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Founders of the “New Medicine”
The “Fabulous Five” of the 20th Century

by Jeffrey S. Bland, PhD
President, Institute for Functional Medicine

    We are witnessing the birth of a new medical paradigm. Instead of emphasizing the primacy of diagnosis and pathology, the new medicine focuses on the molecular events that precede the onset of diagnosis. The functional molecular changes that proceed to become a diagnosable pathology are related to phenotypic factors that result from altered gene expression in the body. This model emerges from the groundwork of five great innovators who carved out the domain of molecular medicine. The five champions of the new medical paradigm are Archibald Garrod, Linus Pauling, Roger Williams, Hans Selye and Abram Hoffer. The beginning of the new millennium provides a good opportunity to pause and reflect on the contributions of these five pioneers who have improved our understanding of the human body and the factors that contribute either to ongoing health or the progression of chronic, degenerative diseases.
The new medical paradigm has five defining features. First, it stresses biological individuality based on genetic and environmental uniqueness. Second, it is patient-centered rather than disease-centered. Third, it encompasses a dynamic balance of internal and external factors. Fourth, it emphasizes the weblike interconnections of physiological factors. Finally, it defines health as a positive vitality, not merely as the absence of disease. We define this system as “functional medicine” to emphasize its focus on the mechanisms and precedents of end-organ pathology.
Countless researchers and clinicians throughout the past century have contributed to the development of this paradigm, but none more important than the “Fabulous Five,” whose contributions I summarize below.

Dr. Archibald Garrod

    Dr. Garrod was first to discover the diseases of genetic metabolism in the early 20th century. He investigated the genetic metabolism diseases of infancy. Although those diseases originated in the genes, he said, the ultimate expression of the diseases depended on the exposure of those genes to factors in the environment. He discovered alkaptonuria, which led to the understanding of phenylketonuria and the role of the phenylalanine-restricted diet in its management. In 1902, Dr. Garrod wrote, “It might be claimed that what used to be spoken of as a diathesis of a disease is nothing else but chemical individuality. It is nearly true to say that the factors which confer upon us our predisposition and immunities from disease are inherent in our very chemical structure, and even in the molecular groupings which went to the making of the chromosomes from which we sprang_.”1

Dr. Linus Pauling

    Dr. Pauling made extraordinary contributions to the way we view the origin of disease. His article in Science magazine in 1949 on the origin of sickle cell anemia taught us that single gene mutations could contribute to disorders that cut across organ systems and produce multiple symptoms. In this article he introduced the term “molecular medicine.”2 Dr. Pauling explained that in sickle cell anemia, a single point gene mutation on the heavy chain of the globin molecule of hemoglobin could contribute to a conformational change in the way the hemoglobin molecule was structured in three dimensions. That conformational change affected the way oxygen bound to the heme portion of the hemoglobin molecule and changed the relationship between the molecule and its oxygen absorption/desorption. The change in shape of that molecule changed the shape of the red cell, because hemoglobin made up about three-quarters of the volume of a red cell. The red cell then became sickle-shaped, and this sickle would “cut” its way through the vasculature, creating the pain and disability of sickle cell crisis._3
Dr. Pauling predicted in 1949 that the molecular origin of disease would have extraordinary implications. As we learned more about the origin of these diseases, he believed, we would find ways to modify the expression and function of these genes to prevent the expression of disease. In 1997, 48 years after Dr. Pauling proposed this model of the potential power of molecular medicine, a paper in the New England Journal of Medicine validated his thesis. That article explained that administering hydroxy urea intravenously to patients who carried the genetic trait of sickle cell anemia could prevent the hemoglobinopathies associated with this genetic disorder.4_ Hydroxy urea upregulated the expression of fetal hemoglobin in these patients and “diluted” the amount of sickle cell hemoglobin resulting in a reduction of sickle crisis.
We now know there are many agents that modify gene expression in such a way as to create a different phenotype. These agents include dietary principles, exercise, stress, and environmental and lifestyle factors. The more we learn about those agents, the more we may be able to help individuals tailor health programs to their own genetic needs and thus prevent premature disease. We have begun to understand that we have within our bodies agents that transmit messages and receptors that receive them. The transmitters are the molecules we call the mediators. The receivers are the membrane receptor binding and soluble receptor sites that translate the messages into altered gene expression and altered function. We can manipulate both the messages and their reception on the basis of things we do every day, by the way we think, act, eat, and feel, by where we live, the nature of our relationships, and the our spiritual belief systems. All these factors influence the mediating molecules and can lead to an expanding health paradigm. An informational rubric encompasses communicating the right messages and receiving the right messages to be in synchrony with our genes to give rise to function.

Dr. Roger Williams

    In the 1950s Dr. Roger Williams was a biochemist at the top of his game. He had been President of the American Chemical Society. He had discovered members of the B-complex vitamin family, including pantothenic acid. His work on biochemical individuality started us thinking about biological diversity beyond differences in the color of our eyes, hair, or skin. Dr. Williams’ book, Biochemical Individuality, published in 1955, got us thinking about the role of various nutrients in preventing what he called “genetotrophic diseases.”5_ Genetotrophic diseases are those for which genetic uniquenesses create demands for specific needs of nutrients beyond the average to facilitate optimal function and prevent premature disease. When those specific needs are not met in a given individual, disease results.
Dr. Williams believed the major chronic degenerative diseases of aging – heart disease, stroke, cancer, diabetes, and arthritis – were related to genetotrophic imperfections. The genes called for different levels of nutrition and a lifestyle that was not delivered by the person’s selection. The consequences of not meeting the individual’s needs were expressed, over several decades, as degenerative disease “of unknown origin.” In the category of what he called genetotrophic diseases, Dr. Williams even included diseases of mental illness, childhood diseases, behavior disorders, and alcoholism. He believed they all were related to the mismatch of genes and environment. At a genetic level, the individual had a need for a different level of nutrients to promote proper phenotypic function. If that need were not met, the resulting undernutrition would manifest as chronic disease in midlife. This very powerful concept revolutionized our thinking about the origin of age-related diseases.6_
In defending his concept of biochemical individuality in a talk I once heard him give, Dr. Roger Williams said, “Nutrition is for real people. Statistical humans are of little interest.” Everyone in the audience realized he or she had spent years in studying statistical humans but had never seen one in real practice. People are unique. We must treat real people with respect for their biochemical uniqueness.

Dr. Hans Selye

    As the father of the physiological definition of the word “stress,” Dr. Selye opened the minds of both medical professionals and healthcare consumers to the role of the mind in the function of the body._ Dr. Selye’s tremendous insight gave birth to the rapidly evolving field of psychoneuroimmunology, which is redefining the way health practitioners view the role of lifestyle and behavior on health. The combination of the physiology of stress and the understanding of the influence of perceived stress on genetic expression serve as a powerful driver for the evolution of molecular medicine.
Although Dr. Selye was never awarded a Nobel Prize for his contributions, most historians of 20th century medicine believe his insights on the role of behavior and environment on health represent one of the most important factors shaping the new medicine.

Dr. Abram Hoffer

    As a psychiatrist who also held a doctorate in organic chemistry, Dr. Hoffer in the 1950s provided a unique perspective on mental illness. He discovered in the urine of schizophrenics unique chemicals that represented the oxidative byproducts of adrenaline.8_ He found these substances produced central nervous system toxicity. As a result of these discoveries, Dr. Hoffer proposed that certain forms of mental illness resulted not from bad early childhood experiences, but as a consequence of altered brain chemistry.9_ He found that increased doses of the common B vitamins, niacin and pyridoxine, could treat these conditions in some schizophrenic patients._10
Once again, the synthesis of a new idea that incorporated biochemical genetic individuality, nutritional modulation of gene expression, and functional physiology resulted in a leap forward into the field of biologically based psychiatry.
These five individuals pioneered the new medicine for the 21st century. The recognition that our genes do not determine our disease, but instruct us regarding the optimal environment for health represents a major shift in medical thinking.11_ The acceptance of this model within the medical paradigm is no longer in question. It is just a question of how long it will take for this model to be fully integrated within the standard practice of medicine. The contributions of Archibald Garrod, Linus Pauling, Roger Williams, Hans Selye, and Abram Hoffer have created a force of change that cannot be held back, because truth is its own vector.


1. Garrod, A. 1902. The incidence of alkaptonuria: a study in chemical individuality. Lancet. vol. 2:1616-1620.
2. Pauling L, Itano H, Singer SJ, Wells I. Sickle cell anemia, a molecular disease. Science. 1949;vol. 110: 543-548.
3. Itano H, Pauling L. A rapid diagnostic test for sickle cell anemia. Blood. 1949;vol. 4:66-68
4. Lubin B. Sickle cell disease and the endothelium. N Engl J Med. Nov. 1997;337(22):1623-1625.
5. Williams R. Biochemical individuality. New York: John Wiley and Sons, 1963.
6. Williams R, Deason G. Individuality in vitamin C needs. Proceedings of the National Academy of Sciences. 1967;vol 67:1638-1641.
7. Selye H. Stress and the reduction of distress. The Journal of the South Carolina Medical Association. Nov. 1979:562-566.
8. Hoffer A. Epinephrine derivatives as potential schizophrenic factors. Journal of Clinical and Experimental Psychopathology and Quarterly Review of Psychiatry and Neurology. 1957;vol. 18(1):27-60.
9. Hoffer A. Chronic schizophrenic patients treated ten years or more. Journal of Orthomolecular Medicine. 1994; vol. 9(1):7-34.
10. Hoffer A. Effect of niacin and nicotinamide on leukocytes and some urinary constituents. Canad.M.A.J. March 15, 1956; vol. 74:448-451.
11. Bland J. Genetic Nutritioneering. Lincolnwood, IL: Keats, a division of NTC/Contemporary Publishing Group, Inc. 1999.
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