Oxygen Course – Majid Ali

Majid Ali, M.D.

Oxygen for Health and Healing


 Oxygen is the organizing influence of human biology and governs the aging process. It is the primary “energy-nutrient” molecule of human biology. It is an exquisitely discriminating regulator of all developmental, metabolic, and detoxification mechanisms. It is the weapon of transcending importance in the man-microbe conflict. In my view, the two primary threats to human health are unrelenting anger—and the spiritual dysequilibrium that always follows it—and relentless pollution of our environment. Both threats inflict damage by disrupting oxygen homeostasis—the former causes putrefaction of the mind and the latter of the body. For all those considerations, I consider progressive oxygen dysfunction—dyshomeostasis caused by impaired function of oxyenzymes and altered expression of oxygenes—as the principal problem facing humankind and the animal kingdom alike. Also for those reasons, I believe the primary focus of all clinicians managing chronic health disorders must be restoration of oxygen homeostasis. In acute illness, prompt attention to the specific lesion(s), of course, is essential. Focus on issues of oxygen homeostasis significantly improves clinical outcomes in those illnesses as well.



I. Introduction
II. The Darkening Clouds of Oxygen Dysfunction
III. The History of Oxygen
IV. The First Era of Oxygen-Free Primordial
V. The Second Era of Rising Oxygen Levels
VI. The Third Era of Falling Oxygen Levels
VII. The Fourth Era of Functional Oxygen Deficits
VIII. Oxygen in Nature Now
IX. The Breath and the Early Notions of Life
X. The Phlogiston and Oxygen
XI. Discovery of Oxygen
XII. Oxygen Toxicity
XIII. Oxygen Therapeutics: The Early History
XIV. Molecular Medicine
XV. Energetic Basis of Spontaneity of Oxidation
XVI. Oxygen in Redox Dynamics
XVII. Oxygen: The Master Molecular Switch
XVIII. Moses’ Radicals and Rebecca’s Rats
XIX. Oxygen Messes Things Up, Oxygen Cleans Up the Mess It Creates
XX. Dysoxygenosis
XXI. Effects of Anger and Lifestyle Stress on Oxygen Homeostasis
XXII. Effects of Oxidized Foods and Dehydration on Oxygen Homeostasis
XXIII. Effects of Toxic Metals and Environmental Pollutants on Oxygen Homeostasis
XXIV. Effects of Antibiotic Abuse on Oxygen Homeostasis
XXV. Oxygen and “Yeastization” of Human Cells
XXVI. Oxygen and the Elephant of Neuroendocrinoimmunology
XXVII. Oxygen and Hypothalamic Dysfunction
XXVIII. Oxygen and Autoimmunity
XXIX. Oxygen and Genes
XXX. Oxygen and the Man-Microbe Conflict
XXXI. Oxygen and Coronary Heart Disease
XXXII. Oxygen and Cancer
XXXIII. Oxygen and Aging
XXXIV. LUCA, Oxygen, and Consciousness
XXXV. Concluding Comments



Oxygen is the organizing influence of human biology and governs the aging process.1 It is the ultimate molecular switch of human life.2-10 It causes cell death by its presence as well as by its absence. It is the primary energy-nutrient and the premium detox molecule of human biology. Oxygen is the spark for the furnace of human metabolism. It is the conductor of the whole orchestra of life. It drives all energetic-molecular pathways of cellular development, differentiation, and demise.

Oxygen is the elixir of life—and of death. Oxygen turns water into a lifegiver. It turns water into a lifetaker. From water, oxygen generates free radicals to usher life in. From water, it also produces free radicals to extinguish life. Oxygen sires hydrogen peroxide and deputizes it to protect molecules. It also cajoles hydrogen peroxide to do its dirty work of killing molecules. Oxygen spawns nitric oxide to sustain cells.  Then it recruits it—and its progeny of nitroso radicals—to efficiently decimate them.

Oxygen is the ultimate molecular Dr. Jekyll and Mr. Hyde of human existence—a spin doctor without peer.

It turns DNA on to do its biddings in the good work of life. It also turns DNA off to starve life. Oxygen turns poisons into harmless materials and innocent substances into poisons. It is an acid former. It is an acid breaker. It is nature’s primary antibiotic. Oxygen referees the match between a hunter immune cell and a microbe. Then, it determines who wins that match. In the same way, it referees the match between a hunter immune cell and a cancer cell, then determines who wins. When called upon to do so, oxygen turns into a messenger—accepting hormonal assignments by picking up an extra electron. It is a lifegiver in yet other ways and a lifetaker in just as many others. For all those reasons, I consider the fundamental oxygen order of human biology as the most elegant example of nature’s order of economy.

Adrenal steroids suppress the immune system. Adrenal steroids also sustain the immune system. But what creates the conditions under which adrenal steroids either suppress or sustain the immune system? The answer: oxygen, or absence of it. The hypothalamic-pituitary-gonadal axis suppresses the immune system. That axis also sustains the immune system. But what creates the conditions in which the hypothalamic-pituitary-gonadal axis either suppresses or sustains the immune system? The answer again is oxygen, or lack of it.

Oxygen homeostasis determines the state of health. Disruption of that homeostasis is the fundamental energetic-molecular derangement in all chronic states of absence of health and disease. In 1999, I introduced the term dysoxygenosis for a state of oxygen dyshomeostasis in which the fundamental energetics of the human biology are disrupted by impaired function of core enzymes involved in oxygen homeostasis (oxyenzymes) and altered expressions of genes maintaining that order (oxygenes).11-14 The core concept of dysoxygenosis evolved through reflections on the subjects of spontaneity of oxidation in nature, the many faces of oxygen, and clinical consequences of chronic cellular oxidosis and acidosis during a period of nearly three decades. The clinical, morphologic, and biochemical observations made during those years were the subjects of a series of previous publications.6-33 Most of those articles can be accessed fromwww.majidali.com.

Since the fundamental energetic-molecular lesion in all states of absence of health is oxygen dyshomeostasis, it follows that the primary focus of all clinicians in health preservation and reversal of chronic disease must be restoration of oxygen homeostasis. In acute illness, prompt attention to the specific lesion(s), of course, is essential. Focus on issues of oxygen homeostasis can significantly improve clinical outcomes in those illnesses as well. I present the various aspects of the subject of oxystatic therapies —measures that restore oxygen homeostasis—in each of the eight volumes of this textbook.


Our world is progressively sickening. Our children are tired in frightening numbers. Our teenagers are in pain with disconcerting frequency. The rises in incidences of problems of mood, mentation, and memory in young persons is disturbing. In some large sections of New York City, one of every four children carries an inhaler to school.34 One of every seven Hispanic children in the City was found to meet the diagnostic criteria of a psychiatric illness called the post-traumatic stress syndrome.35 In many communities, one out of every four persons in a doctor’s office complains of persistent fatigue.36 The Wall Street Journal reported that nearly eight million Americans live a life of pain of fibromyalgia.37 The Department of Defense tells us that about 140,000 of the total of 693,000 women and men who went to the Gulf War in 1991 are partially or totally disabled with the Gulf War syndrome.38 Some associations of Gulf War veterans assert that the true number of disabled veterans is nearly three times as large. Clinical ecologists report rising incidence of disabling environmental sensitivities in all age groups.

On October 16, 2003, CNN reported a disturbing rise in the incidence of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Such infections are characteristically encountered among immunosuppressed hospitalized individuals. But that report brought to light an altogether new problem: the reported MRSA infections occurred among world-class athletes—professional football players, wrestlers, fencers, and others. Does that mean that those world-class athletes are becoming immunocompromised?

Mental Disorders in Children

On October 28, 2003, CNN followed up with an even more alarming—and sad—story. It showed little children lining up for their medication from the school nurse—a scene that is deemed a mere routine by school officials. The voice over the images told the viewers that there are 47 psychotropic drugs in common use in the country, many of which are being given to children on the basis of off-label use. That, of course, means that the use of those mind-altering drugs in children has neither been examined nor approved by the Food and Drug Administration. The CNN report then presented the following statistics for the American children:

✪ Depression 20%
(“in some form”)
✪ Mental illness 10%
✪ ADHD 7.5%

A staff member read the above numbers in the manuscript and said, “The nurse at my daughter’s school told me that there are only 280 students in the school but she gives medications to eighty to ninety students every day.” We are so routinely numbed by bad news that the significance of such statistics is simply lost.

Clearly there are genetic and ecologic factors at play at the root of the plight of our children. But what triggered those genes that were silent for centuries but are now acting out? What are the disruptions in the internal and external environments that sicken our children at alarming rates? Those questions do not seem to interest CNN medical journalists.

A TV ad that followed the story of drugged children told the viewers that an average American ingests 158 pounds of sugar every year. How much attention is paid to sugar roller coasters in those children? And to antibiotic abuse by pediatricians? And to stress caused by addictive TV viewing? The CNN journalists did not explore any of those questions. I believe they did have a clear sense of the magnitude of the health hazard posed by massive sugar overload caused by their advertisers. And of the dangers of antibiotic abuse by pediatricians. However, they also had a clearer sense of how to protect their jobs. Truth has few takers. I devote Oxygen and Hurt Children of a Hurt Earth, the third volume of my Trilogy of Dysfunctional Oxygen Metabolism, to the subjects of how sugar overload, antibiotics abuse, synthetic chemicals, and stress are driving our children to distraction and depression.

Oxygen and Quadrupled Incidence of Obesity

On November 10, 2003, CNN reported quadrupling of the incidence of obesity in the United States during the preceding twenty years. Obesity is cellular toxicity, and cellular dysoxygenosis is the primary mechanism of incremental cellular fat storage. This may surprise some readers, but only because they would not have reflected on the energetic-molecular basis of obesity. Excess weight accumulation generally begins with uncritical overeating, using food to cope with stress, and consuming highly processed foods. But what turns initial, innocent, and mild undue weight gain into pathologic obesity? That question is not addressed by weight control experts. I am certain that it is impaired mitochondrial fat oxidation caused by dysfunctional oxyenzymes. Thus, cellular fat itself becomes oxygen-depriving and fattening. I concede that direct experimental evidence for my view is not yet forthcoming. However, the preponderance of direct and indirect lines of evidence for my core concept of cellular dysoxygenosis is so overwhelming that I am certain when my hypothesis is put to experimental test, it would be borne out. I discussed this subject at length in The Ghoraa and Limbic Exercise.31 Brief comments about mitochondrial energy dysfunction in the following section will also shed some light on my view.

Energy Crisis and Mitochondrial Disorders

The November 3, 2003, issue of U.S. News & World Report ran a story titled “Energy Crisis.” Following are some excerpts from that article:

Failing ‘power plants’ inside cells give rise to debilitating diseases …Researchers have also uncovered intriguing clues suggesting that mitochondrial failure may play a role in Alzheimer’s disease, stroke, diabetes, and heart disease, among other age-related ills. Although therapies remain elusive…This month, Naviaux and some of his colleagues petitioned the National Center for Health Statistics, a division of the Centers for Disease Control and Prevention in Atlanta, to officially recognize nearly 400 newly described mitochondrial disorders.

Four hundred newly described mitochondrial disorders! What might be the possible advantages of a classification system that establishes 400 discrete separate diagnostic labels? Such a system would be useful if it could shed light on what caused those 400 separate ‘diseases.’ That would open up some possibilities of disease prevention. The notion of 400 new ‘diseases’ could also be welcome if there were clearly delineated ways of treating those diseases. But that is not the case at all.

“Although therapies remain elusive”! Is that really true? Do therapies for prevention and reversal of heart disease, for instance, really remain elusive? Or those for diabetes? Or could it be that those 400 mitochondrial ‘diseases’ are, in reality, 400 different parts of the same ‘elephant’ of cellular oxygen failure?

Gulf War I and Gulf War II Syndromes

On November 7, 2003, CNN reported the story of an American soldier in Iraq who was charged with the offense of ‘cowardice.’ The host asked his psychologist-guest about how the military distinguishes between post-traumatic stress syndrome and ‘cowardice’ in the field. The psychologist asserted that he was trained to do that. What tests might he perform to separate the two conditions?, I wondered. I did not think that psychologist understood how terror turns into toxicity in cells, and how toxicity in cells fans the oxidative fires of fear and hostility. How much might he know about oxygen?, I wondered next. How many of the Iraq War veterans will have chronic intractable illness? How many will be disabled? How many will be offered strong nutritional and spiritual support in their fight against war-triggered illness? Eventually, how many of them will be dismissed as malingerers? Diagnosed to have the Gulf War II syndrome year later? The questions continued.

In 1991, in The Canary and Chronic Fatigue,32 I predicted that a large number of veterans of that war will suffer chronic energy and immune disorders. Now it seems certain to me that we will have to coin another term—the Iraq War syndrome, or better still the Gulf War II syndrome—for the sick veterans.

Below, I reproduce some text from September Eleven, 200533 to provide a framework for the reader:

Gulf War Syndrome—
Who’s Addressing the Issue?

The characteristics of the Gulf War syndrome were entirely predictable. And those were predicted. Consider the following text from the September 13, 1995, issue of Navy News:

“Long before the first veterans returned from the Persian Gulf Dr. Majid Ali, associate professor of pathology at the College of Physicians and Surgeons at Columbia University in New York, and Director of the Department of Pathology, Immunology and Laboratories at Holy Name Hospital in Teaneck, NJ, predicted five outcomes; (1) that a large number of service men and women in the Persian Gulf region would return with a variety of chronic environmental, immune and stress related problems; (2) the disabling fatigue would be a dominant clinical feature while other symptoms would include recurrent infection, food allergy reactions, abdominal problems, disorders of mood and memory, and skin rashes, among others; (3) that sick veterans would initially be dismissed as malingerers and labeled with various psychiatric diagnoses and prescribed large doses of mind numbing drugs; (4) that the chronic health disorders of these veterans would worsen with multiple drug therapies; and (5) that when everything else failed, these veterans would be prescribed long term broad spectrum antibiotic therapy that would play further havoc with their bowel systems.

Five years later these predictions are now observable fact. Headlines debate the cause and fate of those men and women who left healthy and returned home sick —nearly 75,000 at last count.”

It is not much of a prediction to say that nearly one third to one half of the Iraq War veterans will suffer from chronic, painful disabling illness for years, just as the veterans of the first Gulf War did. Nor do I think that the Department of Defense or military physicians will learn about nutritional and oxygen therapeutics and administer those therapies to prevent Gulf War II syndrome.

The Root of All So-Called Mystery Maladies Is Impaired Cellular Oxygen Utilization

Unable to understand those frightening epidemics of ill health, physicians in growing numbers dismiss them as ‘mystery maladies.’ Regrettably many of them add to the suffering of those afflicted with the insulting diagnoses of all-in-the-head problems or other irrelevant psychiatric labels34-38.

While many mainstream doctors dismiss epidemics of fibromylgia, Gulf War syndrome and other chronic energy disorders as ‘imagined diseases,’ none of them can deny that pandemics of insulin dysfunction and diabetes are emerging all over the world—associated with obesity in the rich countries and with low body weight in poor countries.39 Over sixty percent of Pima Indians in the Southwestern United States now suffer from diabetes, an insulin disorder that was distinctly uncommon in that population during the early years of the last century. Nearly one-half of 85-year-old persons in the country suffer from Alzheimer’s disease.40 I am told that the generation of baby boomers will live for 90 to 100 years. Then I see a horrible specter of enormous facilities everywhere in the country housing demented eighty- and ninety-year-olds, spending interminable days fumbling and floundering. What I find even more disconcerting is an alarming increase in the number of young persons I see with frequent periods of what they describe as brain fog.41

A century ago, most Americans lived to be about 50. Today people over 100 make up the fastest-growing segment of population. As some researchers bet that children born today will live to be 150, others say there is no upward limit on longevity.

Discover magazine
November 2003

Children born today will live to be 150! Since nearly one-half of 85-year-olds have Alzheimer’s disease now, one can only wonder about the percentage of children born now who will not be demented at age 100. And by 110? And by 125? I am both irked and saddened when I hear silly words like those quoted from Discover above. If only we could do something to preserve the oxygen homeostasis of our children now!
Local and Systemic Oxygen Dysfunction

The main message of this section is that local and/or systemic oxygen dysfunction is the fundamental energetic-molecular lesion in all chronic disorders, though the clinical manifestations are often widely divergent. I submit that on a deeper review of the known facts of biology and ecology, the hand of oxygen can be readily discerned in all persons with ‘poorly understood’ degenerative and autoimmune disorders—as well as those with mystery maladies— who are mismanaged with pharmacologic blockade of cell membrane channels, receptors, and channels, and of mediators of inflammatory and healing responses. The evidence for local and/or systemic dysoxygenosis —a state in which oxyenzymes are functionally impaired and there is overexpression, underexpression, or dysfunctional expression of oxygenes—can be developed with appropriate laboratory procedures.

For many readers, the above statements may seem too far-fetched to be of any real clinical value. However, in this chapter and in various volumes of this textbook, The Principles and Practice of Integrative Medicine, I marshall an enormous body of diverse lines of evidence to support my view of the health/dis-ease/disease continuum. The existence of dysoxygenosis in all such cases can be readily established by demonstrating biochemical consequences of impaired oxygen metabolism—increased urinary output of organic acids and related toxic compounds.42 This subject is presented at length in the chapter entitled “Dysoxygenosis.”

Oxygen Dysfunction in the Animal Kingdom

Of course, we humans are not the only victims of dysfunctional oxygen metabolism. We can learn much about oxygen metabolism by examining how excessive oxidation and dysfunctional oxygen metabolism cause disease and death in the animal kingdom. To underscore that point and to further illustrate my theme, I also explore disturbances in oxygen dynamics in the large bodies of waters and consequences of oxidosis suffered by many forms of life in fresh waters as well as in coastal waters, bays, and open seas. Below, I include some text from one of my articles published in The Journal of Integrative Medicine12 to show that we can learn much about dysfunctional oxygen metabolism from disappearing frogs, shrimp, oysters, and other living beings.

What do alpine meadows of Yosemite National Park, piney woods of South Carolina, and plains of Laramie, Wyoming, have in common? Answer: The warm summers there are unusually hushed. The reason for this is that the frog population in those areas—and many others in the world—has been decimated. By some estimates, up to a third of the nation’s amphibians—frogs, toads, and salamanders —have disappeared. In 1988, in Costa Rica on a Monteverde ridge, half of the 40 amphibian species simply vanished. Some wags have speculated that those amphibians were stolen by aliens—a global whodunit!

In Chesapeake Bay, during some summers, nearly all Eastern oysters are parasitized by dermo. Up to one-half of the total population succumbs. Similarly, grass shrimp suffer from heavy parasitic infestation. In Alaska, ten years after one of the largest oil spills in history, the Valdez accident, species which have failed to recover include the common loon, cormorant, harbor seal, harlequin duck, and pigeon guillemot.

Marine biologists report “mass mortalities” among plants and aquatic life forms. Consider the following quote from a recent issue of Science43:

“In the past few decades, there has been a worldwide increase in reports of diseases affecting marine organisms. In the Caribbean, mass mortalities among plants, invertebrates, and vertebrates have resulted in dramatic shifts in community structure. Recent outbreaks of coralline algae lethal orange disease have affected Indo-Pacific communities on unprecedented scale.”

How do we begin to make sense of the mass extinction of marine and earthly species? To attempt to answer that question, first we must understand oxygen.


A large body of evidence supports the widely held view that the history of atmospheric oxygen on the planet Earth can be divided into the following three eras44-54:

1. An era of oxygen-free, strongly reducing primordial conditions;
2. An era of accumulation of free oxygen in the atmosphere, the concentration in the ambient air eventually rising to 30 to 35 percent of the air; and
3. A period of decreasing concentration of free atmospheric oxygen, the level falling to 21 percent or lower at present.

To the above three eras, I now add a fourth era of dysfunctional oxygen metabolism in which the central issue is not the level of free oxygen in the ambient air, but how the available oxygen is metabolized in the cells of humans and animals alike. This is a state in which molecular demons unleashed by failing oxygen relentessly corrode the body from within. That is what ails the growing masses of humans and animals suffering from those ‘mystery maladies.’ This view may surprise many doctors and public health policy makers, but—in my view—the evidence is unmistakable and incontestable.

I devoted Oxygen and Aging to detailed discussion of diverse aspects of how those four eras in the history of oxygen have affected—and continue to affect—the evolution and efficiency of human redox equilibrium and oxygen homeostasis. Those first three eras also saw profound changes in the competitive struggle for resources among the various life forms. Most significantly, the changing dynamics of man-microbe conflict—caused by oxygen dysfunction in the fourth era—have profoundly affected human host defenses. I discuss the crucial importance of those changes in the various sections of this volume— especially that entitled “Dysoxygenosis”—and in companion volumes of this textbook.

The Essential Redox Struggle of Life

From a redox perspective, the surface of the Earth is a boundary between the planet’s reduced—and powerfully reducing—metallic core and strongly oxidizing atmosphere. The Earth’s crust is largely composed of metal oxides and the surface water, of course, is an oxide of hydrogen. Thus, all that inhabits the planet’s surface is under relentless oxidizing stress. That, of course, includes all life forms on earth as well as in oceans, lakes, and rivers. Life, it follows then, must relentlessly create and/or strengthen its reducing potential to have a fighting chance for survival, until the immutable law of oxidative death does it in. Algae and plants begin that process by harnessing solar energy through photosynthesis. Animals extend that process by feeding on them. People carry on, feeding on plants as well as animals. That is the essential nature of the ‘redox struggle’ of life. And that is why I consider the phenomenon of spontaneity of oxidation in nature to be of paramount importance in the study of human biology and the beginning of disease. I return to this crucial subject in the section entitled “Energetic Basis of Spontaneity of Oxidation.”


Prebiotic chemical evolution appears to have created powerfully reducing molecular conditions in which primordial life arose, developed, and differentiated.55-62 It seems highly unlikely that that could have happened in the oxygen-rich environment that exists today. Oxygen is a powerful oxidizer. Equally evident is the fact that without availability of molecular oxygen, metabolism of complex life forms (which is oxygen-driven) could not have evolved. Changes in the surface chemistry of Earth brought life into existence. Life, in turn, dramatically altered the surface chemistry. Thus, the history of early atmospheric oxygen is of great interest to earth scientists.

It should be of equal interest to physicians. Oxygen began to accumulate in Earth’s atmosphere by oxygenic photosynthesis of plants and cyanobacteria. During the primordial period, oxygen occurred only as a component of various compounds. No oxygen existed as free gas in the air because all oxygen released from oxygen-containing compounds was immediately trapped by the organic matter in the oceanic water as well as that on the earth’s surface. The questions of when accumulation of atmospheric oxygen began and how it proceeded have been extensively explored.62-68 Atmospheric oxygen drives the processes of oxidative weathering of all materials on land and in oceans, forming oxidized mineral species. Two such examples are iron oxide and soluble sulfate that, in isotopic forms, may be seen as geochemical markers of oxygen accumulation. Employing those markers, two models have been constructed. According to the first model, the concentration of atmospheric oxygen reached close to present-day levels by the earliest Archean Period (3.8 billion years [Ga]). In the second model, accumulation of oxygen in the ambient air began much later—around 2.2 to 2.3 Ga in the early Proterozoic—and approached present-day levels sometime in the Neoproterozoic (0.54 to 1.0 Ga). Recent studies of the isotopic record of sedimentary sulfides favor the second model.69,76

The atmospheric conditions during the primordial era (primordial ecology, in my terminology) were strongly reducing. Thus, the early single-celled microbes came on the scene during a period of absence of free atmospheric oxygen. Since primordial microbes were not exposed to oxygen toxicity, those single-celled organisms developed, lived, and multiplied without learning to cope with oxygen. In other words, primordial microbes had no defenses against oxygen. At present, the commonly used term for microbes that grow in the absence of oxygen is anaerobic microbes (or anaerobes). Like their primordial ancestors, the anaerobes that live in human and animal bowels are also defenseless against oxygen. This is the scientific basis of my statement that oxygen is Nature’s primary antibiotic against anaerobes. It also follows from the above considerations that when oxygen concentration falls in the tissues, the anaerobes there will flourish. Thus, the two main lessons from the study of the first period of history of oxygen are:

1. Oxygen prevents growth of oxyphobic microbial species in health; and
2. The lack of oxygen promotes the growth of those oxyphobes in disease.


In the second period, plants began the process of photosynthesis, in which their green pigment (chlorophyll) turned the sunlight into the energy of chemical bonds.71-75 In the process, the plants took in carbon dioxide from the air and released free oxygen into the air. At first, all oxygen was rapidly absorbed by oxygen-binding substances in the oceans and on the Earth’s surface. Later, oxygen released during photosynthesis began to accumulate in the air as free oxygen, first slowly and later much more rapidly.

During an era called the Carboniferous Period, the oxygen concentration in the air rose as high as 30 to 35%.74 As plants grew in number and their capacity for releasing free oxygen into the air increased, oxygen rose to levels much higher than that in the air today (about 21%).

The course of biologic evolution was radically altered with the rise of atmospheric oxygen about 2.4 to 2.2 billion years ago (Ga).75-79 In the past, it was generally thought that such rise was due to burial of organic carbon as the means of separating photosynthetic reductants from O2, thus allowing the level of atmospheric oxygen to rise. It was assumed in that view that the burial rate exceeded the rate of O consumption by reductants made available by atmospheric and oceanic geologic processes. It is now recognized that the two rates are equivalent and do not explain the rise of atmospheric oxygen. Another challenge to that theory arises from the origin of bacterial photosynthesis, which preceded changes in O2 by several hundred years. The early earth environment was so strongly reducing that oxygen would be expected to be scavenged immediately rather than be released to, and accumulate in, the atmosphere, unless there was a mechanism for removing the reductant preferentially relative to the oxidized species so as to oxygenate the environment.80 A mechanism that fulfills those criteria was recently proposed by which hydrogen is transferred from photosynthetic organic compounds to CH4 by methanogenesis. When CH4 is decomposed by ultraviolet radiation in the upper atmosphere, hydrogen escapes to space forever. Such chemistry can be expressed as follows:

CO2 + 2 H2O —> CH4 + 2O2 —>
CO2 + O2 + 4H
(hydrogen lost to space)

Oxygen and Photorespiration

The plant enzyme rubisco (ribulose-1,5-biphosphate carboxylase/oxygenase) is the most abundant organic catalyst on Earth. It is the single most important protein of photosynthesis. It is also a promiscuous molecular two-timer—carbon dioxide has been considered its lawfully wedded wife, while oxygen has been relegated to the role of its mistress. Union with the first mate is fruitful, turning carbon dioxide into the chemical bond energy of sugars, fats, and proteins. When winds blow differently, it mates with oxygen eagerly, but fruitlessly. Rubisco-oxygen complex activates a slew of energy-sapping enzymatic reactions that are energetically sterile.

Why would natural selection not weed out the oxygen-binding function of rubisco if it were all to naught? In its preoccupation with molecular complementarity and contrariety, Nature assigned rubisco the responsibility of participating in the larger goal of regulating the concentration of oxygen in ambient air. In its oxygen-mating role, rubisco not only reduces the release of carbon dioxide into the air from plants, it also takes up oxygen and so contributes to lowering the oxygen level. This process is called photorespiration and it results in diminished plant growth and productivity.81-83 (The reader may remember rubisco by name-associating it with Nabisco. The enzyme, when it mates with oxygen, is as disruptive of energetic photosynthesis in plants as cookies are for bowel energetics in children!)

Oxygen and Primordial Life Forms (PLFs)

Oxygen is a powerful oxidizer and a potent antimicrobial agent. Rising levels of oxygen posed a serious threat to primordial life forms (PLFs) that were defenseless against oxygen.84 They could not cope with oxygen since they had neither been exposed to oxygen nor had they learned to protect themselves from its toxicity. Thus, PLFs were ill-prepared to face oxygen toxicity in ever-increasing degrees. They had the following three possible choices:

The primordial bugs could die out.
The primordial bugs could hide out.
Or the primordial bugs could branch out.

PLFs die out. It is evident that a large population of primordial life forms could not have adapted rapidly enough to survive increasing oxygen toxicity and must have perished. This may not be dismissed as mere speculation. Samples of pus taken from abdominal abscesses and cultured in rigidly controlled anaerobic conditions usually grow anaerobes. Every hospital microbiologist recognizes that pus specimens fail to grow anaerobes when they are exposed to oxygen in the ambient air even for short periods of time. That simple observation made repeatedly in hospital laboratories amply supports my view.

PLFs hide out. It is also safe to state that many of those primordial microbes escaped oxygen toxicity by hiding in niches where atmospheric oxygen did not reach. For example, deep crevices in the Earth’s crust offered PLFs protection from oxygen. With time, many of those microbes searched and found other oxygen-free or oxygen-deficient environments. For example, with passing time various animals appeared on the scene. The large bowels of those animals contained decaying matter with little or no free oxygen. The ecologic conditions in those bowels offered PLFs safe harbors to thrive and multiply rapidly. The anaerobic microbes of today, such as those grown from infected wounds and bowel abscesses, are undoubtedly related to PLFs of the primordial era. Present day examples of such microbes include mycoplasma, stealth organisms, nanobacteria, yeast, yeast-like organisms, bacteroid species, and other such bacteria.

PLFs branch out. Lastly, it is safe to state that some oxygen-hating primordial life forms branched out (adapted to their changing ecologic conditions) and developed methods for coping with the toxicity of free oxygen. Without such branching out (adaptation), today we would not have any aerobic cells—of humans, animals, or microbial species. Indeed, that may be seen as a master stroke of microbial engineering.

Those anaerobic primordial life forms learned to escape oxygen toxicity by acquiring the ability to metabolize oxygen for energy generation. Those early primordials evolved into mitochondria, the cellular powerhouses. Among mitochondria researchers, there is a consensus that mitochondria are derived from primordial microbes that acquired the ability to metabolize oxygen.


The drop in atmospheric oxygen concentrations occurred slowly over a long period of time.85,86 The extent of that drop has been estimated with many different methods. For instance, measurements of the ratios of heavy oxygen 18 and light oxygen 16 isotopes in plankton fossils have revealed the global concentration of oxygen in the air. Light oxygen isotopes evaporate more readily than do the heavy oxygen isotopes and the differences in their relative concentrations are evident in plant matter. Air bubbles trapped in ice contain samples of gas concentrations from periods of time millions of years ago. Measurements of those gases also give clues to relative concentrations of oxygen, carbon dioxide, and other gases, such as methane. Analysis of such tiny samples of air have enabled researchers to determine that concentrations of carbon dioxide and methane have risen by 25 and 100 percent respectively during the past one hundred years. Of course, oxygen levels in the air fell to make room for such increases of those two gases. What might be the meaning of a near 40 percent drop in the concentration of oxygen? Some giant insects lived in the Carboniferous Period when the oxygen concentration in the air was nearly twice what it is today (30-35%). Why did those giant insects become extinct? Again, it is tempting to speculate that giant insects died out when the oxygen level in the air fell. Less available oxygen could not support the giant bodies of those insects.

I never wondered about that until I traveled to Kenya’s Serengeti National Park. Standing in a roof hatch of a van, I watched two mammoth African bull elephants escorting a herd as the driver slowly moved to within about fifty feet of the animals. I stood in awe of the size of the bulls. Then my mind drifted to the subject of size in the animal kingdom and ended up with the mental images of dinosaurs. Two questions arose before me:

Why did dinosaurs of yesteryear become so big?
Why don’t elephants of today become that big?

Questions like those tempt me to look for a simplistic oxygen-related explanation. Can oxygen solve that mystery as well?, I recall wondering. Common sense told me that oxygen should be the most important ecologic factor in the growth and the size of various animal species. But I was not aware of any direct evidence to support such conjecture. Indeed, scientists who had considered that matter had thought otherwise. Animals tend to be larger in areas closer to the poles. That is called polar gigantism. In the past, it was assumed that was due to lower temperature and slower metabolism of such animals.87 That assumption did not seem unreasonable. Still, that explanation did not seem entirely satisfactory to me.

Of Dinosaurs and Dragonflies

It is estimated that dinosaurs ceased to live about 65 million years ago.88 The dinosaur that often draws much attention is Tyrannosaurus rex, a name that stands for tyrant lizard king. This meat-eating dinosaur weighed up to 10,000 pounds (as much as seventy men, each weighing 140 pounds). It ran at speeds up to 30 miles an hour, faster than any athlete today. How much energy did a monster like T. rex need to run at such a speed? How could such a dinosaur breathe in enough oxygen to produce such high amounts of energy? Some hyperventilation state! (Are stories of such feats by dinosaurs mere figment of imagination? Not so. Such information must not be seen as mere conjecture. Twenty-one complete skeletons of T. rex have been unearthed and painstakingly studied by scientists. Our present knowledge of those dinosaurs is based on those studies.)

Was the much higher concentration of oxygen in the air the reason T. rex could sustain itself during its mad rush of a feeding frenzy? If that dinosaur were alive today and were to breathe today’s air, could it have sprinted like that? It would have to take five breaths for every three breaths it took then to take in an equivalent amount of oxygen. Or, in other words, its required labor of breathing would have been 40% more. That is not a small extra effort for a huge animal that lived on hunted meat. How could T.rex have caught up with its prey that could run faster than it could?

On my return from Kenya, I dug into the literature of gigantism common in the Carboniferous Era. With great interest I read the accounts of the giant predatory flying insects and of colossal Meganeura, the extinct dragonfly that had a wingspan measuring up to two-and-a-half feet and a thoracic diameter of larger than one inch.89,9 To put that in perspective, the largest of the modern dragonflies (Odonata) has a wingspan of about four inches and measures up to one third of an inch in the diameter of its thorax. I read with amusement that the question of the linkage between giant insects and oxygen has also intrigued two French scientists, Harlé and Harlé, who, as far back as 1911, had argued that Meganeura could not have sustained its weight in flight in the current atmospheric oxygen levels of about 21 percent. That notion was laughed at, but not by all. In 1966, the Dutch geologist Rutten wrote:

Insects reach sizes of well over a metre during the Upper Carboniferous. In view of their primitive means of breathing, by way of trachea through the external skin, it is felt that these could only survive in an atmosphere with higher O2 level. As a geologist, the author is quite satisfied with this line of evidence, but other geologists are not. And there is no way of convincing one’s opponents.91

No way of convincing one’s opponents! I did not know that geologists have had the same problem as we do in medicine.

Something very interesting was reported several months after I returned from Kenya. Belgian researchers analyzed data for 1,853 animal species from 12 sites worldwide, extending from polar to tropical and freshwater to marine.87 They took into account many variables and confirmed that oxygen is the most important ecologic factor in determination of the size of a species. One of their many observations that support their conclusion is that oxygen dissolved in the hemolymph of certain marine life forms increased from tropical to polar ecosystems. (Hemolymph is mixed blood and lymph fluid in some marine life forms.) It has been proposed that if global oxygen levels decline, giant amphipods may be the first species to disappear. Oxygen solubility in water increases as salinity decreases. If the predictions about global warming were to come true and the massive bodies of frozen water in the Arctic and Antarctic were to melt, it would be expected to reduce the salinity of ocean water. Such a change in salinity could possibly be another significant factor in reduced availability of oxygen and detrimental effect on marine life.

Rodents as Big as a Buffalo

The case of the recent discovery of a giant rodent may be cited here as well. Mice weigh about 30 grams and rats about 300 grams.The adult mass of the South American capybara, the largest living rodent, is about 5,000 grams. But the members of the rodent family who lived during the period of dinosaurs were different. For example, Phoberomys, the largest of known now-extinct rodents, is a member of the Caviomorpha group that includes the guinea pig. Its body mass was estimated to be 50,000 grams—as much as that of a sheep. That was until most of the bone fragments of one member of the species were recently found in Upper Miocene rocks (24 to 5 million years ago) in Venezuela.92,93 That led to the revised mass of the animal at 70,000 grams—as much as that of a buffalo.


In 1983, based on a chance reflection on why stale buffers lose some of their buffering capacity with time, I wondered why butter turns rancid spontaneously but rancid butter does not turn unrancid spontaneously22. Fruit on a kitchen table spoils spontaneously, but spoiled fruit does not unspoil spontaneously. Unmindful of the evident relevance of the second law of thermodynamics to those questions, I put forth a hypothesis that spontaneity of oxidation in nature is the primary driving force in molecular and cellular injury94-96, and hence of aging and all disease processes. I devoted a mongraph entitled Spontaneity of Oxidation in Nature and Aging to those early reflections.2 That simple idea has preoccupied me ever since. Subsequent clinical, high-resolution microscopic, and biochemical studies led to the conclusion that a state of accelerated oxidative molecular injury (oxidosis) is the core pathogenetic mechanism involved in initiating and perpetuating: (1) biomembrane injury13; (2) mitochondrial and other cellular organelle derangements14; (3) matrix dysfunction15; (4) chronic fatigue syndrome16; (5) oxidative morphologic and biochemical abnormalities in the circulating blood (oxidative coagulopathy) 17-19; (6) stasis and stagnation of lymph (oxidative lymphopathy) 20; (7) cancer 21; (8) autoimmune disorders 22; (9) ischemic coronary artery disease23,24; (10) allergy25; (11) environmental sensitivity 26; (12) oligomenorrhea and amenorrhea in women with prior regular menstruation 27; (13) arrested growth in children following immunosuppression28; (14) fibromyalgia29; and (15) cellular microecologic and tissue macroecologic disruptions in other organ systems.30

Evolution of the Dysoxygenosis Model

In 1998, I introduced the term dysoxygenosis for a state of partial or complete failure of oxygen utilization in cells.11 I reproduce below an excerpt from one of those articles:

I put forth the hypothesis that dysoxygenosis is caused by impaired function of enzymes involved in oxygen homeostasis (“oxyenzymes”) and leads to altered expressions of genes induced by hypoxic environment (“oxygenes”). The webs of oxyenzymes are vast, with each entity linked to every other through multiple pathways. The webs of oxygenes are seemingly far more complex. All such webs are exquisitely ‘aware’ of changes in oxygen availability in their microenvironment and vigorously respond to them. When one thing changes in those webs in one way, everything changes in some way. Dysoxygenosis, then, is discerned as a state caused by a rich diversity of elements but one that creates the same cellular oxygen dysfunction. In 1998, I also introduced the terms dysfunctional oxygen metabolism and oxygen disorder for readers without medical or biochemical background.2


Oxygen is a tasteless, colorless, and odorless gas. In the ambient air, it essentially occurs in its diatomic form—as a molecule composed of two atoms. In the stratosphere and under certain conditions of very strong electromagnetic charges, diatomic oxygen breaks up to rearrange itself in a triatomic form, ozone.97,98 It seems highly likely that minute amounts of polyatomic oxygen—comprising four, five, or more atoms of oxygen in a molecule —also form under natural conditions, since claims of generation of such forms of oxygen in the laboratory have been made.99

Oxygen is estimated to constitute 0.5 percent of the mass of the universe—only about three atoms out of 10,000 being considered to belong to the element.100 Even at this small proportion, oxygen is deemed to be the fourth most abundant element in the universe, after hydrogen (about 94%), helium, and neon. In the regions ordinarily accessible to us—within two miles of the surface of the Earth—oxygen is the most abundant element. In mass, about 46 percent of the Earth’s crust and 20 percent of the air is composed of oxygen. The element comprises about 89 percent of water—its mass being approximately 16 times that of hydrogen.

Oxygen is strongly electronegative and this property of oxygen is largely responsible for the fact that the molecule of water is nonlinear, the angle between the two covalent bonds being 104o 30/. In the proposed structural model of the water molecule, the high electronegativity of oxygen creates a strong negative electrical charge on the oxygen atom with a corresponding positive charge distributed between the two hydrogen atoms.101 The two unshared pairs of electrons of oxygen extend in space toward the apices of a tetrahedron of the bent water molecule.

Oxygen has played an important role in the natural climate variability in the history of the planet Earth. The estimates of such climatic changes have been based on the ratios of oxygen isotopes in the ancient ice core. Interestingly, shifts on those ratios of isotopes match Earth’s wobbles and wanderings, which profoundly influence changes in Earth’s annual energy balances through its various seasons.

Changes in Oxygen Pressure

The Chinese Too Kin noticed (around 37 to 32 B.C.) that climbing high mountains had an effect on breathing.102 Clearer descriptions of those adverse effects of high altitudes on human performance—mountain sickness, in contemporary language—were given by Acosta in 1590 when he climbed the Pariacaca Mountains in Peru.103 It appears that Acosta’s description piqued the interest of the great Irish chemist Robert Boyle (1627-1691), generally considered the father of modern chemistry. He began to investigate the effects of varying pressures on animals.104 He released oxygen by heating lead oxide, but seemingly was unaware of the nature of the gas he had generated. He did have some sense of the deep significance of his findings when he recorded that a partial vaccum created in his experiments caused a flame to go out or the animals to die.105

Though unable to characterize his gas, he nonetheless understood that it supported both life and burning. The names of Hooke and Mayow often appear in the history of the early work with oxygen.106 Mayow proposed that “…an aerial something essential to life, whatever it may be, passes into the mass of the blood.”107 Evidently, those Europeans were unaware of the clear description of the integrated functions of the lungs and the heart in the writings of Ibn-Nafis (1208-1288 A.D.), an Arab surgeon and physiologist.108 Mayow also theorized that the substance in the air was a ‘nitr-aerial spirit.’ That may have had something to do with the fact that gunpowder was then known to be a mixture of potassium nitrate (nitre), carbon, and sulfur. That may be seen as a fascinating premonition in the context of our contemporary concepts of nitric oxide biology. I addressed that subject in an article entitled “The Primacy of the Erythrocyte in Vascular Ecology.'”109


All early notions of life were linked to breath. It is hard to see how peoples of prehistory could have missed the obvious relationship between breathing and living. The physical finality of death could not have escaped them. Needless to say, it must have been obvious to them that the dead do not breathe. Many of them would certainly have closely witnessed the sudden transition between life and death—the process of dying—when a companion slipped off a ledge to his death or someone was torn apart by a large cat. Most of them also would have seen their elders simply wither away, ceasing to breathe and move.

In the oldest extant texts—inscribed on stones or other materials—the notion of the breath of life appears in different contexts but as the central quality of living beings.110 One of the earliest and most succinct statements to that effect appears in the Sumerian creation mythology dated at about 3,000 B.C. It reads as follows:

For the sake of the good things in their pure sheepfolds Man was given breath.109

A stone monument to Prince Gudéa (dated at about 2,200 B.C.) bears the following inscription:

….generously endowed with the breath of life.109

Gilgamesh’s Quarrel With Death

Humans have been preoccupied with death for a very long time—the quest for immortality appears to have begun as soon as they recognized the difference between life and death. One of the earliest records of man’s quarrel with death is in the adventures of Gilgamesh, the fabled Babylonian king. He was deeply disturbed when told that he could not live forever. How could a supreme lord like himself not be able to do something about death? So he declared his ‘resolve’ to engage and prevail over the gods of death with the following words that have been famous ever since:

I want to prove….that the boundaries set by the gods are not unbreakable.111

Gilgamesh evidently did not know—or care to consider—the immutable law of oxidative death.1-6 That law dictates that no oxygen-breathing being can defy the oxidative molecular pathways of death forever. Spontaneity of oxidation in human biology decrees that all human cells and tissues must eventually be oxidatively denatured to death.19-22 History teaches us that Gilgamesh was not alone in his pursuit. Most empire builders in history were loathe to simply yield their hard-earned empire to death. They doggedly pursued immortality and commissioned many a physician to concoct remedies against death. Most notable among them were the pharaohs of the Nile.

The early Egyptians were into things hidden. They thrived on secrets. They designated the right ear to be the portal of entry for the breath of life and they assigned the left ear the process of dying. The Physician’s Secret: Knowledge of the Heart’s Movements and Knowledge of the Heart (1,600 to 1,500 B.C.) introduced the notion of two separate forms of breath and pronounced that:

The breath of life enters into the right ear, and the breath of death enters into the left ear.109

Pharoah Akhenaton (about 1,350 B.C.) was an iconoclast. He housed his God in the sun. For the priests and commoners of his time, his hymn writers scribed the following words:

….[the sun] Who giveth breath to animate every one that he maketh.

The theme of the breath of life continues into the Old Testament (Genesis, chapter 2, verse 7) as:

God Yahweh formed man from clouds in the soil and blew into his nostrils the breath of life. Thus man became a living being.

The Greek Anaximenses (494 B.C.), the third philospher of Miletus, also weighed in on the subject with the following words:

The fundamental substance is air. The soul is air, fire is rarified air, when condensed, air becomes water, then if further condensed, earth, and finally stone. Consequently all differences between different substances are quantitative, depending entirely upon the degree of condensation.112

Chi, Ka, Pneuma, Mana, and Rűahh

All creations in the universe are energy beings. The earlier peoples seemed to have grasped this truth a long time before the modern physicists did. Indeed, the concepts of body energetics dominated the theory and practice of medicine in nearly all ancient healing philosophies. For instance, Qi (chi, energy) is a central concept in the traditional Chinese medicine (TCM).113,114 Egyptians used the term ka for the same meaning. The Greeks, Polynesians, and the Jews called it pneuma, mana, and rűahh respectively. The expression life-force is the commonly employed Western equivalent.

The concept of healing energy is eminently displayed in both the traditional Chinese and Indian Ayurvedic models. TCM is a syncretic blend of Confucian, Taoist, wushu (Chinese martial art), Buddhist, and other schools of knowledge and thought concerning human health. Huang Di Nei Jing (the Yellow Emperor’s Classic of Internal Medicine, circa 475-221 B.C.) is widely regarded as the best compendium of TCM philosophy and therapeutics.115 As for the philosophic foundation and the herbology component, TCM closely parallels Siddha, Ayurvedic and other ancient healing practices of ancient India. That should not be surprising. There was robust commerce between the two countries and vigorous cultural exchanges among their peoples throughout the ancient history. Similarly, notwithstanding the distinctions commonly made between Indian yoga and Chinese qigong, the two approaches are founded on identical concepts of tissue energetics. Chinese chi, Indian prana, and Egyptian ka, in reality, are three words for the same energetic phenomenon. Indeed, the literal translation of qigong is breathing exercise, while that of prana is energy of breath. Both chi and prana are intended to facilitate regulation of respiration (as well as other bodily functions), posture, and mind. That is precisely what Westerners would consider homeostasis, in its broadest sense.

The Western expedience often translates the words chi, prana, and ka as energy. However, it seems that the ancient Chinese, Indians, and Egyptians preceded Einstein’s concept of energy-matter dynamics by nearly three thousand years. They pronounced that energy and matter could not be separated. Qi in the Chinese writings stood neither for energy nor for matter. Similarly, the Indian prana and the Egyptian ka, in my view, are also properly seen in the same light. The common theme in all those traditions was the linkages between breath, energy, and life.

The ancient Greek believed in four elements: earth, air, water, and fire. They almost certainly adopted that notion from the earlier Indians and Chinese. (See The History and Philosophy of Integrative Medicine, the second volume of this textbook, for further information on this subject). The Greek Parmenides (born about 515 B.C.) believed fire within the living organisms was what gave them the essential characteristics of life. Aristotle (384-322 B.C.) could not resist weighing on every subject of his time. The following words are attributed to him:

Hence, of necessity, life must be coincident with the maintenance of heat, and what we call death is its destruction.

The early Romans—who freely appropriated to themselves the earlier Hellenistic ideas, just as the Greeks without impunity had laid claims of originality on the prior Egyptian arts—coined the term flamma vitalis for what they believed was the true flame of life. Nearly fifteen centuries later, the incorrigible Leonardo da Vinci clarified the situation by putting the notion of fire in a modern scientific context. He asserted that the air that could not support combustion could not sustain life. So, we move from life force to something in the air that was essential for both life and combustion—oxidation, may we say, in the contemporary parlance.


The phlogiston theory is noteworthy in the present context because it provides a revealing link between the ancient notions of the fire material emitted by the Earth and early evolving notions of the role of oxygen in combustive and oxidative phenomena.

Many ancient peoples—Indians, Chinese, Greeks, and others— believed in the ability of the earth to emit fire. The Chinese and the Greeks thought that ‘fire material’ was sulfur. Not surprisingly, that fire material was linked to precious metals, and the field of alchemy probably owed its origin to that notion. Producing gold from that abudant material was for centuries the vision of countless dreamers. It was in this vein that the Swiss physician Paracelsus (born Theophrastus Bombastus von Hohenheim, 1493-1541) named sulfur the ‘combustible principle.’116 Robert Hooke (1635-1703), the English physicist and curator of experiments to the Royal Society, believed that all combustible materials contained sulfur, a belief similar to the earlier notion of Paracelsus on the subject.117 On that subject of combustibility, Johann Joachim Becher (1635-1682) proposed that the process of combustion involved loss of fatty earth. Presumably he referred to the elements of the plant and animal kingdoms. The German Georg Ernst Stahl (1660-1734) is credited with the introduction of the term phlogiston for the mythical fire material of the earth that had sparked speculation for centuries of conjecture and hope.117 Then, an explanation often offered to commoners was that phlogiston was what exited from a burning wooden house before the large structure was reduced to a small pile of charcoal, which was deemed to be the residual and condensed form of the same substance. The obvious implication was that if the right conditions were to be found, charcoal could be sublimated into the ethereal phlogiston as well.

Subsequently, chemists heated metal oxides— then not knowing that oxides contained oxygen—with charcoal to produce their respective metal. They speculated that phlogiston released from the charcoal in those experiments then combined with the metals to produce the reduced form of the metal.118 Later that reaction that was recognized as follows:

MO2 + C ➔ M + CO2

(where M represents metals, O oxygen, and CO carbon dioxide.)


In the mind of most people, the discovery of oxygen is linked to the celebrated trio of the oxygen pioneers—the Swedish Karl Scheele (1742-1786), the English Joseph Priestley (1733-1804), and the French Antoine-Laurent Lavoisier (1743-1794). The Swedes claim that a Swedish pharmacist discovered oxygen. The English hold that one of their countrymen first identified the gas. The French insist that a Frenchman first understood the meanings of the experiments conducted by the other two, and came up with the name for the element. I have never heard any physician associate Poland with the discovery of oxygen. But in 1604, about 170 years before that trio had reported their findings, the Polish chemist Michael Sendivogius penned the following words:

Man was created of the Earth, and lives by virtue of the air; for there is in the air a secret food of life …whose invisible congealed spirit is better than the whole earth…without which no mortal can live, and without which nothing grows or is generated in the world.119

Those words may seem as whimsical as those of the ancient Indians and the Chinese, but Sendivogius based his comments on sound experimental work. He put forth the view that his ‘aerial food of life’ circulated between the air and earth by way of nitre—now known as potassium nitrate, KNO3. He believed he could obtain that aerial food by heating nitre. His choice of the words aerial food are particularly revealing. Sendivogius’s work would have probably been lost except for his fellow chemist and inventor-friend Cornelius Drebbel. One wonders if there were others whose work has been neglected simply because they did not have any influential friends.

In 1621, Drebbel apparently built the world’s first submarine for King James I. The king stood at the bank of the River Thames, surrounded by thousands of his subjects, and witnessed the maiden voyage from Westminster to Greenwich,of the wooden submarine powered by twelve oarsmen. The boat reportedly remained submerged for up to three hours. Not surprisingly, what fascinated the English king and his subjects was how the inventor had managed the problem of men breathing under water for so long. The details of that are not known, but it seems that the boat-builder had learned to bottle oxygen produced by heating nitre by the method of his friend Sendivogius. That conclusion is supported by the records, which do not reveal any other evidence of Drebbel’s interest in gases. Nearly forty years later, the great Irish chemist Robert Boyle wrote about the accounts of the eyewitnesses to Drebbel’s submarine. In the following passage concerning Drebbel’s method for replenishing the ‘spirituous part’ of air for breathing by the men in the submarine, Boyle furnishes his illuminating view:

Drebbel conceived that it is not the whole body of the air, but a certain quintessence, or spirituous part of it, that makes it fit for respiration, which being spent, the remaining grosser body, or carcass of it (If I may so call it) of the air, is unable to cherish that vital flame residing in the heart…For when, from time to time, he perceived the finer and purer part of the air was consumed…he would, by unstopping a vessel full of this liquor, speedily restore to the troubled air such a proportion of vital parts, as would make it again, for a good while, fit for respiration.120

John Mayow, a Fellow of the Royal Society, was a contemporary of Boyle. He extended Sendivogius’s observations about the gas (oxygen) released by heating nitre. He demonstrated that aerial nitre, when breathed into the lungs, gave arterial blood its red color. He also believed that aerial nitre was a normal constituent of the ambient air, and in 1674 stated:

[Nitre] becomes food for fires and also passes into the blood of animals by respiration…It is not to be supposed that the air itself, but only its more active and subtle part, is the igneo-aerial food.121

It is interesting that despite those unequivocal statements by Boyle and Mayow, the credit for the discovery of oxygen continues to be given to the trio of Scheele, Priestley, and Lavoisier.

During the eighteenth century, the English— under the influence of Boyle— were focusing on gases while the French were occupied with studies on solids. The phenomenon of gases emanating from solids (effervescence) brought the two groups together and set the stage for the work that led to recognition and characterization of oxygen. The players on that stage were the English chemist Stephen Hales (1677-1761), the Swedish pharmacist Karl Scheele, the English chemist Joseph Priestley, and the French chemist Antoine-Laurent Lavoisier. Hales made an important observation concerning gases released from solids under various conditions and published it in Vegetable Staticks in 1727.122

Scheele initially collaborated with Torbern Bergman, a brilliant chemist and naturalist, in Uppsala, Sweden. He died young at the age of 43. But during that time he reportedly conducted 15,000 to 20,000 experiments, 123 and was elected to the Royal Academy of Sciences of Sweden in 1777.

Joseph Priestley is generally believed to have discovered oxygen in 1774.124 Interestingly, most writers who recognize Priestley as oxygen’s discoverer go on to relate how the Swedish pharmacist Karl Scheele had obtained oxygen two years earlier (in 1772) by heating certain metal oxides—by the same method employed by Priestley after him. Scheele considered the gas he isolated to be dephlogisticated air. In that, the Englishman concurred with the Swede.
Priestley also discovered hydrogen and carbon dioxide. He recognized that respiration eventually made the air unfit for both living beings and combustion. He reasoned that Nature, to sustain life on the planet, had to create a mechanism for regenerating air suitable for both functions from air that had been previously rendered unfit. His pursuit of that question led him in 1772 to demonstrate that plants were the source of that regeneration. One of the acheivements of the prodigious mind of Priestley was the development of the nitric oxide test for determining the percentage of oxygen in the atmosphere. The name of Ingenhousz is noteworthy in this context. In 1779, he demonstrated that plants exposed to sunlight released oxygen. 125

The French chemist Antoine-Laurent Lavoisier (1743-1794) learned about the work of Priestley and, by remarkable insights, recognized the central roles of oxygen in the processes of respiration and combustion.126,127 He also noticed the ability of the gas to form acids by reacting with many different substances and coined the term oxygéne—from the Greek word for acid former. He repeated Priestley’s experiments to produce oxygen by heating red mercuric oxide and extended the Englishman’s observations by showing that that reaction could be reversed by heating its products, oxygen and mercury. In his experiments, mercury oxide was formed when mercury was heated to 350o C, while further heating to 360o C resulted in the release of oxygen. Lavoisier went on to combine oxygen with hydrogen to produce water.

One of the major insights of Lavoisier was what we now see as oxidation. In his heating-cooling experiments with mercury, he recognized that in the presence of charcoal mercuric oxide did not require as much heat to reduce oxide to mercury, and the liberated gas under those conditions was carbon dioxide. That was seen by many as the death knell of the prevailing phlogiston theory, even though some eminent scientists of the day, including the English physicist and chemist Henry Cavendish (1731-1810), believed hydrogen to be phlogiston. 128 It may be mentioned here that Cavendish discovered the properties of hydrogen and established that water is composed of hydrogen and oxygen. Employing the universal gravitational constant, he also measured the density of the earth in 1798. Notwithstanding how Cavendish weighed in on the subject, there was yet some color to be added to the phlogiston theory.

The Priestess

History books often carry an interesting footnote to Lavoisier’s wife, Marie-Anne Pierrette-Paulze Lavoisier (1758-1836). Her husband reportedly persuaded her to learn English so she could translate for him the works of Hales and Priestley. Later, dressed as a priestess, Madame Lavoisier burned the works of Stahl in Paris. The German supporters of phlogiston returned her gesture by burning the effigy of her husband in Berlin.45 The tradition of burning the books of writers who thought differently—Paracelsus had been an early champion of book burning—was evidently alive in the eighteenth century. The priestess suffered much greater pain when her husband was guillotined in 1794 during the Reign of Terror of the French Revolution.129

A brief note about the travails of Priestley may also be included here. A liberal clergyman, he sympathized with ideals behind the American and French revolutions. His house was burned on July 14, 1791, and he was forced to flee his country. The French made him a citizen of France—George Washington and Thomas Payne shared that honor with him. Later, Priestley sailed for the United States and learned of Lavoisier’s beheading when he arrived in his adopted country.


All three giants of eighteenth-century oxygen research—Priestley, Scheele, and Lavoisier— independently recognized some adverse aspects of oxygen. The essential paradox of life—that oxygen both sustained and destroyed life—did not escape them. There is a cruel irony in that. Scheele reported that pea plants do not grow in high concentrations of oxygen. In the following quote, Priestley describes some of his experiments with breathing pure oxygen:

The feeling of it in my lungs was not sensibly different from that of common air; but I fancied that my breast felt peculiarly light and easy for some time afterwards. Who can tell but that, in time, this pure air may become a fashionable article in luxury…From the greater strength and vivacity of the flame of a candle, in this pure air, it may be conjectured, that it might be peculiarly salutary to the lungs in certain morbid cases, when the common air would not be sufficient to carry off the putrid effluvium fast enough. But, perhaps, we may also infer from these experiments, that pure dephlogisticated air [Priestley’s word for oxygen] might be very useful as a medicine.130

Those words reveal Priestley’s amazing insights into the role of oxygen in metabolism and host defenses. Ever the clergyman, Priestley kept a sharp eye to the notions of morality of his time. He went on:

…it might not be so proper for us [to take oxygen] in the usual healthy state of the body; for, as a candle burns out much faster, as may be said, live out too fast, and the animal powers to be too soon exhausted in this pure kind of air. A moralist, at least, may say, that the air which nature has provided for us is as good as we deserve. 130

Priestley’s words remind me of the following ancient Indian saying:

One is born with a finite number of breaths. One can breathe fast and live less, or breathe slowly and live longer.

Lavoisier also shared Priestley’s concern about the Mr. Hyde face of oxygen. He wrote:

Healthy air is therefore composed of a good proportion between vital air [oxygen] and atmospheric moffete [nitrogen and carbon dioxide]…when there is excess of vital air, the animal only undergoes a severe illness; when it is lacking, death is almost instantaneous.131

Paul Bert (1833-1886), a French physiologist and politician, investigated the impact of pressurized oxygen on animals by employing hyperbaric chambers. He furnished clear and succinct descriptions of the adverse effects of increased oxygen supply on the central nervous system, including those of ‘oxygen convulsions.’ In his famous Barometric Pressure. Researches in Experimental Physiology (1878),132 he described the results of his experiments with changing oxygen tension and barometric pressure, and delineated the effects of the two on living organisms with the following words:

…the diminution of barometric pressure acts upon living beings only by lowering the oxygen tension in the air they breathe….we have given abundant proof that they are the consequences not of barometric pressure as a physico-mechanical agent, but of the increase in the tension of the ambient oxygen.132

The work of Bert is recognized today with the term Paul Bert effect, which refers to clinical disorders caused by oxygen toxicity. Bert was elected to the National Assembly and in 1881 assumed the responsibilities of Minister of Health. Later, he became governer general of French Indochina and died in Hanoi.

The use of scuba (self-contained underwater breathing apparatus) towards the end of the nineteenth century brought forth additional insights into the Mr. Hyde face of oxygen. During those years, pure oxygen used in the earlier versions of scuba units created special hazards—neurological symptoms progressing to Bert’s convulsions and death— due to compression of pure oxygen by incremental water pressure at increasing depths. Some such events were recorded at depths of 25 feet and greater.133

On Being One’s Own Rabbit

The Scottish biologist physiologist J.B.S. Haldane, an expert in diving medicine, was commissioned by the Royal Navy to investigate oxygen toxicity. He was known for self-experimentation. In one such experiment, he exposed himself to pure oxygen at seven atmospheres pressure to see how long it would take him to notice serious adverse effects. He suffered convulsions within five minutes. In 1928, he published a celebrated essay entitled, “On Being One’s Own Rabbit”, in which he described the results of that adventure:

The convulsions are very violent, and in my own case the injury caused to my back is still painful after a year. They last for about two minutes and are followed by flaccidity. I wake in a state of extreme terror, in which I may make futile attempts to escape from the steel chamber.134

Based on his work, the Royal Navy established various nitrogen/oxygen (nitrox) mixtures to markedly reduce the risk of both oxygen toxicity and nitrogen narcosis, then commonly known as “the bends.”135 Not unexpectedly, the work of Haldane and others concerning oxygen toxicity was followed by a large number of reports of oxygen toxicity in various clinical contexts.136-139

There is a profound irony in the historical accounts of oxygen toxicity as observed by Scheele, Priestley, Lavoisier, Bert, Haldane, and others. All of them gave eloquent descriptions of the adverse effects of the gas, which I refer to as the Mr. Hyde roles of oxygen. None of them could save untold newborns from total blindness after they were administered pure oxygen. Even now new cases of blindness resulting from retrolental fibroplasia caused by oxygen toxicity are reported.140,141. As for adults, countless women and men continue to suffer from an adult type of hyaline membrane disease caused by oxygen toxicity when they were administered pure oxygen for extended periods of time in intensive care units and trauma centers. In this context, a recent article documenting a specific form of oxygen toxicity published in The New England Journal of Medicine142 is of special interest. That article reported six times as many fatalities in extremely premature newborns who were administered extra oxygen to maintain higher (94 to 97%) saturation rates than in the control group given lower amounts of oxygen to maintain the saturation rates between 91 and 94 percent. Below, I reproduce some text from a column I wrote for www.majidali.com in response to that article:

The unexpected findings of carefully designed clinical trials sometimes are more valuable than the conclusions about the designated primary endpoint of the study.The study of oxygen saturation in extremely preterm babies (the BOOST trial, September 4 issue) is a case in point. The really important finding was the substantially larger number of deaths due to pulmonary causes (6) in the higher saturation subgroup (6) than in the lower saturation group (1). The data demonstrate that oxygen toxicity to immature lungs rises steeply when oxygen saturation is bumped up even by three to four percentage points. This should have been the main conclusion drawn from the study data but was not even mentioned in the conclusion section of the abstract. A passing reference to the subject in the middle of the discussion section did not do justice to the crucial finding.142

Infants should not suffer from oxygen toxicity this day and age, but they continue to do so. Such is the resistance of most clinicians to diligent and persistent study of oxygen homeostasis in health and oxygen dyshomeostasis in disease.


Oxygen is essential for life. Sendivogius, Drebbel, and Boyle had explained that clearly. In 1660, Boyle wrote about ‘the troubled air’ to the vital parts of the oarsmen in Drebbel’s submarine. He recognized that such air put in jeopardy the physical performance of men in the submerged boat. Then he explicitly acknowledged that both Sendivogius and Drebbel had introduced the use of the gas for restoring health of those vital parts with full cognizance120 of its health benefits. So it may be stated that oxygen therapeutics has a documented history of at least 350 years.

Not unexpectedly, the work of Sendivogius and Drebbel piqued the interest of clinicians of the time. One such person was the British physician Henshaw. In 1662, four years after Boyle’s book, he built a specially equipped room—designated domicilium by him—to administer compressed air to treat patients with respiratory and digestive disorders.143-145 Notable among others who advanced oxygen therapies were the British physicians James Watt and John Thornton.146 So infectious was the enthusiasm for the vital air—the name for oxygen then— that some took the poetic license to propose new and novel uses of the gas without taking the trouble to conduct any clinical trials. One such example was the poet Samuel Parkes, who wrote A Chymical Catechism, an early nineteenth-century volume in which he extolled the virtues of the gas.147 Not unexpectedly, oxygen also had its early doubters. An English actor named Morton chimed, “One Mr. Oxygen, who gives his patients, by mistake, instead of a certificate of cures, the bills of mortality.”148

The next important period in the history of oxygen therapeutics was ushered in by Scheele, Priestley, and Lavoisier. That spurred great interest among the physicians of the time to explore the clinical potential of oxygen for entities that responded poorly or not at all to then-available remedies. Notable among those researchers was the Bristol physician Thomas Beddoes. In 1798, he founded the Pneumatic Institute for inhalation gas therapy to treat disease considered to be incurable. He engaged the services of an imaginative young chemist, whom we today recognize as Sir Humphrey Davy. What happened next was what happens even now with disconcerting frequency: Novel therapies are introduced to treat severe and intractable clinical problems and draw derisive comments from ignorant doctors—and severe censor and license revocations from uninformed medical boards—before the real potential of the new therapies can be established. I often wonder if the professional jealousies are as intense in other professions as they are in medicine. Beddoes and Davy were compelled to close their Institute within four years. The two reasons given were pulmonary reactions caused by impurities in oxygen administered and the unreliable supplies of the gas. In hindsight, those lung responses probably had more to do with their incremental oxygen doses—administered in their passion to help their patients—than with the imagined impurities. Davy later referred to those efforts as “the dreams of misemployed genius, which the light of experiment and observation has never conducted to truth.”149 I wonder what Davy would say if he were to spend a week observing oxygen therapeutics and listening to patients describe both short-term and long-term benefits of those therapies at our Institute now.

I might share with the reader the following quote from Nick Lane’s Oxygen—The Molecule That Made the World, in which he comments on the status of oxygen therapeutics soon after the Institute of Beddoes and Davy closed its doors:

Problems with impurities, and diverse methods of delivery to the patient, meant that a clinical consensus never emerged… Advocates of oxygen therapy claimed miraculous claims (which may been true in conditions such as pneumonia) but the voices of the mainstream medicine were for the most part unimpressed, arguing that any perceived benefits were transitory, palliative or imaginary…Some claims made in the 1880s were remarkably similar to those made today by proponents of ‘active oxygen’ therapies. 150

Lane’s Oxygen is a wonderful book that should be read diligently by every physician. But in writing the last sentence in the above quote, Lane is clearly out of his depth. He is not a clinician and has no true perspective of his own to add. He only parrots the deep prejudice of those utterly uninformed about the enormous potential of oxystatic therapies. Then Lane surprises me. Consider the following quote from his book that appears two pages later:

A large clinical trial, reported in the prestigious The New England Journal of Medicine in January 2000, showed that inhalation of 80 percent oxygen for two hours halved the risk of wound infections after colorectal surgery, compared with routine practice (30 percent oxygen for two hours)….it illustrates just how far the progress of science can be impeded by a professional knee-jerk response to inflated claims of quacks and charlatans.151

Continuing the oxygen story, Beddoes left a rich legacy of interest in oxygen therapeutics. Anecdotal reports of its clinical efficacy continued to accumulate. Some empirical observations of lay individuals further sustained those early efforts. One notable example concerned the much improved chances of survival from pneumonia when the subjects living at higher altitudes were rushed to lower altitudes where the oxygen pressure was significantly higher. Similar clinical observations were documented in patients with cardiovascular disorders. One physician who was deeply impressed by such observations was Orval Cunningham. One of his clinical successes earned him a large donation of one million dollars. In 1928, he spent that amount to construct the largest-ever hyperbaric chamber in the shape of a steel ball measuring 65 feet in diameter, as tall as a building with five stories.152 Learning from earlier accounts of oxygen toxicity, he pressurized it about twice the atmospheric pressure at sea level. Not fully learning from those accounts, however, he used ambient air to pressurize it. Also, he made the same mistake as Beddoes before him. He made extravagant claims of curing diverse disorders—from pernicious anemia to cancer to diabetes—in the belief that all disorders are caused by oxygen-hating microbes. The American Medical Association took no time to put a cabash on Cunningham’s work—denouncing it as “tinctured much more strongly with economics than with scientific medicine”—foreclosing any possibility of others improvising on Cunningham’s model. However, some decades later, hyperbaric medicine was brought to sound scientific footing.

The flames of romanticism of the vital air were never really extinguished. In the footsteps of Parks, the Sweet musical group of the 1980s came up with their version of oxygen benefits. They wrote:

Love is like oxygen.
You get too much,
You get too high.
Not enough and you’re going to die.

There are, of course, many more doubters than at any time in history. Some of the doubters truly surprise me. Consider the following quote from Gilbert and Coltons’s Reactive Oxygen Species in Biologic Systems, a highly esteemed volume in the field:

Because oxygen was shown to be indispensable for both the aerobic living organisms and for combustion, Thomas Beddoes, James Watt, John Thornton, and others believed that excess oxygen could be used as a therapeutic agent to cure many diverse diseases. Most physicians soon realized that this extra oxygen had no effect.153

Why would the writers, clearly recognized world authorities on the subject, hold that most physicians soon realized that this extra oxygen had no effect? Because they are not physicians. They have no opinion of their own. They would not have penned those words if they had an opportunity to speak to any of my patients who suffer from fibromyalgia and disconcerting problems of mentation, and who can teach their classes only after they have prepared their lectures while taking oxygen by mask. Notwithstanding my strong disagreement with them on this issue, I highly recommend Gilbert and Colton’s volume.

To cite just one study documenting the clinical value of oxygen, below I reproduce some text from my presentation of the subject in Oxygen and Aging154:

In general, there is little, if any, understanding of the antimicrobial efficacy of oxygen among mainstream doctors. Indeed, they often make derogatory (and irresponsible) remarks about the clinical efficacy of oxgenative therapies. However, I see a big change on the horizon. In its January 20, 2000, issue, The New England Journal of Medicine reported dramatic reduction in the rate of serious infections with oxygen therapy.155* Patients who received 80% oxygen with a nasal mask during colon surgery had half as many infections as those who received 30% oxygen for the same period. In an accompanying editorial, the Journal recommended the use of oxygen for reducing the frequency of infections in surgical patients.156* It is noteworthy that there are no known drugs that have shown such a high level of efficacy in preventing serious abdominal infections as oxygen.

The study reported in the Journal did not surprise me—and others well versed with antimicrobial potency of oxygen—since it only reported what we have seen in our patients for decades. For emphasis, I ask the reader to recall my discussion of how oxygen arrests microbial growth (PLF overgrowth, as well as that of other types of microbes) in health and how such microbes rapidly multiply in states of dysoxygenosis. I devoted the chapter, “Oxygen Settles the Great Pasteur-Bechamp Debate,” to this subject. My basic conclusion is the following:

Specific microbial species invading the body from the outside cause specific infections when oxygen metabolism is normal. However, when the cellular oxygen metabolism is dysfunctional, the primordial life forms from within the body multiply rapidly and become more troublesome sources of “infections.” Thus, in chronic illness, oxy therapies are as important as in acute illnesses. [The reference numbers in the original text have been changed to 155 and 156 for maintaining sequential citations. ]


In the early 1960s, as a young surgeon I tried to understand the causes of disease by the examination of damaged tissues on the operating table. In the early 1970s, as a pathologist, I sought to understand the same through the microscopic study of injured cells. In the early 1980s, I became interested in the oxidative phenomena and spontaneity of oxidation in nature. That led to a preoccupation with the impact of oxidative phenomena on the human health/dis-ease/disease continuum. In 1983, I published some of my early observations and reflections on the subject in Spontaneity of Oxidation in Nature and Aging.2

Electron Transfer Medicine

In the mid-1980s, l introduced the term electron transfer medicine in the part of the Curriculum of the American Academy of Environmental Medicine assigned to me.155 It occurred to me then that if we were to keep digging deeper into the boundaries between the state of health and the state of absence of health, we are bound to see energetic-molecular changes in terms of electron transfer events, hence the coining of electron transfer medicine.

In the early 1990s, I was struck with the frequency with which many patients suffering from fibromyalgia and chronic fatigue syndrome complained of air hunger and oxygen starvation.156 Many of them were athletic teenagers and young adults who appeared quite robust. They had no demonstrable pulmonary, cardiac, or hematologic lesions that could account for symptoms of air hunger and oxygen starvation. Clearly there was no clinical or laboratory evidence for anemia. Why then oxygen hunger?, I wondered. I began to suspect there was some ‘cellular energy lesion.’ The search for that ‘lesion’ eventually culminated in the introduction of the concept of oxygen dysoxygenosis discussed at length in the chapter entitled “Dysoxygenosis.”

During the 1990s, I defined integrative medicine as the philosophy of medicine that requires physicians to offer their patients all that is safe and effective without any subservience to one or more schools of thought.157 The core and crucial message in the oxidative-dysoxygenative model of integrative medicine presented in the various volumes of this textbook is this: Clinical assessment of health and reversal of chronic illness must be attempted in light of the soundly established knowledge of the molecular dynamics of the health/dis-ease/disease continuum. It must be recognized now that the prevailing classifications of chronic diseases on the basis of morphologic patterns of tissue injury after it has occurred—and the pharmacologic blockade therapies prescribed to ‘treat’ them—need to be discarded in favor of the evolving molecular models. The study of the history of oxygen, patterns of oxygen dyshomeostasis, and redox dysequilibrium —in my view—provides us with a clear and workable model for the clinical practice of molecular integrative medicine.

In 1990, I sent Dr. Linus Pauling a copy of my book The Cortical Monkey and Healing.158 In that volume for the general readership, I introduced the terms lifespan molecules and aging-oxidant molecules to explain, in simple words, the essentials of redox dynamics in the context of the health/dis-ease/disease continuum. In return, Pauling graciously sent me an autographed copy of his How to Live Longer and Feel Better.159 In an accompanying hand-written letter, he mentioned that he had first introduced the term molecular medicines in the 1950s when he recognized that sickle-cell disease was caused by a change in the molecular structure of hemoglobin. Pauling and Itano, one of his students, had demonstrated a difference between the electrical charges of normal hemoglobin and the abnormal hemoglobin responsible for sickle-cell disorder. Later Vernon Ingram working in the Cavendish Laboratory at Cambridge discovered that the difference in the charges accrued from misplacement of a single amino acid—of glutamic acid at position 6 in the normal chain by valine.160

It is one of the profound ironies of medicine that more than five decades after Pauling’s introduction of the concept of the molecular basis of disease, doctors, with uncommon exceptions, continue to ignore the seminal message of that idea. In hospital wards and physician offices, immune dysfunctions caused by oxygen dyshomeostasis and redox dysequilibrium are treated with steroids, chemotherapy agents, and other immunosuppressants. No consideration is given to the two fundamental molecular lesions that form the true pathogenetic basis of all acquired clinical acute and chronic disorders: redox dysequilibrium and oxygen dyshomeostasis.

In that light, Pauling’s core idea of molecular medicine takes on an altogether new significance for me. Without molecular thinking, we physicians are doomed to mere symptom suppression with pharmacologic agents that merely block channels, receptors, enzymes, and pumps of biomembranes, or inhibit and inactivate molecular mediators of inflammatory and healing responses. A physician’s true calling can never be heeded in that mode of thinking, since healing, injured tissues requires molecular nurturing and detoxification, the two goals that can never be achieved by drugs designed to block molecules.


What is the energetic basis of the phenomenon of spontaneity of oxidation in nature? For patient education, I use the analogy of a boy and his ball to illustrate the phenomenon of spontaneity of oxidation. A boy is playing with his ball, which is attached to a string. He keeps the ball flying in an orbit around him by moving his extended arm in a circle above his head. In this circumstance, the kinetic energy of the ball seeks to move the ball away from the boy, but it is counterbalanced by the pull of the string on it so that the ball stays in a circular orbit. If the boy lets go of the string, the ball will spontaneously fly away. The same thing would happen if the boy were to spin the ball with a greater force than can be sustained by the string. The above analogy may be completed by imagining that the ball moves in elliptical orbits—the string has extreme elasticity and pulls the ball closer to the boy’s head by shrinking at one time and allows the ball to move farther away from the boy by stretching at another time. (Physicists believe that atoms exist in a simultaneous particle-wave state determined by a particle-wave probability distribution.)*
*Bohr introduced the concept of electron orbits in the atomic shell, with the innermost shell holding only two electrons, the second orbit containing eight electrons, the third containing 18, and the fourth 32. The atomic number of an element indicates the total number of electrons in the shell as well as how empty or filled the shell is which, in turn, determines the chemical behavior of that element. Regions of space that occupy two electrons are called orbitals. The outer shells of neon, argon, krypton, and xenon contain eight electrons, are completely “filled,” and hence are very stable and inert. Sodium has one electron in its outer shell and is highly reactive. In the halogen family (fluorine, chlorine, bromine, and iodine), each has seven electrons in the outer shell and is also highly reactive. In sodium chloride, the chloride atom picks up the single electron from the sodium atom with the result that the outer shells of both are filled, hence the extraordinary stability of sodium chloride, even at high temperatures. Fundamental aspects of electron particle-wave flow have not been clarified. In the March 8, 2001, issue of Nature, observations of electron flow through a narrow constriction in a two-dimensional electron gas were reported. The images showed that the electron flow from the point contact forms narrow, branching strands instead of smoothly spreading fans. The branching of current flux is due to focusing of the electron paths by ripples in the background potential.

A similar set of conditions governs the motion of electrons as they spin around the nucleus of an atom. Thus, spontaneity of oxidation (electron loss) is in reality a function of the kinetic energy of electrons that favors their outward movement in an oxidative environment, hence their loss. Thus no external source of energy is required in oxidation.

Electrons within atoms and molecules do not orbit the nucleus of an atom in the sense that the earth orbits the sun. Rather, electrons occupy regions of space called orbitals, the first (innermost) of which can hold no more than two electrons.

A characteristic of electrons in a given orbital is that they demonstrate opposite spins. Within a molecule, two electrons sharing the same orbital exist in a bond called a covalent bond. A lone electron within an orbital is considered unpaired. This leads to the definition of a free radical: any atomic or molecular species capable of an independent (“free”) existence that contains one or more unpaired electrons in one or more orbitals. It is noteworthy that carbon- and sulfur-centered radicals generally react with oxygen with greater affinity than others included in Table 1.

After I put forth the concept that spontaneity of oxidation in human biology provides the primary drive that initiates, amplifies, or perpetuates molecular and cellular injury, I have surveyed a host of natural oxidative phenomena and drawn support for the hypothesis.1-31 The notion that a single mechanism can serve as the core pathogenetic mechanism of molecular injury in all disease processes appears too simplistic to be valid. Yet, diligent search of the literature of oxidative phenomena in nature and biology fails to uncover any evidence to the contrary. Specifically, I
have investigated oxidative phenomena in peripheral blood in a variety of clinical settings 161 and have described reversibility of oxidatively induced changes with antioxidants, including ascorbic acid, taurine, and others.


If oxygen drives all aspects of free radical chemistry in human biology, why does it not cause immediate combustion of the body? If oxygen regulates all developmental, differentiative, and death-related phenomena, how does it manage both life-giving and life-taking processes with such finesse that people do not see its hand anywhere in ordinary life? The answer: In its common ‘resting’ phase, oxygen is very stable due to its poor reactivity. It owes that highly unusual and useful characteristic to its peculiar spin restriction. Thus, in the ‘resting’ mode, though oxygen contains two unpaired electrons, both electrons are in their own orbitals, but with the same spin quantum number. That makes it difficult to mate with other molecules carrying electrons with opposite spins. Oxygen circumvents that problem by accepting one electron at a time to complete its four-electron reduction to water. When oxygen assumes its ‘energized’ form—it is able to overcome that spin restriction—it bares its teeth and becomes a potent electron robber and oxidizer.

Figure 1. Five Steps in Four-Electron Reduction of Oxygen to Water Are Shown.
O2 + é + H → HO2 (1)

HO2 → H+→ .O-2 (2)

HO2 + é + H+ → H2 O2 (3)

H2O2 + é + OH++.OH (4)

.OH + é + H+→ H2 O2 (5)

In figure 1, note that oxygen generates one of its reactive species in each step.

1. Superoxide (.O2) in the second step;
2. Hydrogen peroxide (H202) in the third step;
3. The hydroxyl radical (.H) in the fourth step; and
4. Hydrogen peroxide in the fifth step.

Oxygen efficiently harness the potential of certain transitional metals, capable of facile one-electron transfer to amplify its myriad roles in preserving redox equilibrium and its own homeostasis. Two such examples involve the use of iron and copper ions, and are shown in Figure 2.

Figure 2. One-electron Transfer Events Involving Iron and Copper Ions Used as Catalysts by Oxygen*

Fe2+ ↔Fe(III) + é
Cu+↔Cu2+ (III) + é

* The one-electron transfers shown above occur and potentiate oxygen-driven reactions involving oxidases, oxygenases, and antioxidant systems, as well as electron transport of proteins.

Oxygen has yet other tricks in its repertoire of redox-active plays. Through its lieut-enants—superoxide, hydroxyl radical, hydrogen peroxide, and others—oxygen facilitates as well as regulates the behavior of autoxidizable molecules, including catecholamines (epinephrine, norepinephrine, and dopamine) and tetrahydrofolates. Equally important are redox-active reactions including P450-associated electron transfer events and mitochondrial electron transfer chains162-171 Those and many other faces of oxygen are discussed in other chapters of this volume as well as other volumes in this textbook.

Oxidative States

Atoms within a molecule are held together by the force of attraction exerted by the nuclei of two or more of them on the electrons by atoms is conceived as electron pair bonds between adjacent nuclei. The structures of atomic hydrogen (H), atomic chlorine (CI), and hydrogen chloride (HCI) are schematically expressed below to illustrate the electron pair bonds involving all bonding and nonbonding valence electrons:
H. + :C1. ➔ H:C1

Note that in the above diagram of hydrogen chloride, two electrons are shared between the hydrogen and chloride atoms, and are under the mutual attractive influence of the nuclei of both atoms. The concept of oxidative state was introduced to show net charges that remain on the two atoms when the shared electrons are assigned to the atom that exerts a stronger attraction on then172. In the above illustration, both electrons are assigned to chlorine since it is more electronegative—has stronger pulling influence, so to speak—than hydrogen. Thus, in hydrogen chloride, hydrogen is assigned the oxidative state of +1, while chlorine in given the value of -1.

The relative attractive powers of important elements were determined through physical measurement on isolated atoms and simple molecules. Table 1 displays Pauling electronegativities of selected elements.

Table 1. Pauling Electronegativities of Selected Elements173
Element Electronegativity
Sodium 4.0


Is Water Always H20?

I sometimes wonder how much oxygen still has to reveal to us about its workings. We are told that water is H20. But does that hold under all conditions? Does oxygen always treat hydrogen the same way? Some recent experimental observations cast doubt on that. On the time scale of molecular reactions, water is really H1.5O. That surprising finding was reported in the November 2003 issue of Discover magazine. Physicists at the Technical University of Berlin fired neutrons at water molecules to create a high-speed snapshot of their structure. They were surprised to find that the particles did not scatter as much as expected, indicating that they were hitting an unexpected small number of hydrogen atoms. Studies with other hydrogen based materials revealed that about one-third of the hydrogen atoms were missing there too. It seems that quantum effects in hydrogen chemical reactions—taking about 100 quintillionth of a second—make theoretical point-like nuclei dissipate into waves, just as electrons do. The wavelike protons (hydrogen atoms) under those conditions seem to ‘get pulled out of their own molecules.’ Oxygen continues to amaze me.


My placemat on our dinner table is printed with The Periodic Table. One day while breakfasting on eggs, the position of sulfur next to oxygen in the Table turned my thought to sulfur, and then of the ingenious ways of oxygen. Eggs are ‘sulfur food’—garlic, broccoli, and cabbage are other examples—and sulfur is a very reactive element. I fancied that when oxygen dirties up the plates of life, it tells sulfur to clean them up. How did that happen?, I wondered. Did the proximity of sulfur to oxygen in the Periodic Table have anything to do with that master-slave relationship between the two? Of does oxygen keep sulfur up close because it knows things in human biology need to be cleaned up after it dirties them? Clever, this oxygen! I muttered to myself.

Humans have had a fascination with sulfur oxides for a long time.174 Prehistoric man painted his caves with it. The Egyptians used it for religious ceremonies as far back as 4,000 years, and may have been the first to prescribe it for the sick. They also employed sulfur dioxide for bleaching cotton. The Chinese recognized the explosive nature of the element and put it to use in fireworks about 500 B.C. The Greeks mythologized every experience. There was amble sulfur around Mount Vesuvius. So it is not surprising that Homer had Odysseus use sulfur to fumigate that chamber in which he had slain his wife and her suitors. Pliny the Elder recorded many uses of sulfur. Strong sulfur fumes of the great Vesuvius eruption of 79 A.D., must have contributed to his death at that time. It has been suggested that the Biblical references to “fire and brimstone,” point to sulfur, and “hell’s fires,” were also fueled by sulfur oxides. With such a distinguishing history, it is not surprising that sulfur was attributed the mythical substance that emanates from burning substances—phlogiston was the name given to that in Europe centuries later. As for me, next to oxygen’s infatuation with hydrogen and nitrogen—presented in chapters on hydrogen peroxide and nitric oxide—oxygen’s love-hate relationship with sulfur fascinates me most. So, it seemed to me that day while I ate eggs that oxygen was bound to have special fondness for cysteine and molecular specified spawned by it—glutathione, thioredoxins, and others.

Cysteine is a lowly amino acid with just 14 atoms. But oxygen has a way of turning mere pebbles into fabulous diamonds. And cysteine—the only one of the twenty in service of oxygen that contains sulfur—could not have escaped oxygen’s discerning eye for exceptional talent.*

It seems what turns oxygen on to sulfur is what the mineral does in thiol (-SH) groups, Thiol are Indian givers—generous with their electrons but ever so ready to take their electrons back. Thiols are also versatile beings. When oxidized by the extraction of hydrogen atom—its proton as well as electron—thiols bond with each other to producer sulfur-to-sulfur bonds known as disulfide bridges that give structural strength to proteins, the workhorses of human metabolism and intelligence systems. When oxidized When oxidized by nitric oxide, thiols are turned into S-nitrosothiols (-SNO) which, among their many functions, serve as coolies for oxygen carriage. When not in sacrifice mode, thiols build themselves up by capturing electrons from glutathione and thioreduxin. I discussed the profound functional significance of S-nitrosothiols in nitric oxide pathobiology in a previous publication entitled, “The Primacy of the Erythrocyte in Vascular Ecology.”31

Oxygen has much more on its mind when it coddles sulfur. Oxygen defines the structure of proteins, then delineates their functions. Next, through those proteins, it constructs sugars and lipids, switching their functions as it sees fit. In all that, oxygen ordains sulfur—through its disulfide bridges—to keeping and efficient eye on the shenanigans of those molecules.

Sulfur Flowers

Oxygen—the master molecular switch—has yet other cards up its sleeve. It delegates to sulfur the responsibility of keeping genes in their proper places. Never trustful of any single molecular species, oxygen also designates hydrogen peroxide and nitric oxide to watch over the workings of transcription factors—proteins that bind to DNA and trigger transcription of proteins to produce new proteins.

(*Selenium, like sulfur, belongs to the oxygen group of elements. Also like sulfur, selenium plays important roles in the oxygen order of human biology, It was discovered in 1817 by the Swedish chemist Jons Jakob Berzelius when he noted a real substance derived from sulfide ores. I prescribe selenium for nearly all patients with dysoxygenosis. I do not know what roles, if any, tellurium and polonium—the other two elements in the oxygen group—play in human metabolism)

Even the journey of those transcription factors to the nucleus is authorized by oxygen. The mating of those proteins with DNA depends on the status of their thiols which, in turn, is determined by how oxygen perceives its needs, These thiol groups—dubbed sulfur flowers by some, in view of their delicacy175—are kept well watered (in an unwilted, unoxidized form) in the cytosolic soup of cells. Glutathione and thiroedoxin protect them from oxidative winds there. In the state of cellular health, when those sulfur flowers begin to oxidatively wilt, those electron donors—regenerating through trapping of energy of cellular respiration—jump in to arrest further oxidation and proceed to return the flowers to their fresh unoxidized state.

In chronic oxidosis all that changes. sulfur flowers begin to wilt. There is a limit to how far glutathione and thioredoxins, sustained by other antioxidants—water soluble, such as ascorbic acid, and fat soluble, such as tocopherol—can hold out against persisting oxidative stress. Eventually all those antioxidant defenses are depleted. That is when oxygen—as if irked by those molecular miscreants—looks the other way as thiol flowers wilt and burn out, leaving behind seared ends that get glued into excessive and/or abnormal disulfide bridges. That causes disfigurement of protein molecules. The disfigured proteins, of course, malfunction, usually causing functional deficits but sometimes feeding the frenzy of biochemical reactions they are suppose to control, Sometimes that leads to cells committing suicide (by apoptosis).

Oxygen Protects DNA, Oxygen Perverts DNA

Reactive oxygen species have an affinity for DNA when it is not well protected by histone proteins from within and enzymatic and non-enzymatic antioxidant systems outside the nucleotide strands. Proteins disfigured above, also inflict DNA injury when allowed to do so. DNA injury by both mechanisms set the stage for carcinogenesis. Such injury occurs at such a massive scale, that if it were not for the enormous reparative capacity of enzymes that safeguard DNA, no one could escape a cancer death beyond infancy. It has
been estimated that each cancer cell takes as many as 10,000 free radical hits every day176.

Let us suppose that such an estimate is a thousand times higher than the real number of free radical hits. Finally let us suppose that there are ten trillion individual cells in the body of a baby. (The commonly stated number that is nearly fifty times that.) That would indicate that a baby has one hundred trillion chances of developing cancer every day. So how does an infant get to be a ten-year-old boy?

Oxygen: A Benevolent Dictator

Oxygen is a benevolent dictator. It is ever so perceptive of its own excesses. When it senses it has overplayed its hand, it employs oxidized thiols to switch off the production of oxidizing proteins that do its destructive bidding and switch off the generation of others that scavenge free radicals.

I might point out here that I consider sulfur supplementation with sulfur-containing redox-restorative substances (RRSs)—glutathione, methylsulfonylmethane, lipoic-acid, N-acetylcysteine, and taurine—a critical part of my nutritional strategy for arresting and reversing dysoxygenosis. This subject is dealt with in Nutritional Medicine, the fifth volume of this textbook.


The twin subjects of redox equilibrium and oxygen homeostasis are of primal importance to the core concept of oxidative-dysoxygenative stress in the health/dis-ease/disease continuum presented and elaborated in several previous articles.1-31 Specifically, the first volume, Nature’s Preoccupation With Complementarity and Contrariety, is devoted to a detailed discussion of the myriad Dr. Jekyll/Mr. Hyde roles of oxygen and reactive oxygen species (ROS) in that continuum.
The first use of the term radical is attributed to the chemist Guton de Morveau, who used it for a chemical entity that forms an acid when reacted with oxygen. On May 2, 1787, he presented a seminal paper which introduced a part of the new chemistry nomenclature that was co-opted, among others, by such luminaries of that field as Lavoisier, Berthollet, and Fourerory.177 In particular, Lavoisier’s Elements of Chemistry, published in 1789, won a wide readership and contributed much to the advancement of the term.178 In 1815, Gay-Lussac discovered cyanogen (C2N2), which was considered to be a free radical by him and others, including Bunsen and Dumas.179 However, much confusion was created by the concept implicit in the term and chemists generally did not believe in free radicals by the end of the nineteenth century.180 Free radicals became reality when during the closing years of that century, Moses Gomberg produced triphenylmethyl (trityl) free radicals.181 As such things usually went, Gomberg’s free radicals as well as his theory of them was ignored or outright rejected until several years later. The recognition of the ability of free radicals to trigger chain reactions was recognized in the 1920s and their ability to induce polymerizations and depolymerizations was demonstrated in the 1930s.181 Other notable early and important players in the arena were Fenton, Haber, Weiss, Farmer, and Michaelis. In 1894, Fenton (of Fenton’s reaction fame) recognized that tartaric acid was oxidized by catalytic concentrations of ferrous sulfate and hydrogen peroxide.182 In 1934, Haber and Weiss published their observation that hydrogen peroxide is catalytically broken down by iron salts and proposed a free radical chain mechanism.183 In 1943, Farmer and colleagues proposed that free radical intermediates precede lipid peroxidation.184 Reduction of oxygen by univalent oxidation states was proposed by Michaelis.186

In the early 1950s, Rebecca Gerschman, a physiologist at the University of Rochester, first proposed that oxygen toxicity was mediated by free radicals.186-189 Like most medical writers interested in molecular and cellular injury caused by free radicals, for several years I remained unaware of the seminal importance of the work of Gerschman to the health/dis-ease/disease continuum. She observed that adrenalectomy protected rats from oxygen toxicity. She was aware of a 1934 report of Ozorio de Almeida190 which documented the histological similarity between testicular tissue injury caused by ionizing radiation and oxygen toxicity. She also knew of the universal theory of Michaelis169 which held that free radicals were intermediates in oxidation processes. Considering her observations concerning the protective effect of adrenalectomy—the procedure reduced the metabolic rate and hence diminished the need for oxidative reactions triggered by oxygen—in light of the earlier work by Ozorio de Almeida190 and Michaelis,185 she concluded that oxygen toxicity was mediated by free radicals.

There are many excellent review articles on this subject which summarize the explosive growth in the body of knowledge in the field.191-211 In this section, I summarize some salient aspects of reactive oxygen species to provide a framework for presenting the concept of dysoxygenosis as it is linked to the four Greek humors.

Reactive oxygen species (ROS) are produced literally in every chain of biologic reactions that sustain human biology, both in health and disease.1-10 The major mechanisms of ROS production are listed below:

1. Reduction of molecular oxygen, such as superoxide/hydroperoxyl radicals (.O-2 /HO 2.), hydrogen peroxide (H2O2), and hydroxyl radical (.OH);
2. Reaction of carbon-centered radicals with molecular oxygen, such as peroxyl radicals (RO2.), alkoxyl radicals (RO.), and organic hydroperoxides (ROOH);
3. Reactions triggered by other oxidants, such as hypochlorous acid (HOCl), peroxynitrite (ONOO- ), and singlet oxygen (O21△ g); and
4. Rearrangement of oxygen items (such as in ozone) and formation of reactive nitrogen species (such as nitric oxide [.NO], and nitrogen dioxide [.NO2 ]).

The major sources of ROS in human biology are as follows:

1. Leakage from mitochondrial electron transport chain;
2. Autoxidation reaction (such as by incremental production of free radicals in hyperglycemia of uncontrolled diabetes);
3. Metabolic and detoxification enzymatic pathways (such as peroxidases, cytochrome P450, xanthine oxidases, and others);
4. Immune defense reactions (such as the respiratory burst during phagocytosis);
5. Impact of ionizing radiation on human biology (from both cosmic and terrestrial sources).

The clinical applications of Rebecca’s core notion of toxicity of free radicals mushroomed during the 1970s and early 1980s. Noteworthy among several volumes published during the early flowering years of “clinical oxidology” include: Clearer, Cleaner, safer, Greener—A Blueprint for Detoxifying Your Environment, by Null212; Electronic Biology and Cancer by Szent-Gyorgyi213; The Scientific Basis of EDTA Chelation Therapy214 by Halstead; Oxidology215 by Bradford, Allen, and Culbert; Antioxidant Adaptation216 by Kidd and Paris; Cancer and Vitamin C by Cameron and Pauling217; and The Justification for Vitamin Supplementation218 by Bland. In 1983, in a monograph entitled Spontaneity of Oxidation in Nature and Aging22, I put forth a hypothesis that spontaneity of oxidation drives all developmental, metabolic, differentiative, and death pathways, and so provides the central mechanism of cellular injury in all disease states. In 2000, I devoted Oxygen and Aging1 to a more detailed treatment of this subject with focus on dysoxygenosis.


What would have happened if the Babylonian king Gilgamesh has succeeded in his querrell with death? What if had then passed on his elixer of immortality to his children? What if some non-royal had stolen that elixer and left the country? Would there be any room on the planet Earth for any children to be born? Or, what if one species of fish in the oceans had successfully defied the immutable law of oxidative death? Would there be any room left there for any other marine life form?

Oxidation is a spontaneous process—it requires neither an expenditure of energy nor any outside cues. A flower wilts spontaneously; a wilted flower does not “unwilt” spontaneously. Fish rot spontaneously; rotten fish do not “unrot” spontaneously. Cut grass decomposes spontaneously; decomposed grass does not “undecompose” spontaneously. Thus, spontaneity of oxidation in nature is the natural phenomenon that provides the core mechanism of molecular injury in biology. Stated in another way, the spontaneity of oxidation is nature’s grand scheme to assure that no oxygen-utilizing form of life remains immune to the immutable law of oxidative death. Oxidation plays a similar role in the decay of inanimate matter as well. Iron rusts spontaneously; rusted iron does not “unrust” spontaneously. Reduction, the other side of the redox equation of life, requires expenditure of energy.

I include below some excerpts (with minor modifications) from Oxygen and Aging1 concerning some fundamental aspects of the phenomenon of oxidation as a framework for my discussion of the oxidative-dysoxygenative model of the health/dis-ease/disease continuum.

In 1983, in Spontaneity of Oxidation in Nature and Aging,6 I recognized oxygen as providing the primary drive for all pathways of disease and death. Oxygen also provides the primary drive for all pathways of life and healing. It seemed to me then that simply had to be so. At a basic level, oxygen is a powerful oxidizer and via its reactive species—directly or indirectly— initiates, perpetuates, and completes all oxidative phenomena that lead to the cellular aging processes as well as pathogenesis of disease. In simple words, oxygen messes all things up. Microbial and environmental toxins initiate destructive processes that—directly or indirectly—are amplified and perpetuated by reactive oxygen species.

Also at a basic level, oxygen initiates, perpetuates, and completes all oxidative-metabolic pathways that usher life in and sustain it. It also sustains all host redox, enzymatic, and immune defenses against invading microbes. In other words, oxygen also cleans up the mess it creates in the first place. Might not other molecules of fundamental importance to human biology do the same? I wondered then. Might not those molecules also play changing and opposing roles under different sets of conditions? What would that do to the ‘established knowledge’ of biology as it is taught today? How would molecular biologists deal with that? More importantly, how will busy clinicians pulled in many directions cope with such a conflicting and contradictory body of knowledge? Those early questions have lingered ever since. This book, in essence, is about exploration of those questions.
Table 1. Major Types of Free Radicals of Core Biologic Significance in
Human Health and Disease Are Shown
Types of Radical* Examples
Oxygen-centered Superoxide *O2*
Hydroxyl OH*
Lipid peroxyl lipid-O*
Hydrogen-centered Hydrogen atom H*
Carbon-centered Trichloromethyl CCl3*
Sulfur-centered Thyelradical GS*
Delocalized electrons Phenoxyl (delocalized into benzene ring) C6H5O*
Nitric oxide (NO*)

* Adopted from Halliwell.190-192

Dysfunctional oxygen metabolism (DOM), as I wrote earlier, is my term for abnormal cellular oxygen metabolism. It is not merely a lack of oxygen, which is called anoxia in medical terminology. This is an important distinction.

In September Eleven, 2005, for the general reader, I described what I consider to be an oxygen disorder in the following simple words:219

The term oxygen disorder appears throughout this book. Below, I explain the basic oxygen disorder of the September canaries with a simple analogy.

A car engine mixes fuel and oxygen to produce energy. A properly maintained engine performs without generating excessive toxic exhaust. An engine clogged with soot produces less energy and more toxic fumes. The basic difference between the two is that fuel is completely burned in the first instance, leaving no toxic residue behind, whereas in the second car incomplete combustion leads to generation of excess toxic residue.

Like the good engine, a healthy person uses oxygen to extract clean energy from his meal. By contrast, a human canary with an oxygen disorder cannot do so without producing excess toxic waste which, in turn, causes fatigue and immune weakness.

The presence of the oxygen disorder can be easily established by doing urine analysis for toxic acids.
The twentieth century has been an age of chemical avalanches. Pesticides, herbicides, synthetic hormones, and industrial pollutants have produced a total chemical load that has seriously threatened the oxygen metabolism of people, animals, and plants.220 In the United States, we are regularly exposed to an estimated 75,000 different chemicals. Radiation pollution has been an underestimated threat. Chronic anger, resentment, and hostility have further increased oxidative stress. Thus, our century has been a period of progressive oxidative stress on human biology.

Oxidosis affects all human ecologic systems. The oxidizing capacity of the entire planet Earth is increasing for a variety of reasons. Thinning of the ozone layer is increasing oxidant stress. And so is the greenhouse effect of rising levels of carbon dioxide in the air. Industrial environmental pollutants and pesticides are oxidizing. Indoor pollution is reportedly greater than outdoor pollution in many cases. Sugar overload is prevalent in all countries, and excess sugar intake increases oxidant stress. Antibiotic abuse is pervasive and antibiotics, as necessary for acute infections as they might be, damage the normal bowel flora, cause proliferation of microbial species with metabolic characteristics of primordial cells—primordial life forms (PLFs) is my term for that83—and so serve as powerful oxidizing agents. Chronic dehydration has become an epidemic problem, and lack of optimal hydration is oxidizing because it results in accumulation in the body of organic acids and toxic reactive species. Excess acidity in our external and internal environments is oxidizing. The external factors include pesticides and herbicides, industrial pollutants, and toxic metals. The internal factors include stress, sugar overload, processed food, and PLF overgrowth. Lactic acidosis is common in chronic illness such as fibromyalgia and chronic fatigue syndrome, and it is oxidizing. Synthetic hormones are oxidizing, albeit indirectly, by interfering with hepatic detoxification pathways. And, finally, the pervasive adrenergic hypervigilence caused by anger and violence are powerfully oxidizing.221-226

For emphasis I repeat that all of the oxidative factors mentioned above threaten cellular oxygen metabolism and create oxidative-dysoxygenative states. The resulting dysoxygenosis is the common denominator in the molecular pathophysiology of nutritional, ecologic, autoimmune, infectious, degenerative, and neoplastic disorders. From that perspective, many entities that are considered “mystery disorders”—fibromyalgia, chronic fatigue syndrome, environmental illness, and the Gulf War syndrome—are but varied clinical expressions (symptom-complexes) of cellular dysoxygenosis. Below, I list four major oxidative factors:

1. Effects of anger and lifestyle stress on oxygen homeostasis;
2. Effects of oxidized foods and dehydration on oxygen homeostasis;
3. Effects of toxic metals and environmental pollutants on oxygen homeostasis; and
4. Effects of antibiotic abuse on oxygen homeostasis.

It is noteworthy that stress caused by each of the above four factors is mediated by oxidosis and dysoxygenosis. The above subjects are discussed at length in the various volumes of this textbook. I briefly describe how the story of oxygen dysfunction—from spontaneity of oxidation in nature to dysoxygenosis —unfolded during my clinical work in integrative medicine. I also include citations of previous publications in which I presented the direct relevance of the central notion of dysoxygenosis to the various clinicopathologic entities.


Anger and lifestyle stress were linked to human suffering in all ancient cultures for which some records exist.227,228 In the modern context, those factors have been documented to play both causative and perpetuative roles in nearly all disorders in which this subject has been explored.212-215 That has been true of both the degree of illness or intensity of symptoms in acute and chronic disease. What might be the molecular mechanisms underlying that relationship? I have explored that subject at length in What Do Lions Know About Stress?228

Acute stress causes rapid release of adrenaline and its sister “stress molecules” from the adrenal glands. Adrenaline is one of the most potent, if not the most potent, oxidant molecules in the human body. I call such a state of excess adrenaline “adrenergic hypervigilence.” In its most acute form, adrenergic hypervigilence produces what I call the Fourth-of-July chemistry. I use that analogy to explain that acute adrenergic hypervigilence creates unpredictable patterns of fireworks in the body. The agitation and hyperexcitability in the tissues caused by such fireworks can affect any or all parts of the body. Anger and hostility also increase oxidative stress in the same way.
Adrenaline and its sister molecules (together called catecholamines) trigger oxidative pathways in the body in different ways. First, such molecules undergo spontaneous oxidation (auto-oxidation) and produce many secondary oxidants. Second, adrenaline and its sister molecules are converted into a host of oxidants by an enzyme system called the mixed oxidase system. Adrenaline is also changed into organic radicals by the action of superoxide. All factors that cause chronic oxidosis eventually lead to dysoxygenosis. This subject is discussed at length in the chapter entitled “Dysoxygenosis.”

For a detailed discussion of this essential issue, I refer the interested readers to What Do Lions Know About Stress?, in which I provide much practical information in the following three chapters:228

1. “Stress and the Fourth-of-July Chemistry”;
2. “Anxiety, Lactic Acid, and Limbic Lions”; and
3. “Adrenergic Hypervigilance, Mitral Valve Prolapse, Dysautonomia, and Chronic Fatigue Syndrome.”


Foods, like people, have their life spans and age and spoil with oxidative injury. The ancients recognized this and recommended that foods be eaten fresh. They must have recognized that foods contained some healthful components that were lost when foods became stale. Today we recognize those components as natural antioxidants, such as vitamins C and E, carotenoids, flavonoids, glutathione and others. We now recognize that foods become stale when they lose their natural antioxidants and can no longer resist oxidation and decay by oxygen in the air, as well as by many natural and man-made environmental oxidants, such as nitrates and sulfates.

The ancients also recommended moderation in eating. In the context of dysoxygenosis, what could be the basis of that recommendation? I cite one example. Most fish oil fatty acids have antioxidant effects. However, when taken in excess, such oils facilitate oxidation by becoming pro-oxidative. That is another fascinating example of molecular duality in nature. In nature, there is a delicate play of oxidants turning into antioxidants and vice versa. Even in experiments, the point at which an antioxidant takes on pro-oxidant functions can be very hard to predict.

Sometimes I hear food enthusiasts claim that if only they could convince people to take enough of a particular food, they can cure this or that disease. Some antioxidant enthusiasts even claim that if only they could pour enough antioxidants into the body, they could not only control disease but “anti-age” themselves. Nature seems to have no respect for such foolishness. (I suspect such enthusiasts really do know that they cannot anti-age themselves or anyone else, but know they can sell their favorite antioxidants by making those claims.) Again, all elements that cause chronic oxidosis set the stage for acidosis and dysoxygenosis. See the chapter entitled “Dysoxygenosis” for a detailed discussion of this subject.

Dehydration and Dysoxygenosis

All persons with dysoxygenosis are severely dehydrated unless they drink up to three to four quarts of water a day. The degree of dehydration is always obvious from the dry states of their skin and tongue. “My eyes, there is a desert out there!” one of them said once. I see clear evidence of dehydration in the blood samples of most of my fibro canaries. I observe crystal formation in most blood smears, a clear signal of dehydration. Such signs of dehydration disappear when those canaries learn to keep themselves well hydrated (see the chapter, “Guidelines for Healthful Aging.”

Though the oxidative-dysoxygenative effects of dehydration in the cells of human canaries are difficult to measure directly, studies with plants shed much light on this subject.229-232 For example, experiments with peas exposed to dehydration232 (water stress) have shown the following changes:

a. Up to 78% reduction in photosynthesis (the process by which plants use sunlight to build their food and release free oxygen in the air).
b. Up to 80% depression of activities of antioxidant enzymes, including catalase and those of vitamin C-glutathione.
c. Increased oxidative damage to oils (lipid peroxidation) and oxidative disfigurement of proteins.

In plants, reduced photosynthesis leads to excess excitation energy, which is converted into free radicals. The plants, of course, have their free radical scavenging systems that in health neutralize such oxidants. However, those scavenging systems also depend on an ample water supply to function well. Thus, dehydration carries a double jeopardy for the plants. In human cells, dehydration causes dysfunctional oxygen metabolism in the same way.


The fundamental mechanism of molecular and cellular injury inflicted by toxic metals involves chronic oxidosis and local and/or systemic dysoxygenosis. Toxic metals, such as mercury and arsenic, increase oxidative stress and disrupt oxygen homeostasis by several mechanisms. For example, glutathione is the quarterback molecule of the antioxidant system in the liver, and mercury destroys it by ripping apart its sulfhydryl groups.233 Some arsenic compounds paralyze respiratory enzymes and ‘chemically suffocate’ cells. Cellular suffocation causes severe oxidative stress. Synthetic hormones cause oxidative stress in many direct and indirect ways. Such substances jam or damage cell membrane receptors (hooks) that cells use to catch natural hormones as those molecules swim by in the fluid that bathes cells. The result is that natural hormones are unable to reach their destiny. Beyond that, synthetic hormones fundamentally alter the hormone-receptor-gene-product mechanisms.234 Industrial pollutants increase oxidizing capacity of the earth as well as of human microecologic cellular and macroecologic tissue-organ ecosystems.235 Radiation energy causes direct oxidative stress by literally bouncing electrons from various molecules. Recall that the term oxidation means loss of electrons. Radiation of various types also increases oxidative stress by damaging cellular antioxidant defenses.236

I have addressed this subject at length in Toxic Metal Overload and Toxicity, the seventh volume of this textbook. Below, I reproduce some text from that volume to underscore the essential oxidative-dysoxygenative nature of mercury-related ill-health:

Several lines of biochemical, experimental, and clinical evidence strongly establish mercury as a ruthless disruptor of redox homeostasis. By activating several oxidizing mechanisms, mercury triggers, amplifies, and perpetuates oxidative coagulopathy, oxidative lymphopathy, oxidative dysautonomia, and oxidative injury to intracellular matrix and cellular organelles. Mercury also causes and perpetuates oxidosis by inactivating or impairing many physiological redox restorative enzyme pathways. I include below a partial listing of recognized redox-dysregulating roles of mercury. Consistent with the theme of MROD model, it is safe to predict future research will document similar effects of all known redox-related molecular and cellular dysfunction. Specifically,

1. Mercuric ions stimulate superoxide anion production in animal and human polymorphonuclear leukocytes. My colleagues at the Institute and I have regularly observed changes of oxidative coagulopathy in patients with chronic energy disorders associated with clinically significant mercury overload. Clinicians well versed with peripheral blood morphology as observed with high-resolution, phase-contrast microscopy will readily agree with the preceding statement.237-239
2. Mercury—especially in its methylmercury form—is a potent destroyer of thiol groups. In that capacity, it inactivates or otherwise impairs the essential antioxidant defense roles of glutathione, catalase, and superoxide dismutase.240
3. Mercury severely impairs the redox-restorative efficiency of the glutathione peroxidase system. Specifically, it binds with selenium to form an insoluble mercury selenide and so blocks the essential cofactor roles of minerals in the antioxidant enzyme system.241
4. Mercuric chloride directly potentiates ADP-induced platelet aggregation.242
5. Mercury induces oxidative coagulopathy by all of the preceding mechanisms and increases the degree of oxidosis caused by other coexisting oxidizing influences.
6. Mercury inhibits migration and tube formation by cultured human vascular endothelial cells.243 By that mechanism, it blocks not only the endothelial healing responses but also those in the subendothelial stroma and vascular muscle cells that lie beneath.
7. Mercuric compounds directly induce apoptosis and so eliminate their myriad cellular defense functions.244
8. Mercuric compounds, by inducing production of reactive oxygen species, adversely alter mitochondrial membrane transition and diminish mitochondrial reductive reserve.245
9. Mercuric compounds initiate and perpetuate lipid peroxidation, trigger oxidative chain reactions throughout lipid-modified biologic responses, and inflict diffuse oxidative cellular damage.246
10. Mercury promotes atherosclerosis —with consequent coronary artery disease, cerebrovascular accidents, peripheral arterial insufficiency, chronic renal ischemia (with increased vulnerability to hypertension), and myriad other sequelae of perfusion deficits.247
11. Mercury—by the cumulative toxicity exerted by all of the above redox-disruptive roles— acts as a powerful proinflammatory mineral.248 12. Mercury impairs the activity of some erythrocyte enzymes in workers with occupational exposure to mercury vapor.249
13. In neuronal tissue, methylmercury deposits are associated with decreased activity of glycosidase and myelin degeneration.250
14. Mercury induces cell cytotoxicity and oxidative stress, and through those mechanisms causes DNA damage.251
15. Mercury blocks uptake of glutamate by certain types of neurons, and so disrupts neurotransmitter homeostasis.252

The proinflammatory roles of mercury best explain a very broad range of clinical symptom-complexes of mercury-related ill health. Mercury effects that induce or increase the degree of oxidative coagulopathy offer a clear explanation of the observed higher incidence of blood coagulation disorders in humans occupationally exposed to mercury vapors. The above molecular dynamics of mercury also account for the documented higher mortality and incidence of cancer in chlor-alkali workers exposed to inorganic mercury.

Mercury-Induced Dysoxygenosis

Mercury is a potent inducer of local as well as systemic oxidosis. Persistent oxidosis inevitably interferes with oxygen homeostasis and leads to dysoxygenosis. Thus, mercury causes dysoxygenosis by: (1) Promoting the generation in excess of free radicals; (2) Rupturing sulfhydryl groups of essential antioxidants, such as glutathione; (3) Causing lipid peroxidation that interferes with cell membrane functions; (4) Triggering oxidative coagulopathy which leads to perfusion deficits in microcirculation; (5) Increasing oxidative stress on mitochondria and decreasing their reductive reserves; (6) Impiring the enzymatic pathways of the Krebs cycle and so directly interfering with oxygen metabolism; (7) Depleting selenium and zinc in the brains of subjects with memory deficits as compared with control brains.56 (It seems safe to deduce that the rising concentrations of the redox-disrupter mercury led to depletion of the two redox-restorative minerals, and so set the stage for regional oxidosis and dysoxygenosis); (8) Interfering with many enzymatic functions. Specifically, such compounds can interfere with NADH-linked respiration in mitochondria, just as neurotoxins, such as 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) inflict cellular injury by that mechanism.253 Creatine kinase is another critical enzyme which is impaired or inactivated by mercury.

Mercury decreases oxygen saturation of hemoglobin, apparently by disrupting the physiological binding of four molecules of oxygen to one molecule of the carrier protein. Indeed, one investigator reported an impressive 20% increase in oxyhemoglobin when mercury amalgams were properly replaced with other suitable materials.254

Pesticides and Dysoxygenosis

Pesticides are designer killer molecules. What kills bugs will eventually also kill people. There is simply no way out of that dilemma. All pesticides kill pests (insects) by blocking or inactivating their respiratory enzymes. An example of that is destruction of the enzyme cholinesterase. It turns out that the cholinesterase enzyme of insects is identical to that in people. The reason pesticides kill pests efficiently but do not seem to have immediate toxic effects on people is because there is so little of pests to be killed but so much of humans to be destroyed. It is only a difference of size and time.

Most herbicides in common use kill plants by excessive production of toxic oxygen forms (reactive oxygen species, ROS). Increased activity of oxidants so produced overwhelms plants’ antioxidant defenses.255 For example, paraquat, a commonly used herbicide, penetrates the plant protoplast and directly oxidizes the plant substances, diverting electrons from photosynthesis to produce reactive free radicals. (In scientific terms, paraquat accepts electrons from the compounds formed as the result of photosynthesis and passes those electrons to oxygen, so turning safe oxygen in the air into toxic superoxide.) At the same time paraquat reduces the production of an essential antioxidant called NADPH. Thus, the plant faces the double jeopardy of too many oxidants and too little antioxidants. Some other herbicides, such as monuron, block electron transport in the chloroplast by interfering with steps involved with substance Q. Again, of importance to the oxidative-dysoxygenative hazards are the close similarities between the plant and human electron transport pathways.


Antibiotics increase oxidative stress and set the stage for dysoxygenosis by several direct and indirect mechanisms, including the following:

a. Most antibiotics promote overgrowth of PLFs, which increases oxidative stress by causing leaky gut syndrome as well as oxidative coagulopathy (discussed in Integrative Cardiology, the fourth volume of this textbook).
b. Some antibiotics decrease the reserves of glutathione in the liver. Glutathione, of course, is the quarterback antioxidant of the defenses of the liver.
c. Some antibiotics reduce the amount of taurine in the hunter immune cells. Taurine is a powerful antioxidant and a cell membrane stabilizer.
d. Some antibiotics are known to turn many species of microbes into their cell-deficient forms that, in many cases, are far more virulent. Microbes trigger oxidative bursts simply by contacting the surfaces of red blood cells, hunter immune cells, cells lining blood vessels, and cells in other tissues.
e. Many antibiotics are metabolized in the liver where, as is the case with most synthetic chemicals, drugs trigger oxidative chain reactions.

Many of my patients with chronic energy disorders—fibromyalgia, chronic fatigue syndrome, environmental sensitivity syndrome, and persistent fatigue following chemotherapy—gave me a strong history of excessive sugar intake and antibiotic abuse over extended periods of time before they developed a chronic state of energy deletion. In most instances, that had happened because their pediatricians and family doctors had failed to properly diagnose underlying immune deficits caused by mold and food allergies.

Beyond the issue of antibiotic abuse by doctors is the matter of daily exposure of children to massive amounts of antibiotics in their food. The following simple calculation reveals the true threat of antibiotic oxidosis we face. The total yearly amount of antibiotics fed to poultry and cattle that reach the dining tables in the United States has been estimated to be about twenty million pounds. That comes to more than an ounce of antibiotics for every U.S. citizen. An ounce equals about 30,000 milligrams per year. Most antibiotics are prescribed in doses of 100 to 1,000 milligrams per day. For example, for common infections, the usual dose of doxycycline is 100 milligrams daily and that of ampicillin is 250 milligrams three times a day for five to seven days. Thus, common infections are treated with 500 to 3,500 milligrams of antibiotics. Now compare the two quantities, 30,000 milligrams in food and a median value of 2,000 milligrams for treating an infection.256

An equally important issue is that of a short-term, high-dose antibiotic use for acute infections versus year-long, very low-dose exposure. It is well established that microbes mutate and become resistant to antibiotics more quickly and frequently with continuous low-dose therapy. Thus, antibiotics taken via foods are much more dangerous than those taken for infections. Is this merely a matter of theoretical interest? Not so. Ceftiofor is commonly fed to cows and pigs and is very similar to ceftriaxone used to treat Salmonella infections in people. Not unexpectedly, a ten-fold increase in ceftriaxone-resistant Salmonella was reported at the 1999 Interscience Conference on Antimicrobial Agents and Chemotherapy.257 Similarly, virginiamycin, an antibiotic added to chicken feed for the last 25 years, has led to an increase in the number of vancomycin-resistant microbes in human stool and chicken meat samples.

It is safe to predict that the oxidative-dysoxygenative hazard of antibiotics will continue to grow. It does not seem likely to me that there will be a major shift away from antibiotics in the near future. Nor does it seem probable that antibiotists of the meat industry will discontinue feeding their animals potent antibiotics.


In health, human cells harness energy with an energy-efficient respiratory mode of ATP production. A yeast cell, by contrast, is engaged in an energy-inefficient anaerobic glycolytic mode of ATP production. A human cell generates about 28 moles of ATP per one mole of glucose, a yeast cell obtains only two moles of ATP from the same amount of sugar. What would happen if human cells were to be ‘metabolically degraded’ to the level of yeast cells. Evidently, that means such cells would be extremely energy-deficient. But does that ever happen? Indeed, it does—and does so with regularity in chronic energy disorders, such as fibromyalgia, chronic fatigue syndrome, environmental sensitivity syndrome, severe autoimmune disorder, and in subjects receiving chemotherapy agents.11-14 The concept of oxidative regression to primordial (glycolytic) mode of energy production evolved during my work with nearly 5,000 healthy volunteer subjects and patients with a host of chronic energy disorders. I investigated the phenomena of chronic oxidosis and dysoxygenosis—as well as the clinical consequences of those states—with high-resolution phase-contrast and darkfield microscopy and analysis of urinary excretion of organic acids which would be expected to accumulate during glycolytic mode of cellular energetics. In 1998, I elaborated that concept in an article entitled “Oxidative Regression to Primordial Cellular Ecology (ORPEC).”84

I use the expression “yeastization of human cells” to explain, in simple terms, to my patients the essential nature of the cellular metabolic shift in ORPEC. Specifically, that phrase allows me to explain the dire energetic consequences of that shift in chronic energy states. Oxidosis, I elaborate for them, is the state of energy loss through excessive loss of electrons. Chronic oxidosis impairs or inactivates enzymes involved with the physiological respiratory ATP generation, and so initiates the process of ‘human-to-yeast’ shift of cellular energetics. Unrelenting oxidosis eventually affects genes responsible for those enzymes, making that process self-perpetuating. That is the real explanation of why the recovery of patients with fibromyalgia, chronic fatigue syndrome, and related energy disorders can be disconcertingly slow.

Below, I reproduce the abstract of the original paper84 in which I introduced the concept of ORPEC for providing a frame of reference:

In clinical states characterized by chronically accelerated oxidative stress, enzyme systems involved in oxygen transport and utilization, redox regulation, and acid-base equilibrium are severely impaired. Such oxidative states include fibromyalgia, chronic fatigue syndrome (CFS), Gulf War syndrome, severe immune disorders, and malignant neoplasms. It is proposed that normal “oxygenative” cellular ecology in such states undergoes an “oxidative regression to primordial cellular ecology” (ORPEC) in which state progressive anoxia, acidosis, excess reactive oxidative species, and accumulation of certain organic acids create cellular ecologic conditions that closely simulate the primordial state. The ORPEC state results in rapid multiplication in blood and tissues of pleomorphic anaerobic organisms with yeast-like morphologic features, which are designated “primordial life forms” (PLFs) for lack of precise nucleotide sequence and taxonomic data. PLFs are readily observed with high-resolution phase-contrast and darkfield microscopy in freshly prepared and unstained smears of peripheral blood. Strong homology among yeast and mammalian DNA sequences indicates that the genetic codes for PLF growth may already exist in human cells and that organisms observed in this study may not indicate an infection from an outside source. Rather, the clinical syndromes associated with PLF proliferation may represent a novel “microecologic-genetic” model of illness. Organic acids and other toxins produced by the growing number of PLFs further feed the oxidative flames of the ORPEC state, thus generating oxidative cycles that feed upon each other and are damaging to antioxidant and oxygenative enzyme systems of the body.

The proposed ORPEC hypothesis draws its primary support from the microscopic findings presented in this paper when these are considered in light of the following: (1) the fundamental “oxygen order” of human biology; (2) the history of oxygen during the primordial era; (3) the primordial cellular ecology as reconstructed from the origin-of-life studies; (4) morphologic evidence of accelerated oxidative injury to all components of circulating blood (oxidative coagulopathy), and to cell membranes, intracellular matrix, and cell organelles such as mitochondria; (5) oxidative oxygenative dysfunctions (pathologic states characterized by impaired cellular oxygenation and caused by oxidative injury); (6) a high level of homology among yeast and mammalian nucleotide sequences (reflecting conserved primordial nucleotide sequences) that may lead to de novo growth of PLFs under primordial conditions; (7) phenomenon of gene swapping in nature that may enlarge the cellular genetic pool ; (8) oxidative 3 C cascades that contribute to and perpetuate primordial conditions; (9) evolving concepts of mycosis and PLFs; (10) increased urinary excretion of certain organic acids that provide biochemical evidence of overgrowth of yeast and PLFs in patients in the ORPEC state; and (11) clinical syndromes of accelerated oxidative molecular injury.

The core ecologic concept presented in this article is simply stated: No cause of human suffering may be sought in any individual biologic event, divorced from the larger ecologic elements that affect the human condition. Specifically, the cause of oxidative regression to primordial cellular ecology may not be searched in individual oxidative triggers. Rather, the microecologic-genetic shift of the ORPEC state represents the sum total of cumulative oxidative stressors. The clinical significance of the ORPEC hypothesis is that: (1) it provides a sound scientific model for a clearer understanding of the pathogenesis of syndromes associated with accelerated oxidative molecular injury, such as fibromyalgia, CFS, Gulf War syndrome, severe autoimmune disorders and malignant tumors; and (2) it provides a framework for a rational and logical approach for repairing oxidatively damaged cellular ecologies and for restoring health. Notwithstanding the lack of nucleotide sequence and taxonomic data concerning PLFs, the ORPEC hypothesis has strong explanatory power for: (1) the morphologic patterns of growth of PLFs documented in this report; (2) the pathogenesis of clinical syndromes characterized by accelerated oxidative injury; and (3) the sound scientific basis and/or rationale for the empirical efficacy of “anti-PLF” oxygenative, antioxidant, and other therapies employed to restore cellular ecology from the ORPEC state to a physiologic, healthful condition.

My clinical, morphologic, and biochemical observations have led me to the conclusion that oxidosis produced by overgrowth of primordial life forms—PLF oxidosis is my term for it—is the single most important hazard in the genesis of dysoxygenosis. That conclusion became inescapable for me during extended clinical and biochemical study of nearly five thousand patients with fibromyalgia, CFS, Lyme disease, severe immune disorders, and cancer. I state the evidence of my view in the following simple sentences reproduced from the preceding chapter on primordial life forms:

1. The sicker the patient, the dirtier the blood.
2. The larger the number of PLFs in the blood smears, the greater the oxidative stress on the cells and blood plasma.
3. The healthier the sick become with treatment, the cleaner their blood becomes.
4. Severe oxidative stress is seen in some conditions without PLF overgrowth, but PLF overgrowth is not seen without oxidative stress on blood cells and plasma.

My associates at the Institute, professors Alfred Fayemi and Judy Juco, have also studied a large number of blood smears with high-resolution microscopy. I showed them a draft of this page and asked them if they disagreed with any of the above statements. Both of them fully agreed with me.

Some readers may contend my assertion that the PLF overgrowth causes excess oxidative stress. In other words, what is my proof that PLF oxidosis is real? The answer to that question is in the last of the above four statements. PLF overgrowth was always associated with oxidosis of blood in my patients. However, I did not always see PLF overgrowth in every case of blood oxidosis. In other words, dysoxygenosis sometimes existed in the absence of PLF overgrowth, but overgrowth of oxyphobic species was never seen without associated dysoxygenosis. In the later stages, such infections suppress the immune system and PLF overgrowth occurs as a consequence of immune suppression.

Humanization of Yeast Cells

If human cells can be “yeastized”, are there circumstances in which the yeast cells can be humanized? Indeed that does happen. I discuss this subject in an article entitled “The Oxidative-Dysoxygenative Model of Aging” and reproduce below some text from that article258:

The changes in metabolic behavior of Saccharomyces cerevisiae in response to availability of glucose have yielded crucial information concerning the mechanisms involved in life span extension with caloric restriction. Measurement of respiration in caloric restriction experiments performed with wild-type and Sir2-deleted yeast revealed the relationships between caloric intake, Sir2 protein, fermentative-to-respiratory shift, and life extension. Glucose is metabolized to pyruvate, which serves as the bifurcative molecule for the respiratory and fermentative pathways. Respiratory breakdown of glucose to CO2 generates 28 ATP molecules per molecule of glucose, whereas fermentation of glucose to ethanol generates only two ATP molecules per molecule of glucose. This 14:1 energetic ratio is of great significance to the previously described state of oxidative regression to primordial cellular ecology described in the preceding chapters. It turns out that S. cerevisiae actively adapts to the available glucose supply with major fermentative-to-respiratory shift. When glucose concentration is high, the yeast prefers fermentation. I furnished the analogy of spoiled teenagers at a family picnic table wasting food in an article on dysoxygenosis. By contrast, when glucose availability is low, the yeast shifts its metabolism to predominantly respiratory mode, extracting much larger amounts of energy from the scarce glucose resource. As indicated earlier, a 0.5% concentration of glucose produced a two-fold increase in respiration of the yeast compared to that of cells grown in 2% glucose concentration. That metabolic shift was accompanied by a 25% increase in life span. Experiments conducted with Sir2-deleted yeast showed absence of life extension under identical conditions of glucose availability, thus linking Sir2 to life extension obtained with caloric restriction.


Oxygen sustains all neural, endocrine and immune systems of the body. Every neural, endocrine, and immune system, in turn, supports oxygen homeostasis in cellular development, differentiation, and demise. That must be obvious from the large body of information about oxygen homeostasis furnished in the preceding sections.

In this section, I furnish a personal, largely clinical perspective on the impact of chronic dysoxygenosis on the various neuroendocrinoimmunologic axes of the body that superficially may seem—and so are generally designated—as discrete diseases. Notwithstanding the apparent diversity of clinical presentations, on a deeper scrutiny it becomes evident that those ‘diseases’ are but the shapes of the proverbial elephant palpated by nine blind men of the ancient tale. The elephant is dysoxygenosis of neuroendocrinoimmunologic axes and the putative diseases merely its various clinical faces. The same elephant appeared as a rope to one of the blind men who touched its tail, and as a large tree to the second blind man who held the trunk of the elephant in his hands. A third blind man moved his hands on the side of the elephant and pronounced it a moving wall. So goes the story.

As for the clinical derangements of the neuroendocrinoimmunologic axes, one finds what one looks for. This is the core message of this section.

The neuroendocrine axes, of course, include the hypothalamus-pituitary-adrenal axis, the hypothalamus-pituitary-gonad axis, the hypothalamus- pituitary-thyroid gland, and—if one were to add uncommon problems— the lesions of the chromaffin tissues that produce various mediators of biologic responses and so disrupt the neuroendocrine orchestra. The crucial issue of the rich diversity of biologic roles of oxygen that trigger, amplify, or perpetuate the abnormal neuroendocrinologic responses is seldom, if ever, addressed in discussion of the so-called neuroendocrinoimmunologic disorders.

Oxygen—as discussed at length in the earlier sections of this chapter—is an exquisitely discriminating regulator of all neuroendocrinoimmunologic axes. It drives, amplifies, and when needed, squelches, all signaling pathways involved in a host of immune defenses against microbial invaders. That, succinctly stated, is my view of neuroimmunoendocrinology. In clinical settings, however, the clinical and laboratory parameters commonly exhibit complex, sometimes paradoxical, and often confounding patterns.

In several previous publications, I have marshaled extensive clinical, morphologic, and biochemical evidence to support oxidative-dysoxygenative model of neural, endocrine, and autoimmune disorders. Briefly, my patients with biochemical evidence of severe and persistent dysoxygenosis eventually showed the following patterns of clinical derangements in varying combinations:

1. Functional deficits of the thyroid gland with raised or lowered serum values of thyroxine, triiodothyronine, and thyroid stimulating hormone (TSH), as well as decreased values of the hypothalamic TSH-releasing hormone (TRH).
2. Functional deficits of the adrenal glands with raised or lowered 24-hour urinary values of several hormones of adrenal derivations, including pregnanediol, 11-OH-androsterone, androsterone, etiocholalone, 11-ketoandrosterone, and dihyd-roepiandrosterone.
3. Functional deficits of gonads with raised or lowered values of serum estrogen and/or progesterone.
4. Functional deficits of the pituitary gland with raised or lowered values of serum growth hormone and other hormones, such as melatonin.

The patterns of functional neuroendocrine deficits described above should not come as a surprise. Every single cell in the body runs on oxygen. It follows that the state of oxygen dysfunction will inevitably disrupt the structural and functional integrity of each and every cell in the body. Indeed, that—in my view—is what makes dysoxygenosis the most central of all central considerations in health and disease. I anticipate here the obvious question: If that is true, why use the cumbersome word neuroendocrinoimmunologic in the title of that section? I do so for two reasons: (1) to briefly cite several personal observations that link oxidosis and oxygen dyshomeostasis to underscore the central underlying role of dysoxygenosis in all of those relationships; and (2) to recognize the contributions of a very large number of workers who established certain critical relationships between what had previously been deemed as discrete systems.

Figure 3 schematically summarizes my general clinical experience with derangements of neuroendocrinoimmunologic axes in patients with dysoxygenosis. Five important points are evident from the diagram:

Figure 3. Dysoxygenosis and Dysfunctions of Neuroendocrinoimmunologic Axes: Phases of Initial Overdrive and Subsequent Exhaustion.

1. The values for individual parameters for hormonal homeostasis change in a harmonic fashion. That means it is critically important to recognize trends and not to rely too much on isolated values.
2. There is an initial phase in which the functionally impaired tissues exhibit a seemingly hyperactive response as they respond to persistent oxidosis and dysoxygenosis. This situation can be confounding unless the clinician is familar with the compensatory nature of that overactivity.
3. Following a variable period of an apparent overactivity, the affected tissues begin to lag behind, unmasking the initial compensatory period.
4. A period of recovery with optimal, integrative approach that addresses all the issues of underlying oxidosis and dysoxygenosis; or
5. Eventual ‘collapse’ of the affected tissues when dysoxygenosis deepens—and its biochemical sequelae become more pronounced—but the clinical management of the case is regrettably confined to mere symptom suppression.

Below, I include some general comments about the patterns of thyroid, adrenal, gonadal, pituitary, and hypothalamus dysfunction which I have encountered as parts of the global changes caused by persistent dysoxygenosis.

Thyroid Dysfunction in Dysoxygenosis

Nearly twenty years ago, I recognized a fundamental change in clinical patterns of thyroid dysfunction in patients with clinical and biochemical evidence of persistent oxidosis—and, looking back now, dysoxygenosis. Years later, in The Canary and Chronic Fatigue, and Healing Miracles and the Bite of the Gray Dog 259 I described many of those patterns and presented my view of therapeutic strategies. Briefly, I encountered a growing number of patients who showed a biochemical profile of primary pituitary failure comprising low values for serum thyroid-stimulating hormone (TSH) coexisting with low values for thyroxine (T4) and triiodothyronine (T3). Four aspects of that profile of primary pituitary hypofunction puzzled me then. First, in my clinical pathology work during the preceding three decades, I had observed such profiles on uncommon occasions. Second, in my clinical practice of integrative medicine, I had accumulated a number of such cases within several months. Third, the common denominators in the clinical features of my patients were persistent fatigue; myalgia; and problems of mood, memory, and mentation. Fourth, the abnormalities in the laboratory pituitary-thyroid profiles disappeared when such patients responded to our nutritional, herbal, and oxystatic therapies. Those were clearly not the clinical features of the common patterns of primary pituitary failure. It seemed highly probable to me that the oxidative-dysoxygenative factors that interfered with the enzymatic production of T4 and T3 in the thyroid gland were the same that caused diminished enzymatic production of TSH in the pituitary and that of TRH in the hypothalamus. During the 1990s, it appeared to me that those factors were related to local and/or systemic oxidosis and dysoxygenosis.47

In the early stages of the functional thyroid deficits in clinical states associated with early stages of dysoxygenosis commonly coexist with normal thyroid results. It is important to note that the range of serum thyroxine levels adopted by most laboratories is very broad—ranging from 4.5 to 11.5 ug/dL—and it is easy to see how a person may drop his serum thyroxine levels by more than 50% and yet show a blood level of the hormone in the ‘normal’ range for the reporting laboratories. Such patients invariablye respond well to low-dose thyroid hormone replacement with desiccated thyroid and triiodothyroxine. In this context, I might point out that my observations are in full concordance with those made by of Broda Barnes in his celebrated Hypothyroidism: The Unsuspected Illness.260 Barnes made a major contribution in our understanding of the role of thyroid gland supplementation in subjects without clear biochemical evidence of functional thyroid deficits.

Adrenal Dysfunction in Dysoxygenosis

My general experience with functional adrenal deficits in patients with dysoxygenosis is closely similar to that with thyroid deficits. In the early stages of oxidative-dysoxygenative stress, there is evidence for adrenal overdrive with increase in 24-hour urinary excretion of one or more of the metabolites of adrenal steroid hormones. As oxidosis and dysoxygenosis increase in intensity and duration, the adrenal glands begin to fail to cope with the growing demands on them for increased production of corticosteroids. The 24-hour urinary excretion profile then shows decreasing amounts of one or more products of the chain of adrenal steroids. If the factors that feed the fires of oxidosis and dysoxygenosis are not controlled—and the adrenal glands allowed to regenerate—adrenal exhaustion sets in ( see Figure 1). I discuss this subject at length in Pathobiology by Tissue-Organ Macroecologic and Cellular Microecologic Systems, the eighth volume of this textbook. Tables 1-3 display data for 24-hour urinary steroids for some illustrative case studies. I might add that I have been most impressed by the clinical work of William Jeffferies.261 in human and that of Alfred Plechner262,263 in animals. In Pets at Risk Plechner and Zucker have made major contributions in our understanding of the clinical benefits of cortisone supplementation in subjects without clear biochemical evidence of functional adrenal deficits.

Gonadal Dysfunction in Dysoxygenosis

Below, I reproduce the abstracts of two previously published articles264,265 that summarize my view of the oxidative-dysoxygenative disruptions of estrogen homeostasis in women in their reproductive period as well as peri- and postmenopausal females.

Table 2. Dysoxygenosis and the Adrenal Gland Dysfunction
Effects of Integrative Management on 24-Hour Urinary Steroid Profiles in a 32-year-old Woman (RA)

Steroid Metabolite Feb 2, 1997 Aug 6, 1997 Normal Range

Pregnanediol 1.49 8.3 0.3 to 6
Androsterone 10.9 H* 6.87 0.6 to 5
Etiocholalone 8.62 H* 7.3 0.6 to 5
DHEA 0.94 0.5 0.1 to 2
Pregnanetriol 0.71 0.7 0 to 2
11-ketoandrosterone 0.0 L** 0.6 0 to 1.6
11-ketoetiocholalone 0.14 0.62 0.3 to 1.10
11-OH-androsterone 0.0 L** 0 0.3 to 2
11-OH-etiocholanolone 0.0 0 0.2 to 1.8
DHEA 25 mg and pregnenolone 10 mg prescribed in Feb 1997 as a part of an integrative plan.
* higher than the range
** lower than the range *

Abstract 1:264 Amenorrhea, Oligomenorrhea, and Polymenorrhea in CFS and Fibromyalgia Are Caused by Oxidative Menstrual Dysfunction

It is proposed that amenorrhea, oligomenorrhea, and polymenorrhea in chronic fatigue syndrome (CFS) and fibromyalgia are aspects of an “oxidative menstrual dysfunction” (OMD-I) that occurs as a consequence of global oxidative damage to microecologic cellular and macroecologic tissue-organ ecosystems of the body. Thus, OMD-I is considered as one facet of the broad spectrum of accelerated oxidative injury to: (1) matrix, plasma membranes, and mitochondria (3M ecologies); (2) coagulation cascade, complement system, and capsases (3C pathways); (3) enzyme pathways involved with oxygen transport and utilization; (4) enzyme pathways involved with detoxification pathways; (5) enzyme pathways involved with synthesis of sex and non-sex hormones; (6) enzyme pathways involved in hormone receptor synthesis; and (7) regulatory hormone-receptor- gene dynamics. In support of the OMD-I model, clinical outcome data for 35 women is presented. Menstrual cycles were normalized completely in 12 of 14 amenorrheic women (and improved in the remaining two) and in 19 of 21 women with oligomenorrhea or polymenorrhea with therapies that addressed issues of redox homeostasis and damaged bowel, blood, and liver ecosystems, but did not employ synthetic estrogens or other hormones.
Menstrual irregularities in CFS and fibromyalgia are common and are generally assumed to be due to gonadal insufficiency. The standard therapies for such disorders employ a variety of regimens of synthetic hormones to correct the putative estrogen deficiency. The OMD-I model challenges that view and proposes oxidative pathogenetic mechanisms for hormone-receptor-gene dysregulations in fibromyalgia and CFS. Furthermore, normalization of menstruation in such disorders with therapies that restore oxidatively damaged bowel, blood, and liver ecosystems provides a new insight into the relationship between pathophysiology of those organs and menstrual dysfunction. Some essential aspects of redox and hormonal homeostasis are reviewed to underscore the enormous complexities of the menstrual function, and to show that the prevailing use of synthetic hormones for menstrual dysregulation in fibromyalgia and CFS is neither rational on theoretical basis nor acceptable on empirical grounds.

Abstract 2265: Oxidative Menopausal Dysfunction: Hormone Replacement Therapy (HRT) or Receptor Restoration Therapy (RRT)?

Some recent articles addressed the issue of hormone replacement therapy (HRT) for menopausal women and concluded that such therapy is appropriate for most women. The primary argument is that the potential for such therapy for prevention of coronary artery disease (CAD) and osteoporosis far outweighs its risk of breast, uterine, and other cancers. This article challenges that opinion and puts forth a counterview of “oxidative menopausal dysfunction ” (OMD-II) that is based on microecologic cellular and macroecologic tissue-organ disruptions of the body that lead to CAD, osteoporosis, and other menopausal symptomatology. For addressing health issues ofpostmenopausal women, the OMD-II approach shifts the focus from the use of carcinogenic synthetic hormones to restoration of human ecosystems by grounding its therapies on the established knowledge of redox, acid-base, and enzymatic homeostasis.

This article addresses the following ten issues: (1) oxidative disruptions of microecologic cellular and macroecologic tissue-organ systems of the body; (2) age of estrogen overload; (3) hormone-receptor-gene dynamics; (4) the impact of RRT vs. HRT approaches on health parameters of postmenopausal women; (5) RRT vs. HRT approaches to prevention of coronary heart disease; (6) oxidative theory of osteoporosis and nonestrogenic options for control; (7) synthetic estrogen and risks of breast, uterine, and other cancers; (8) postmenopausal life expectancy; (9) quality of life issues; (10) and empirical observations concerning control of symptom-complexes of the menopausal syndrome with therapies directed at ecologic restorations without the use of synthetic hormones. Arguments are marshalled for the view that the optimal management of peri- and postmenopausal syndromes requires that the primary focus be on addressing all sources of accelerated oxidative stress on microecologic cellular and macroecologic tissue-organ systems of the body. The need for support for gonadal and nongonadal endocrine organs is discussed, as well as the means of providing it.

I have presented some other aspects of oxidative-dysoxygenative disruptions caused by xenobiotics in humans and animals in RDA: Rats, Drugs and Assumptions


In clinical practice, disorders of food allergy, sensitivity and intolerance cannot be separated from the larger issues of normal bowel ecology and altered bowel ecology. Elements of significant clinical importance in preservation of normal bowel ecology include the following: bowel motility and transit time, bowel perfusion, bowel permeability, bowel (and stomach) pH, bowel digestive capability, bowel absorptive capacity, bowel flora. Bowel structural changes follow as natural consequences of altered bowel ecology. Specific morphologic lesions such as ulcerative colitis, Crohn’s colitis and ileitis, pseudomembranous colitis, ischemic colitis, collagenous colitis and other bowel disorders, in general, represent patterns of cellular and tissue injury caused by long-neglected changes in bowel ecology. Intestinal parasitism and colonization with organisms such as Helicobacter species and C. difficile also represent impaired bowel immunity due to altered bowel ecology.

The subject of immunologic tolerance has been presented in earlier chapters of this volume. This important subject has not been investigated well in the context of food-induced recations. Pathogenetic mechanisms and clinical symptoms associated with food disorders, however, are profoundly influenced by the dynamics of bowel ecology. To put this discussion of the pathogenetic mechanisms and immunologic aspects of food disorders in perspective, I include below some brief comments about the bowel ecology.

The term “Altered Bowel Ecology Syndrome” is not simply another buzz word to refer to chronic disorders of bowel. There are two important reasons why this term is preferable to many others in common use at this time.

First, it keeps the focus on the central issue in our understanding of the pathogenesis of chronic indolent disorders of the bowel, namely the ecology of the bowel. “Ecologic thinking” calls for management of all the elements involved in the preservation of the normal ecologic balance in the bowel. Specifically, it includes issues of increased bowel permeability, compromised bowel perfusion, irregularities of bowel motility, impaired digestive and absorptive dysfunctions, altered bowel flora and parasitic infestations.

Second, it keeps the focus on the central issue in the clinical management of chronic indolent bowel disorders, namely the inter-relatedness of all the elements involved in the preservation of normal ecologic balance in the bowel. Patients with chronic indolent bowel disorders do not obtain relief of symptoms and resolution of their bowel lesions until all these elements are addressed.

The use of diagnostic terms like Candida-related complex and intestinal dysbiosis is valid for clinical disorders in which there is unequivocal laboratory evidence of overgrowth or infections with Candida species or persistent infestation with specific intestinal parasites. Simple-minded efforts to “get rid of the yeast” and “treat intestinal dysbiosis” are rarely effective on a long-term basis. Just as environmentally sensitive individuals require that we address all the relevant environmental triggers, patients with the Altered Bowel Ecology Syndrome require that we address all the relevant “ecologic” elements in the bowel.


A large number of good cookbooks and resource publicationas now exist for practitioners as well as patients. To cite one example of books devoted to the subject of gluten intolerance, following is the list of books for obtaining useful information on gluten-free food choices available from www.Amazon.com or The Gluten-Free Pantry (800-291-8386):

1. Hillson B. GFP Companion: Great Recipies for a Wheat-Free/Gluten-Free Kitchen.
2. Hagman B. The Gluten-aFree Gourmet.
3. Case S. Gluten-Free Diet Guide.
4. Robertson K. Cokokking Gluten Free.
5. Rae Lynn. What? No Wheat.
6. Korn D. Wheat-Free/Worry-Free.
7. Korn D. Kids With Celiac Disease: A Family Guide to Raising Happy, Healthy, Gluten-Free Children.
8. Gluten-Free Living (The national magazine for people with gluten sensitivity.

At the time of this writing, two good sources for purchasing foods for food-sensitive individuals are:

The Gluten-Free Pantry: 1-800-291-8386 // 9www.glutenfree.com
DeLand Bakery, Inc. Deland, Florida. www.delandbakery.com / 386-734-7553

The internet, of course, is a very rish source of addresses for companies specializing in products for individuals with food and mold allergies.


A careful review of history reveals the existence of food-related reactions in the majority of persons with chronic illness. Only a small number of such rections are mediated by IgE-mediated responses. The clear majority of such reactions are related to issues of increased gut permeability, oxidative leaky cell membrane state, and overburdened hepatic oxidative pathways involved in coping with macromolecules that gain entrance to circulation.

Regrettably, most food-triggered reactions go unrecognized by most clinicians because of the lack of focus and training. When those issues are properly addressed, nearly all patients report clinical benefits. Looking at food allergy through the prism of oxygen homeostasis gives us compelling reasons to look deeper into issues of the bowel, blood, and liver ecosystems that significantly increase the frequency and intensity of food-related reactions.

In my experience, adverse food reactions and food allergy symptoms cannot be controlled and prevented without optimally addressing the issues of concurrent mold allergy discussed at length in the next chapter.



1. Ali M and Ramanarayanan MP: A computerized micro-ELISA assay for allergen-specific IgE antibodies. Am J Clin Pathol 81:591, 1984.
2. Ali M, Ramanarayanan MP, Nalebuff DJ, et al: Serum concentrations of allergen-specific IgG antibodies in inhalant allergy: Effect of specific Immunotherapy. Am J Clin Pathol 80:290, 1983.
3. Ali M: In-vitro immunoassay techniques in clinical allergy. Clin Ecol, 3:68078, 1985.
4. Ali M, Little CH: Changes in milk-specific IgE antibodies following oral challenge in milk-sensitive patients with chronic headache. Presented at the annual meeting of the American Academy of Otolaryngic Allergy, 1986.
5. Atkins FM, Steinberg SS, Metcalfe DD: Evaluation of immediate adverse reactions to foods in adult patients. Correlation of demographic, laboratory, and prick skin test data with response to controlled oral food challenge. J All Clin Immunol 75(3):348-355, 1985.
6. Bellanti JA, Nerurkar LS, Willoughby JW: Measurement of p plasma histamine in patients with suspected food hypersensitivity. Ann Allergy 47:260-263, 1981.
7. Brenenstock J: Food Allergy. Clinics in Immun and Allergy 2:5-40, 1982.
8. Buckley RH, Metcalfe D: Food Allergy. J. Am Med Assoc 248(20):2627-2631, 1982.
9. Denman AM, Mitchell B, Ansell BM: Joint complaints and food allergic disorders. Ann Allergy 51:260-263, 1983.
10. Gerrard JW: Allergies in breast-fed babies to foods ingested by the mother. Clin Rev Allergy 2:143-9, 1984.
11. Kniker WT: Immunologically mediated reactions to food: state of the art. Ann Allergy 59:60-70, 1987.
12. Kushimoto K, Toshiyuki A: Masked type I wheat allergy. Relation to exercise-induced anaphylaxis. Arch Dermatol 121:355-69, 1985.
13. Loveless MH: Allergy for corn and its derivatives: experiments with masked ingestion test for its diagnosis. J Allergy 21:500-0, 1950.
14. Paganelli R, Matricardi PM, Aiuti F: Interactions of food antigens, antibodies, and antigen-antibody complexes in health and disease. Clin Rev Allergy 2(1):69-78, 1984.
15. Paganelli R, Atherton DJ, Levinsky RJ: Differences between normal and milk allergic subjects in their immune responses after milk ingestion. Arch Dis Child 58(3):201-206, 1983.
16. Pearson JR, Kingston D, Shiner M: Antibody production to milk proteins in the jejunal mucosa of children with cow milk protein intolerance. Pediatr Res 17(5):406-412, 1983.
17. Sampson HA, McCaskill CC: Food hypersensitivity and atopic dermatitis: evaluation of 113 patients. J Pediatr 107(5):669-675, 1985.
18. Sampson HA: IgE-mediated food intolerance. J Allergy Clin Immunol 81(3):495-504, 1986.
19. Brostoff J, Challacombe SJ. Food Allergy and Intolerance. 1987Bailliere Tindall, London.
20. Freed DLJ. Dietary lectins and disease. In: Food Allergy and Intolerance. Eds: Brostoff J, Challacombe SJ. 1987 Bailliere Tindall, East Sussex, England.
21. Cuatrecases P, Tell GPE. Insulin-like activity of coconcanavalin A and wheat agerm agglutinin-direct interactions with insulin receptors. Proc Natl Acad Sci USA 1973;70:485-9.
22. Erickson RH, Kim YS. Interaction of purified brush-border membrane amniopeptidase N and dipeptidase IV with lectin-Sepharose derivatives. Biochim Biophys Acta 1983;743:37-42.
23. Freed DLJ. Non-Allergic Effects of Food. In Brostoff J, Challacombe SJ (eds.): Food Allergy and Intolerance. London, Bailliere Tindall 1987,375-400.
24. Ganguly P, Fossett NG. Evidence for multiple mechanisms of interaction between wheat gern agglutinin and human platelets. Biochim Biophys Acta 1980;627:256-261.
25. Hedo JA, Harrison LC, Roth J. Binding of insulin receptors to lectins: evidence for common carbohydrate determinants on several membrane receptors. Biochemistry 1981;20:3385-3393.
26. Hilgert I, Horejsi VA, Angelisova P, Kristofova H. Lentil lectin effectively induces allotransplantation tolerance in mice. Nature 1980;284:273-5.
27. Livingston JN, Purvis BJ. Effects of wheat germ agglutinin on insulin binding and insulin sensitivity of fat cells. Am J Physiol 1980;238:E267-75.
28. Nirmul G, Severin C, Taub RN. In vivo effects of con A. I. Immunosuppressive effects. Transplantation 1972;14:91-5.
29. Oppenheim JJ, Rostenstreich DL, eds: Mitogens in immunology. New York: Academic Press, 1976.
30. Shier WT. Concanavalin A as in inflammogen. In: Bittiger H, Schnebli HP, eds. Concavalin A as a tool. London: John Wiley and Sons. 1976;573-9.
31. Stillmark H. Uber rizin, ein giftiges ferment aus Samen von Ricinis communis L., und ainigen anderen Euphorbiaceen. Dorpat (Tartu), 1888. Inaugural dissertation.
32. Ali M, Ali O. AA oxidopathy. xxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxx
33. Landsteiner K, Raubitschek H. Boebachtungen uber Hamolyse and hamagglutination. Zenbralbl Bakteriol 1907;45:660-7.
34. Boyd WC. Lectins. Ann NY Acad Sci 1970;169:168-90.
35. Renkonen KO. Studies on hemagglutinins present in seeds of some representatives of family of leguminoseae. Ann Med Exp Biol Fenniae 1948;26:66-72
36. Boyd WC, Shapleigh E. Diagnosis of subgroups of blood groups A and B by use of plant agglutinins (lectins). J Lab Clin Med 1954;44:235-7.
37. Hedo JA, Harrison LC, Roth J. Binding of insulin receptors to lictins: evidence for common carbohydrate determinants on several membrane receptors. Biochemistry 1981;20:3385-3393.
38. Hilgert I, Horejsi VA, Angelisova P, Kristofova H. Lentil lectin effectively induces allotransplantation tolerance in mice. Nature 1980;284:273-5.
39. Livingston JN, Purvis BJ. Effects of wheat germ agglutinin on insulin binding and insulin sensitivity of fat cells. Am J Physiol 1980;238:E267-75.
40. Nirmul G, Severin C, Taub RN. In vivo effects of con A. I. Immunosuppressive effects. Transplantation 1972;14:91-5.
41. Oppenheim JJ, Rostenstreich DL, eds: Mitogens in immunology. New York: Academic Press, 1976.
42. Edwards JE, Jr. Invasive candida infections: Evolution of a fungal pathogen. N Eng J Med 1991;324:1060-1062.
43. Ali M, Ali O, Bradford R. et al Immunostaining of candida organisms in peripheral smears. (Abstract). 1995. American Academy of Otolaryngic Allergy, Spring Meeting, Palm Desert, CA.


                In clinical practice, disorders of food allergy, sensitivity and intolerance cannot be separated from the larger issues of normal bowel ecology and altered bowel ecology. Elements of significant clinical importance in preservation of normal bowel ecology include the following: bowel motility and transit time, bowel perfusion, bowel permeability, bowel (and stomach) pH, bowel digestive capability, bowel absorptive capacity, bowel flora. Bowel structural changes follow as natural consequences of altered bowel ecology. Specific morphologic lesions such as ulcerative colitis, Crohn’s colitis and ileitis, pseudomembranous colitis, ischemic colitis, collagenous colitis and other bowel disorders, in general, represent patterns of cellular and tissue injury caused by long-neglected changes in bowel ecology. Intestinal parasitism and colonization with organisms such as Helicobacter species and C. difficile also represent impaired bowel immunity due to altered bowel ecology.

                The subject of immunologic tolerance has been presented in earlier chapters of this volume. This important subject has not been investigated well in the context of food-induced recations. Pathogenetic mechanisms and clinical symptoms associated with food disorders, however, are profoundly influenced by the dynamics of bowel ecology. To put this discussion of the pathogenetic mechanisms and immunologic aspects of food disorders in perspective, I include below some brief comments about the bowel ecology.

                The term “Altered Bowel Ecology Syndrome” is not simply another buzz word to refer to chronic disorders of bowel. There are two important reasons why this term is preferable to many others in common use at this time.

                First, it keeps the focus on the central issue in our understanding of the pathogenesis of chronic indolent disorders of the bowel, namely the ecology of the bowel. “Ecologic thinking” calls for management of all the elements involved in the preservation of the normal ecologic balance in the bowel. Specifically, it includes issues of increased bowel permeability, compromised bowel perfusion, irregularities of bowel motility, impaired digestive and absorptive dysfunctions, altered bowel flora and parasitic infestations.

                Second, it keeps the focus on the central issue in the clinical management of chronic indolent bowel disorders, namely the inter-relatedness of all the elements involved in the preservation of normal ecologic balance in the bowel. Patients with chronic indolent bowel disorders do not obtain relief of symptoms and resolution of their bowel lesions until all these elements are addressed.

                The use of diagnostic terms like Candida-related complex and intestinal dysbiosis is valid for clinical disorders in which there is unequivocal laboratory evidence of overgrowth or infections with Candida species or persistent infestation with specific intestinal parasites. Simple-minded efforts to “get rid of the yeast” and “treat intestinal dysbiosis” are rarely effective on a long-term basis. Just as environmentally sensitive individuals require that we address all the relevant environmental triggers, patients with the Altered Bowel Ecology Syndrome require that we address all the relevant “ecologic” elements in the bowel.


                A large number of good cookbooks and resource publicationas now exist for practitioners as well as patients. To cite one example of books devoted to the subject of gluten intolerance, following is the list of books for obtaining useful information on gluten-free food choices available from www.Amazon.com or The Gluten-Free Pantry (800-291-8386):

 1.            Hillson B. GFP Companion: Great Recipies for a Wheat-Free/Gluten-Free Kitchen.

 2.            Hagman B. The Gluten-aFree Gourmet.

 3.            Case S. Gluten-Free Diet Guide.

 4.            Robertson K. Cokokking Gluten Free.

 5.            Rae Lynn. What? No Wheat.

 6.            Korn D. Wheat-Free/Worry-Free.

 7.            Korn D. Kids With Celiac Disease: A Family Guide to Raising Happy, Healthy, Gluten-Free Children.

 8.            Gluten-Free Living (The national magazine for people with gluten sensitivity.


                At the time of this writing, two good sources for purchasing foods for food-sensitive individuals are:

The Gluten-Free Pantry: 1-800-291-8386 // 9www.glutenfree.com

DeLand Bakery, Inc. Deland, Florida. www.delandbakery.com / 386-734-7553

                The internet, of course, is a very rish source of addresses for companies specializing in products for individuals with food and mold allergies.


                A careful review of history reveals the existence of food-related reactions in the majority of persons with chronic illness. Only a small number of such rections are mediated by IgE-mediated responses. The clear majority of such reactions are related to issues of increased gut permeability, oxidative leaky cell membrane state, and overburdened hepatic oxidative pathways involved in coping with macromolecules that gain entrance to circulation.

                Regrettably, most food-triggered reactions go unrecognized by most clinicians because of the lack of focus and training. When those issues are properly addressed, nearly all patients report clinical benefits. Looking at food allergy through the prism of oxygen homeostasis gives us compelling reasons to look deeper into issues of the bowel, blood, and liver ecosystems that significantly increase the frequency and intensity of food-related reactions.

                In my experience, adverse food reactions and food allergy symptoms cannot be controlled and prevented without optimally addressing the issues of concurrent mold allergy discussed at length in the next chapter.


                1.             Ali M and Ramanarayanan MP:  A computerized micro-ELISA assay for allergen-specific IgE antibodies.  Am J Clin Pathol 81:591, 1984.

                2.             Ali M, Ramanarayanan MP, Nalebuff DJ, et al:  Serum concentrations of allergen-specific IgG antibodies in inhalant allergy:  Effect of specific Im­munotherapy. Am J Clin Pathol  80:290, 1983.

                3.             Ali M:  In-vitro immunoassay techniques in clinical allergy.  Clin Ecol, 3:68078, 1985.

                4.             Ali M, Little CH:  Changes in milk-specific IgE antibodies following oral challenge in milk-sensitive patients with chronic headache.  Presented at the annual meeting of the American Academy of Otolaryngic Allergy, 1986.

                5.             Atkins FM, Steinberg SS, Metcalfe DD:  Evaluation of immediate adverse reactions to foods in adult patients.  Correlation of demographic, laboratory, and prick skin test data with response to controlled oral food challenge.  J All Clin Immunol  75(3):348-355, 1985.

     6.        Bellanti JA, Nerurkar LS, Willoughby JW:  Measurement of p plasma histamine in patients with suspected food hypersensitivity.  Ann Allergy  47:260-263, 1981.

     7.        Brenenstock J:  Food Allergy.  Clinics in Immun and Allergy  2:5-40, 1982.

     8.        Buckley RH, Metcalfe D:  Food Allergy.  J. Am Med Assoc  248(20):2627-2631, 1982.

     9.        Denman AM, Mitchell B, Ansell BM:  Joint complaints and food allergic disorders.  Ann Allergy  51:260-263, 1983.

     10.      Gerrard JW:  Allergies in breast-fed babies to foods ingested by the mother.  Clin Rev Allergy  2:143-9, 1984.

            11.               Kniker WT:  Immunologically mediated reactions to food:  state of the art.  Ann Allergy  59:60-70, 1987.

     12.      Kushimoto K, Toshiyuki A:  Masked type I wheat allergy.  Relation to exercise-induced anaphylaxis.  Arch Dermatol  121:355-69, 1985.

     13.      Loveless MH:  Allergy for corn and its derivatives:  experiments with masked ingestion test for its diagnosis.  J Allergy  21:500-0, 1950.

     14.      Paganelli R, Matricardi PM, Aiuti F:  Interactions of food antigens, antibodies, and antigen-antibody complexes in health and disease.  Clin Rev Allergy  2(1):69-78, 1984.

     15.      Paganelli R, Atherton DJ, Levinsky RJ:  Differences between normal and milk allergic subjects in their immune responses after milk ingestion.  Arch Dis Child  58(3):201-206, 1983.

  16.         Pearson JR, Kingston D, Shiner M:  Antibody production to milk proteins in the jejunal mucosa of children with cow milk protein intolerance.  Pediatr Res  17(5):406-412, 1983.

                17.           Sampson HA, McCaskill CC:  Food hypersensitivity and atopic dermatitis:  evaluation of 113 patients.  J Pediatr  107(5):669-675, 1985.

                18.           Sampson HA:  IgE-mediated food intolerance.  J Allergy Clin Immunol  81(3):495-504, 1986.

   19.        Brostoff J, Challacombe SJ. Food Allergy and Intolerance. 1987Bailliere Tindall, London.

   20.        Freed DLJ. Dietary lectins and disease. In: Food Allergy and Intolerance. Eds: Brostoff J, Challacombe SJ. 1987 Bailliere Tindall, East Sussex, England.

   21.        Cuatrecases P, Tell GPE. Insulin-like activity of coconcanavalin A and wheat agerm agglutinin-direct interactions with insulin receptors. Proc Natl Acad Sci USA 1973;70:485-9.

   22.        Erickson RH, Kim YS. Interaction of purified brush-border membrane amniopeptidase N and dipeptidase IV with lectin-Sepharose derivatives.  Biochim Biophys Acta 1983;743:37-42.

   23.        Freed DLJ. Non-Allergic Effects of Food. In Brostoff J, Challacombe SJ (eds.): Food Allergy and Intolerance. London, Bailliere Tindall 1987,375-400.

   24.        Ganguly P, Fossett NG. Evidence for multiple mechanisms of interaction between wheat gern agglutinin and human platelets. Biochim Biophys Acta 1980;627:256-261.

   25.        Hedo JA, Harrison LC, Roth J. Binding of insulin receptors to lectins: evidence for common carbohydrate determinants on several membrane receptors. Biochemistry 1981;20:3385-3393.

  26.         Hilgert I, Horejsi VA, Angelisova P, Kristofova H. Lentil lectin effectively induces allotransplantation tolerance in mice. Nature 1980;284:273-5.

  27.         Livingston JN, Purvis BJ. Effects of wheat germ agglutinin on insulin binding and insulin sensitivity of fat cells. Am J Physiol 1980;238:E267-75.

  28.         Nirmul G, Severin C, Taub RN. In vivo effects of con A. I. Immunosuppressive effects. Transplantation 1972;14:91-5.

  29.         Oppenheim JJ, Rostenstreich DL, eds: Mitogens in immunology. New York: Academic Press, 1976.

  30.         Shier WT. Concanavalin A as in inflammogen. In: Bittiger H, Schnebli HP, eds. Concavalin A as a tool. London: John Wiley and Sons. 1976;573-9.

  31.         Stillmark H. Uber rizin, ein giftiges ferment aus Samen von Ricinis communis L., und ainigen anderen Euphorbiaceen. Dorpat (Tartu), 1888. Inaugural dissertation.

  32.                         Ali M, Ali O. AA oxidopathy. xxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxx

  33.         Landsteiner K, Raubitschek H. Boebachtungen uber Hamolyse and hamagglutination. Zenbralbl Bakteriol 1907;45:660-7.

  34.         Boyd WC. Lectins. Ann NY Acad Sci 1970;169:168-90.

  35.         Renkonen KO. Studies on hemagglutinins present in seeds of some representatives of family of leguminoseae. Ann Med Exp Biol Fenniae 1948;26:66-72

  36.         Boyd WC, Shapleigh E. Diagnosis of subgroups of blood groups A and B by use of plant agglutinins (lectins). J Lab Clin Med 1954;44:235-7.

  37.         Hedo JA, Harrison LC, Roth J. Binding of insulin receptors to lictins: evidence for common carbohydrate determinants on several membrane receptors. Biochemistry 1981;20:3385-3393.

  38.         Hilgert I, Horejsi VA, Angelisova P, Kristofova H. Lentil lectin effectively induces allotransplantation tolerance in mice. Nature 1980;284:273-5.

  39.         Livingston JN, Purvis BJ. Effects of wheat germ agglutinin on insulin binding and insulin sensitivity of fat cells. Am J Physiol 1980;238:E267-75.

  40.         Nirmul G, Severin C, Taub RN. In vivo effects of con A. I. Immunosuppressive effects. Transplantation 1972;14:91-5.

  41.         Oppenheim JJ, Rostenstreich DL, eds: Mitogens in immunology. New York: Academic Press, 1976.

  42.         Edwards JE, Jr. Invasive candida infections: Evolution of a fungal pathogen. N Eng J Med 1991;324:1060-1062.

  43.         Ali M, Ali O, Bradford R. et al Immunostaining of candida organisms in peripheral smears. (Abstract). 1995. American Academy of Otolaryngic Allergy, Spring Meeting, Palm Desert, CA.

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