Journal of Integrative Medicine 1999;3:5-11 DARWIN, OXIDOSIS, DYSOXYGENOSIS, AND INTEGRATION: The Medicine of the New Century Majid Ali, M.D. Three issues will dominate medicine in the next century: accelerated oxidative injury (oxidosis), abnormal cellular oxygen metabolism ("dysoxygenosis"), and an integrative view of the human microecologic cellular and macroecologic tissue-organ systems. And that medicine will grow under Darwin's glow. Among the ecologic shifts, oxidosis and dysoxygenosis will be the core issues in basic and clinical research. Integration of empirical and experimental observations will be the mainstay of all therapeutic strategies. Prediction is a risky business; still, those three predictions seem entirely safe. The health/dis-ease/disease continuum is a spectrum of energetic-molecular dynamics. The enormous healing potential of spiritual surrender and certain energetic phenomena is well known to all astute observers in medicine. Only those who limit their work to mechanistic aspects of illness and have little, if any, passion for healing question the role of spiritual and energetic phenomena in clinical medicine. However, technology sufficiently sensitive to measure subtle energy fields - and molecular and cellular resonances created in them - is not yet forthcoming. Thus, as far as observable and reproducible phenomena are concerned, we are left with the molecular components of the energetic-molecular healing phenomena, the two dominant concerns being oxidosis and dysoxygenosis. 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.1 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 (Crassostrea virginica) are parasitized by dermo (Perkinsus marinus), which causes severe systemic acidosis. Up to one-half of the total population succumbs.2 Similarly, grass shrimp (Palaemonetes pugio) suffer from heavy parasitic infestation by epicardean isopods (Probopyrus pandalicola).3 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.4 In the Pacific island of Guam, the introduction of some alien species, most notably a brown tree snake, has fundamentally transformed communities of birds, mammals, and lizards during the past 50 years.5 Extinction of 22 native terrestrial vertebrate species has been attributed to ecologic relationships among the especially versatile introduced predators and the naive native prey. Such reports often spark academic debates in the small world community of ecologists. Sometimes, such news also stimulates dinner-table conversation in a few households. But, amazingly, the obvious relevance of such reports to human health receives little, if any, attention. Enter Charles Darwin. He was the first systematic integrationist. The essence of his life's work was integration of seemingly incongruous observations concerning natural phenomena into some meaningful whole. His seminal ideas of strife for resources, adaptation to changing environments, and natural selection could not have germinated except in the "soil of ecologic thinking." The genocide of frogs, oysters, shrimp, and other life forms can be understood only when peering through Darwin's microscope. Oxidosis and Dysoxygenosis In 1983, based on a chance reflection on why stale buffers lose some of their buffering capacity, the author was puzzled as to why butter turns rancid spontaneously but rancid butter does not turn unrancid spontaneously. 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, he put forth his hypothesis that spontaneity of oxidation in nature is the primary driving force in molecular and cellular injury, and hence of aging and all disease processes.6 That simple idea has preoccupied him ever since. Subsequent 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 environmental illness,7 chronic fatigue syndrome,8 ischemic coronary artery disease,9 altered states of bowel ecology,10 arrested growth in children given chemotherapy and/or immunosuppressant steroid therapy,11 amenorrhea and oligomenorrhea in chronic fatigue syndrome,12 and other disorders.13 Those investigations made it abundantly clear that the three core molecular deviations that separate a state of health from that of absence of health as well as disease states are oxidosis, dysoxygenosis, and acidosis. Next, attempts to integrate those molecular dynamics with clinically recognizable patterns of oxidative injury to human microecologic cellular and macroecologic tissue-organ systems culminated in the following three concepts: 1. Oxidative regression to primordial cellular ecology plays a role in the pathogenesis of diverse entities, such as chronic fatigue syndrome and cancer.14 2.. Oxidative-dysoxygenative dysfunction (ODD) plays the core pathogenetic role in chronic disorders affecting all organ-systems of the body, such as chronic fatigue syndrome, fibromyalgia, and Gulf War syndrome.15 3. A clinical model of the microecologic cellular and macroecologic tissue-organ systems designated The Pyramid of the Trios of Human Ecosystems provides a framework for successful therapeutic strategies16 Too much oxidation and too little oxygen - those are the molecular clues to the case of the missing toads. Frog corpses were found decomposed or eaten, but the cause of death remained elusive. A partial answer to the mystery was provided by Australian, American, and Canadian researchers last year. The culprit, they reported, was not an alien, but a lowly fungus belonging to the genus Chytridiomycota.17 Significantly, the prior rap sheet of this fungus shows it to infect plants and insects, not frogs. How does the fungus, which affects the frogs' skin, kill them? The investigators believe the fungus suffocates frogs by clogging their skin pores through which they breathe. It seems likely that the fungus not only mechanically blocked oxygen transport but also caused severe oxidative injury in frogs, as fungi do in humans.18 In California, pesticides were reported to be the villains. How do pesticides kill? By poisoning respiratory enzymes of insects. It so turns out that some of those enzymes, such as cholinesterase, are identical to the human cholinesterases. What robs insects of their oxygen supply also suffocates human microecologic cellular systems. In Chesapeake Bay, during summer months the water oxygen content drops and acidity rises steeply due to heavily contaminated effluent from hog farms draining into coastal marshes. That causes the oxygen-deprived Eastern oysters to lose their immune resistance to the dermo parasite. The aquatic life which succumbed to the Valdez spill also died the same way: too much oxidative stress, too little oxygen. The Case for Ecologic Integration The ideas of ecologic integrity - and, more recently, sustainability - are "hot" issues for ecologists and environmentalists.19 Darwin guides them well. In clinical medicine, howe ver, critically important disruptions of the human micro- and macroecosystems are seldom, if ever, addressed. It is as if Darwin never lived for the general physician community. A case in point: It is not uncommon for the author to find 80 to 90% of phagocytes in the blood smears of elderly patients with circulatory disorders to be well-preserved and actively motile. By contrast, 30 to 60% of phagocytes in children with recurrent infections and repeated courses of antibiotics are often inactive and/or disintegrated. The yeast-like anaerobes in the peripheral blood infect the phagocytic cells and kill them. The predator then becomes the prey. Tales of the brown tree snake in Guam fascinate us, but the matter of human hunter immune cells becoming the hunted escapes our notice. Antibiotic abuse persists. The case for integration in medicine is equally compelling, though rejected to date by the general physician community in the United States. Notwithstanding some impressive gains (such as the recent inaugural graduation of the nation's first university of integrative medicine20), most physicians still find the term integrative medicine unsettling. Old prejudices die hard. But, integration in medicine is not merely playing Tantaric Indian music while doing an unnecessary coronary bypass operation, nor is it adding acupuncture after spinal fusion surgery has failed to relieve backache. Integration in medicine must be philosophic before it can be clinical.21 While prestigious medical journals continue to deride or resist integrative nondrug therapies,22 the world community of biologists is eagerly seeking integration with physicists, mathematicians, and computer scientists to solve problems they recognize cannot be solved with the prevailing reductionistic model. Indeed, Science recently addressed the need for an "integrative agenda" for reaching beyond reductionism in science,23 and devoted a large part of its April 2, 1999, issue to the theme (and need) of integration among the various scientific disciplines to advance our understanding of complex systems in nature. Seashell Fossils and Petrified Pine Trees On July 22, 1834, HMS Beagle reached Valpariaso Bay on the Pacific coast of South America. Darwin promptly hired a mule and was off to "unravel the mystery" of the Andes.30 During his travels on his "fine chaos of mountains" of the Cordilleras, he made two important observations. At the height of 12,000 feet, he found fossil seashells. On his way down, at 7,000 feet, he discovered petrified pine trees embedded in marine rock. The trees, he reasoned, had once stood on the Atlantic coast, were sunk beneath the sea, then raised to 7,000 feet as the Andes rose from the ocean floor. Robert FitzRoy, the captain of the Beagle, was not impressed by Darwin's reasoning. He held on to his (then prevailing) view that the mountains stood as they were created on the day of creation. He seemed to have little use for Darwin's notion of relatedness of his two finds and the relevance of the two to his notion of the origin of the Andes. Thousands of papers are written each year to report the research findings about ulcerative colitis, Crohn's colitis, collagenous colitis, microscopic colitis, and other types of colitis. The essential issue in such research should be ecologic disruptions which set the stage for the various morphologic patterns of the inflammatory process. Amazingly, that essential issue is totally ignored in such papers. Articles after articles describe histologic lesions and laboratory abnormalities encountered in patients with colitis and promote the use of one or more drug regimens containing steroids to suppress symptoms. Regrettably, a growing number of gastroenterologists now prescribe immunosuppressant drugs such as 6-MP and cyclosporine. The author does not see any papers which delve deep into the nature of ecologic relationships among the causative factors. Surprisingly, the approach to ecologic problems of the bowel continues to be in line with FitzRoy's fixed view of the Andes rather than the evolving, ecologic concepts of Darwin. Resistance to Integration The resistance of the general medical community to integration in clinical medicine is difficult to understand. Recent advances in molecular biology and genetics clearly demonstrate that human molecular dynamics and healing responses are exceedingly complex. In light of such advances, the prevailing notions of one-disease/one-diagnosis/one-drug are neither defendable on theoretical basis nor on empirical grounds. Consider the following examples of ecologic relationships and complexity in biologic systems: It is now evident that the imminent conquest of the human genome, though establishing the identity of 100,000 or more genes, is far from a complete victory. We know that expression of individual genes is not merely a "gene matter." Gene expression in most cases requires participation of five or more proteins.24 The dynamics of viral infectivity and pathogenicity are far more complex than previously thought. For instance, five genes which promote replication of some bacteriophages within the bacterial bodies are, in turn, controlled by six other genes, four of which function as promoters while the remaining two encourage dormancy. But the story does not end there. The complexity of viral replication further grows when we recognize that one gene that favors dormancy (C1) feedbacks to amplify its own expression while diminishing the output of the gene (Cro) that triggers immediate viral replication.24 The chemotactic motility of Escherichia coli is triggered when an attractant molecule binds with one of its many Che (for chemotaxis) membrane receptor proteins. For decades, such motility was thought to depend on precise titration of the various molecular components of the system. Studies with mutant E. coli which either grossly overproduce or markedly underproduce Che proteins show that following an initial period of altered chemotactic motility, mutant microbes expediently return to patterns of motility of non-mutant microbes, thus negating the old concepts of fixed roles of genes, their protein products, and functionality.25 The sameness and variability of even simple microbial behavior defy reductionistic notions. The author's purpose in citing the above biologic phenomena is to show that the dominant one-disease/one-diagnosis/one-drug (the one-cause/one-effect/one-solution) mode of the prevailing medical dogma is not tenable in light of advances in molecular biology and genetics in recent decades. Indeed, it is astonishing how prestigious medical journals continue to hold that blinded single-drug trials conducted for brief periods of weeks and months can provide reliable long-term solutions to disruptions of astoundingly complex microecologic cellular and macroecologic tissue-organ systems of the human body, both in health and disease. A case in point: the author and his colleagues have shown that coronary artery heart disease results from an ecologic disruption of the circulating blood. Microclot and microplaque formation occurs in the circulating blood as a part of the spectrum of changes of oxidative coagulopathy.2 Just as a water pump pumping clean water functions well, a blood pump pumping clean blood can be expected to function well. Evidence for that view has been published.26 Integrative management protocols employed by the author and his colleagues that focus on ecologic aspects of the blood ecosystem and prevent oxidative coagulopathy (without resorting to drug therapies for blockade of adrenergic receptors or calcium channels of cardiac myocytes) produced excellent clinical results (complete control of symptoms and discontinuance of all drugs in 61% and more than 75% reduction in symptoms and dosage of drugs in another 17% in patients with advanced coronary heart disease).26 Now consider what happens when the essential ecologic issues are ignored and purely mechanical approaches are adopted for clearly ecologic problems. The reported rates of closure of coronary arteries within six months of balloon angioplasty are in the range of forty to fifty percent.27 In recent years, there has been a staggering increase in the use of coronary stents.28 Predictably, such stents failed to address any of the ecologic issues involved. The following quote from an editorial published in the December 3, 1998, issue of The New England Journal of Medicine (pages 1702-3) is illuminating: "Cardiologists have mistakenly believed that stenting reduced the incidence of death and myocardial infarction. However, careful examination of the results of randomized trials comparing stenting with balloon angioplasty, including the results of trials by Erbel et al. shows an excess number of deaths and myocardial infarction among patients assigned to stents." An important point not included in the above quote is that such dismal results are obtained not with just one stenting procedure but with an average insertion of 1.7 stents.29 Gulf War Syndrome--Darwin Was Ignored, But at What Cost? What can we make of over 100,000 young men and women who went to the Gulf War in good health but over nine years later are still partially or totally disabled? The Gulf War syndrome is dismissed as an all-in-the-head syndrome by many. Anyone who believes that there is nothing demonstrably wrong in Gulf War syndrome should take a drop of blood from a patient and study it with high-resolution phase-contrast microscopy. He will find advanced evidence of oxidative coagulopathy. The Gulf War was a grand experiment in human biology to see how much cumulative oxidative stress people can take before their redox defenses break down. It was the first true virtual war in which fighting men and women were shown the potential for devastation over and over again. There was widespread fear of poisoning by chemical warfare and of risk of mutilation and death caused by the Star Wars technology. Soldiers were administered antidote for war poisons that were known to cause nerve-muscle injury. They were exposed to massive amounts of pesticides and toxic chemicals in war materials. Dead cattle were found in fields, raising concerns of biological warfare. The hot days and cold nights of the desert increased rates of outgasing. Finally, there were the oil fields put to torch. Chemical toxins that went up with smoke had to come down. So it was that the total cumulative oxidative stress on over 700,000 soldiers in that war far exceeded any recorded before. Darwin should have been the scientist to guide us in how to assess ecologic damage sustained by the men and women in harm's way. What actually happened was astonishing. All ecologic issues were ignored. Instead, the ill veterans were prescribed symptom-suppressing antidepressants and anxiolytics without searching for the underlying molecular and cellular basis of symptomatology. Their battered bowel, blood, and liver ecosystems were neglected. The obsolete one-disease/one-diagnosis/one-drug model prevailed. Gulf War syndrome was chalked up to post-stress syndrome, the old all-in-the-head standby. It was as if the Gulf region ecosystems did not exist. It was as if the bowel, blood, and liver ecosystems did not exist in the bodies of the sick veterans. It was as if ecologic relationships in nature do not matter, as if Darwin never lived. Gulf War syndrome was ignored. But, at what cost? Genes Are Not the Only Alphabets of Biology Genes make up the language of biology, but only in limited ways. The preoccupation of a student of biology - and of human health - should not be merely with numeration of genes, but with how genes integrate with their protein products as well as the membrane receptors and the ligands that trigger their expression. The known dynamics of ligand-receptor-gene-product proteins are mind-numbing in their complexity. Genes are components of those strings of life (molecular ecosystems), not their beginnings, not their ends. Compared with gene dynamics in viruses and bacteria, those in humans in health and disease are mystifyingly complex. Thus, the prevailing notions of one-cause/one-effect/one-solution in clinical medicine are too simplistic to be taken seriously. Mapping of the human genome, it seems to the author, is like learning the Urdu alphabet. Can one claim to understand Ghalib simply because he knows the Urdu alphabets? (Ghalib is considered the most transcendent poet in both Urdu and English in the eyes of many who know both languages. A Goethe reader might say the same about the German alphabets.) Elegant poetry is not merely the joy of individual words finding new meanings but also such words giving luminescence to words that precede and follow them. It is the same way with genes. Deciphering the human genome will be a hollow victory unless it brings forth a deeper understanding of how genes self-regulate, speak to each other, listen to each other, influence each other, and integrate with each other for the good of the whole being. Darwin's Work Is Now Author's Work Darwin's work, the author recognizes, is now his (author's) work. Darwin's larger message is clear. It is as relevant to us as to his inches on the Galapagos Islands. No human suffering can be understood except through clear concepts of interrelatedness among the human microecologic cellular and macroecologic tissue-organ systems as well as the ecosystems in which humans live. The nineteenth-century one-disease/one-diagnosis/one-drug models of illness simply are irrelevant to the dominant chronic disorders of the twenty-first century, e.g., coronary heart disease (clearly a disorder of the blood ecosystem), inflammatory bowel disease and colitis (evidently states of the battered bowel ecosystem), and the fatigue-fibromyalgia complex (undoubtedly a disorder of the disrupted bowel, blood, and liver ecosystems), and so on. Darwin continues to illuminate the author's clinical work and will undoubtedly govern the principles and practice of medicine in the new century. References 1. Watson T. Frogs falling silent across USA. USA Today.August 12, 1998. 2. Dwyer JJ, Burnett LE. Acid-base status of the oyster Crassostrea virginica in response to air exposure and to infections by Perkinsus marinus. Biol Bull. 1996;190:139-147. 3. Anderson G. Metabolic response of the caridean shrimp Palaemonetes pugio to infection by the adult epibranchial isopod parasite Probopyrus pandalicola. Comp Biochem Physiol 1975;52A: 201-207. 4. Begub B. Ten years after the spill. Newsweek, March 29, 1999 (unrecovered species common loon, cormorant, harbor seal, harlequin duck, pigeon guillemot.) 5. Hanski I. Streamlined complexity. Science 1999;283:1858-9. 6. Ali M. Spontaneity of Oxidation in Nature and Aging.Monograph, Teaneck, NewJersey, 1983. 7. Ali M. The agony and death of cell. Syllabus of the Instruction Course of the American Aacademy of Environmental Medicine, Denver, Colorado, 1985. 8. Ali M. Hypothesis: Chronic fatigue is a state of accelerated oxidative molecular injury. J. Advancement in Medicine. 1993; 6:83-96. 9. Ali M. Ali O. AA oxidopathy: The core pathogenetic mechanism of ischemic heart disease. J Integrative Medicine 1998; 1:6-112 10. Ali M. Monograph: Altered States of the Bowel Ecology. 1988 and 1990. Life Span, Inc. Denville, New Jersey. 11. Ali M. Efficacy of an integrative program including intravenous and intramuscular nutrient therapies for arrested growth. J Integrative Medicine. 1998; 1-56-69. 12. Ali M. Oxidative Menstrual Dysfunction. J Integrative Medicine 1998; 3:101-124. 13. Ali M. Spontaneity of oxidation and chronic disease. In: Syllabus of the Instruction Course of the American Academy of Environmental Medicne, Denver, Colorado, 1992. 14. Ali M. Oxidative regression to primordial cellular ecology: Evidence for the hypothesis and its clinical significance. J Integrative Medicine. 1998; 2:4-49. 15. Ali M. Ali O. Fibromyalgia: An oxidative-dysoxygenative disorder (ODD) J Integrative Medicine. 1999;1:17-37 16. Ali M. Of doctors and gardeners. Aging Healthfully 1999;1:1-3 17. Kaiser J. Fungus may drive frog genocide. Science 1998;281:23. 18. Ali M, Ramanarayanan MP. A computerized micro-ELISA assay for allergen specific IgE antibodies. Am J Clin Pathol 19. Mann CC, Plummer ML. Call for 'sustainability' in forests sparks a fire. Science 1999;283:1996-8. 20. Ali M. Fanning TO. Nation's first university of integrative medicine graduates its first class. Townsend Letter for Doctors and Patients. April 1999, 12-14 21. Ali M. Seven Core Principles of Integrative Medicine J Integrative Medicine 1998;3:77-81 22. Angell M, Kassirer JP. Alternative Medicine-the risks of untested and unregulated remedies. N Eng J Med. 1998;339:839-841 23. Gallagher R, Appenzeller T. Beyond reductionism. Science. 1999;284:79. 24. Service R. Exploring the systems of life. Science. 1999;284:80-3. 25. Pennisi E. Unraveling bacteria's dependable homing system. Scinece. 1999;284:82. 26. Ali M, Ali O, Fayemi A, et al Improved Myocardial Perfusion in Patients with Advanced Ischemic Heart Disease with an Integrative Management Program Including EDTA Chelation Therapy. J Integrative Medicine 1997;1:113-142 27. Topol EJ. Coronary artery stents--gauging, gorging, and gouging. 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