 demonstrated, for instance, that lower glutathione levels correlated exactly to disease stages of the elderly patients but the appropriate compensation therapy is by no means agreed upon in standard clinical practice (Nuttall 1998).

Cysteine compensation therapy requires, however, medical laboratory controls in order to avoid possible under—or overdoses. Small doses of NAD are quickly used without penetrating the deeper cellular compartments of mitochondria for the regeneration of glutathione. Overdoses can cause disruption in the gastrointestinal regions in prolonged usage. The cysteine levels can vary, even independently of nutrition and in correlation to intermittent intake of foreign matter.

Astonishingly, the authors of the NAC-substitution studies did not consider the direct prescription of glutathione treatment, which the Perth research team had also brought into the discussion. As cysteine requirement is necessary for numerous molecular compounds. It cannot be implicitly guaranteed that cysteine compensation therapy will be predominantly implemented in glutathione neosynthesis. Particularly in the metallothionines, which play an important role in all cell systems, there is a high cysteine requirement. Glutathione values could already be lower when the cysteine level is still using muscle protein reserves. In these cases, depending on the readings of T4 cells in the plasma and inside cells or other peripheral blood cells, an oral glutathione therapy of 2-5 g per day or higher is indicated. The form of presentation, under certain circumstances, determines the dosage; the intake of gastric juice resistant capsules can save glutathione.

     Glutathione prescriptions should be controlled in medical laboratories at fortnightly intervals in order to undertake any necessary adjustments to the dosage. Glutathione can be combined with cysteine, selenium, and antioxidative vitamins. Recently, a combination with the coenzyme NADH, which plays a decisive role in numerous biosyntheses as a hydrogen-carrier, has been discussed. NADH and NADPH, the oxidized form of NAD⁺, are synthesized in glucose metabolism via the pentose phosphate metabolic pathway. As NADH cannot be directly channelled into the mitochondria, hydrogen ions have to be transported to the cell symbionts by molecular ferries in order to be absorbed by NAD, FAD and FMN. This transport pathway is disturbed by aerobic glycolysis through the switch to glycolytic isoenzymes and the influence of Bcl 2 protein family on the ratio of NAD⁺ to NADH. A relative NADH surplus through oral intake of NADH or coenzyme 1 (for instance, 5mg tablets of yeast NAD, once or twice a day) appears to have a vitalizing effect in diseases associated with mitochondrial inactivation, like Parkinson’s disease, Alzheimer, depression etc. Previous clinical studies, however, are contradictory (Birkmayer 1993, Swerdlow 1998). The mobilization of NADH-dependent enzymes is apparently dependent on the stabilization of the redox balance via the glutathione system. This is of importance in connection with the glutathione balance, as in order to preserve orderliness and information in the “fundamental regulation of living systems” (Ohlenschläger 1991) the ratio of reduced to oxidized glutathione (GSH to GSSG, roughly 400:1) is decisive for the redox performance. The continuous reduction of GSSG to antioxidative GSH happens with the aid of the glutathione reductase enzymes, and requires NADH as coenzyme. At the same time the NADH concentrations of mitochondria are needed for the revitalization of the respiratory chain.

     Besides the combination of GSH/NADH, another combined supplement, made up from reduced glutathione (GSH), l-cysteine and anthocyanins (trade name Recancostat), is regarded as “superior to all other natural oxidative protective functions” and “superordinated protection against antioxidation and radicals” (Ohlenschläger 1992), because of its special Galenic mode of preparation, which ensures infiltration into mitochondria. Since Recancostat as a speciality remains relatively expensive, reduced glutathione/cysteine (e.g. curantox 1) and anthocyanins (e.g. curantox 2), can also be taken individually. Anthocyanins, plant pigments, belong to the over 5,000 phenolic flavonoids in plants (fruits, vegetables, seeds, skins, tubers and blossoms) (Strack 1997). These are potent antioxidants and metal chelators and have anti-inflammatory, anti-allergic, antiviral and anticarcinogenic effects (overview Ono 1990, Herzog 1992, Stoner 1995, Rice-Evans 1996, Cotelle 1996). There are beneficial synergistic interactions between GSH and anthocyanins (likewise between vitamin C and E) through redox cycle exchange programs. The argument against the combination of GSH/anthocyanin is that some phenolic flavonoids can cause DNA base oxidation and inhibition of cell division in high micromolecular concentrations. However, such concentrations are not reached in circulating flavonoid levels in human organisms so this assumption, in view of the high absorption of plant flavonoids, is unrealistic (overview Duthie 1997). Just as effective is the combination of glutathione and the polyphenol gingko biloba known as S-acetyl glutathione (SAG), which has recently become available. The alternative of SAG therapy is of practical importance when there are doubts about the sufficiency of other Galenic glutathione supplements.

However, HIV/AIDS physicians have to permit the question of how, without cysteine/glutathione compensation, they plan to honor the promises of an “HIV cure” (Ho 1995 b, Saag 1999, Cooper 1999, Fauci 2000), which they have been restating for 15 years with massive propaganda campaigns and the largest capital investment in the history of medicine, by treatment with glutathione-consuming, mitochondriotoxic, type 2 cytokine stimulating chemotherapeutics which, even if we assume the objectively non-existent “HIV infection” to be the cause of AIDS, could not inhibit either theoretically or experimentally the “HI viruses.” In principle, this question was self-critically posed, even among “HIV”-believing therapists years ago under the restrictive perspective of oxidative stress:

“Oxidative stress can be improved through a balanced combination of antioxidants. Naturally, some antioxidants cannot be patented. That’s why there are no profits in them. Despite plenty of evidence and the widespread need among the population very few therapy trials have been attempted with such compounds … Ideally, the government should have a well-founded interest in such antioxidants. When you consider that many patients who live with AIDS belong to the lower income groups, it means that they are dependent on public health care. That is why such relatively cost-effective treatment forms should be high on the government’s priority list for the prevention of opportunistic infections, the delaying of progressions and reducing the time spent in hospitals. Instead, the system of therapeutic clinical trials uses surplus cash, resources and time on highly toxic, insignificantly profitable and worthless medicines for the treatment of HIV: nucleoside analog substances [AZT etc.] and soon the highly dubious vaccines against HIV. (According to recent figures, 98 AZT therapy studies have been carried out by the National Institute of Allergy and Infectious Diseases, over 30 by the FDA and a dozen by the National Cancer Institute” (Act Up New York 1993).

The inconclusive treatment strategies of the research teams from the Deutsches Krebsforschungszentrum (Dröge 1997 a), Stanford University (Herzenberg 1997) and other clinicians of “additional cysteine monotherapy” for “HIV positives,” cancer patients and others with systemic diseases will be contrasted here with extracts from a very graphic and insistent lecture from the German physician and biochemist Ohlenschläger on treatment with reduced glutathione in special Galenism with l-cysteine and anthocyanins:

“Also in the compartments of living systems where everything is in flow, there are flow balancing systems; proton, electron, ion, matter, energy and information flows. All these flows as well as many other molecular states of orderliness, like for example the 3-dimensional shape of protein and enzyme molecules, underlie the also in flux balanced glutathione system as non-balanced system. Glutathione molecules consist of three amino acids: glutamine, cysteine with a free SH group (sulfhydryl group) and glycin. This is the reduced form of glutathione. And this glutathione together with another glutathione molecule, via the release of hydrogen and thus oxidative, can merge into a double form—a double molecule. Now you have to imagine the following: Form and function are nowhere in biology so closely related as in this situation of free SH groups and the disulfide bridge: Anywhere in cells.

Proteins are available either in one form with a free SH group or in another looped form linked by the sulfide bridge. The redox potential of glutathione ensures that this system is maintained. And nature has—and now we are back to non-balance—set an imbalance in this glutathione system in all cells, in all locations of reactions and in all mitochondria. We have a stronger representation of reduced glutathione to its oxidized form with a ratio of 400 to 1, in all cells … There is not one chemical step in cells that is not catalyzed enzymatically, and these enzymes need a particular 3-dimennsional form, and they get this only from a corresponding negative redox potential through a highly current concentration of reduced glutathione. The normal cell division process that a cell splits when it is permitted to split, this whole regulated, orderly genetic program is performed by all of us—all our lives! Even protection from overoxidation and maintenance of important detoxification functions depend on the glutathione system. Also the development, for the adaptation, regulation and kinetics of all biochemical reactions of a living system’s important “weak interactions” depend on glutathione balance … Antigen-antibodies are bonded through weak interactions; a receptor on the surface of the membrane of a cell and a signal molecule are bonded by weak interactions, or a transport molecule that needs to carry a substance through the cell membrane are bonded for a short time by weak interactions, or a molecule that has to convert another molecule, its substrate, is bonded via weak interaction for a short time as enzyme substrate complex. Molecules nourish themselves, fall under the quantum physical influence of their, partially overlapping, outer orbitors [outer orbits of electrons]. Molecules congregate, ally themselves and again separate. Thus the reversibility and thereby the whole dynamics of cellular metabolism, phenomena of continual change, are linked to these weak interactions and these weak interactions stand and fall physiologically with the redox potential in cells, that is strongly negative and has to be; stand and fall with a thermodynamic imbalance of the glutathione system” (Ohlenschläger 1994).

Thus the question, which up until now has been avoided, has to be asked of the HIV/AIDS physicians as to how they envisage their propagated “HIV healing” without cysteine/glutathione compensation. For the crucial type 1 to type 2 cytokine balance for intact cellular immunity via appropriate cytotoxic NO gas production also depends on the fine tuning of the redox potential through the glutathione system of antigen-presenting cells and their double signal to the T-4 immune cells after stimulation by intracellular microbes or toxins.

Secondly, a question has to be asked of clinical researchers, who combined cysteine substitution with chemotherapeutics like AZT etc. that need glutathione or with cysteine neosynthesis-inhibiting folic acid antagonists like co-trimoxazole etc. What sense does it makes to give with the one hand and take with the other, paradoxically with substances which objectively cannot accomplish what they are meant to accomplish; namely the inhibition of HI viruses? Thirdly, why does the HIV/AIDS medical profession still believe that a systemic disease linked to opportunistic infections and wasting syndrome that should and must have been recognized 20 years ago as the prooxidative cause of the deficiency of freely convertible protons, has to be counterproductively treated with chemotherapeutics, although the cause of the cellular immune weaknesses and wasting syndromes has long been clarified by evidence of glutathione and cysteine deficits, mitochondrial inactivation, type 2 cytokine switch, cytotoxic NO inhibition, glycolytic metabolic situation, amino acid dysregulation, increased urea production etc?

The first publicized randomized double-blind study (randomly selected patients in treatment and control groups) demonstrated how hard it is for even the most progressive HIV/AIDS physicians to transform the simplest findings about the “weak interactions” in cellular biology to rational clinical actions. A small group of “HIV positive” patients with wasting syndrome were treated with cysteine and other antioxidants plus glutamine. The 21 patients who completed the clinical study, with the exception of 3, were all treated chemotherapeutically following the HAART procedure.

Simultaneously these patients received every day for 12 weeks, 2.4 g N-acetyl cysteine, 0.8 g ascorbic acid (vitamin C), 500 international units (IU) alpha tocopherol (vitamin E), 27,000 IU ß-carotene, 280 mg selenium and 40 g glutamine. The supplementary medications—supplementary to ‘proper’ medication with “anti-retroviral” chemotherapeutics—were taken four times daily and the patients were given new packets every two weeks. The body weight (BW) of the patients increased within three months on average by 2 kg and the body cell mass (BCM = metabolically active body tissues) by 1.8 kg. Side effects of the “supplementary agent” were not reported or not observed. In the control group after three months the increase in BW was on average 0.3 kg and the BCM 0.4 kg. The clinicians concluded:

     “This randomized, double-blind, placebo-controlled therapy trial demonstrates for the first time [20 years after the first diagnosis of an AIDS-indicating disease in homosexual patients!] that supplementation of the amino acid L-glutamine and the provision of adequate antioxidants and nutritional counseling can improve body weight and restore BCM. This low-cost and low-risk supplement may be the preferred method of initial nutritional support in patients with weight loss of > 5%. Larger trials are needed to evaluate the clinical impact of this approach on reducing opportunistic infections and possibly long-term mortality” (Shabert 1999).

The million-dollar question is: how much more could the BW and BCM of patients have improved without HAART treatment? The clinicians at the Harvard Medical School in Boston misjudged decisive correlations: Healthy test subjects after anaerobic exercise programs resulting in increased aerobic glycolysis after 5 to 8 weeks had a loss of BCM, which correlated to lower cystine (oxidized cysteine) and glutamine values in the plasma. Furthermore, a placebo-controlled, double-blind study demonstrated that the reduction of BCM was impeded by treatment with N-acetyl cysteine. During the observation time, changes of glutamine levels in plasma strongly correlated to changes in the cystine levels in plasma (Kinscherf 1996). Similar to these studies on healthy people the treatment of “HIV”-infected people with N-acetyl cysteine resulted in a steep climb not only of cyst[e]ine values in the plasma but also the glutamine and arginine values (Dröge 1997 b).

The studies prove the following: As even a short-term shortage of oxygen (hypoxia or pseudohypoxia) in anaerobic exercise programs of healthy test subjects leads to an inactivation of the respiratory chain (ATP cannot be stored, so there has to be a switch to aerobic glycolysis, oxygen-independent enzymatic ATP production), the archaeal genetic emergency program is triggered resulting in the mobilization of the proton reserves in the skeletal musculature for the conversion of amino acids to pyruvate/glucose to feed the increased needs for sugar of glycolysis. The result is the observed loss of body cell mass and the exchange of cysteine and glutamine from the skeletal musculature for glutamate from the plasma is blocked. At the same time the splitting of cysteine to sulfate and protons in the liver is reduced because of the lower cysteine levels. The protons for inhibiting the first step of urea formation from arginine in the liver are missing. Therefore, the export of urea rises and levels of arginine sink. However, as the formation of glutamine in the liver without the help of protons from the splitting of cysteine is also heavily impeded, the glutamine level in plasma drops. Reduced levels of cysteine, glutamine and arginine in the plasma and higher levels of glutamate and urea are the characteristic laboratory findings of wasting syndrome analogous to the state of cachexia of cancer patients (Dröge 1997 b).

Simultaneously glutathione levels are reduced by the increased demand through prooxidative stress from initially increased NO and ROS formation in hypoxia and pseudohypoxia, from reduced neosynthesis as a result of cysteine and glutamine deficits and through disruption of the enzyme glutathione reductase from a shift in the ratio NAD⁺/NADH. The consequences are a switch from type 1 cytokines to type 2 cytokines, the inhibition of cytotoxic NO production and a total Type-II counterregulation of cellular dyssymbiosis (still reversible). This dysregulation of the redox potential by overloading the glutathione system after prolonged hypoxia or pseudohypoxia is represented symptomatically by over-trained athletes with a disposition to opportunistic infections and wasting syndrome (Pedersen 1994).

Counterregulations after strong and prolonged prooxidative stress in “HIV positives” proceed in a similar fashion with the inhibition of the respiratory chain in mitochondria and pseudohypoxia (as a result of an alleged oxygen deficit through the blockade of the utilization of O₂). Here too the lowering of the cysteine/glutamine level strongly correlates with the after-effects of the sinking levels of glutamine and arginine. A too-low arginine level also means a reduction of cytotoxic NO synthesis in T-4 cells, as NO is formed from arginine (overview Lincoln 1997). A too-low glutamine level means on the one hand an overly strong glutamine decay in the protein reserves of the skeletal musculature and conversion to sugar (Dröge 1997 b), and on the other hand that glutamine as oxidation substrate is missing in the mitochondria of intestinal cells (Van der Hulst 1993, Welbourne 1994), in the immune cells and in the liver cells (Häussinger 1989) and as substrate for the acid-base balance in the kidneys (Brosman 1987, Welbourne 1994). However glutamine also supplies the necessary glutamates for glutathione regeneration (Hong 1992), so a glutamine deficit aggravates the glycolytic metabolic situation and provokes a type 2 cytokine switch (Hammarqist 1989, Hack 1996). Glutamine is, however, also a building block for the nucleic acid synthesis from RNA/DNA bases for DNA neosynthesis and repair procedures.

All these processes of the quantum dynamic regression from the fluid oxidative phase to the contra fluid reductive phase, triggered by the missing fine tuning of the redox imbalance resulting from a loss of freely convertible protons through prooxidative weakness of the cysteine-glutathione system, explain the wasting syndrome of “HIV positives” (Grünfeld 1992), cancer sufferers, sepsis and trauma patients, colitis patients, overtrained athletes and other people with systemic illnesses (overview Dröge 1997 b).

Treatment with sufficient dosages of N-acetyl cysteine simultaneously increases via “weak interactions” (Ohlenschläger 1994) both the glutamine and arginine levels (Dröge 1997 b) and thus improves the regeneration of both the glutathione level and the cytokine balance (Peterson 1998) as well as NO synthesis (overview Richter 1996, Lincoln 1997). Secondary glutathione deficiency as a result of primary deficits of freely convertible protons due to the prooxidative usage of the cysteine/glutathione supply has a massive influence on the maturation and functioning capacity of immune cells ready for defense. Glutamine serves as oxidation substrate for the energy metabolism of immune cells and as substrate for the biosynthesis of nucleosides as building blocks for RNA/DNA regeneration of immune cells. Glutamine deficits inhibit the production of the growth factor interleukin-2 of T-4 cells and reduce the numbers of T-4 cells in the plasma (immunological indicators of the acquired immune weaknesses of “HIV positive” and AIDS patients) (Newsholme 1990, 1996, Calder 1994, Rohde 1995, 1996, Hack 1997).

The interaction between the normal and lower cysteine levels on the one hand and the normal or lower glutamine values and synchronously the arginine values in plasma on the other hand derive from the ornithine-urea cycle in the liver and the regulation or, as the case may be, dysregulation of protein synthesis and decay in the musculature. This interplay is of great importance for the understanding of wasting syndrome and acquired immune weakness as well as for the therapy of these syndromes. Normally surplus amino acids that are not required for protein synthesis are converted to sugar, glycogen or fatty acids or are oxidized for ATP production. The nitrogen released by this process in the form of highly toxic ammonia (NH₄) is transferred to a-ketoglutarate and fed into the ornithine-urea cycle as glutamate.

In this metabolic cycle glutamate is routed in two ways. The first is directly into the cell symbionts where the ammonia of the glutamate is transferred to a substrate as the first step of the cyclic formation of urea, which via a number of stations in the cycle from the amino acid arginine is synthesized in the cytoplasm in the kidneys. In the second, alternative route, glutamate transfers an amino group to an intermediate product, which reacts to substrates in the ornithine-urea cycle. Finally, it is split into urea and ornithine in the kidneys. Ornithine is then available for a new passage through the cycle in the mitochondria. In this step of the cycle cysteine attacks, by making protons available through division in order to incorporate ammonia in glutamine with the aid of a special enzyme. If proton-donating cysteine is missing, less glutamine and more urea is produced and at the same time more arginine used. This is the reason why a lower cysteine level causes simultaneous lower glutamine and arginine values and explains why the N-acetyl cysteine substitution for the treatment of wasting syndrome in “HIV positives” and cancer sufferers raises levels of glutamine and arginine (Dröge 1997 b).

The crucial consequences for the prevention and therapy of cellular immune weakness and wasting syndrome arise from a multitude of networked interactions whose starting point is a profound disruption of the redox milieu (nutritional AIDS, pharmaceutical AIDS, intoxication AIDS, inflammation AIDS, alloantigen AIDS, radiation AIDS, athletes AIDS etc.).

The role of arginine in cellular immunity of humans has been known through animal experiments for more than 20 years (Seifter 1978, Barbul 1980, 1981), but has not been given enough attention in HIV/AIDS medical science (Kinscherf 1996, Dröge 1997 b). Arginine substitution has shown favorable effects on the maturation and the capacity for stimulation of T-cells in healthy animals and humans. What was remarkable was the heavy increase in natural killer cells (NK cells) after daily intake of 30 g of arginine by voluntary test subjects (Barbul 1980, 1981, 1986, Daly 1988, Park 1991). The activity and number of NK cells is characteristically low in HIV positives, cancer and other systemic diseases (Dröge 1997 b). Recovery of a type 1 to type 2 cytokine balance after a type 2 cytokine dominance due to burns was shown in animal experiments when total intake of calories was enriched with 2% of arginine by improved reactivity to the DTH skin test and through inhibition of bacterial infections (Saito 1987). Likewise, there were improvements in the wound-healing processes, collagen regeneration and T4 cell functions after experiments on animals with injuries (Seifter 1978, Barbul 1980, 1985). The same favorable effects were found on recovery of the type 1/type 2 balance in patients after cancer operations in the gastrointestinal regions who were given 25 g of arginine daily and in sepsis patients one week after operations (Daly 1988, 1990, Barbul 1990).

     In animal experiments anti-tumor effects were also demonstrated after arginine intake. The appearance of tumors after contact with carcinogenic substances could be reduced, the growth of cancer cells and the spreading of metastases could be delayed, the time span until tumor regression reduced and survival rates increased (Barbul 1990, Lowell 1990). In immunogenic tumors, both the unspecific cellular immunity of the macrophages and the specific T-4 cell immune response could be increased through arginine dosage (Tachibana 1985, Reynolds 1987, 1988). The favorable effects via arginine administration with nutrition for the modulation of the immune cell functions as well as the inhibition of the induction and development of malignant tumors through an improvement in the type 1 to type 2 cytokine balance are rationally understood by the fact that arginine not only acts as a semi-essential building block for countless proteins and enzymes and disposes of surplus nitrogen in the liver by splitting into urea and ornithine, but that arginine as crucial substrate for calcium-dependent and non-calcium-dependent NO synthesis enzymes also works on the production of the nitrogen monoxide gases NO (Palmer 1988, Wu 1998).

     Evidence of the activation of cytotoxic NO in numerous immune cells and non-immune cells via a type 1 cytokine profile (Nussler 1993, Murphy 1993, Kröncke 1995, overview Lincoln 1997) clearly demonstrates the direct causal link between the reduced arginine levels through increased urea export and the inhibited immune cell activities due to a lack of synthesis of cytotoxic NO after a type 2 cytokine switch (AIDS) resulting from excessive prooxidative loss of the balancing functions for the fluid micro-Gaian milieu after the breakdown of the cysteine/glutathione system.

This also explains the inhibition of glycolytic, re-fetalized tumor cells, and metastatic after resettlement viable cancer cells due to the supply of arginine (Brüne 1998). The characteristic NO synthesis inhibition of tumor cells as a consequence of Type-II counterregulations is intensified by a shortage of arginine. Rapidly growing cancer cells have low NO values, slow growing tumors relatively high NO levels (Chinje 1997). From roughly 10,000 colonizing tumor cells, however, only about one survives as a metastatic cell as the exogenous stimulation by cytokines of non tumor cells (interleukin-12 from macrophages, interleukin-2, interferon-γ and tumor necrosis factors from T-helper cells and other immune and non-immune cells) can activate the cancer cells’ own NO synthesis and ROS production so that regression, and cell death of tumor cells can be triggered via apoptosis/necrosis. The inducible threshold for the exogenous stimulated production of the cancer cells’ own cytotoxic NO gases, which in cancer cells cannot be easily neutralized because of the depleted thiol pool, is higher in metastatic cells than in most tumor cells, above all because of prooxidative selection through chemotherapeutic treatments.

However, through arginine administration the incidence and growth rate of induced tumors could be reduced as well as the regression of these tumors improved and, at least in animal experiments, the apoptosis/necrosis rates of metastatic cells increased by repeated cytokine stimulation (Barbul 1990, Xie 1996).

     The clinical results with the type 1 cytokine interleukin-2 showed an increase in the NO levels in the serum of cancer patients (Hibbs 1992, Ochoa 1992), although an increase in the permeability of capillaries was observed (Orucevic 1998). This phenomenon of unstemmable, lethal haemorrhaging was also diagnosed in Azathioprine-treated organ-transplant patients with Kaposi’s sarcoma of the bowels after stopping immunosuppressive Azathioprine treatment (Penn 1979). Obviously the sudden change from a type 2 cytokine status to a type 1 cytokine status without prior compensation therapy with cysteine or glutathione (GSH) is risky. These risks, however, do not speak against the correct dosage of the arginine substitution for “HIV positives” in acquired cellular immune weaknesses, wasting syndrome and above all Kaposi’s sarcoma. If the glutathione, cysteine, glutamine, and arginine compensations are correctly combined,and the right dosages prescribed, higher concentrations of NO accordingly act in an inhibitory manner whereas lower concentrations of NO force tumor growth rate and regeneration of blood capillaries in tumor cell clusters.

     A number of clinical research teams have attempted to bypass the unwanted effects of interleukin-2 therapy in the treatment of cancer, namely capillary leakage (Orucevic 1998), and a drop in blood pressure (Shahidi 1998), by the selective inhibition of NO with NO-inhibitors and the exclusive stimulation of ROS production through an interleukin-2-induced stimulation of tumor necrosis factor. The aim is apoptosis/necrosis of the tumor cells through oxidative stress and the inhibition of nitrosative stress (Chinje 1997, Orucevic 1998). This one-sided process, however, is to be viewed just as critically as the use of interleukin-2 in HIV/AIDS medicine for the “flushing” of “HI viruses” in dormant T4 cells (Cooper 1999). Just as with prooxidative chemotherapeutics, compensated mitochondria in non-tumor cells could be forced to a decompensated Type-II counterregulation (secondary AIDS and secondary cancer) or active tumor cells could be selected to metastatic cells.

It is rationally difficult to comprehend why so few controlled studies have been carried out over the last twenty years in HIV/AIDS medicine on the compensation of the glutathione system and the amino acid dysregulation of “HIV positives,” AIDS and Kaposi’s sarcoma patients in view of the immense advances in knowledge outside of HIV/AIDS medicine. Even if you assume from the (objectively false) disease theory that “HIV causes AIDS,” such treatments should still be mandatory as viruses also use up sulfhydryl groups (SH groups) for replication (Papadopulos-Eleopulos 1988). The fixation on the “HIV infection” and the treatment of the “HIV positive” stigmatized patients with a diversity of counterproductive combinations of aggressive chemotherapeutics that are difficult to keep track of, had led to inadequate and unsatisfactory attempts at therapy resulting in cellular dyssymbiosis in the immune and non-immune cells of these patients. The survey of the clinical researchers at Harvard Medical School reflects the consequence of the “confusion at a higher level of understanding” (Balter 1997):

“Significant weight loss commonly occurs in patients with human immunodeficiency virus (HIV) infection. The extent of loss of body cell mass (BCM), which is the metabolically active tissue of the body, correlates with the length of survival. Attempts to reverse this erosion of protein-rich tissue with appetite stimulants, oral nutritional supplements and enteral or parenteral nutrition have resulted in deposition of adipose tissue, with variable or no restoration of BCM (Kotler 1990, 1991, Chlebowski 1993, Van Roenn 1994). Recombinant human growth hormone administration resulted in gain in lean tissue, but the effects were not sustainable once treatment was terminated (Krentz 1993) … At present, standard parenteral nutrition solutions and most enteral feeding formulas do not contain L-glutamine (GLN); therefore, repletion is not possible … This study demonstrates for the first time that the provision of a specific nutrient supplement, when coupled with nutritional counseling, can improve weight and restore BCM … The 40.0 g GLN dose was selected because open label studies providing 30.0 and 40.0 g GLN/d have demonstrated marked weight gain and improvement in BCM, and a blinded pilot study using 20.0 g GLN/d failed to demonstrate consistent results (Young 1992) … Larger multicenter studies [a pooling of research between a number of clinics] are needed to determine whether GLN-antioxidants will support BCM and reduce the incidence of infection over the long term, as has been observed in other populations like bone marrow transplant patients (Ziegler 1992), low birth weight infants (Neu 1997) and surgical patients with multiple trauma (Houdijk 1998)” (Shabert 1999).

The reference to “other patient groups” demonstrates that 20 years after the beginning of the so-called AIDS era, the clinical researchers of the Harvard Medical School still have not quite mastered the synergistic interactions of wasting syndrome in systemic diseases like AIDS and cancer. To this end there is no need of elaborate multicenter studies, just a simple balance sheet. The elite scientists at the Deutsches Krebsforschungzentrum, Stanford University and the Harvard Medical School are all agreed that the chances of survival from AIDS, cancer and other systemic diseases are dependent on the degree of development of wasting syndrome (cachexia) and that this is the main cause of death. At the same time there is also agreement that all systemic diseases involve a massive disruption to cellular immunity (AIDS) and that wasting syndrome and cellular immunity disruptions have the same fundamental origins. There is yet further agreement that in contrast to all other systemic diseases, the sole primary cause of HIV/AIDS is of an infectious nature (“retroviral HIV infection”). Thus there is also consensus among the clinical research teams that the “HIV positive” patients have to be treated indefinitely with prooxidative “anti-retroviral” chemotherapy and at the same time an antioxidative “supplementation therapy” (Hack 1997, Dröge 1997 b, Herzenberg 1997, Shabert 1999). The disagreement lies in the combination and dosage of the antioxidative “supplementation therapy” in “HIV positives.”

The synoptic analysis of these, at least, differentiated clinical publications on preventative and therapeutic cysteine and glutamine compensation therapy of patients with cellular immunity weakness and wasting syndrome demonstrate:

• The clinical research team prescribed prooxidative chemotherapy to patients with weakened immunity and Type-II cellular dyssymbiosis without clinical or experimental evidence that these substances could inhibit cellular immunity weaknesses, wasting syndrome, Kaposi’s sarcoma, lymphoma, muscle and nerve cell degradation, inflammatory bowel syndrome and other serious infectious and non-infectious symptoms.
• The many publications about certain evidence that these prooxidative substances are mitochondriotoxic, genotoxic and thiol-consuming and cause AIDS, cancer and muscle and nerve cell degradation etc. were not referenced by any of the research teams
• None of the research teams published an overview of the important immunological parameters and the cytokine status of the patients before, during or after the controlled treatment phases.
• None of the research teams reported about the combined use of immune-modulating and redox-stabilizing non-protein thiols, cysteine and glutathione or about the synergistic amino acids, glutamine and arginine.
• None of the research teams discussed a specific use of synergistic compensation therapy regarding the particular detoxification and elimination capacities of the individual patients.

Knowledge of the factors involved in the individual disposition to illness have an especially important bearing on fundamental understanding of the diagnosis and the preventative and therapeutic necessity in pre-AIDS and AIDS and other systemic diseases. The “HIV characteristics” are real, bioenergetic, biochemical and immunologic phenomena, which can be precisely and extensively explained by means of more recent insights in research on cellular symbiosis, glutathione, cytokines, NO and immunity, without the effects of any “HI viruses.” These insights also supply an answer to the crucial question of why precisely the antibodies of patients from so-called risk groups, in Western countries, react to the proteins in the “HIV test.”

The term risk group means that the people are exposed to an exceptional load of risks or were exposed to them at an earlier point in time before the “anti-HIV antibody test.” Closer examination, however, shows that the exposure to risk is not the only determining factor as to whether the number of antibodies in blood serum is sufficiently high to cross the highly contrived sensitivity threshold for a positive reaction in “HIV tests.”

“HIV positive” homosexual men are indeed numerically the largest risk group of all “HIV positives” in Western countries, but in relation to the total homosexual population their number has remained relatively small. At the end of 1985, 50% of homosexual men were quoted to be HIV-infected. This claim turned out to be completely wrong. In the space of 20 years, conservative estimates of the proportion of homosexual men within the population as a whole amount to 3% and the number of “HIV” infected homosexuals within that group amounts to about 3% to 5% (the smaller the assumed size of the total homosexual population the higher the percentage of officially registered “HIV positives” among homosexuals).

The proportion of “HIV positives” within the second largest group of “HIV infected” individuals, the intravenous drug addicts, was given as about 75%. This claim was also completely wrong. A constant proportion of between 3 and 5% “HIV positives” was also found after autopsies on dead heroin addicts and in detoxification units.

In contrast, in the numerically smaller groups with congenital coagulation defects, almost exclusively male hemophiliacs, roughly 50% were diagnosed HIV-positive in Germany and about 75% in the USA, although in Germany about ten times the amount of coagulating proteins were substituted and more than 80% of the coagulating protein preparations were imported from the USA. However, in Germany the proportion of AIDS patients among the “HIV positive” hemophiliacs in the six cities with the highest “HIV” loads (Berlin, Hamburg, Düsseldorf, Cologne, Frankfurt, Munich) is twice that of other cities although the percentage of AIDS incidence among “HIV infected” hemophiliacs cannot be dependent on place of residence.

All these figures show that the claims of an “HIV infection” are completely wrong and thus the numerical data of HIV/AIDS medicine in Western countries, and likewise in developing countries, completely lose track of the biological reality (CDC 1999, WHO 1998, Robert-Koch-Institute 1999, Fiala 1998, 2000, Duesberg 2000).

The exposure factor primarily comes from specific risks through excessive prooxidative stress, and secondarily through chemotherapy against the alleged HIV infection (as shown by the example of the doubled number of AIDS cases of hemophiliacs, who in the named cities were increasingly involved in clinical studies with chemotherapeutics (Kremer 1998 a, 1998 c)).

Evidently a genetic disposition factor is included. For a long time the correlation between the blood group and certain illnesses like cancer, asthma, rheumatoid arthritis etc. has been known. Blood group characteristics in red blood cells are carbohydrates that can be differentiated in individuals but also in races, and they are determined by means of a certain genetic variability (multiformity of the genotype, polymorphism). This polymorphism, however, simultaneously corresponds to the inherited polymorphism of serum protein groups, of intracellular enzyme groups and of the human leucocyte antigen, locus A (HLA) systems. The latter are present in differing numbers as sugar proteins on the surface of the cells of almost all tissues. The HLA gene complex, the major histocompatibility complex (MHC) located on chromosome 6, which covers about a thousandth of the human genome, provides an extraordinary number of HLA phenotypes and is divided into four main areas. There are interactions between the various HLA types and certain illnesses. HLA-D region antigens appear only in certain cells, above all activated T-cells, B-cells, macrophages and their precursor cells—the monocytes. They play an important role in the interaction between the antigen-presenting cells and the cells operating the immune response.

Already in the 1970s it was recognized in the USA and Canada that kidney patients, who developed opportunistic infections and Kaposi’s sarcoma during immunosuppressive treatment with Azathioprine, were overproportionally of Jewish, Italian or African descent and that in these patients the HLA-DR5 locus was dominant. It was assumed that as a result of genetic deviation of HLA-DR5 locus even a relatively low immunosuppression could trigger Kaposi’s sarcoma:

“Moreover, it has not escaped our notice that X-linkage [an abnormal constellation of male X chromosomes] is frequent among the congenital immune deficiency disorders, and that the male: female ratio is high both in renal transplant and in AIDS patients (including nonhomosexual patients). These observations suggest both DR-5 and X-linkage as important factors in the etiology of AIDS” (Levine 1984, O’Harra 1982, Harwood 1984).

The only group of patients at risk from “HIV”/AIDS who have unquestionable congenital disposition factors are male hemophiliacs. These patients with deficient factor VIII (more unusually factor IX) of the coagulation cascade due to a congenital defect have to regularly inject individual doses of these clotting factors, depending on the degree of severity, to prevent continuous bleeding. In these patients the interplay between exposition and disposition is obvious:

“As Levine has pointed out: “To understand the occurrence of AIDS in hemophilia, it is important to recognize that each vial of factor VIII concentrate will contain, depending on manufacturer and lot number, a distillate of clotting factors, alloantigenic proteins, and infectious agents obtained from between 2500 and 25,000 blood or plasma donors”. Until recently, of all the protein injected in factor VIII preparations, factor VIII accounted for only about 0.03-0.05% of the total. The rest included: albumin, fibrin(ogen), immunoglobulins and immune complexes (Eyster 1978, Mannucci 1992). Even the recent ‘high-purity’ factor VIII contains ‘potentially harming proteins’ such as isoagglutinins, fibrin(ogen), split products, immunoglobulins and, when monoclonal antibodies are used for factor VIII preparation, murine proteins in addition to albumin.” (Papadopulos-Eleopulos 1995 b).

Strangely enough, nobody could discover any molecular evidence of “HI viruses” in the clotting proteins, and yet still it was suggested to the “HIV positive” hemophiliacs that they were infected with the apparently deadly HI viruses through the clotting protein injection. Logically, “HIV characteristics” can be provoked exclusively in cell cultures through prooxidative stress and cytokine stimulation as a result of Type-II counterregulations. Therefore this laboratory trick will not work in cell-free clotting protein concentrates. The lack of evidence of “HIV characteristics” in the factor VIII preparations conclusively rebuts the supposed “HIV transmission,” as well as the laboratory findings of “HIV positivity” in hemophiliacs as apparent evidence that the positive test reaction must have been caused by an “HIV infection” through injection of clotting protein concentrates. According to the logic of the HIV/AIDS theory, the wives or partners of hemophiliacs must have infected themselves with “HI viruses” through unprotected intercourse before the introduction of the “HIV tests” at the end of 1984, however, there is no evidence for this. It was proven, however, in a number of studies that the “HIV positivity” of hemophiliacs depends on the total amount of foreign proteins received in a lifetime. After introduction of genetically-produced (recombinant) factor VIII preparations, the number of new “HIV” infections abruptly dropped to levels below those of HIV negative hemophiliacs (overview Papadopulos-Eleopulos 1995 b, Duesberg 1995).

The findings of these studies answer the question of why precisely these patients had an “HIV seroconversion,” that is to say a reversal of the “HIV test” result from “HIV negative” to “HIV positive” as reaction to the human cell proteins of the test antigens of the “HIV test.” There is a logical link between disposition and exposure which is completely independent of the impact of “HI viruses” given that the “HIV positives” at the time of the “HIV seroconversion” have a systemic glutathione deficiency (Eck 1989, Buhl 1989, Roederer 1990) and feature a reprogramming from a type 1 cytokine profile to a type 2 cytokine profile (Clerici 1994, overview Lucey 1996), and that a long-term type 2 cytokine profile effects a long-term inhibition of cytotoxic NO production (overview Lincoln 1997). It can be assumed that the hemophiliacs, as a consequence of their genetic disposition, belong to the group of people whose redox status is more sensitive, who even with a relatively minor reduction in the thiol pool (reduced glutathione, cysteine) react with a shift in the type 1 to type 2 cytokine balance. The constant irritation to the antigen-presenting cells and the T-4 cell systems through injection of a diversity of foreign proteins (alloantigens) and the prooxidative effect of the increased amounts of prophylactic factor VIII in themselves cause a continuously increasing consumption of thiol. Beyond a critical threshold of the glutathione levels in the antigen-presenting cells, depending on the redox status, a shift to the dominant biosynthesis of type 2 cytokine profile in T-4 cells is provoked (Peterson 1998). The result is an inhibition of cytotoxic NO gas production and the increased production of polyspecific and autoantibodies (Hässig 1996 c, Wang 1999). Above a certain number of antibodies the sensitivity threshold of the “HIV test” is exceeded and the quantative intensity of the reaction of antibodies in the blood serum of hemophiliacs to the human cell proteins of the so-called “HIV test” registers an “HIV positive” result.

As the first “HIV positive” hemophiliacs, in the belief of a supposed deadly HIV infection, submitted a lawsuit against the German government concerning violation of the legal provisions of the German drug laws on surveillance of the production of factor VIII, a spectacular parliamentary board of enquiry was organized. On the basis of the board’s report, the German parliament decided to pay 2,000 DM per month to “HIV positive” hemophiliacs and 3,000 DM per month to hemophiliac AIDS sufferers from taxpayer’s money. But the pharmaceutical companies, the producers of the factor VIII concentrate, were exempted from payment. The international experts, who had been questioned by the board, had remained reticent in full knowledge and willful of the medical facts, which very definitely spoke against an “HIV infection” of hemophiliacs (Deutsches Bundestag 1994). The hemophiliacs accepted the material compensation and carried on being treated “prophylactically” with aggressive chemotherapy that had already cost many of their lives. At the same time show trials were staged in a number of countries against doctors who, either belatedly or inadequately, should have sterilized blood and blood products against “HI viruses” that nobody had actually isolated and against the “HIV characteristics” in factor VIII preparations that nobody had been able to find. With this strategy the belief in a deadly HIV mass contagion was consolidated by those affected and in the public consciousness with the help of a media who, just like doctors, politicians and pharmaceutical companies feared a loss of credibility and lawsuits for damages if the blatant research errors and resulting treatment were to become known. The silent majority of ethically aware but ill-informed doctors acted passively; the dimensions of the organized scientific swindle obviously transcended their power of imagination.

The evolutionary-biologically programmed interplay between disposition and exposure also explains much of what is puzzling in the risk groups of homosexuals and intravenous drug addicts, for instance why with the same excessive prooxidative exposure only a small percentage of those affected, contrary to the speculative claims of HIV/AIDS physicians, had developed an “HIV seroconversion.” In principle, everyone can have polyspecific antibodies and autoantibodies in blood serum that can react to the human cellular proteins of the test antigens of the “HIV test.”

Additionally the patients have to be genetically predisposed in such a way that the average glutathione depletion of 30%, apparent in “HIV positives,” is sufficient to trigger a type 2 cytokine dominance that in turn stimulates an unusually high number of antibodies. Thus, besides the prooxidative exposure, there must be a genetic disposition that activates the redox-dependent genetic expression for the biosynthesis of type 2 cytokine proteins more quickly and for a longer time span than people with the same prooxidative glutathione depletion. As the disposition to early type 2 cytokine stimulation leads simultaneously to the inhibition of cytotoxic NO gas production, these people will not be sufficiently capable to eliminate intracellular fungi, mycobacteria, and other opportunistic agents, therefore the antibody levels will continue to rise via antibody production against the “opportunistic agents” that are usually easy to repel with NO gas. Even in cases of a relatively low glutathione depletion, such people genetically predisposed to greater redox sensitivity will switch to a type 2 cytokine dominance, which chokes NO gas production and forms a high number of polyspecific and autoreactive antibodies (i.e. “HIV positivity”), while those with a less sensitive predisposition either will not adjust the cytokine balance, or alter it only temporarily. Precisely the same reaction over-readiness is observed in both organ transplant and surgical patients. The majority of transplant patients exhibited a variable cytokine balance without developing Kaposi’s sarcoma (KS) and opportunistic infections (OI), while roughly 6% had a particular immune status corresponding to a persistent type 2 cytokine dominance and suffered from KS and OI. Similarly the surgical patients, of whom more than 50% had weak or anergic DTH skin reactions (as expression of a deficient Th1 reactivity) before operations, switched from a type 1 cytokine to type 2 cytokine balance, which in most cases normalized on the seventh day after the operation. However, those patients who maintained a dominant type 2 cytokine reaction (roughly 5% of the preoperative anergic patients) developed a significant sepsis (microbial proliferation) with a high mortality rate.

There is a striking similarity between the percentage of patients with primary persistent cellular immune weaknesses of a type 2 cytokine dominance in both organ transplant and sepsis patients, and the percentage of patients in the homosexual and drug-abusing subpopulations (in the USA annually 5% of all “HIV positives” are registered as AIDS cases, including the symptom-free “HIV positives” with a T-4 cell count in the bloodstream under 200 per microliter) (CDC 1999). This supports the view that disposition factors also play an integral role in determining whether a thiol deficit caused by primary prooxidative stress, triggers such a sustained Type-II counterregulation of cellular dyssymbiosis that the associated glutathione depletion, in cases of persistent prooxidative exposure to risk and/or secondary prooxidative chemotherapy without compensatory therapy, advances until clinically the procedural events of symptom-free “HIV positives” move from the transitory phase of pre-AIDS to the phase of a T-4 cell count of below 200 per microliter or to the manifest stage of opportunistic infections, wasting syndrome, muscle and nerve cell degeneration, and/or tumorigenesis.

The information gathered in the 1970s that organ transplant patients with OI and/or KS (AIDS) predominantly showed signs of a particular anomaly in the HLA system (MHC class II) (O’Hara 1982), did not interest the virus hunters anymore after the disease theory “HIV causes AIDS” was proclaimed as the official global doctrine. The fact that the only common grounds of the risk groups that precede the later appearance of clinical AIDS are the early systemic glutathione deficit, the type 2 cytokine switch, the inhibition of cytotoxic NO gas production, the mitochondrial deactivation and the glycolytic energy production of an increasing wasting syndrome, was largely ignored by the HIV/AIDS establishment. Similarly, the only genetically homogenous risk group, the hemophiliacs—dependent on exposure to highly contaminated clotting factor preparations for life, as a subpopulation—had by far the highest “HIV” incidence (10 to 15 times higher than the genetically inhomogenous subpopulations of homosexuals and drug abusers), although, even within the framework of the HIV/AIDS theory, there was no evidence of “HIV characteristics” in the only possible medium of transmission: the cell-free (!) clotting protein preparations (overview Papadopulos-Eleopulos 1995 b).

In striking contrast, in the homosexual and intravenous drug abuser risk groups, the anal passageway via semen, and the bloodstream contaminated via dirty needles were considered ideal modes of transmission by HIV/AIDS scientists. However, the propagandists of HIV transmission could not explain why, in sharp contrast to their forecasts that have never been revised, with the same potential transmission risks in the homosexual and intravenous drug abuser risk groups, only a relatively small and constant percentage of homosexuals and drug abusers developed an “HIV seroconversion” over the last 15 years in comparison to the total population of these risk groups.

The dogmatically submitted prognoses over the last fifteen years were 10 to 15 times higher than the actual number of “HIV” cases among homosexuals and intravenous drug abusers (CDC 1999, WHO 1998, Robert Koch Institute 1999, Duesberg, 1998, 2000, Fiala 2000).

For instance, there are some 20,000 intravenous drug abusers in Germany’s prisons. The legal authorities have repeatedly claimed in public that they cannot prevent the injection of heroin and other substances, above all the multiple use of needles, in prisons. If we assume that only every other imprisoned drug addict uses a used needle per day, then over 15 years there would have been roughly 55 million opportunities to transmit the “HI viruses.” Experts and politicians from all parties have denounced prisons as the most dangerous places for the spreading of the “deadly mass contagion of HIV.” Upon arrival in prison every drug abuser is routinely tested for syphilis, hepatitis B and for “HIV positivity.” The number of people refusing the tests is small. The quota of “HIV positive” drug abusers has remained constantly low for 15 years. For many years there was also a test upon release of drug abusers to see whether there had been an “HIV seroconversion” from “HIV negative” to “HIV positive” during the time in prison. The penal laws stipulate that the “health of prisoners has to be provided for” and that “dangers to the public have to be averted.”

The results were always the same: not one single case of an “HIV seroconversion” was found during a drug abuser’s time in prison, however, there certainly were hepatitis B seroconversions. These findings completely contradict the HIV/AIDS theory. Seemingly puzzling, they are easy to explain. In 1988, the author had predicted precisely these results—that there would not be a single HIV seroconversion in prison—and suggested that after 10 years the collected data should be analyzed, as this would have been an involuntary mass experiment, carried out in the largest possible closed society in a public building maintained and controlled by the state, with a high percentage of drug abusers and thus a high risk of infections with “HI viruses.”

     In 1998 the leading representatives of HIV/AIDS medicine of public health systems were not even willing just to discuss the results. They simply disclaimed the indubitable facts and continued selling the transmission of the supposed deadly mass contagion in prisons to the unsuspecting public. The affected “HIV positive” drug abusers continued being prescribed combined chemotherapy. As a large proportion of the drug abusers shuttled between various drug scenes, outpatient and inpatient therapy, as well as prison over the last 15 years, the cases of transmission of “HI viruses” among “HIV positive” drug abusers, according to the official predictions of HIV/AIDS medical community must have increased in terms of percentage. But this is simply not the case: the incidence of “HIV infection” in test studies at ambulatory and inpatient drug centers and during drug therapy, in prisons and of autopsies after drug-related deaths, remains constantly low. These data and facts clearly refute the theory of rampant “HIV” transmission by used needles.

Longitudinal studies of “HIV positive” drug abusers who had stopped their intravenous drug consumption or were accepted for an oral methadone substitution program, also contest HIV transmission through used needles. In these cases the immune cell status improved quickly in comparison to drug abusers who had continued with intravenous drug consumption, despite the “HIV infection” (Des Jarlais 1987, Weber 1990, overview Duesberg 1996, 1998). In these cases the “HIV test” remained positive because of the continuously available sustained numbers of polyspecific antibodies in the blood serum of the now drug-free former drug abusers. This fact is one of the many fundamental pieces of evidence that “HIV infection” does not exist.

If we assume, however, that there are genetic and non-genetic disposition factors that favor the development of a progressive thiol deficiency as a result of drug consumption in a relatively small percentage (3 to 5%) of drug abusers but not the majority, then the facts can be explained. In excessive intravenous exposure to drugs the disposition factors for increased redox sensitivity in cases of relatively low degradation of the reduced glutathione levels could cause a sustained shift in balance to a type 2 cytokine profile as well as a reduced cellular immune response in favor of a greatly increased humoral antibody response. The non-elimination of intracellular agents conditioned by this further increases antibody activity. This process is triggered in predisposed drug abusers, just as in predisposed homosexuals at an early stage of excessive glutathione consuming exposure. The hugely increased numbers of antibodies can be quantitively and qualitatively sufficient to interact with the human cellular test proteins of the “HIV tests” and to induce a positive test result. As drug abusers generally have had a drug career before being imprisoned, the predisposed drug abusers are already “HIV positive” on entering prison. The majority of non-predisposed drug abusers with the same or higher exposure have constantly been “HIV negative” on entry and remain so despite continued exposure to contaminated needles. However, unwittingly, imprisoned “HIV positive” and “HIV negative” drug abusers makes for the most wide-ranging exposure and disposition study that has taken place in Western countries in the last 15 years. 20,000 drug abusers, under state-run supervision, could be observed day to day in Germany alone. There were analogous findings in all other Western countries. The 1988 prognosis, predicted by the author of this book in his capacity as medical director of the largest social therapeutic rehabilitation clinic for delinquent drug addicts in Germany from 1981-1988, was completely confirmed; the alternative prognosis of HIV/AIDS medicine was completely disproved. These findings clearly demonstrate that toxic exposure and individual disposition are the real causes of pre-AIDS and AIDS.

Disposition factors can be epidemiologically justified. They also explain why the pathogenetic distribution patterns manifest in a Gaussian distribution curve, equally for excessive expositions as in collective populations and differing risk groups. While the majority of the exposed individuals will maintain a variable redox balance with flexible cytokine patterns, a minor percentage will develop a distinct Type-I overreaction or a distinct Type-II counterreaction. To presume a fatal mass-infection transmissible to everybody, ending in inevitable death was a priori a medical construction beyond the biological-evolutionary reality.

     In the case of the “HIV-induced” AIDS, it seemed particularly questionable to presume that the humoral (antibody-supported) immunity was operating successfully (Mildvan 1982) while the cellular immunity of the T4 helper cells against intracellular germs failed, so opportunistic infections could develop. Once patients were treated with AZT chemotherapy massive bacterial infections happened as a consequence of maturation inhibition of bone marrow cells (Rosenthal 1994, Marco 1998, Cox 1998). Because the evolutionary and biologically programmed coaction of exposition and disposition factors had not been sufficiently understood, HIV/AIDS medicine provoked the appearance of combined acquired cellular and humoral immune deficiency SCID (severe combined immunodeficiency). The untoward result was the prescription of chemotherapeutics on the basis of the objectively incorrect theory that “HIV causes AIDS.”

     The clinical and epidemiologic results demonstrate the deficits of modern medicine with abundant clarity. Modern medicine, in its submission to the monied interests of pharmaceutical companies, and the media oversimplification of lobbied politicians, let alone its own information overload and stubborn arrogance, has woefully underestimated the toxic and pharmacotoxic stressors that were its own prescription. The one-sided fixation on outdated 19th century infection theories combined with sophisticated 20th century biotechnological methods has made for a deadly combination.

The HIV and AIDS establishment’s massive projection of a supposed pandemia (mortal infection spreading on whole populations) reveals that even in the case of doubtless increased collective charging with immune stressors (endemic multi-infectiosity, contaminated drinking water, undernourishment, adverse living conditions et al.), special disposition factors must supervene when triggering acquired immunodeficiency.

Professor Duesberg, retrovirus cancer scientist and molecular biologist at Berkeley, California, one of the most severe critics of the “HIV causes AIDS” theory, considers the “HI virus” to be a “passenger virus.” He too regards toxic reasons such as excessive consumption of illegal drugs, nitrite inhalation as sexual doping agent, medical chemotherapy and also the injection of highly contaminated clotting protein factors against hemophilia to be the real causes of AIDS in Western countries (Duesberg 1996). On the occasion of the Pretoria specialists’ conference, summoned by President Mbeki before the XIII World AIDS Conference in July 2000 (see chapter XII), he stated:

“In the light of this hypothesis the new epidemic of HIV-antibodies would simply reflect a new epidemic of HIV-antibody testing, introduced and inspired by new American biotechnology. This technology was developed during the last 20 years for basic research to detect the equivalents of biological needles in a haystack, but not to “detect” the massive invasions of viruses that are necessary to cause ALL conventional viral diseases (Duesberg 1992 a, Duesberg 1992 b, 1996, 1998, Mullis, 1996, 1998). But this technology is now faithfully but inappropriately used by thousands of AIDS virus researchers and activists to detect latent, i.e. biochemically and biologically inactive HIV or even just antibodies against it (Duesberg 1996 a)! The same technology also provides job security for other virologists and doctors searching for latent, and thus biologically inactive, viruses as their preferred causes of Kaposi’s sarcoma, cervical cancer, leukemia, liver cancer, and rare neurological diseases—without ever producing any public health benefits (Duesberg 1992 a) … To all of us who have been subjected to the American AIDS rhetoric, and indeed the rhetoric of our first meeting in Pretoria last May, about the ‘catastrophic dimensions’ of African AIDS (Washington Post, April 30, 2000), the healthy African growth rates come as a big surprise. Take as an example of this rhetoric President Clinton’s recent designation of AIDS as a ‘threat to US national security’ … spurred by US intelligence reports that looked at the pandemic’s broadest consequences, … particularly Africa … [and] projected that a quarter of southern Africa’s population is likely to die of AIDS … (Washington Post, April 30, 2000).

     The alarming tone of WHO’s joint United Nations Program on HIV/AIDS, ‘AIDS epidemic update: December 1999’ (UNAIDS December 1999), announcing that Africa had gained 23 million ‘living with HIV/AIDS,’ because they are “estimated” carriers of antibodies against HIV, since the “early 1980s” (WHO, Weekly Epidemiological Record 73, 373-380, 1998) is equally surprising in view of information available to the agency. Neither the WHO nor the United Nations point out that Africa had gained 147 million people during the same time in which the continent was said to suffer from a new AIDS epidemic. Likewise, South Africa has grown from 17 million to 37 million in 1990 (United Nations Environment Programme, June 15, 2000), and to 44 million now (“HIV/AIDS in the Developing World,” U.S. Agency for International Development & U.S. Census Bureau, May 1999). In the last decade South Africa has also gained 4 million HIV-positive people (A. Kinghorn and M. Steinberg, South African Department of Health, undated document probably from 1998, provided at the Pretoria meeting). Thus South Africa has gained 4 million HIV-positives during the same decade in which it grew by 7 million people. Moreover, although the 23 million ‘estimated’ HIV-antibody positives are said to be ‘living with HIV/AIDS’ by the WHO, the agency does not offer any evidence for morbidity or mortality exceeding the modest numbers, i.e. about 75,000 cases annually, reported by the it’s Weekly Epidemiological Records (0.012% of Africa’s whole population) (WHO Weekly Epidemiological Records 73, 373-380, 1998). The agency’s estimates of HIV-positives are indeed just ‘estimates’ because, according to the 1985-Bangui definition of African AIDS as well as to the current ‘Anonymous AIDS Notification’ forms of the South African Department of Health, no HIV tests are required for an AIDS diagnosis (Widy-Wirski et al., 1988; Fiala, 1998).

     In addition, the WHO promotes the impression of a microbial AIDS epidemic by reporting African AIDS cases cumulatively rather than annually (WHO’s Weekly Epidemiological Records since the beginning of the epidemic). This practice creates the deceptive impression of an ever growing, almost exponential epidemic, even if the annual incidence declines (Fiala, 1998). It would follow that the estimated increases in African HIV antibody (!)-positives do not correlate with decreases in any African population. On the contrary, they correlate with unprecedented simultaneous increases in the country’s populations—hardly the ‘catastrophe’ imagined by the Washington Post and propagated by the WHO and the American AIDS establishment. But this deceptive AIDS propaganda biases a scientific analysis of African AIDS by all those who are not aware of the facts” (Duesberg 2000).

In other words, the actual figures recorded in the WHO epidemiological reports on total morbidity and death rates in African states are hardly higher than in Western countries. Namely 0.012% of Africa’s total population fall ill and die of AIDS per year (WHO Weekly Epidemiological reports since 1991), compared to 0.001 to 0.002% of total populations in Western countries (CDC 1999, Robert Koch Institute 1999). The absurd propagandistic claims insisting on a “African pandemic” distributed to the international media by the WHO are based on arbitrary extrapolation of small random samples received by abusing the “American biotechnology” that uses the “anti HIV antibody test” (Duesberg 2000).

     Based on the not very reliable acquisition of pathogen data, compared to Western countries and because of the small fund of medical research results in developing countries, it is much less obvious to draw conclusions on the exposition and disposition interaction for morbidity and mortality in causal connection with systemic diseases of Type-II cell dyssymbiosis. However the population explosion data in African countries shows comparability with demographic processes in Western countries 150 years ago. With gradual improvement in living conditions and medical and social standards, infectious disease rates will decline and toxic stress will increase. Increased collective charge, irrespective of gender, with variegated immunostressors with simultaneously “surprising” (Duesberg 2000) low AIDS incidence (WHO Weekly Epidemiological Records since 1991) when compared to Western countries and the parallel population explosion in Africa give reason to presume that disposition factors must play a role. The consequences for developing countries as for Western countries are the same: protection from the abuse of “American biotechnology” (Duesberg 2000) and the “blessings” of Western chemotherapy and chemoantibiotics while promoting knowledge on evolutionary biologically programmed redox protection.

Disposition factors act via the peroxidation control system (creation of hydrogen peroxides, H₂O₂ and lipid oxides) and nitrosylation of transcription proteins (bonding NO and NO derivatives with hydrogen sulphide groups of proteins containing cysteine, RSNO). In the case of too high glutathione consumption this control system initially raises, as a sensor, the activity of antioxidative genes and the metabolization of H₂O₂, lipidperoxidation and RSNO (Hausladen 1996). After depletion of the neosynthesis of glutathione and other antioxidative enzymes (catalase, superoxide dismutase, selenium dependent glutathione peroxidase, glutathione transferases, NADPH-dependent glutathione reductase), the hypoxic/pseudohypoxic emergency routine is switched on. From an evolutionary biological point of view, the early and sustained switch of the cytokine balance to humoral and antibody-supported immune response was advantageous, because the bacterial threat predominant in the course of the evolution could be efficiently averted. Bacteria proliferate faster than opportunistic pathogens. They can be inhibited and destroyed efficiently through the defense mechanisms of non cell-related humoral immunity, complement formation, opsonization (coating of bacteria membranes by special target molecules for antibodies) and by the antibodies themselves, which are formed by B-cells matured in the bone marrow. The larger fungal and parasitic pathogens, equipped with mitochondria, and mycobacteria with a special cell membrane are stopped most efficiently by interaction between the non-specific and specific immune cell networks. If not inhibited in time by the gas attack, many parasites can invalidate the NO gas synthesis via special surface molecules (glyco-inositol phospholipids).

     Multicellular (extracellular) parasites can emit specialized enzymes, which attack tissues (proteinases), and trigger a type 2 cytokine response (Th2 immune response) as a suitable form of reaction, since combating worms, for example, would require too large quantities of NO gas which would in turn damage the body’s own tissue cells. Metastatic cancer cells also utilize the biochemical supply of proteinases for pervading tissue and thereby deactivate the NO gas production in neighboring cells. Cancer cells are characterized by low NO gas synthesis (Ignarro 2000) and greatly affected by high NO gas levels (Xie 1996, Chinje 1997). All in all, a one-sided Th2 (cytokine 2) immune response is a disadvantageous disposition for blocking intracellular pathogens (fungi, parasites, mycobacteria, some virus species) and the inhibition of metastatic cancer cells (Zvibel 1993, Liew 1994, 1995 a, 1995b, Mosmann 1996, Abbas 1996, Lucey 1996, Xie 1996). Immune defense depends on an appropriate and flexible combination of defense and regulation strategies.

On balance, the importance of the evolutionary advantage of a redox-sensitive sustained type 2 cytokine immune response has changed through advances in civilization and the developments in modern medicine, especially on introduction of vaccination programs and antibiotics over the last 50 years, while toxic and pharmacotoxic effects of the impact of civilization have gained in importance as a threat to cellular symbiosis.

People with a particularly redox-sensitive disposition are now at a disadvantage because they respond to toxic influences faster and with a more sustained Type-II counterregulation that would be better suited to the inhibition of extracellular bacteria or multicellular parasites.

Thus, the immune system chooses the evolutionary biologically programmed, but “wrong” strategy, because it is mislead by toxic stressors, which did not exist as part of natural evolution. This development is reflected in the steady rise of cancer and other systemic diseases over the last 100 years in the industrialized countries. Today, the main sources of toxic exposition which favor the development of cancer and other systemic diseases in the industrialized countries are: toxin residues in nutrition, in the environment and at working places, and the use of tobacco (Loeppky 1994, Walker 1998, Waite 1998, North 1998) as well as pharmacotoxic medication and toxic pharmaceutical decomposition products (Kalow 1993). The individually predisposed efficiency of redox-dependent detoxification capacity is the critical disease factor for the actual incidence of Type-II cell dyssymbiosis through toxic and pharmacotoxic nitrosation and peroxidation.

Long after Warburg made his historic declaration at the conference of Nobel laureates held in Lindau on Lake Constance in 1967—that there is no disease whose prime cause is better known than cancer (Warburg 1967)—an expanding field of research has been established which examines in humans the effect of individual metabolic disposition on the detoxification of pharmaceuticals. This field of research was very quickly expanded to include the direct and indirect effects of toxic substances on cancer genesis (overview Kalow 1993, Daly 1994). These studies concentrate, corresponding to the molecular genetic mainstream of cancer research, on the variability of genetic expression for biosynthesis of xenobiotic-metabolizing enzymes (genetic enzyme polymorphism):

“The paradigm for mechanism of action of chemical carcinogens has been well established in model cell culture and animal systems, and studies in humans appear to support the possibility that most cancers are initiated by chemical/dietary exposures and proceed through various stages of preneoplastic lesions consisting of partially transformed cells to full metastatic cancers (Vogelstein 1993). In rodent models, the progression stage can be enhanced by treatment with tumor promoters, which themselves do not necessarily exhibit the properties of carcinogens (Hennings 1993). These chemicals are thought to mediate cell proliferations that fix the mutation in the genome. Another class of chemicals called nongenotoxic carcinogens has been described in rodent model systems (Jackson 1993, Barret 1995, Costa 1995). These agents are not metabolically activated to genotoxic derivatives but presumably alter cell-cycle control. Many nongenotoxic carcinogens are also tumor promoters. However, their mechanisms of action are not presently known.

     It is widely held that humans differ in their susceptibilities to cancer. Certain individuals may be more susceptible, whereas others are more resistant to cancer. This may be due to a number of factors including health, nutritional status, and gender. From what is known about the mechanism of action of carcinogens, it is thought that genetic background could play a significant role. The responsible genes are probably those encoding the xenobiotic-metabolizing enzymes (XMEs) that activate or inactivate carcinogens (Gonzalez 1995, Nerbert 1996). Variable levels of expression of these enzymes could result in increased or decreased carcinogen activation. In fact, it is well established that genetic differences occur in expression of XMEs” (Hirvonen 1999).

In other words, genes are effectors in complex, self-organized networks, which under the influence of redox-dependent sensors encourage or discourage the biosynthesis of enzymes. If the enzyme systems are individually more strongly predisposed to activating carcinogens rather than deactivating them, then there are more demands on the antioxidative capacity. The thiol pool and other activities could become exhausted more rapidly from protecting the respiratory chain, the macromolecules and lipids. The result is that in the long-term the redox milieu changes and the dominant cytokine profiles switch, earlier and in a more sustained manner, to type 2 cytokines. The production of nitrogen and oxygen oxides are choked and the highly fluid micro-Gaia milieu transforms permanently to a less fluid milieu.

Dependent on time, re-fetalized tumor cells could form (Type-II counterregulation of cell dyssymbiosis). If in this situation prooxidative chemotherapeutics are in use, the desired apoptosis/necrosis can be selectively forced in a part of the cells (Type-I overregulation of cell symbiosis), but by the same token this can also accelerate a fully developed transformation into metastatic cancer cells inside other cells. Basically, all phases of still-to-be-compensated cellular dyssymbiosis, primarily in tumor tissues but also secondarily in differentiated tissues, can switch over unpredictably to a decompensated cellular dyssymbiosis phase. It is a characteristic of the principle of chemotherapeutic treatment that patients with a particularly redox-sensitive disposition, who become ill because of this genetic and supragenetic predisposed redox sensitivity, will not only have cellular dyssymbiosis in manifest tumor tissues but also in other tissue types and that tumor cells will respond to the targeted attack of chemotherapeutics in manifestly decompensated tissues in a diversity of ways in the various phases. Therefore, there can only be a conditional homogenous responsiveness of tumor cells to chemotherapeutics, and the results of therapy schemata cannot be sufficiently calculated individually. Consequently, for patients with a systemic disease, the distinctive genetic polymorphism of carcinogen-activating detoxification enzymes become manifest in the course of the disease. Redox-sensitive variability of the xenobiotic-metabolizing enzymes applies mainly to cytochrome P450-dependent and flavin-containing monoxygenases, epoxide hydrolases, glutathione transferases, N-acetyl transferases, NAD(P)H-ubiquinone oxidoreductases, myeloperoxidases etc. (overview Wilkinson 1997, Hirvonen 1999). Such patients most urgently require a balancing of the thiol pool and redox state. Chemotherapeutical treatment and the consequent extreme prooxidative stress must inevitably have had a counterproductive effect on patients with systemic diseases because such therapy is normally done without compensating for the depletion of the thiol pool, the dysregulation of amino acids and the cysteine balance; and it is done without moderating the Type-II counterregulations. Chemotherapy triggers the desired destructive cell effects as well as individually non-calculable cell dyssymbiotic counterregulations, causing among other things systemic wasting syndrome.

Genetic tests of questionable value were developed to determine the individually predisposed variability of the isoforms of detoxification enzymes. In the USA, for example, prophylactic mastectomies were performed to avoid breast-cancer on the basis of such genetic tests. Such deterministic prognostics by means of genetic tests are to be viewed most critically for a number of reasons. If they have any significance at all, then at the most as an inducement for purposefully influencing the individual balance and regulation therapies in the interplay between exposition and disposition through nutritional measures.

“It is anticipated that rapid advances will be made in methodology to determine potential metabolic at-risk genotypes. These advances may include less invasive collection methods for test samples (e.g., buccal cell and urinary cell samples), automated DNA extraction combined with robotic sample handling, and high-density oligonucleotide array-based genetic test methods. At present, many research laboratories are conducting association studies and contradictory reports are emerging in specialist literature. Several sources of potential bias exist that partly account for these divergent findings, usually an initial small study showing a positive association. This raises the important issue of power calculations in planning subsequent studies. High profile reporting to the public of results of studies that may ultimately turn out to be erroneous is also problematic in this context. Also, there recently has been debate about publication bias—selective publishing of only positive associations. If the potential biases mentioned above are carefully controlled, genetic screening studies may in the near future help us identify susceptible individuals and subgroups in environmentally exposed populations. Companies offer gene tests to individuals and employers. As long as this testing is not scientifically and ethically above reproach, it can benefit only companies selling the tests. There is an urgency to address several important ethical questions with regard to societal and public health” (Hirvonen 1999).

This gene-technological development of tests demonstrates the predominant tendency to overemphasize structural gene aberrations instead of considering the bioenergetic conditions for genetic expression for the biosyntheses of enzyme proteins and studying exposure risks and compensating individual dispositions by non-aggressive prevention.

All available experimental, clinical and epidemiological data result in the main principles of diagnostics, prophylaxis and therapy of systemic diseases in clinical practices. Pre-AIDS and AIDS, because of the relative straightforwardness of the cause and effect relationship between exposure and predisposing factors, present a good model of the overregulation and counterregulation of the cellular symbiotic interactions in immune and non-immune cells and the consequential systemic processes.

There is no reason for panic should a patient find himself stigmatized as “HIV positive” as a result of the “HIV test.”

Death prognoses are an expression of limited medical knowledge rather than justified in biological fact. The period of incubation from the “HIV seroconversion” to manifest symptoms averages 12-15 years. In the USA, where patients are treated aggressively and early with prooxidative chemotherapeutics and chemoantibiotics about 5% of patients stigmatized as HIV positive become ill. Consequently, under these conditions, it would take 20 years for all “HIV positives” to actually become manifestly ill. However the actual incidence depends on the persistence of primary exposure risks, on the secondary exposure risk through the aggressive therapy schedule and on the omission of targeted compensatory and regulatory therapies, if they are necessary in the first place.

A careful anamnesis of the patient is necessary; it is not enough just to state that he belongs to a risk group. Allergy predisposition or atopic skin diseases, asthma etc. can be important indicators for a patient’s disposition to type 2 cytokine reactions and increased antibody production. The absence of typical bacterial children’s diseases can, with other indicators, also be a sign of a type 2-disposition. As more than 70 symptomatic conditions can result in a positive HIV test reaction and even the HIV/AIDS researchers categorize a priori 5% of all confirmed positive “HIV tests” as insignificant diagnostic findings, medical actions cannot and must not be guided by the positive result of the “HIV test,” irrespective of the non-isolation of an actual immune weakening “HI virus.”

The determination of the immune cell status and antibody status are obligatory. The number of differentiated cells measured within the immune cell network and the immunoglobulin classes cannot alone be considered reliable indicators for the actual existence of an immune cell deficiency in symptom-free patients as, within any healthy population, roughly 5% have T4 cell values below 500 per microliter in their blood stream. For HIV/AIDS medicine this T4 cell count is already interpreted as a reason for chemotherapeutic and chemoantibiotic intervention in patients testing HIV positive. In healthy people the T4 cell counts can even drop below 200 per microliter without a serious loss of cellular immunity functions. Without seriously limiting their functionality, the number of T-helper immune cells in the blood stream depends on multiple influences. Valid information can be obtained through the DTH recall antigen test (antigen recall test of the skin, delayed-type hypersensitivity). A strong DTH test reaction is considered a reliable indicator of the actual functionality of type 1 cytokines, activating a cytotoxic NO defense gas against the intracellular pathogens after antigen stimulation (Christou 1986, 1995, Mosmann 1989, Hässig 1998 b).

(Note: Four weeks after the first publication of this book (in November 2001), the DTH test was withdrawn from circulation worldwide by its producer, the pharmaceutical industrial group, Aventis-Mérieux (which includes the subsidiary Mérieux-Pasteur). As Aventis-Mérieux (now merged with French pharmaceutical group Sanofi) holds the patented monopoly of the DTH test, there is no alternative diagnostic instrument. Biosyn, the German DTH test vendor, pointed out in a written statement that Aventis-Mérieux had for no apparent reason abruptly stopped delivering the DTH test. They, Biosyn, had been trying to get a license for the production of the DTH test, but Aventis-Mérieux prevented their attempt. This strange behavior can only be understood by considering the medical political background. Aventis-Mérieux had at that time (November 2001), been involved in studies using so-called naked DNA as an “anti HIV vaccine” on human experimental subjects in Uganda and Thailand. Such a vaccination was considered to promise billions of dollars in sales. An easy-to-handle DTH test could be detrimental to this purpose. In African countries, for example, the “anti-HIV-antibody test” frequently reacts positive for people previously infected with tuberculosis or malaria pathogens, which have endemic proportions there. In addition, conventional scientists deny any connections of this reaction to an “HIV infection.” In such cases, the use of DTH skin reaction tests would show a sufficient Th1 immune cell reaction, if subjects of the test didn’t manifest chronically present TB or malaria exposure of clinical relevance. A routine use of a DTH test before a mass-vaccination with naked DNA would consequently have been able to unmask the global “HIV infection” as a scientific campaign of disinformation. In the meantime, experiments with naked DNA against “HIV infection” have been suspended. Only after leukaemia appeared in infants, treated with genetically upgraded stem cells, to fight a serious immune deficiency, has a global moratorium on human trials on gene therapy been declared.)

The acute danger of intracellular opportunistic infections is not only due to the positive result of an “HIV test.” A weak or anergic (ineffective) DTH skin test reaction indicates the probability of a prevalent shift to type 2 cytokine status and the danger of opportunistic infections. (Note: Nowadays the cellular immunity can be measured using the lymphocyte transformation test (LTT). This test uses comparable antigens to the no-longer-available DTH skin test but the costs are higher. Alternatively it can be measured by cytokine 1-cytokine 2 profiles for determination of a possible Th1-Th2 switch).

Measurement of the values of reduced glutathione in the plasma, in the lung mucosa and intracellularly in the T4 lymph cells of the blood stream is essential (on the laboratory process, see Buhl 1989, Herzenberg 1997, Nuttall 1998). At the same time, the cyst(e)ine level in the plasma must be determined. Major deviations from the non-protein thiol norms must be treated, even in symptom-free patients.

The organism’s need for thiol is often underestimated or neglected. After the predominant scenarios in the “thioester-iron world” one of the essential conditions for the origin of life in the prebiotic world before the creation of cellular organisms, was the capacity of sulfur to generate bonds and exchanges between protons of the sulfhydryl groups through “weak interactions” (De Duve 1991). Saltwater contains a naturally elevated sulfur concentration, but for terrestrial life forms there is a consistent danger of latent deficiencies of non-protein thiols and sulfates. Both are indispensable because they are responsible for the regulation of the redox milieu, the functioning of cell symbiosis in immune and non-immune cells and innumerable biosyntheses and biochemical reactions (Wrong 1993, Hässig 1999).

The pathognomic symptom of cellular immune deficiency (AIDS) and other systemic diseases is lack of cysteine and glutathione. (Herzenberg 1997, Dröge 1997 b, Peterson 1998, Hässig 1998 d, Kremer 1999). In symptom-free and symptomatic patients lack of thiol must be permanently compensated with individually adjusted doses. The “semiconductor thresholds” of redox-sensitive gene expression must be modulated in a sustainable and enduring manner by the negative redox potential, which depends on the glutathione system, in order to retune the enzyme activities necessary for intact cellular symbiosis.

Since the stimulation of the neosynthesis of glutathione, due to the redox-dependent enzyme syntheses, is not guaranteed, at least 2 grams of glutathione and simultaneously 5 to 10 grams of N-acetyl cysteine must be orally administered per day for 2 to 4 weeks at the beginning of compensation therapy. As protection against opportunistic pathogens the glutathione concentrations, especially in the mucous membranes, are considerably higher than in the blood plasma (for example, pulmonary mucosal fluids contain about 150 to 200 micromoles of glutathione, blood plasma less than 5 micromoles). Lack of glutathione in the lung secretion layer is an important conditioning factor for cellular immune deficiency against the Pneumocystis carinii fungi, the pathogens of the most common AIDS-indicating disease, PCP of the lungs.

In cases of distinctive resorption dysfunction caused by infectious and non-infectious changes in the intestinal mucosa, corresponding doses of reduced glutathione and N-acetyl cysteine can be administered intraveneously. After balancing the intracellular and the plasma levels of the thiol pool and the glutathione concentrations in the lung and the intestinal mucosal liquids, cysteine treatment should be continued for another six months with a daily dosage of 5 to 10 grams of N-acetyl cysteine. In addition, cysteine and methionine, the latter converted in the liver to cysteine, can be taken as part of the daily nutritional regime and can be found in low fat curds and other native organic dairy products (Bounous 1993).

Due to the deficit of convertible protons, thiol deficiency causes a glutamine decrease with exaggerated protein reduction in the skeletal muscles (loss of body weight, wasting syndrome). The oral intake of up to 40 grams per day of glutamine can be used to retune the synergic effect between glutamine and cysteine levels for T-helper cell maturation (Shabert 1999).

Simultaneously this effect improves the regeneration of intestinal and lung mucous membranes, energy metabolism of cell symbiosis and acid-base balancing. The glutamine facilitates detoxification activity in the liver via the glutathione system and slows down the urea production by reducing the arginine splitting to urea and ornithine.

If there is a clear-cut arginine deficit and the linked lack of NO gas production the cellular immune performance (T-4 cells, natural killer cells, neutrophile granulocytes) can be significantly improved by supplementing the thiol and glutamine balance in pre-AIDS and AIDS with doses of up to 30 grams of arginine per day and up to 2% of the caloric intake respectively (Barbul 1990, Bower 1990). Synergistic adjustment of the dysregulation of amino acids cysteine, glutamine and arginine can be achieved in the case of massive immune cell deficiency, forced aerobic glycolysis, malignant cell transformation and cell degeneration as well as a pronounced wasting syndrome, by using small intestinal probes or, if necessary, by parenteral infusion solutions. In critical cases of disease, glutathione can be administered intravenously.

Highly dosed compensation for thiol deficiency and amino acid dysregulation must be seen as the basic therapy of the redox environment and for detoxification. These are providing the organism with much needed and natural survival resources to facilitate its self-regulation. The success of therapy must be continuously supervised by laboratory checks adapted to individual requirements, as the intake of N-acetyl cysteine simultaneously raises the glutamine and arginine levels in plasma (Dröge 1997 a).

Rigorously administered compensatory therapy, in cases of pre-AIDS or AIDS, during a well-monitored treatment phase produces better and more cost effective results than the counterproductive prescription of chemotherapeutic agents (AZT etc., “cocktail therapy,” HAART) and permanent prophylaxis with chemoantibiotics (Bactrim etc.) which may bring short-term results, but have been proven to aggravate symptoms. If chemoantibiotics such as Bactrim etc. have to be prescribed for a short time because of acute opportunistic infections, then it is vital to administer a strictly metered compensation of the thiol deficiency.

Obligatory compensation therapy can be effectively supported by a set of specific regulatory measures during the symptom-free phase of acquired immune deficiency as well as in the phase of systemic secondary diseases.

Hepatitis is often evident in members of pre-AIDS and AIDS risk groups—promiscuous homosexuals, intravenous drug users and recipients of highly contaminated blood products (Hässig 1996 b, 1998 e)—and calls for additional liver protection to bring relief to the glutathione system and phase-II detoxification enzymes (Wilkinson 1997). In contrast to the phase-I enzymes, which generate reactive electrophiles (electron-consuming substances) and activate carcinogens, phase-II enzymes inhibit electrophile bonds and turn them into water-soluble excretable substances. “Oltipraz” is a synthetic agent that has proved highly effective. It was originally designed as an anthelminthic against Schistosoma, which trigger type 2 cytokine dominance (Lucey 1996) analogous to the earlier stages of acquired immune deficiency. “Oltipraz” is a sulfur-containing dithiolthione and primarily activates the enzyme family of glutathione S-transferases. It exerts a protective function in the liver and in many other cell systems, especially the intestinal mucous membrane. Besides the protective effects against opportunistic germs and endoparasites, the agent has been shown to have antiviral and anticarcinogenic effects (overview Wilkinson 1997). These findings are significant especially after prior prooxidative damage of mitochondrial cell symbiosis caused by AZT etc. and permanent prophylaxis with “Bactrim.” “Oltipraz” is equally efficient in the activation of the detoxification enzymes in the T-helper cells (Gupta 1995). A prescription of 125 to 250 milligrams/m2 twice a week for 12 weeks is an adequate dosage, as “Oltipraz” causes a sustainable triggering of the phase-II detoxification enzymes and has very few side-effects. (Note: dithiolthione, trade name Oltipraz, up until now is only available for clinical studies. There has been no approval by the FDA, only publications about cancer treatment with Oltipraz in clinical research).

Among the natural substances, sulfur-containing isothiocyanates provide effective protection by triggering the variegated phase-II detoxification enzymes (overview Hecht 1995). These thiocyanates are inherent in vegetables like garlic, onions, as well as in broccoli and several other cabbage species.

     The other important family of natural liver-protecting agents are polyphenols. Animal and human organisms are not able to synthesize aromatic bonds with benzene rings from preliminary stages. Polyphenols must be taken in from the outside, for example by ingesting algae or plants and are thus similar to vitamins (Hässig 1997 c). The redox cycling between the glutathione system and the polyphenolic substances is crucial for the balancing of the redox milieu and the detoxification done by the polyphenols, as well as for triggering the phase-II detoxification enzymes or, as the case may be, the inhibition of the phase-I enzymes.

     Above all, polyphenols assist enzymes in cooperating with reduced and oxidized glutathione, glutathione peroxidase, glutathione reductase, glutathione S-transferases, catalase, NAD(P)H, quinone oxidase; and they inhibit the enzymes of the cytochrome P450 family (overview Wilkinson 1997).

Antioxidative protection of cell symbioses of liver cells and other cell systems including the immune cells, by polyphenols, is of particular importance in the highly acute AIDS state, if intracellular opportunists can proliferate without inhibition, due to the failure of the cytotoxic NO-gas producing Th1 helper cells. In this precarious situation, type 2 cytokine production is amplified on the one hand, but on the other hand the non-specific immune reaction of the phagocytes (macrophages) and the microglia cells in the brain are hyperactivated by the modulation of pro-inflammatory cytokines (interleukin-12, interleukin-1, tumor necrosis factor alpha and others, inflammation mediators and nitrogenic and oxidative radicals).

The elevated quantity of neopterine (as a folic acid metabolism product) and the beta-2 protein in the circulating blood are indirect markers for hyperactivation of the proinflammatory cytokine activity of the unspecific immune cells with a simultaneous suppression of the cytotoxic NO-gas production of the specific immune cells (full-blown AIDS) (Mauri 1990, Odeh 1990, Fuchs 1990, Harrison 1990, Matsuyama 1991, Krown 1991, Hässig 1993, Valdez 1997).

Consequently, well-balanced cell-protecting counterregulations fail and the simultaneous cytotoxic overregulations (prevalence of interleukin-12 compared to type 2 cytokine interleukin-10) incapacitate the feedback functions. In cases of a thiol deficiency and an overconsumption of other antioxidants, the redox balance collapses in the cytokine chaos (Cossarizza 1995).

The clinical studies concerning polyphenols over the last years have mainly concentrated on ellagic acid, the polyphenols in green tea, curcumin, silymarin etc. (overview Stoner 1995, Conney 1997, Wilkinson 1997, Zhao 1999, Plummer 1999).

Another possibility is the Galenic combination of glutathione with polyphenolic anthocyans (Recancostat, Ohlenschläger 1994) or with the ginkgo biloba polyphenol (S-acetyle glutathione, SAG). The polyphenolic complex phytotherapeutic “Padma 28,” produced in Switzerland from a traditional recipe of Tibetan medicine, containing 20 herbal flavonoids and tannins, has proved its worth in protecting the liver in chronic cases of hepatitis B (Brzosko 1992, Liang 1992, Hässig 1997 c).

Additionally, reinforcing the supply of glucuronic acid can relieve liver cell symbiosis. Glucuronic acid plays an equally important role as a phase-II regulator of prooxidative and carcinogen-activating foreign agents in the liver by transforming toxins into secretable substances. Kombucha, the organic product from China, containing a symbiosis of fungi and specific bacteria, is a natural source of glucuronic acid that contains, besides high concentrations of glucuronic acid, vitamin B compounds and antibiotic substances. Kombucha can be made at home (Frank 1992).

The characteristic progression of prostaglandin synthesis, especially PGE 2, under the influence of type 2 cytokine dominance in pre-AIDS or AIDS, as part of the Type-II counterregulation, can also be countermodulated therapeutically or preventively. Elevated quantities of PGE2 inhibit, like the type 2 cytokines, the synthesis of the cytotoxic NO gas and thus enhance opportunistic infections. The prostaglandins are products of the arachidonic acid, an essential fatty acid. Arachidonic acid is enzymatically metabolized into prostaglandin within the cell’s plasma membrane by the enzyme cyclooxygenase (COX). In AIDS, cancer and other systemic diseases, the COX-2 isoform appears elevated. COX-2 increases PGE2 production and also raises the type 2 cytokines interleukin-6 production, which can trigger wasting syndrome (Hack 1996). Symptomatic for all systemic diseases like AIDS and cancer, wasting syndrome can be influenced by the selective inhibition of the COX-2 (O’Hara 1998). PGE2 is enzymatically generated by COX-2. In the same sense as growth factor TGF-ß, it activates the generation of polyamines from the arginine product ornithine. Therefore, the blockade of COX-2 through medication also inhibits tumor growth, reduces wasting syndrome and improves the Th1-Th2 balance of cellular immunity (Subbaramaiah 1997, Huang 1998, Jones 1999, Lipsky 1999 a, 1999 b, Sawaoka 1999, Golden 1999, Masferrer 2000, Kune 2000, Prescott 2000, Reddy 2000, Higashi 2000, Stolina 2000).

However, in symptom-free patients with a weak or an anergic Th1 immune cell population, prostaglandin modulation through essential fatty acids is a better option for treatment. In animal testing the Th1 immune cell population’s stimulability in the DTH skin reaction test was inhibited, when 15% of the intake of calories consisted of linolenic acid, but not with the same quantity of fish oil with its high content of omega-3 fatty acid (Alexander 1990). Just as cold water fish can supply their needs of essential fatty acids by eating sea microalgae, patients can cover their requirement of essential fatty acids for prostaglandin modulation by the nutritional intake of contamination-free microalgae in powder or in tablet form (e.g. chlorella vulgaris). Admittedly it is necessary to ingest a couple of grams per day for several weeks in order to stimulate immune cell reaction and inhibit tumor formation. The effect of the mitochondrial cell symbiosis protection is improved by simultaneous substitution with cysteine, glutamine, arginine and RNA (Bower 1990, Cossarizza 1995, Chuntrasakul 1998, Gianotti 1999).

The low or high fluidity of the micro-Gaian milieu of cell symbiosis and the fluidity of the cell membranes reflect the type and the composition of the multi-unsaturated fatty acids (Bower 1990, Fernandes 1998, Simopoulos 1999, Zelenuich-Jaquotte 2000). The interaction between the synthesis of NO and its derivates and the prostaglandin PGE2, which is synthesized from the arachidon essential fatty acid, is equidirectional in small amounts but antagonistic in larger amounts (overview Lincoln 1997, Minghetti 1998). This interaction is of vital importance for the prevention and therapy of Type-II counterregulations of cell dyssymbiosis (systemic diseases) including the type 1 to type 2 cytokine switch (cellular Th1 immune deficiency, pre-AIDS) combined with pro-inflammatory macrophage hyperactivation (opportunistic infections, full-blown AIDS). It is possible to effectively counterregulate massive regressions of the cell symbiosis with omega-3 multi-unsaturated fatty acid and its derivatives (Veierod 1997, Imoberdorf 1997, Gogos 1998, Albert 1998, Ogilvie 1998, De Lorgeril 1998, Tashiro 1998, Rose 1999, Bougnoux 1999, Burns 1999, Bartsch 1999, Biasco 1999).

The use of micronutrients (vitamins, minerals and trace elements) must be considered in a differentiated way regarding compensation and regulation therapies for the prevention of pre-AIDS and AIDS as well as for other systemic diseases.

“Nowadays the intake of vitamin E, in combination with vitamin C and ß-carotene, is worldwide the standard antioxidative treatment. In The Antioxidant Supplement Myth, Herbert critically analyzes this process (Herbert 1994). He conclusively demonstrates that this process is afflicted with serious disadvantages as pharmacological doses of a single polyphenol, like for example vitamin E in combination with vitamin C and ß-carotene, have some positive, but often damaging effects, depending on the receptor’s iron balance. As redox compounds have both prooxidative and antioxidative effects the treatment can be summed up by the sentence: supplementation (of micronutrients) can help some consumers, harm others, but for most people they have no effect whatsoever. Thus, it was demonstrated that vitamin C (ascorbic acid), in the presence of redox-active transition metal ions, like iron (Fe³⁺) or copper (Cu²⁺), can act as a prooxidant and indirectly, by the so-called Fenton reaction, help to develop highly reactive hydroxyl radicals (HO) (Fenton 1894, Halliwell 1993, Cottier 1995). The synthesis of hydrogen peroxide (H₂O₂) occurs through a slow pH-dependent dismutation of superoxide radicals: 2O₂- • + 2H⁺ ⟶ O₂ + H₂O₂. Incidentally, as chelators of free metals, tannins can contribute useful services in this situation. Kim et al., who in studies on 14,407 Americans could find no life-prolonging effects in the use of isolated and unbalanced vitamins and mineral nutrition supplements, have extensively affirmed Herbert’s critical statement. They identified the annual expenditure of $3.3 billion for nutrition supplements as a virtually useless augmentation of the health care costs (Kim 1993). In conclusion, we would like to state that a sufficient nutritive supply of a natural mixture of tannins and flavonoids is indispensable for a reliable and side-effect free antioxidative effect” (Hässig 1997 c).

Vitamin E and vitamin C generate radical chain reactions as intermediate states, which must be compensated for by the glutathione system (Ohlenschläger 1994), therefore a given thiol deficiency can be further aggravated by the intake of high dosages of these vitamins. Micronutrient requirements, in pre-AIDS and AIDS, should be evaluated in the context of a fine tuning of strict compensation and regulation therapy because deficits of individual micronutrients depend on the redox status, the mitochondrial activity, the cytokine balance, the existence of wasting syndrome, any given resorption dysfunction, severe diarrhea, toxic and infectious stressors, alloantigen overcharge, chemotherapeutic agents, chemoantibiotics, antiparasitics, fungistatics, virustatics etc, excessive alcohol, drug or cigarettes usage and many other factors. Uncontrolled self-medication does not make much sense and can in some cases even be dangerous.

A profiling study of ambulatory pre-AIDS and AIDS patients in relatively good health without a clinically definable wasting syndrome or heavy diarrhea quantified:

• Vitamin A and total carotenes, vitamins C, E, B6, B12, folate, thiamin, niacin, biotin, riboflavin, pantothenic acid, free and total choline and carnitine, biopterin, inositol, copper, zinc, selenium, magnesium and glutathione.

The results of the study confirm a reduction in the circulating concentrations of glutathione and relatively common lower serum concentrations of magnesium, total carotene and total choline plus increased niacin levels. The remaining values were within normal ranges or lower in a minority of the test subjects partly through self-medication with vitamins and minerals (Skurnick 1996).

Today’s HIV/AIDS clinical research concerning micronutrients as influencing factors for acquired immune deficiency states (pre-AIDS and AIDS) confirmed the individual dependency on deficiencies in a holistic context of dysfunctional cell symbiosis.

“Deficiencies of single micronutrients are known to adversely affect the immune system by depression of cellular and humoral immunity and the impairment of phagocytosis (Beisel 1982, Klurfeld 1993). Individuals infected with the human immunodeficiency virus type 1 (HIV-1) may be particularly vulnerable to nutritional deficiencies that impair already compromised immune function. In a previous study of HIV-1 infected patients, we found that carotenes and ascorbate were below normal in 27% of the subjects, and vitamins E and A were low in 12% (Bogden 1990). Serum levels of micronutrients in HIV-1 patients have been associated with markers of immune function and stage of disease (Fordyce-Baum 1990, Baum 1991, 1992, Semba 1993). Studies have shown that abnormalities in nutriture both accompany and predict HIV disease progression (Semba 1993, Coodley 1993, Tang 1993, Abrams 1993). These investigations assessed dietary intake or serum concentrations of one or a few micronutrients in selected cohorts” (Skurnick 1996).

The primary influence of micronutrients on the prevention and therapy of cancer was also put into perspective in comparison to the importance of the redox status, NO—and prostaglandin syntheses, the cytokine balance and cell symbiosis activity (World Cancer Research Fund 1997).

An additional measuring of the serum ferritine level must be considered essential, which in pre-AIDS or AIDS patients as in all pro-inflammatory stages of macrophage hyperactivation is evidently elevated (Gupta 1986) and plays an important role in all Type-II counterregulations (Gherardi 1991, Weinberg 1992, Herbert 1992, Gelman 1992, Lacroix 1992, Kiefer 1993). In addition to compensation therapy of the redox status, the reinforcement of the matrix has an important function in regard to the regulation of the iron balance (Pippard 1989, Hässig 1993).

The basic extracellular matrix, which embeds all tissues and organs, functions as filter for all the bioenergetic, substantial, hormonal and sensory inputs and outputs of cellular symbiosis. Among other things, the matrix is composed of a complex network of sulfate-rich protein molecules (glycosaminoglycans, proteoglycans), which are necessary for the negative redox potential. Re-fetalization of the extracellular matrix into sulfate-free hyaline acid, as present in early embryonic tissue, is characteristic for many carcinomas (Heine 1997).

For prevention and therapy, the extracellular matrix can be reinforced by a regular supply of polyanions, chondroitin sulfates in the form of cartilage preparations or shark cartilages, of macroalgae, of agar-agars or by eating macroalgae (Hässig 1992). The balance of the redox potential of the matrix synergistically supports the glutathione system and relieves cell symbioses in states of prooxidative and systemic stress (Hässig 1992, 1997 a, 1998 b).

Direct activation of the mitochondrial cell symbiosis can be stimulated by coenzyme Q10 (Folkers 1986) and L-carnitine (Bremer 1990).

Coenzyme Q10 plays an important role in the electron transfer in the mitochondrial respiratory chain. In symptom-free “HIV positives,”, Q10 deficit is already apparent and progressively increases in pre-AIDS and AIDS. Toxic stressors and prooxidative medication (AZT etc., Bactrim etc.) are decisive factors that lead to dysfunction in the mitochondrial respiratory chain and secondary defects in the mitochondrial DNA. Q10 improves the cell symbiosis performance in immune cells and non-immune cells and can be prescribed in a daily dosage of 200 milligrams for a several months without detectable side effects (overview Folkers 1988).

L-carnitine supports the participation of long-chained fatty acids (triglycerides) for the oxidation inside mitochondria. L-carnitine deficits increase glucose metabolism and facilitate a switch to aerobic glycolysis (Warburg Phenomenon). The disturbance in triglyceride transport causes lipid accumulation, which is often observed in treatment with HAART and protease inhibitors (Brinkmann 1999). Pre-AIDS and AIDS have been shown, in the context of a L-carnitine deficit, to be systemic dysfunctions of lipometabolism and of the lipid composition of the T-cells (De Simone 1991). Administrating high doses of L-carnitine, 6 grams per day for two weeks, has improved T-helper cell proliferation, lowered the triglyceride serum levels and decreased the serum values of circulating beta-2 microglobulin and alpha tumor necrosis factor as indicators for hyperactivation of macrophages in HIV positives and AIDS patients. L-carnitine also appears to stabilize the cytokine balance by ameliorating mitochondrial performance (overview De Simone 1993).

Reduced mitochondrial performance as consequence of chemotherapeutics, caused by damage to mitochondrial DNA after the intake of AZT etc. and Bactrim etc., can additionally be compensated by the daily dose of 600 mg lipoic acid (alpha-lipoic acid) plus 300 mg thiamine (vitamin B1) for a month or longer.

Targeted activation of mitochondria is especially significant for “HIV positives” but also for cancer patients, who years after enforced chemotherapy are still under the threat of multiple organ failure (myocardial infarction, sepsis, cerebral infarction, hepatic coma, myopathies etc.) as a result of potentiating mitochondrial DNA defects.

The cytokine balance and the related equilibrium between cell-mediated and antibody-supported immunity are, as all organ systems, closely related to the sensory and hormonally controlled stress systems. The retroactive hormonal stress axis between the hypothalamus, pituitary, and adrenal cortex modulates the cytokine profiles via equilibrium between cortisol and DHEA-S (dehydroepiandrosterone sulfate), both generated in the adrenal cortex. The final cortisol synthesis takes place in the mitochondrial cell symbionts of the adrenal cortex cells (Tyler 1992), so that disturbance and damage of these cells can favor grave psychosomatic stress diseases and systemic diseases like AIDS, cancer and many other symptoms. During states of high stress the synthesis and the release of cortisol increases when compared to the DHEA levels. This causes the inhibition of cytokine synthesis through the interaction of cortisol with transcription factors (Brattsand 1996). Persistent cortisol increase facilitates the antibody-supported immune response and weakens cellular immune reaction. On inhibition of the type 1 cytokine profile, however, under the strong stress stimulation of the macrophages through antigens and toxins, the release of nitrogen and oxygen radicals and of the inflammation mediators interleukin-1 and tumor necrosis factor-alpha can be increased within the macrophages. The neopterin and ferritin levels serve as a direct quantification of the extent of the inflammatory macrophage-activation and as an indirect measurement serve such markers that display the scale of the acute phase reaction, as for example the C-reactive protein (Hennebold 1994, Hässig 1997 d, 1998 b).

Inversely, a shift from a type 1 (Th1) cytokine profile to a type 2 (Th2) cytokine dominance through an increased cortisol/DHEA-S ratio means that a moderation in stress-related hypercortisolism amplifies the effect of DHEA-S on type 1 cytokine synthesis. This means an improvement to the cortisol/DHEA-S ratio in favor of the latter can expand cellular immunity by activating the type 1 cytokine interleukin-2.

There is indeed a direct correlation between the balance of T4 helper immune cells and the increased cortisol level (Th1-Th2 switch) or, as the case may be, the level of DHEA-S, the predominantly synthesized form. The development of acquired cellular immune weakness syndrome is associated with an increasing DHEA-S deficit (Biglieri 1988, Hilton 1988, Raffi 1991, Mulder 1992, Christeff 1996, Ferrando 1999). However, the 24-hour cortisol level seems to be elevated in AIDS patients, (Vilette 1990).

These findings resulted in the hypothesis that DHEA-S substitution (DHEA-S as an anti-cortisol hormone) could enhance cellular immunity for the prevention and therapy of opportunistic infections in cases of pronounced pre-AIDS and AIDS (Frissen 1990, Wisniewski 1993). The DHEA-S level as counterbalance to the ACTH cortisol system is of vital importance not only for the cytokine-controlled functions of cell symbiosis of the immune cells, but also for other cell systems (Parker 1985, Ebeling 1994, Lavallee 1996). DHEA is a precursor molecule for androgenous sexual hormones and the DHEA-S dysregulation is a co-determining factor in tumors in hormone-dependent organs such as the mammary or prostate glands as well as in tumors in other organs (Vermeulen 1986, Heinonen 1987, Barrett-Connor 1990, Stahl 1992, Le Bail 1998, Lissoni 1998, Svec 1998, Eaton 1999).

The moderation of hypercortisolism and the indirect type 1 cytokine stimulation via DHEA-S can in many cases be supported by nutritive measures, including an increase in the extracellular content of glycosaminoglycans (heparin, heparinoids). They reduce the influx of calcium ions into the inner cell and inhibit cortisol bonding on the intracellular receptors. This can be achieved through an intake of cartilage extracts (chondroitin sulfate) or of agar from sea algae (Hässig 1993, 1998 b). Simultaneously, the proinflammatory hyperactivation of macrophages (as counterregulation) in a cortisol-related type 1 to type 2 cytokine shift can be repressed by binding surplus NO and O₂ radicals by intercepting excessive free iron and the increasingly formed catabolic proteases by using complex phytotherapeutics like Padma 28, a Tibetan preparation made of polyphenolic flavonoids and tannins (Liang 1992, Hässig 1993, Gebbers 1995).

The moderation of cortisol and the reactivation of DHEA-S in interaction with the inhibition of pro-inflammatory macrophage stimulation are important additionally, as macrophages, because of their phagocytosis-performing capacities, represent a preferred reservoir for intracellular opportunistic pathogens (Rubin 1988, Meltzer 1992). The counteraction to a strong and long-lasting nitrosative, prooxidative and systemic stress effect results in an elevated cortisol/DHEA-S ratio, a weakening of cellular immunity and an inhibition of cytotoxic NO gas defense through a type 2 cytokine switch; it also results simultaneously in a pro-inflammatory mobilization of opportunistic residents in the macrophages (fungi such as Pneumocystis, Candida, histoplasms, cryptococci, parasites and toxoplasms, bacteria including mycobacteria, Listeria, Legionella and chlamydia, and many actually-existing viruses, in contrast to the phantom “HI viruses”). These counterregulations must, sooner or later, lead to clinical full-blown AIDS, if the primary stress factors can not be minimized, the proton demand deficiencies are not balanced and the dysregulation of the cell symbiosis is aggravated additionally by the use of “chemo-tactical” weapons.

     In full-blown AIDS, there is a crucial antagonism between the behavior of the non-specific immune response of the macrophages, and the specific immune response of T4 helper immune cells: The cortisol brake for the biosynthesis of tumor necrosis factor in the macrophages is suppressed by the activation of interferon-γ under strong or/and long-term stress stimulation (Luedke 1990), and the ratio of cortisol/DHEA-S in the macrophages is regulated in favor of the latter by their inflammatory cytokines (Hennebold 1994). In contrast, the T4 helper cells remain inhibited under the influence of cortisol and synthesize after receiving signals from the glutathione-depleted antigen-presenting dendritic cells, predominantly type 2 cytokines (Peterson 1998). They inhibit cytotoxic NO gas synthesis, contrary to the macrophages (loss of helper Th1 cell functions) and stimulate instead antibody production (overview Mosmann 1996, Lucey 1996, Abbas 1996, Hässig 1996 d, Lincoln 1997). The net result in the T4-immune cells is a change in the ratio of the cortisol to DHEA-S in favor of the former (Wisniewski 1993, Christeff 1996, Ferrando 1999).

The prooxidative, glutathione-consuming and mitochondriotoxic chemotherapy with AZT etc. and sustained prophylaxis with Bactrim etc. are not able to control the competing cytokine chaos resulting from nonspecific immune hyperactivation within the macrophages (Type-I overregulation of among other things: type 1 cytokine interleukin-12 antagonistic towards type 2 cytokine interleukin-10; tumor necrosis factor alpha increased; type 1 cytokine interferon-γ increased; NO-and oxygen radicals including toxic hydroxyl groups increased) and the deactivation of the specific Th1 immune response (Type-II counterregulation of, among other things: type 2 cytokine interleukin-10 antagonistic towards interleukin-12; in wasting syndrome type 2 cytokine interleukin 6 increased; in tumor cells TGF-ß increased; NO and O₂^- production inhibited). The most effective option is compensating the thiol deficiency, whereby cysteine slows down the cytotoxic effects of tumor necrosis factor within the hyperactivated macrophages and improves glutathione neosynthesis (Cossarizza 1995).

The preventive and therapeutic aim must be to balance the redox milieu, to improve the fluidity of the micro-Gaian milieu, to reconstruct the cytokine balance and simultaneously to moderate the competition between Type-I overregulation of unspecific immunity and Type-II counterregulation of specific immunity. This can only be achieved by a synergistic compensation and regulation therapy.

“Last but not least it is essential to resolutely confront the still widely propagated and officially held belief that every HIV-infected person must sooner or later progress to AIDS and inevitably die (Hässig 1992 b). On the contrary, we should give HIV positives the hope that by adapting their lifestyles to the opportunities given by nature they may be spared from the limitations of AIDS for a long time, maybe forever. To achieve this they have to come to terms with their nutritional problems. In our overview work, “The Rethinking of AIDS,” which was published about one year ago, we asked whether this could lead to a general paradigm shift in medicine (Hässig 1992 b). Nowadays, we tend to assume that such a shift will happen. The use of AZT and analogous virucidal medication as recommended by the responsible authorities, is based on the antibiotic paradigm, which means the toxicological extinction of microbial inflammation germs. Man lives, however, in an ongoing symbiosis with a whole range of microorganisms, hence the question is justifiable if it would not be more sensible to support the probiotic, physiological mechanisms of self-healing to support organisms” (Hässig 1993).

The variety of the effective and non-toxic intervention options demonstrates a possible change within medical practice “from antibiosis to symbiosis Therefore, it is the overriding task of physicians to reduce the paralyzing and destructive fear of death and instead encourage people affected by systemic cell dyssymbiosis by reinforcing their natural will to survive by clarification of the actual state of knowledge. The most effective protection against the abuse of “violent medicine” (Albonico 1997) as a modern instrument of terror and fear is the rational knowledge, that every kind of risk for and any targeted attack on the cell symbiosis of immune cells and non-immune cells is answered according to the laws of evolutionary biology.

An imagined “HIV retrovirus,” if it were to exist, would be no exception. The actual clinically monitored symptoms in pre-AIDS and AIDS would, if a biologically active “HIV agent” actually were to be the cause of the disease, be conditioned by the disturbance of the redox balance, cell symbiosis damage and by the shifting within the micro-Gaian milieu. The preventive and therapeutic consequences of the deactivation of such a biologically undetected “HIV retrovirus” would be principally the same as for all other prooxidative load factors. Irrespective of the type of exposure, these basic consequences are universally valid whether they are of a toxic, pharmacotoxic, traumatic, inflammatory, infectious, nutritive, radiative, alloantigenic, psychic or any other nature. People with an especially redox-sensitive disposition must all be advised to avoid risks of exposure and orientate their nutrition according to their blood group as a code for the genetically predisposed polymorphism of the enzyme systems (D’Amato 2000).

The lifesaving synergy of a conscientious compensation and regulation therapy is derived from the logic of the natural laws of the co-evolution between microbes and man, the processing of toxins and other bioactive stress factors, including the consequences of undernutrition and malnutrition.

The profound change in “natural” scientific knowledge of the sciences progresses from antibiosis (from the Greek: anti = against + bios = life) to symbiosis (from the Greek: sym = with, together). The foreseeable end of lethal virus hunting and of one-sided aggressive cancer expunging represents, both for those concerned and for medical therapists as well as for general population, a self-critical liberation from the staging of a collective and exploitive terrorism of fear.

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In Western countries, every third person suffers from some form of cancer, and every fourth person dies of it. The prognoses of the WHO state that by the year 2050 half of all mortalities will be due to a cancerous disease.

According to the prevailing cancer theories chance defects (mutations) in the DNA in the nucleus, which are regarded as irreparable, are considered to be the primary cause of the disease. Standard therapy in oncology (operations, chemotherapy and/or radiation therapy) is based on this assumption. The cure rates of cancer (minimum of 5 years survival after diagnosis) are given as being 45% (22% surgical treatment, 12% radiation therapy, 5% chemotherapy, 6% combined standard therapies). 60-70% of patients with incurable cancer are palliatively treated with radiation therapy, 50% with chemotherapy and less than 1% of the patients are treated surgically (EU data, 2003). In the USA, for instance 20% of the overall health budget is spent annually on chemotherapy for cancer patients.

The Nobel Prize winner Professor Watson, who together with Crick discovered the double helix of DNA in the nucleus, the most prominent promoter of the 1971 “War on Cancer” succinctly declared in 2003: “First we have to understand cancer before we can cure it.”

     The background to this sobering thought after decades of most intensive research efforts and a massive capital injection is the fact that the classic mutation theory of oncogenesis has been forever shaken by newer research. Under the mutation theory a tumor colony develops from a single “degenerated” body cell that through uncontrolled division is thought to pass on identical DNA defects to all daughter cells. However, it has become apparent that each individual cancer cell, even within the same tumor of a patient, features genetically varies.

The internationally respected cancer researchers Professor Weinberg from the MIT in Cambridge, USA and Professor Hahn from the Dana Farber Cancer Research Center in Boston, both supporters of the classic mutation theory, published in 2002 an overview of the ostensibly still puzzling six insiduous “acquired capabilities” of cancer cells. These attributes include the ability to:

1. resist exogenous growth-inhibitory signals
2. generate their own mitogenic signals
3. bypass apoptosis
4. acquire vasculature
5. gain potential immortality
6. invade and metastasize

The “Cell Dyssmybiosis Concept” (Kremer 2001) explained for the first time the six “acquired capabilities” of cancer cells as an evolutionary-biologically programmed natural (albeit overregulated) protective switch of the divisionally active human cells during permanent chronic cell stress. The origin of this concept was the evolutionary-biological discovery that humans owe their biological existence, like all nucleated single—or multi-cellular creatures (eukaryotes), to a unique act of integration deep in the history of evolution. Roughly 2 billion years ago two unicellular organisms without nuclei from the archaea and bacteria domains fused to form a new single cell type that is now termed protista. Comprehensive comparative sequence analyses regarding the genetic make-up and specific proteins of archaea, bacteria, and a multitude of eukaryotic organisms (including humans), produced an astonishing result: about 60% of the genes in a human nucleus originate from the primeval archaea (A genome) the remaining genes having a bacterial origin (B genome), which in particular in the nucleus are delegated by the bacterial endosymbionts that have survived up until today in all human cells as mitochondria (on average 1,500 per cell).

There is a controlled division of labor between the A and B genomes: the A genome dominates the late cell division phases, while the B genome drives the early cell division phase and the functions of the various differentiated cell types.

From these fundamental cellular biological facts, and integrating a large number of new experimental and clinical research data, the cell symbiosis concept leads to the following conclusions about oncogenesis and cancer therapy:

1. There is a controlled toggle-switch between the mitochondria and both nuclear subgenomes.
2. Transformation to cancer cells is a functional (not structural) failure of this toggle-switch, after the divisional phase cells are no longer sufficiently able to switch back to the differentiated cell performance phases
3. The cause of this permanent functional failure is the gradual deficiency of one of the central functions of mitochondria, namely to supply ca. 90% of the “universal energy-storing and energy-transporting molecule” adenosine triphosphate (ATP) for practically all biosyntheses and metabolic processes. Under normal circumstances roughly one’s body weight of ATP has to be synthesized and then broken up every day. ATP cannot be stored and the actual stock in human beings is enough for only 5 seconds. When the mitochondrial functions are disturbed, cancer cells intermittently or permanently revert to the archaic form of ATP synthesis in the cytoplasm (glycolysis) with, potentially, up to a 20-fold increase in the glucose turnover at the cost of the organism as a whole (cachexia resulting from the forced degradation, especially of muscle proteins for the benefit of carbon intermediary products for glycolysis, is one of the most frequent causes of death in cancer patients).
4. Hitherto perceptions about the synthesis and function of ATP molecules, the basis of all cellular biological medical theories, are, however, objectively false. ATP has 3 molecule groups: 1 base adenine ring molecule that absorbs the light quanta at near-ultraviolet levels of 270 nm, 1 sugar molecule with 5 carbon atoms as well as a—molecule string with 3 phosphate groups. The current dogma, based on a theory formed more than 60 years ago by the later Nobel Prize winner Lippmann, is that electron energy is transferred in the respiratory chains of mitochondria (of which there are literally thousands in every mitochondrion as shown by EM photographs) on discharge of “energy-rich” electrons from nutrients via a kind of electrochemical battery, to protons which for their part drive ATP synthesis energetically and store their surplus energy in the phosphate bonds of ATP. These “energy-rich” phosphate bonds of ATP transported into the cytoplasm then release this stored energy via hydrolysis mainly to maintain the energetic processes of cell metabolism. Biochemical experiments have clearly shown, however, that the phosphate bonds of ATP are not especially rich in energy and that, upon hydrolysis, only heat energy is released that can at the most be used for heat production by isotherm cells (constant cell temperature). The fundamental question of the actual mechanism for the acquisition of cell energy remains unanswered. This fact explains the predominant failure of cancer prevention and therapy up until now.
5. Biochemistry and medical science have failed to this day to explain the function of the adenine groups of ATP, as no biochemical reaction with this adenine ring molecule is shown. However, an understanding can be gained, within the framework of the cell symbiosis concept, from the biophysical attributes of light absorption of the adenine group. All essential components of mitochondrial cell respiration are light-absorbing molecules with characteristic “frequency windows” of absorption maxima from near the UV spectrum to the longer wave yellow/orange spectral range of visible light up to ca. 600nm. Yet the source of the electromagnetic energy is not sunlight. In fact a low frequency pulsating electromagnetic field is induced by the constant flow of uncoupled, paramagnetically aligned electrons in the respiratory organelles. The electromotive power generated by this process is catalytically enormously strengthened by the enzyme complexes of the respiratory chain (acceleration factor of 1017). This effects an interaction between the electrons and the protons likewise aligned parallel to the induced magnetic field dependent on the strength of the magnetic field between the antiparallelly aligned electrons and protons. This process produces a quantum dynamic transfer of information via photonic energy exchange. The ultimate source of photons are fluctuations of resonance frequencies of the physical vacuum (zero-point energy field). The transferred information is stored in the spin of the protons that proceed to the ATP synthesis complex via proton gradients. There, the resonance information is transferred by a unique rotation system to the adenine group of ATP whose electrons can move freely in the alternating double bonds of the ring molecules. The ATP serves as an “molecular antenna” for the reception and relaying of resonance information from the “morphogenetic field.” Human symbiosis is consequently not a heat power machine but a light frequency-modulated information-transforming medium. All the time this cell symbiosis is resonance coupled with the lowest, not-yet-materialized energy status (the physical vacuum as an inexhaustible “global information pool”).

6. In oncogenesis, for a diversity of reasons, there is a functional disturbance especially to the 4th enzyme complex of the respiratory chain. The task of this complex, according to conventional opinions, is to transfer the inflowing electrons to molecular oxygen at the end of the respiratory chain and thus reduce it to water. In the cell symbiosis concept, however, the crucial factor is that, in reducing O₂ to water, completed electron couplings induce an antimagnetic impulse, and the electromagnetic alternating field for resonance information transfer switches on and off at an extremely fast periodic time interval (in picoseconds). If the electron flows to O₂, however, are permanently disturbed then a failure in the modulation of ATP occurs and increasing numbers of oxygen and other radicals form that can attack and damage the macromolecules (nucleic acids, proteins, lipids, carbohydrates). In order to prevent this danger the key enzyme hemoxygenase upregulates. This enzyme uses O₂ as cofactor for the production of carbon monoxide (CO). In cases of long-term surplus production CO gas has crucial effects on cancer cell transformation:

• CO gas effects a characteristic phase shifting of the absorption of visible light from components of the respiratory chain and as a result “short-circuits” the photon switch for the modulation of the information transfer to the mitochondrial ATP.

• CO gas activates in the cytoplasm certain regulator proteins for the stimulation of the cell division cycle also without external growth signals (see above: 1st “acquired capability”).

• CO gas effects via enzymatic overactivation of the important secondary messenger substance cyclic guanosine monophosphate (cGMP) the inhibition or blockade of communication between neighboring cells (2nd “acquired capability” of cancer cells).

• CO gas blocks programmed cell death by bonding onto the bivalent iron in important key enzymes (3rd “acquired capability” of cancer cells).

The result is a polar program reversal: The transformed cancer cells remain trapped, dependent on the degree of malignancy, in a continuous cell division cycle and can not switch back to the differentiated cell performances of the respective cell types without biological compensatory aid. According to recent clinical knowledge the cancer cells become especially malignant and massively disperse metastatic cells when the O₂ supply to tumor cells via capillary blood vessels is impeded. In these cases chemotherapy and radiation treatment are no longer effective as without the presence of molecular oxygen programmed cell death of the cancer cells can no longer be induced. In this situation cancer patients are considered incurable by oncologists using standard cancer therapy.

• The cell symbiosis concept postulates that when the cofactor O₂ is deficient, then the even more effective cyanide gas (HCN) is formed instead of CO. HCN is in humans the strongest mitochondrial respiratory poison and produces an even stronger phase switching of the absorption of visible light, probably by the well known inhibition of the reduction of trivalent irons to bivalent irons of certain hemocytochromes of the respiratory chain. This hypothesis can support the evolutionary-biological views of the cell symbiosis concept as cancer cells regress de facto to unicellular organisms (as a result of the loss of cell-to-cell communication with neighboring tissue cells) and that is why they behave like “parasitic cells” (4th, 5th, and 6th “acquired capability” of cancer cells). In this sense, cancer cells represent a regression to the early eukaryotic stage of a colony of protist cells, and so use the conserved archive of evolution in human nuclear genomes as a strategy of survival, depending on the actual given milieu conditions of the individual cancer cells (for the individual genetic variations, see above).

7. In 2003, American cancer researchers confirmed a functional disruption of cancer cells in the 4th complex of the respiratory chain despite simultaneously intact messenger RNA and intact mitochondrial DNA, without being able to explain this phenomenon. However, at the end of 2002 a cancer research group from Helsinki University, after many years of animal experiments and clinical studies, were able to exactly document for the first time—using electron microscopes and mass spectrometers—that the transformation to cancer cells is actually caused by the loss of control of the cell division cycle of the mitochondria.

The clinical research team could demonstrate that the tumor cells after a relatively short time had re-programmed to intact, normal differentiated cells without signs of programmed cell death by using a particular experimentally mediated bioimmunological compensation therapy on various human cancer diseases. These patients under conventional tumor therapy had a survival status of on average less than 12 months. In 2003 researchers from the Anderson Cancer Research Center of the University of Texas in Houston published the first wide-ranging overview about the hundreds of animal experiments on the effects of curcumin, the active ingredient of turmeric (Curcuma longa, from the ginger family, biochemically, curcumin I from the molecular family of polyphenols, also termed bioflavonoids, synthesized from plants) on cancer cells and metastases. The researchers were amazed to discover that curcumin effectively inhibited nearly all signal paths in tumor cells and metastases.

The researchers were unable to provide an explanation of this wide-ranging effect. The actions of curcumin can, however, be explained if you know that curcumin in the violet spectral range of visible light absorbs with nearly the same wavelength—415 nm—as the electron-transferring molecule cytochrome c that is more rapidly broken up by the protective enzyme hemoxygenase in cancer cells. In cancer cells curcumin, so to say, bridges the III and IV complex photon switch “short-circuit” of the respiratory chain in mitochondria and thus normalizes the information transfer for maintaining modulation of ATP.

The quoted research data show that (in opposition to the prevailing cancer theories of supposedly irreparable gene defects in the nucleus) the demonstrated functional disruptions of the transfer of information in cell symbionts can be re-normalized by means of an adequate biological compensation therapy. The concept of cell symbiosis therapy (Kremer 2001) derived from knowledge gained from cell symbiosis research has in the meantime led to some spectacular therapeutic successes (in individual cases even in cancer diseases that had been declared incurable). There is a broad spectrum of classes of substances responding to natural light available and the potential is by no means exhausted. What is desperately needed, however, is a comprehensive overhaul of the current state of research with the aim of developing optimized therapeutic formulations and to make them available for clinical and therapeutic practice. Admittedly, achieving this purpose through an interdisciplinary research group within the established health system is not to be expected in the foreseeable future, as conventional medical science has largely remained stuck in the one-sided thermodynamic energy concepts of the 19th Century.

(First published in Townsend Letter Aug. /Sept. 2007)

In July 2003, “the roof of the genetic world caved in” as one researcher commented. What had happened? At an international genetics congress in Melbourne, genetic researchers from all over the world declared the “the end of the beginning” and “the beginning of the new era” in genomics research. Prior to this, the conclusive findings of one of the most ambitious research projects in modern medicine had been published; since the end of the 1980s, an alliance of international research groups had catalogued all the genes of the human nuclei, comprising over 3 billion sequences in total, using computer-assisted automatic sequencing machines. The expectation was that the human genome contained at least 120,000 genes—special sections in DNA with a coded sequence of the DNA building blocks: the four classic nucleic bases adenine (A), guanine (G), cytosine (C) and thymine (T). This assumption was based on the fact that there are over 100,000 proteins in human cells, which require a genetic blueprint for their synthesis outside the nucleus. On top of this, there are the some 20,000 regulating genes that are necessary to guide the genetic expression—the total process of the transcription of genes from messenger RNA transcripts to completed protein. In a parallel research program, genetic researchers sequenced the genes of DNA molecules in the nuclei of murine (mouse) cells. The findings were alarming: the murine nuclear genome had about 24,000 genes, nearly the same as the human nuclear genome of approximately 25,000 genes. Today, genetic researchers speak of only 21,000 human nuclear genes. This is hardly more than the number found in the tiny threadworm used in genetic research, which is only a few millimetres in length with exactly 969 cells. In comparison, humans have roughly 50 billion cells. In contrast, simple plants such as Arabidopsis thaliana (thale cress) feature proportionally more nuclear genes than human nuclei.

The Nobel prize laureate David Baltimore, one of the most respected leaders of opinion on genetic determinism of human existence at the time, observed in an almost desperate commentary on the preliminary findings of the Human Genome Project published in 2001:

“Unless the human genome contains a lot of genes that are opaque to our computers, it is clear that we do not gain our undoubted complexity over worms and plants by using many more genes. Understanding what does give us our complexity … remains a challenge for the future” (Baltimore, D. 2001 Our Genome Unveiled. Nature 409:814-816).

What Baltimore and the vast majority of his colleagues do not state, after the collapse of the genetic worldview, is the fact that all fundamental theories of modern gene technology focussed medicine on cell energy, cell information and cell-to-cell communication are in need of comprehensive revision.

This author, on the basis of analysis of a great diversity of evolutionary biological research data, postulated (in contrast to the perceptions of contemporary evolutionary researchers) that the human nucleus in actuality has a double genome: an evolutionary biologic legacy, borne from the integration of two primeval akaryotic unicellular micro-organisms, which simultaneously formed the nucleus,. This postulate of the “hermaphroditic” nature of human cell systems has proven to be most fruitful in therapeutic practice, for the understanding of health and illness, ageing and death.

In the early 1970s, previously unknown procaryonts were brought up from the depths of the ocean where absolutely no sunlight penetrates by remotely operated vehicles (ROV). For a long time, these organisms were classified as a new form of bacteria. Later, however, comprehensive sequence comparisons of the nucleic acids and proteins of these micro-organisms showed fundamental differences to bacteria, so that evolutionary biologists reclassified the 5 kingdoms of life to three domains: Archaea, single-celled organisms lacking nuclei; Bacteria, which also lack nuclei; and Eukarya, organisms with nuclei (single-celled protists, single—and multi-celled algae, single—and multi-celled fungi, plants, animals and humans).

The revolutionary realization—that all Eukarya, including humans, owe their existence to a unique act of fusion in the history of evolution, namely the colonization of a voluminous type of Archaea as host/stem cell by single-cellular organisms from the bacterial domain—was decisive. This formation of an intracellular symbiosis from members of two different domains, and the integration of the two inherently incompatible alien genome cultures into a common nucleus, termed “cell symbiosis” by the author, took place 2.1 billion years ago at a very striking point of time in the Earth’s history.

The first of three periods when the earth was completely covered by ice occurred some 2.4 billion years earlier. Geologists have shown that before this Ice Age, the Earth’s atmosphere was free of molecular oxygen (O₂), but dominated by carbon dioxide (CO₂) and methane gas (CH₄). The CO₂ was a result of volcanic activities in the Earth’s crust, whereas the methane gas (CH₄) was produced by the ubiquitous Archaea which convert CO₂ into CH₄.

After the melting of the global ice sheet, the O₂ concentrations of the atmosphere rose exponentially, while methane concentrations fell exponentially. Cell symbiosis took place at exactly the point in time that these two atmospheric gas curves intersected.

To date, evolutionary biologists still have not answered the question as to how the strictly anaerobic Archaea (as they are still now termed in textbooks) for which minimal amounts of O₂ are highly toxic and their bacterial symbionts which had already developed an O₂-dependant respiratory chain could encounter each other in the same milieu. The puzzle can be immediately resolved once you know that a certain type of Archaea, under gradually increasing threat to existence by O₂ gas pressure, in the ocean and in the earth’s atmosphere, evolved to facultative aerobics and learned to metabolize CH₄ with the aid of O₂in a moderately O₂-enriched milieu, and to obtain electrons and protons for the essential supply of adenosine triphosphate (ATP). This ATP metabolism has been demonstrated by microbiologists in methane-producing archaea and bacteria. In oxygen-free milieus, however, the same archaea can survive by switching ATP production to the oldest metabolic pathway in all organisms—glucose degradation (glycolysis). This action of facultative aerobic archaea was the decisive condition for cell symbiosis with the bacterial symbionts which had already developed an O₂-dependent respiratory chain.

Until the end of the 1990s, evolution researchers were able to secure and publish important findings about human cell symbiosis: roughly 60% of the genes in the human genome are derived from the genes of stem cells of facultative aerobic archaea (termed as A-genome by the author). The A-genome is dominant during the cell division cycle from the S-phase (the DNA replication phase). The remaining genes (termed as B-genome by the author) come predominantly from the genes ascribed to the bacterial symbionts in the mutual nucleus. The B-genome is dominant during the phases of differentiated cell activities depending on the respective cell types.

On the basis of the scenario sketched here, the author was able to reinterpret the process of cancer. In the 1920s, the biochemist and later Nobel prize winner, Otto Warburg, first described the phenomenon that cancer cells, despite the presence of O₂, seemed to undertake ATP production mainly via glycolysis in the cytoplasm. This “Warburg Phenomenon” is to this day still controversially discussed as the progeny of these bacterial symbionts, which evolved to the highly complex performers in all cell types—termed mitochondria—and have been shown to have a not inconsiderable O₂ consumption, also in cancer cells.

In 2002, Australian cancer researchers published the findings of a precise measurement of the actual O₂ consumption in the MCF-7 breast cancer cell line, commonly used for such analyses, over a five-day period using the latest oxygen electrodes. At the same time, the researchers criticized measurements of this type as being too short-term. The puzzling result was that the O₂ consumption in these cancer cells was not much below that of many intact differentiated cells and glycolysis not much higher. But the researchers could not identify 65% of the metabolic substrate for the production of electrons and protons needed for O₂-dependent ATP production. (Guppy et al. Contribution to different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Biochem J. (2002). May 15; 364 (pt1): 309-15).

These findings demonstrate that the “hermaphroditic” nature of the human cell system is to this day still not understood by clinical cancer researchers. In order to resolve this dilemma the author has adopted the well-founded assumption that the cancer process reflects—like a rear view mirror—the development phases of evolution: the functional disturbance on the regulatory level of aerobic O₂ utilization for ATP production by means of the enzymatic oxidase system in mitochondria, forces a protective switching at the regulatory level of facultative aerobic O₂ utilization for ATP production by means of the enzymatic oxygenase system in the cytoplasm. Such an evolutionary-biologically programmed protective switching can for the first time explain the up until now non-identified substrate portion for the O₂-dependent production of electrons and protons in tumor cell colonies and also the Warburg Phenomenon.

Warburg had postulated an either/or situation as he had assumed a structural defect in the cytochrome oxidase complex of the respiratory chain of mitochondria: Either O₂ respiration in the intact differentiated cells in mitochondria, or glycolysis without utilization of O₂ despite the presence of O₂ in the cytoplasm. However, to the postulated model of the double genome a system of doubled O₂ utilization has to be assigned. Under long term chronic cell stress of a diverse nature the cells active in division can regress to the evolutionary biological older intermediate stage of ATP production—both ATP production with O₂ utilization in mitochondria and in the cytoplasm with varying proportions and also ATP production through glycolysis without O₂ utilization in the cytoplasm, the latter proportionally dependent on the state of regression of the forming cancer cells. The B-genome gradually is losing control over the differentiated cells performance in favour of an increasing dominance of the A-genome as an archaic programmed strategy of survival.

In this context it can also be explained why since the declaration of “War against Cancer” in the USA in 1971 the expectation of survival in the most common solid carcinomas has not been markedly improved. Aggressive therapy with pharmaceutical toxins and ionizing radiation is still based on the objectively false theory of chance genetic mutation as the cause of cancer. This form of therapy can only inhibit or destroy more or less differentiated cells which are found in the regulations phase of the facultative aerobic ATP production. Simultaneously, however, there is still the danger that surviving cancer cells through the production of oxygen and nitrogen radicals associated to the therapy are forced into the strictly anaerobic phase or find themselves already in this phase. These cancer cells, resistant to conventional therapy, metastasize and dictate the fate of cancer patients.

Proof that this is the case is supplied by the recent discovery of tumor stem cells in solid carcinomas, firstly breast cell carcinomas in 2003 and since then in many other cancer cell types. These tumor stem cells are today regarded as the really dangerous cancer cells against whose uninhibited division tendency there are still no treatment methods in conventional cancer therapy (Clarke, M.F., Fuller, M. Stem Cells and Cancer: two Faces of Eve. Cell (2006), 126, 1111. Huntley, B.J.P., Gilliland, D.G. Leukaemia Stem Cells and the Evolution of Cancer Stem-cell Research, Nature Reviews Cancer (2005 Apr.) 5:4,311).

In contrast, forms of therapy derived from the concept of cell symbiosis have yielded impressive success in treatment (Lowenfels, D. The Dual Strategy of the Immune Response. A Review of Heinrich Kremer’s Research on the Pathophysiology of AIDS, Cancer and Other Chronic Immune Imbalances. Townsend Letter, June 2006, 68-75 (USA). This is true not only for “over-therapied” patients, but also for other tumor sufferers in all stages, patients with cellular and humoral immune deficiencies, inflammatory illnesses, autoimmune diseases, cardiac diseases, atherosclerosis, diabetes (also therapy resistant forms), osteoporosis, burn-out syndrome, CFS, fibromyalgia, neurodegenerative diseases including Alzheimer’s disease and other forms of dementia, Parkinson’s disease, depression, psychoses and many more symptomatic states and deficiencies in performance which can be classified primarily as mitochondriopathies.

The realization of the author that, in short, contrary to the then-current theories, the respiratory chain of mitochondria operates as a light quantum—(photon-) processor was decisive for the development of recipes for the Cell Symbiosis Therapy® (Kremer, H. The Secret of Cancer: Short-Circuit in the Photon Switch, Townsend Letter. Aug/Sept 2007, pp.121-124).

The multidimensional modulated information generated by this is transferred to the delocalized electrons of the double bonds in the adenine molecule of adenosine triphosphate. This explains why ATP, directly or indirectly ‘activating’ or rather ‘informing’, has to be involved in practically all metabolic processes. Thus, for example, the complex modulated ATP nucleobases,inform’ the necessary nucleobase building blocks before every neosynthesis of a DNA or RNA sequence, conveying a coded oscillating energy to them.

The geneticist Baltimore’s question quoted above on “what gives us our complexity” can in principal be answered as follows: information is a non-material size that is communicated from a space/time independent matrix of potential information to our ‘antennae molecules’ like ATP as ‘creative information’ via quantum dynamic series. So, cells are not simply thermal generators but information transforming media. But not all ATP is the same: ATP information modulated in human mitochondria is certainly more complexly modulated than ATP information modulated in mice. Similarly, ATP modulated under facultative aerobic conditions is certainly less complexly modulated than mitochondrial ATP from intact differentiated cells, or conversely, ATP modulated under glycolytic anaerobic conditions is certainly the least complexly modulated. Cancer researchers speak of the latter as ‘dedifferentiated’ cells.

Baltimore should have asked himself why, after copying a protein coded DNA sequence to a messenger RNA sequence and after the processing of this sequence, a poly A tail has to be attached to the ‘mature’ messenger RNA as otherwise protein synthesis would not work. The instructions for this process cannot be found in the genes. So, how do the cells know what they have to do? The answer is that the 270-odd adenine molecules of the poly A tail, which originate from modulated ATP, are resonance coupled to the non-material information field. If you imagine these poly A tails to be variable light quantum modulated adenine elements, then this results in a coded light quantum profile and anyone can understand the total organism as a highly complex ‘informed’ light quantum field. (For a quantum dynamic model concept see the publication of the Nobel price laureate David Bohm (1990) A New Theory of the Relationship of Mind and Matter. Philosophical Psychology: Vol. 3 N. 2.271-86).

This is why in Cell Symbiosis Therapy®, natural substances are deployed which absorb and emit photons above certain wavelengths in the near UV range and in the visible spectrum. The therapeutic potential of such natural substances has been confirmed in recent research publications (Middlestone, E., Jr, et al (2000) The Effects of Plant Flavonoids on Mammalian Cells: Implications for Inflammation, Heart Disease, and Cancer. Pharmacol. Res. 52,673-751; Aggarwal B.B. et al. (2003) Anticancer Potential of Curcumin: Preclinical and Clinical Studies. Anticancer Res. Jan-Feb: 23(1A):363-98).

The concept of Cell Symbiosis Therapy® has been supported particularly by the fascinating new findings of experimental and clinical research into ageing processes. In conjunction with the discovery of the new enzyme class, sirtuin (silent information regulators) that mute certain genes and molecules by removing an activating molecular group—astonishing effects have been detected in all eukarya. Thus, for instance, the sirtuin enzymes of mice which are particularly predisposed for cancer and diabetes, are activated by particular natural substances from the large family of vegetable polyphenols. In comparison to normal control mice, the predisposed mice lived considerably longer and developed strikingly fewer cancer, diabetic or neurodegenerative diseases.

These research data prove that there is a superordinated regulatory system, also in humans, as sirtuin enzymes have also been detected in the nuclei, the cytoplasm and the mitochondria of humans. As a result, photon-absorbing vegetable polyphenols activate the O₂-dependent mitochondrial activity via multiple networked regulatory cycles. The long held scientific bias that the ageing process and the typical diseases connected to it, like cancer, diabetes, cardiovascular diseases and neurodegenerative disease types are unavoidable natural deterioration processes can now be challenged (Wood, J.G. et al. (2004), Sirtuin Activators Mimic Caloric Restriction and Delay Aging in Metazoans. Nature, 430, 686-89. Porcu, M., Chiarugi, A. (2005) Sirtuin interacting Drugs: From Cell Death to Lifespan Extension. Trends in Pharmacological Sciences, 26 N. Sinclair, D.A. (2005) Towards a Unified Theory of Caloric Restriction and Longevity Regulation, Mechanisms of Aging and Development, 126:9,987.

Structurally analogous, photon-modulating vegetable polyphenols (free from chemical residues, heavy metals and contaminants) are an essential part of dispensing of the Cell Symbiosis Therapy® both in combined and special galenic preparation forms. Polyphenols cannot be synthesised by mammals, which is why for humans they have the characteristics of vitamins. They are essential for intact mitochondrial function and for this reason vegetable polyphenols in an appropriate combination with other natural products are indicated for the prevention and treatment of serious defects in mitochondrial performance, systemic diseases and premature ageing. They are prescribed as nutritional supplements therapeutically by doctors and alternative practitioners in an individual preventative or treatment concept.

Note:

Information about certified education seminars on the principles and practice of Cell Symbiosis Therapy® for doctors and therapists, about laboratory documented treatment reports and participation in medically supervised research in a multi-centre practice study on applied Cell Symbiosis Therapy® can be found at www.cellsymbiosis-netzwerk.de

(First published in Townsend Letter Aug./Sept. 2008)

By David Lowenfels  [First published in Townsend Letter #275 6/2006, Revised 4/2008]

In 1984, Bob Gallo and Margaret Heckler held a press conference in which they attributed AIDS to infection with the allegedly exogenous retrovirus, HIV. This pronouncement bypassed the scientific peer-review process and jumped straight into the hands of the media and the minds of the masses. To understand the context of this event, it is important to remember the politics of Nixon’s Retrovirus-Cancer research, Bob Gallo’s misleading laboratory deceptions in his thirst for fame and fortune, and the gross medical oversight of the challenges of the “fast-lane” gay lifestyle ofthe 1970s, which have boon elaborated previously [Duesberg 1996, Crewdson 2002, Roberts 2006, Root-Bernstein 1993, de Harven 2003, Kremer 1996, 2001, 2003]

Since the time of Gallo’s media announcement, many so-called “AIDS dissidents” have vociferously disputed the HIV theory of AIDS causality (Duesberg and Rasnick, The Perth Group, Root-Bernstein, Giraldo, to name but a few), but a coherent model for the pathophysiology of immune dysfunction and a corresponding nontoxic clinical therapy for disease reversal has been lacking. Mainstream HIV-centric AIDS therapies have focused on chemotoxic eradication, which at best is a stop-gap measure with ultimately grave consequences. HIV theorists continually invent convoluted explanations for how a phantom virus that can hardly be found in vivo (and only then by surrogate markers) could cause a total collapse of the immune system.

Most non-HIV theories of treatment revolve around drug abstinence, good nutrition, and avoidance of infections and other oxidative strcssors. While these measures are supportive to prevention and health maintenance, they have not been very useful in the actual reversal of AIDS and pre-AIDS, due to a lack of biochemical understanding of the actual disease mechanisms. The one exception that this author has encountered is the work of German doctor Heinrich Kremer MD, which is deeply grounded in modern biochemistry, immunology, and cell physiology.

This article is a summary of the pathophysiological model of chronic immune dysfunction, as elaborated by Dr. Kremer in his 2001 book, A Quiet Revolution in Cancer and AIDS Medicine (Die Stille Revolution der Krebs und AlDS-Medizin). An Italian version was published in 2003, and the translation of this monumental work into English is currently underway.

An understanding of Kremer’s model is based on three fundamental concepts, which are introduced here and will subsequently be elaborated:

• the function of nitrogen oxides and thiols (antioxidative sulfur compounds) as bioregulators of redox metabolism in cellular life forms and, particularly, the importance of nitric oxide (NO) in humans;
• the generalized functional dichotomy of the immune system and its cytokines (immunoregulatory messaging proteins), between the cell-mediated and humoral immunity, and its evolutionary interplay with NO; and
• the symbiotic nature of multicellular organisms, particularly regarding the mitochondrion, which is an endosymbiotic proteobacterium and is regulated by the intracellular redox balance.

Some of the finer points cannot be covered in this short format, nor can some of the more recent insights. However, what will be elaborated is a solid overview of the biological mechanisms and treatment of the chronic immune imbalance known as AIDS.

Research on the effect of nitrogen oxides in humans began in the late 1800s, when amyl nitrate and nitroglycerine were used as vasodilators in the treatment of cardiac disorders such as angina pectoralis [Brunton 1867, Fye 1986, Berlin 1987]. Over a century would pass until light was shed on the biochemical mechanism of these drugs. Research beginning in the late 1970s by the teams of Furchgott, Ignarro, and Murad led to the eventual discover of NO as an endogenous (self-made) signaling chemical used not only in the vascular system. but also throughout the body; for this those researchers were awarded the 1998 Nobel Prize in Physiology and Medicine.

NO is a highly reactive, but short-lived, paramagnetic radical. Due to its electrical neutrality, tiny size, and gaseous nature, NO can diffuse freely through cell membranes to foster cell-to-cell communication without need for specialized receptors—a phenomenon that was never before seen in biology. For decades, this mechanism was overlooked, as scientists were adamant that animal cells could not synthesize such a primitive molecule.

Today, we know that NO is crucial to a massive variety of processes in the animal organism and is not just limited to the regulation of blood pressure. The body has several different enzymes used to produce NO, of the family called NO synthase (NOS). Nearly all human cell systems produce (dependent on the level of intracellular calcium) small amounts of NO from L-arginine as part of normal and pathological processes [Moncada 1991]. A sampling of such systems includes neural, mucosal, splee, cardiac, bone, cartilage, liver, and skin cells [Lincoln 1997]. Of particular importance to immunological discussions is the calcium-independent enzyme called inducible NOS (iNOS), which can manufacture NO in large amounts over an extended period of time.

From the perspective of evolutionary biology, reactive nitrogen species (RNS)—i.e., nitrogen oxides—and other reactive oxygen species (ROS) are ancient but universal methods of intracellular and cell-to-neighbor communication, which operate via manipulation of biological redox potentials [Kremer 2001]. Redox potential describes the quality of a system as electron-rich (reduced) or electron-poor (oxidized), usually measured in millivolts.

Changes in the cellular redox status in turn affect the activation of genes and transcription of proteins [Sen and Racker 1996, Marshall 2000]. In an analogous manner, the intracellular redox status influences the production of cytokines by the immune cells, which then regulates immune function [Peterson 1997, Marshall 2000].

The primary biological counterpart to oxidation by RNS and ROS is reduction (ie., antioxidation) by thiols, also known as mercaptans. These sulfur-containing molecules are strongly nucleophilic and can donate an electron in order to quench a free radical, themselves becoming oxidized in the process. These oxidized thiols are then either excreted or recycled by other antioxidants. The ocean is the primary source of biological sulfur, and land-based life forms face continual risk for latent sulfur deficiency [Hässig and Kremer 1999]. It is therefore necessary to maintain a sufficient sulfur reservoir, or “thiol pool,” in the organism to counterbalance normal regulatory and pathological oxidative processes. For example, healthy mitochondria are one of the primary sources of ROS in the human organism, and thus their maintenance is dependent on cellular antioxidants that scavenge these byproduct radicals from oxidative phosphorylation [Cardoso 1999, Sastre 2003].

Figure 2: The Molecular Structure of Glutathione (GSH)

Aside from the aforementioned changes in genetic transcription, alterations in the cell redox status can also manifest as alterations of sulfur-iron groups in the mitochondrial respiration chain, or as cystine (S-S) cross-linking in enzymes and proteins that contain the amino acids cysteine or methionine [Moncada 1991]. Cysteine and methionine share the feature of a sulfhydryl (S-H) group, which is a potent antioxidant. The primary intracellular antioxidant is glutathione (GSH), which is a tripeptide synthesized from cysteine, glutamate, and glycine. (Figure 2) The balance between oxidized and reduced glutathione (GSH and GSSG respectively) can guide many important cellular processes [Sen and Racker 1996].

Figure 1: Diagram of Cytokine Regulation and Feedback Pathways

An additional scientific prerequisite to Kremer’s model involves an understanding of the functional dichotomy of the immune system and its cytokines. between the cell-mediated defense and the humoral defense. Cytokines (formerly known as lymphokines) are messaging proteins secreted by various immune cells. Patterns of cytokine expression form a complex and interrelated feedback network, which regulates the functioning of the immune system. (See Figure 1)

In 1986, the research group of Mosmann and Coffman demonstrated that CD4+ T-cells could be differentiated into two distinct functional patterns, which they named Th1 and Th2 (T-helper Type-1 and Type-2, respectively) [review in Mossmann 1989]. T-cells are lymphocytes that, when matured and activated, can perform as effector cells to assist the immune system in carrying out its tasks. The letter T stands for thymus, which is where these cells are trained and matured after their birth in the bone marrow. There are several kinds of T-cells, including helper, suppressor, and cytotoxic types. The term “helper” was originally coined before the discovery of Th1 cells to explain how Th2 cells assist B-cells in antibody production. Mosmann and Coffman’s groundbreaking Th1/Th2 discoveries opened up a whole new paradigm in immunology, in which scientists attempted to classify diseases based on the pattern of cytokine responses [overview with Kidd 2003). Many other types of regulatory and suppressor T-cells have been discovered since [Mosmann 1996], but the CD4+ Thl/Th2 dichotomy will suffice for this simplified introduction. The Type-1 cytokines are associated with the cell-mediated immunity (CMI), while the Type-2 cytokines are associated with the humoral immunity. Both types of cytokines have a tendency to counteract each other (i.e., reciprocal inhibition by negative feedback.) (Figure 1)

The CMI is the front-line defense of the immune system, which responds against intracellular parasites (e.g., fungi, virii, and myoobacteria). The macrophages, natural killer (NK) cells, and Th1 cells primarily carry out this function, which is regulated by Type-1 cytokines. The CMI is also involved in cancer defense, delayed-type hypersensitivity (DTH) reactions, and homeostatic cellular “housekeeping” of dead or damaged cells.

The humoral immunity is the second-line of defense, which blocks extracellular parasites (e.g., bacteria and worms) from entering cells, via antibodies. The B-cells (B for maturation in the bone marrow) and Th2 cells primarily carry out this function, which is regulated by Type-2 cytokines. The humoral arm of the immune system is responsible for the manufacture of antibodies, as well as allergic and autoimmune reactions.

While the body has several enzymes for producing NO under different circumstances and in different cell systems, the inducible form (iNOS) is of crucial importance to the immune system. Inducible nitric oxide synthase (iNOS) is used by the cell-mediated immunity (CMI) to create clouds of cytotoxic (cell-killing) NO gas. The humoral Th2 cells do not have this ability to manufacture large amounts of NO gas. The cytotoxic NO gas spray is an integral weapon in the defense against intracellular pathogens (e.g., fungi, viruses, and mycobacteria). (Table 1) Macrophages, NK, and Thl cells use this gas to disrupt and/or kill intracellular microbes, via inhibitory binding to their metalloenzymes and thiopeptides crucial for metabolism [Kröncke 1995]. In the process, the infected cells are also destroyed and, depending on the severity of the assault, sometimes innocent “bystander” cells are as well.

The question remains: how does the immune system know whether to activate Type-1 or Type-2 cytokines? The answer remained a mystery until a major discovery at Stanford in 1998, when researchers there found that the level of GSH in antigen-presenting cells (APCs)—i.e., macrophages, dendritic cells, and B-lymphocytes—controls the switching between synthesis of Type-1 or Type-2 cytokines [Peterson 1998, Murata 2002].

In other words, a decline in the GSH:GSSG ratio signals the APCs to manufacture Type-2 cytokines, which then instruct naïve Th0-cells to mature into the Th2 type. The abundance of Type-2 cytokines causes reciprocal downregulation of Type-1 cytokines, which in turn inhibits any further synthesis of NO. (Figure 1) This event is called the Thl-to-Th2 switch, or a shift towards Type-2 cytokine dominance. The outcome is the hyperactivation of antibody production at the expense of inhibited CMI. In most cases, this shift is temporary. However, if a long-lasting shift occurs, the weakness of the CMI can invite intracellular opportunistic infections (OIs, the hallmark of “HIV”/AIDS). (Table 2) A simple and reliable measurement for Th2 dominance with Type-1 cytokine inhibition is the DTH skin test (originally used in sepsis research): an anergic result is an indicator for strong risk of OI due to insufficient Interleukin-2 (IL-2) [overviews with Christou 1995 and Kremer 2001].

The reason for the inhibitory switching of NO lies in an ancient evolutionary program for self-protection from oxidative damage. GSH can be seen as the “gas mask” for the Type-1 immune cells used to protect them from oxidative damage by NO [Kremer 2001]. However, reduced thiols are only available in a finite supply, dependent on the nutritional intake of cysteine/methionine and other antioxidants. The unfortunate side effect of using NO is that the immune cells themselves can become severely oxidized. If the initial CMI response is not effective against an invader, the immune system is in danger of harming itself with the double-edged sword of NO gas. This can also happen if the CMI response is excessive (perhaps due to multiple co-infections) or long-lasting (due to chronic infection). In fact, any of the myriad forms of oxidative and/or nitrosative stress can contribute to the Th2 shift by systemic antioxidant depletion. These prooxidative factors can be any combination of infectious, traumatic, psychoemotional, chemotoxic, or nutritional stressors [Hässig 1997].

The Th1-to-Th2 switch evolved as a “fire alarm” for extreme prooxidative threat. From an evolutionary biological perspective, the Th1 cell is first seen in simple invertebrates such as sponges. The Th2 cell appears later during the early evolution of vertebrates such as amphibians and the bony fish [Roitt 1985]. Evidence suggests that the development of Th2 cells and antibodies was an evolutionary solution to parasitic colonization by other invertebrate organisms. Bony fish have a complex circulatory system, which makes them susceptible to invasion by multicellular parasites such as worms. Imagine the tiny Thl cells attacking a large worm that would be like using firecrackers to attack a giant monster. In that case, an excessive Th1 response using NO gas would not defeat the worm, but would instead cause harm to the fish via extreme tissue oxidation and inflammation. A backup system is needed for this emergency, and over time, Mother Nature equipped the more complex animals with such a solution: the Type-2 cytokine switch [Kremer 2001]. A Th2 dominance is generally an effective defense against prevention and healing of worm infections [Mosmann 1996].

In pre-Industrial times, humans with an aggressive Type-2 switch had a survival advantage, because they could successfully fight off worms and bacteria. Humans in those times also were not exposed to the oxidative stressors in the environment, food, and medicine now present in modern civilization. (See Sidebar.) In addition, the modern practice of vaccination also leads to more aggressive Type-2 switching. Today, these additional stress burdens flip the Type-2 switch too easily. The net result is a population-wide increase in chronic immunological diseases such as allergies, atopic skin disorders, asthma, autoimmune conditions, and cancer [Kremer 2001].

Immunological observations of AIDS patients demonstrate a Type-2 cytokine dominance. The initial findings of AIDS clinics noted DTH anergy, reduced T-cell proliferation after stimulation, increased B-cell activity, and specific antibody production, all of which glaringly point towards the shift to Type-2 cytokine dominance (a.k.a. Type-2 counter-regulation) [Gottlieb 1981, Masur 1981, Mildvan 1982].

The immunological response of AIDS patients is not new, as the Th2 switch has existed in animals for millennia. Rather, the unprecedented collective exposure to oxidative stressors precipitated the relabeling of the symptoms of the counterregulatory Th2 switch as “AIDS.” Among other tbings, the primary prooxidative factors involved in gay men include combinations of nitrite inhalation (“poppers”), consumption of immunotoxic medicines and recreational drugs (including Septra/Bactrim, AZT, and more recently, Viagra), and exposure to antigens and endotoxins via repeated infections. All of these factors induce the synthesis of NO gas, ultimately leading to exhaustion of the thiol pool. Protein malnutrition seen in the Third World can also lead to a long-term functional inhibition of NO synthesis [Kremer 2001].

Results from research on seropositive patients showed Th1 cell impairment even in asymptomatic individuals with normal T-cell counts [Giorgio 1987. Miedema 1988, Clerici 1989 a, 1989 b]. In 1989, it was observed that asymptomatic “HIV”-seropositive individuals are systemically deficient in glutathione [Buhl 1989]. In 1993, Clerici and Shearer were the first to hypothesize about Th2 dominance in A1DS patients. which remained a tantalizing but controversial topic for many years until the Peterson group’s 1998 breakthrough [Clerici, 1994, M06smann 1994, Fakoya 1997, Klein 1997].

In 2000, Breitkreutz et al. reported that asymptomatic seropositive patients showed a “massive loss” of approximately 10g of sulfur compounds via daily urination, leading to an “alarming negative balance of approximately 2 kg of cysteine per year” [Breitkreutz 2000]. Such a cumulative loss of thiols would obviously lead to chronic Type-2 counterregulation, the consequences of which include rising levels of antibodies (hypergammaglobulinemia) over time, leading to allergic and autoimmune complications, as well as a progressive diminishment in the CMI response, creating susceptibility to intracellular “opportunistic” infections. These sequelae are characteristic of the progression to AIDS and are the direct result of the inhibition of NO gas synthesis due to thiol depletion.

It has been reported that hypergammaglobulinemia precedes “HIV”-antibody seroconversion in hemophiliacs [Brenner 1991]. The Perth Group also has pointed out that “studies conducted in drug users show that the decrease in T4 cells precedes a positive antibody test” [Papadopolous 2004]. Further evidence for acquired immunodeficiencies (AIDS) of the CMI, without the manifest syndrome of OIs, in both “HIV+” and “HIV-” individuals from risk groups, is discussed in Root-Bernstein’s 1993 book. The entirety of evidence convincingly suggests that the shift towards Th2 dominance begins long before seroconversion.

Glutathione (GSH) is a tripeptide made of cysteine, glutamate. and glycine. GSH plays important roles in cell and liver detoxification, mineral metabolism, antioxidant quenching of free radicals, and regulation of mitochondrial symbiosis. Due to its large size, GSH usually must be synthesized from components inside the cell, with cysteine and its antioxidant sulfhydryl group (sulfur-hydrogen bond) being the rate-limiting factor. One of the safest ways to boost systemic glutathione is oral N-acetylcysteine (NAC). Modern stressors which consume reduced gluathione (GSH) include the following:

1. All manners of oxidative stress
2. Chemical poisoning, via environment or via food/water
3. Carcinogens
4. Synthetic pharmaceuticals
5. UV and X-rays (ionizing radiation)
6. Electro-smog (non-ionizing radiation)
7. Oxygen, under—and oversupply
8. Infections
9. Overexertion from sports
10. Questionable nourishment
11. Heavy metal intoxication
12. Free-radical reactions
13. Chronic illnesses

Oxidized GSSG is reduced back to GSH by the enzyme glutathione reductase and the coenzyme NADPH. However, this reduction depends on a well-functioning status of the enzyme glutathione reductase and sufficient coenzyme NADPH. Both enzyme and coenzyme are damaged via electrophillc bonding with toxins. With a burden of frequent detoxification, they can no longer perform their task: too much oxidized glutathione (GSSG) remains, and the vital balance of (GSH):(GSSG) becomes disturbed from its approx. 400:1 ratio. Thereby, the redox regulation so dependent on this balance is interrupted.

(Original German by Dr. Gerhard Ohlenschlaeger, 2003)

Many researchers have argued that the immune weaknesses in risk groups simply leads to greater susceptibility to putative “HIV infection.” According to Kremer, this is a gross confusion of cause and effect. The characteristics attributed to HIV in cell cultures, namely reverse transcription, “virus-like” particles, and catabolic cellular debris, are part of the evolutionary response against prooxidation.

Reverse transcription is a well-known factor in the repair of oxidatively damaged nuclear DNA [Kremer 2001]. Cell cultures of HIV are necessarily subjected to unusual oxidative and mitogenic stressors (including hydrocortisone), in order to express the “HIV proteins” [Barre-Sinnousi 1983, Popovic 1984, Gallo 1984]. The genetic expression of pathological proteins (e.g., HIV1 TAT) by dysfunctional cells is just another symptom of intracellular/systemic imbalance. Because it is the epigenetic oxidative mechanisms which result in unusual gene transcription, HIV researchers are confusing cause and effect.

The inflammatory Th1 cytokines, interferon-gamma and tumor necrosis factors, activate the production of oxygen radicals that can lead to increased cell death by both apoptosis (programmed cell death) and necrosis (unprogrammed cell death). Necrosis exposes intracellular proteins to the extracellular matrix, which activates autoimmune reactions in both Thl and Th2 cells [Kremer 2001].

A fact widely overlooked by AIDS researchers is that everyone has “HIV proteins” in minute amounts; those stigmatized as “HIV+” simply have higher amounts than the arbitrary threshold of the “HIV [auto]antibody” ELISA test kit, which calls for unusually high serum dilution (Giraldo 1998. Kremer 1998, 2002, 2003]. Therefore, an “HIV+” test result is pathognomonic (a distinctive indicator) for reduced thiol insufficiency (i.e., cysteine deficiency) and resultant cellular catabolism.

The final nail in the coffin for the HIV theory is that the cell types used to derive “HIV proteins” (Gallo used cancer cells, and Montagnier used embryonic cells) all have altered mitochondrial bioenergetics that predispose them for Type-2 counterregulation [Barre-Sinnousi 1983, Gallo 1984, Kremer 2002].

Fueled by oxygen, mitochondria are the energy powerhouses that generate nearly all the ATP used for cellular processes. Currently accepted theory maintains that the mitochondria are endosymbiotic bacteria, long ago incorporated into eukaryotic cells [Margulis 1981]. The overwhelming evidence for this is that mitochondria have their own genome (mtDNA). Because the mitochondria are themselves relatives of bacterial organisms, they are also susceptible to suffocation by nitrogen oxides when present in cytotoxic concentrations [Kremer 2001].

Mitochondria are responsible for regulating cellular metabolism, including the initiation of apoptosis [Green 1998, Desagher 2000]. Laboratory research is currently lacking on the exact mechanisms that maintain the mitochondrial symbiosis. As mentioned earlier, normal mitochondrial respiration is the leading source of oxidative radicals in the cell. For this reason, a continual supply of antioxidants are needed to mop up these radicals, the primary one being glutathione peroxidase (GSH-Px), which contains both selenium and GSH. AIDS researchers in the past decade have noted deficiencies in selenium, which was erroneously postulated as excess transcription of GSH-Px by HIV [Look 1997, Taylor 1997, Foster 2000]. The GSH deficiencies that cause the inhibition of NO synthesis also lead to the dissolution of the mitochondrial symbiosis (a.k.a. “Warburg Phenomenon”) [Kremer 2001].

Not surprisingly, disturbances of the mitochondria are evident even in asymptomatic seropositive individuals [Cote 2002]. This problem is made worse by the administration of nucleoside analogues such as AZT, which suffocate mitochondrial respiration enzymes and interfere with the synthesis of mtDNA via inhibition of polymerase-gamma [Cherry 2003]. Other AIDS drugs can deplete systemic GSH by liver toxicity. It is imperative to focus on restoring the mitochondrial symbiosis as a primary goal of AIDS therapy [Kremer 2001, 2003], and current research in China substantiates this paradigm [Miao 2005].

Mitochondrial dysfunction is also tied to cancer, as demonstrated by Nobel Laureate Otto Warburg, who showed that a breakdown of oxidative cell respiration and increase of lactic acid fermentation was a precursor to cancer [Warburg 1966, Kremer 2003]. Stimulated by Kremer, cutting-edge cancer research in Germany and Spain is currently corroborating Warburg’s theories [Isidore 2005, Schulz 2006].

A paradox overlooked by the initial AIDS researchers was that an “unknown agent” was supposedly killing the T-helper cells, yet the antibody production of the B-cells and antibodies remained intact. Another paradox is that AIDS researchers could only find the nonspecific laboratory artifacts that indirectly implicated a retrovirus amongst Th2 cell clones, but not Th1 clones [Maggi 1994, Chehimi 1995, Abbas 1996, Lucey 1996]. “How can a killer be responsible for murder if it was never even at the scene of the crime?” [Kremer 2001]

Although HIV-theorists have come up with many imaginative explanations for this conundrum, the obvious logical solution is that the decline of T-cells seen in the peripheral blood is not due to any postulated “HIV-mediated cell killing,” but rather is just another consequence of the thiol-mediated cytokine shift.

A predominance of Type-2 cytokines leads to the production of Th2 cells, which reside primarily in the bone marrow (where they can contact the B-cells) and out of view from peripheral blood counts. To cite an analogy given by Kremer, the “police officers” of the bloodstream are missing from the streets, not because gangsters have killed them, but instead because they have taken desk jobs [Kremer 2001].

The bone marrow disruption that occurs with highly active antiretroviral therapy (HAART) is responsible for damage to the maturation of B-cells. As a result, the Th2 cells cannot make contact with mature B-cells and so return to circulation in the peripheral bloodstream. This toxic disruption explains the transient increase of CD4+ blood counts seen with nucleoside inhibitors [Kremer 2001, 2003]. The cell-count increase is misleading because Th2 cells cannot produce cytotoxic NO gas and are therefore lame against preventing Ols. Because Th1 and Th2 cells cannot be differentiated by their surface proteins, the only way to get reliable information on immune function is by cytokine profiling or DTH skin testing.

It must be underscored that there is a direct connection between the uptake of antioxiants from food or supplements and the levels of GSH in the immune cells. Therefore, there are two general ways in which antioxidant depletion and the corresponding immune imbalances can occur. The first way is through a lack of antioxidant intake, in other words. malnutrition or starvation. The second way is through redox overload due to prooxidative stressors (toxic, infectious, psychoemotional, etc.) which, alone or in combination, exceed the capacity of cellular antioxidant supply. The end result of both these situations is a systemic starvation for freely available electrons, corresponding with deficiencies of thiols and other reducing substances, which ultimately triggers the biologically evolved program of Type-2 counterregulation.

A extensive range of antioxidants have been claimed to inhibit “HIV infection” in vitro [Schreck 1992, Jaruga 2002]. In fact, many of the newer AIDS drugs have potent antioxidant capacity [ScienceBlogs 2006], either directly via their metabolites or indirectly via inhibition of enzymes, like cytochrome P450. Over the long term, the enzymatic inhibition that these drugs cause is quite toxic, particularly due to the disruption of mitochondrial replication and repair [ScienceBlogs 2006, Cherry 2003]. As early as 1989, a lack of cysteine was noticed in AIDS patients. This lack could have suggested a non-toxic supplemental therapy, if researchers were not blinded by the glamour of virus-hunting [Dröge 1989]. The replenishment of thiols in AIDS prevention by the GSH pro-drug, n-acetylcysteine (NAC), was first suggested by Dröge in 1993 [overview with Kelly 1998]. Clinical trials in subsequent years proved astounding results, and NAC is universally recommended for seropositive patients [Dröge 1997, De Rosa 1997, Herzenberg 1997, Breitkreuitz 2000]. Given the knowledge of this enormous benefit, it is troubling that doctors are not prescribing NAC to their patients; presumably its lack of popularity is due to the lack of patentability (i.e., profitability) of an endogenous (bodily made) substance derived from a simple amino acid. Mainstream AIDS-drug “cocktail” therapy cannot possibly address this massive cysteine deficiency. In fact, the Herzenberg study showed that individuals taking HAART therapy generally had the worst levels of intracellular GSH and thus benefited most from NAC supplementation.

This article bas provided an outline of Kremer’s theory of pathophysiology behind the immune dysfunction seen in AIDS, as explained by the shift to Th2 dominance. It has only briefly touched on the therapy, which is still being researched and has been outlined elsewhere [Kremer 2001 b, de Fries 2005]. There is no “magic bullet” solution to this disorder, since there is no actual HI-Virus to be eradicated. Even if HIV were to actually exist, the laws of evolutionary biological immunology would still call for an identical thiol-replenishing treatment rationale. The process of reversing Th2 dominance is complex and highly individual; it requires time, patience, and the help of a truly knowledgeable physician. Excerpted from Kremer’s book, here is the general strategy for healing the Thl/Th2 imbalance:

• Minimization of prooxidative stress
• Replenishment of thiol deficienc
• Balancing of amino acid dysregulation
• Liver protection to lighten the burden of systemic thiol deficiency
• Modulation of Type-2 counterregulation
• Micronutrient replenishment
• Fortification of the extracellular matrix
• Mitochondrial revitalization
• Attenuation of stress hormones
• Fear reduction and psychological assistance (i.e., de-hexing) [Kremer 2001].

This author hopes you share his excitement for the English publication of Kremer’s book, which is the result of a monumental effort of love by a dedicated team. There is still much to be discovered regarding the healing powers of orthomolecular cell-symbiosis compensation therapy for AIDS. However, the scientific basis of pathophysiology is solid, and clinical applications in such regard continue to demonstrate immense benefit. My deepest gratitude goes out to Dr. Kremer and his devoted German-speaking colleagues [Felix de Fries, Oliver Langkopf, Alfred Hässig (deceased)], who have gifted us greatly in our understanding of health and disease.

David Lowenfels is a scientist, engineer, and musician, with Master’s degrees from MIT and Stanford. He began questioning the “HIV=AIDS” model in 1999 and encountered Dr. Kremer’s work in 2003. He is greatly excited by the emerging paradigm of future medicine: moving beyond the current strategy of eradication and suppression, beyond “complementary alternative” therapy, and into new realms of biological understanding which yield methods for guiding and, balancing the body’s innate healing processes. He is currently a student of Dr. Yurkovsky’s Field Control Therapy (FCT).

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