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
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.
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.