History of the Structure-Function Concept

During the early years of the Victorian Era in England—in 1848, to be exact—Dr Alfred Baring Garrod made an
important observation about gout, a dreaded disease at that time in history that was often associated with male
royalty in Europe. Dr Garrod discovered that gout, which could produce multiple dysfunctions in those afflicted
with the disease, was associated with the accumulation of uric acid in tissues. The chemical structure of uric
acid was discovered by Carl Wilhelm Scheele (1742–1786), a Swedish chemist, and was later found to be the
final product of purine catabolism in the body. What Alfred Garrod actually elucidated through his work was the
structure-function role of uric acid. In medicine, this was considered to be a major discovery of significance that
contributed to an increased understanding of the etiology of complex “rheumatic” disorders. He was eventually
given credit for coining the term rheumatoid arthritis. In a sense, Dr Garrod was the first rheumatologist to look
at molecular structures that correlate with functional inflammatory diseases, including substances released by
specific types of bacterial infection and rheumatoid arthritis. During his lifetime, Dr Garrod enjoyed recognition
for his work; he was knighted in 1887, and in 1890 he was appointed “Physician Extraordinary” by Queen
Victoria.1

Although he is most commonly celebrated for his discoveries related to gout, it is interesting to note that Dr
Garrod’s work on the relationship of specific chemical structures and their impact on function extended to other
metabolic diseases. In 1857, for example, he published research on the relationship between glucose in the
urine and diabetes.2 Alfred Garrod had 4 sons, all of whom became scientists. Dinner parties hosted at the
Garrod home have become the stuff of legends to younger generations of his followers. It is tremendous fun to
imagine the remarkable conversations that must have taken place among a rotating guest list that included
people such as Erasmus Darwin (and—eventually—his famous grandson, Charles), William Bateson, Louis
Pasteur, Rudolf Virchow, Emil Fischer, and many others who were birthing what would become the 20th-
century science of Western medicine.

The youngest of Alfred’s sons was Dr Archibald Edward Garrod, who grew up to become known as the father
of genetic metabolism disease. Archibald discovered a genetic link between an inborn error of amino acid
metabolism and the metabolic disease alkaptonuria, which is associated with the accumulation of homogentisic
acid (a colored substance) in the urine. His work in this field demonstrated that Mendelian laws of genetics
could apply to disease.3 In 1902, Archibald Garrod’s article “Alkaptonuria: A Study in Chemical Individuality”
and William Bateson’s classic text Mendel’s Principles of Heredity were both published. From that point
forward, the concept of a genetic connection to disease—one that is associated with the altered structure of
specific molecules and their impact on physiological function—was firmly established. 4 Archibald Garrod went
on to identify many other genetic errors of metabolism, including cystinuria, pentosuria, and albinism, all of
which were described in his landmark 1931 publication “Inborn Factors in Disease: An Essay.” Garrod
attributed a biochemical role to genes, and by so doing he laid the groundwork for the later discovery of the
molecular basis of inheritance. An important and highly prescient statement appeared in this work:

It might be claimed that what used to be spoken of as a diathesis of a disease is nothing else but chemical
individuality. But to our chemical individualities are due our chemical merits as well as our chemical
shortcomings; and it is more nearly true to say that the factors which confer upon us our predispositions to and
immunities from the various mishaps which are spoken of as diseases, are inherent in our very chemical
structure; and even in the molecular groupings which confer upon us our individualities, and which went to the
making of the chromosomes from which we sprang.5

This amazing description of the relationship between chemical individuality and dysfunction associated with
specific diseases was overlooked in medicine for more than 40 years until another legendary scientist—Linus
Pauling—revisited the concept and described it in his classic 1949 article on the molecular basis of sickle cell
anemia.6 Linus Pauling, working with his research group at the California Institute of Technology, was the first
person to identify the specific genetic mutation that results in a single amino acid substitution in the protein
hemoglobin and produces sickle cell anemia, which he termed a molecular disease.7 He later described the
relationship among molecular disease, genetics, and evolution in a very important paper titled “Molecular
Disease and Evolution” published in 1964.8 Dr Pauling’s active research work spanned from the 1930s through
the early 1990s. Throughout his career, he described the important interrelationship between structure and
function within chemical and biological systems. He was known to use examples from his broad research
interests, including his early work on immune system function and antibody structural specificity, as well as the
mechanism of action of anesthetic drugs.

Linus Pauling’s work on the structure-function concept influenced many people, including Dr Roger Williams, a
biochemistry professor at the University of Texas who became both a friend and colleague to Dr Pauling. Dr
Williams discovered folic acid, vitamin B6, and pantothenic acid, and he was a strong advocate within the
medical and nutrition communities for 2 concepts that he pioneered: “biochemical individuality” and
“genetotrophic disease.”11,12 According to his definition, genetotrophic diseases were “diseases of genetic origin
that can be ameliorated by the administration of one or more specific nutrients.” Linus Pauling advanced this
concept further in a landmark 1968 paper he published in which he introduced a concept he called
“orthomolecular psychiatry,” which was based on the adjustment of molecules whose structures are native to
the human body to improve function, as well as prevent and treat disease.

Translating the Structure-Function Concept to Health Care

In 1964, Linus Pauling and Roger Hayward, a talented scientific illustrator, collaborated on a book titled The
Architecture of Molecules.15 Using text and wonderful hand-drawn illustrations, this book is more than just a
visual guide to the structure of atoms, molecules, and biomolecules; it also introduces their relationship to
molecular medicine by showing the reader how structure influences function at the molecular level. The
concepts found in this book are truly foundational in many ways. With some expanded thinking, it’s very
possible to understand how the concept of structure-function might apply to organizational systems well
beyond that of biochemistry.

The Social Applications of the Structure-Function Concept

An intriguing question: Does the structure-function concept have broader social implications? It is interesting to
note that Linus Pauling, who we have established as a pioneer of the structure-function concept, is the only
person to have won 2 independent Nobel Prizes in 2 different fields: chemistry and peace. To many people,
chemistry and peace might seem like 2 wholly unconnected activities. But for students of the structure-function
concept, the interconnectedness of chemistry and peace is more obvious.

In various interviews he gave during his lifetime, Linus Pauling indicated that conversations with his wife, Ava
Helen, in the 1940s and 1950s, resulted in his recognition that a very strong association existed between
sociopolitical structure and the function of society. This was a period in history when advancements made in
nuclear chemistry and physics had resulted in the development of incredibly powerful and destructive weapons
of war. The atom bombs dropped on Hiroshima and Nagasaki were a turning point in Linus Pauling’s life, which
was due in part to the passionate advocacy of Ava Helen. Together with other scientists, he spoke and wrote
against the nuclear arms race, and he was also a driving force in the Pugwash movement, which sought to
reduce the role of nuclear arms in international politics. Now known as the Pugwash Conferences on Science
and World Affairs, this organization was awarded the Nobel Peace Prize in 1995.

In 1959, Linus Pauling drafted a document that came to be known as “The Hiroshima Appeal” following his
attendance at the Fifth World Conference Against Atomic and Hydrogen Bombs. He was deeply committed
and used his influence to urge the leaders of nations with nuclear capability—the United States, the Soviet
Union, and Great Britain—to sign and implement the Limited Test Ban Treaty in 1963. On the day this treaty
went into effect—October 10—Linus Pauling was notified that he had been awarded the Peace prize.
Based on his experiences, Dr Pauling urged scientists to become involved in the structure of politics and
society. He is noted for saying the following:

It is sometimes said that science has nothing to do with morality. This is wrong. Science is the search for truth,
the effort to understand the world; it involves the rejection of bias, of dogma, of revelation, but not the rejection
of morality. … One way in which scientists work is by observing the structure of the world, making note of
phenomena, and analyzing them.

Today, research is emerging that indicates that the structure of social class and the form and function of
relationships can relate very directly to health and disease and can be a powerful determinate of health
outcome.

Applications of the Structure-Function Concept to the Development of Functional Medicine

In 1870, Sir Willoughby Wade, a noted physician at the General Hospital in Birmingham, England, delivered a
clinical lecture (published in Lancet the following year) on what he termed functional medicine.19 He described
functional medicine this way:

Whenever we come to treat we should first of all consider what function of the body it is that is improperly
performed. To the setting right of that function we should address ourselves. It may be, and indeed generally
is, the case that more than one function is (it may be several are) astray. We have, then, further to consider
whether it is possible or convenient to attempt to rectify all these at once; and, if not, we have to decide which
to begin with.

He continued:

If we treat a symptom merely, we often fail to remove that which causes the symptom. To give an extreme
instance: If a man has a thorn in his hand, and we merely order opiates for the relief of the pain thus produced,
we are very inadequately treating the disease, though we may be adequately treating the symptom. In some
cases treatment based upon such a principle may actually aggravate the disease.

And later he expressed the following opinion: “Functional medicine incorporates all the benefits of the imperfect
method of symptom-treatment, and moreover leads directly on to the recognition and employment of the most
precise, searching, minute, and scientific methods.”

The concept of functional medicine and its relationship to the structure-function model lay dormant for nearly
100 years until new diagnostic tools became available to more quantitatively correlate structure with function in
disease diagnosis. Advances were made in the late 20th century in understanding the connection among the
structure of the vascular, neurological, and endocrine systems and functional changes in these organ networks
due to the development of new assessment tools such as functional magnetic resonance imaging, computed
tomography scans, immunoassays, and genomic technologies. Very recently, these techniques have been
used to determine the structural clinical definition of the functional neurological disorder chronic traumatic
encephalopathy (CTE), which is characterized by interrelated and complex emotional and psychological
symptoms. It has also been reported in a number of studies that neurological structure (as determined from
noninvasive magnetic resonance imaging) is associated with cognitive and emotional function in a variety of
situations: people with type 2 diabetes, older-age individuals participating in lifestyle activities, yoga
practitioners, children exposed to green space, certain occupational activities, level of physical activity,
presence of chronic inflammation, use of menopausal hormone therapy, and status of chronic kidney disease.

In 2016, a well-known and much respected member of the functional medicine community, Patrick Hanaway,
MD, authored an editorial titled “Form Follows Function: A Functional Medicine Overview.”In this
publication, function medicine is defined this way: “A systems-biology-based model that empowers patients
and practitioners to work together to achieve the highest expression of health by addressing the underlying
causes of disease.” The uniqueness of the functional medicine model is very much connected to the concept of
quantitatively measuring physical, physiological, cognitive, and behavioral function in a patient and then
relating those findings to their structure. Understanding the connection between a patient’s molecular, physical,
mental, and emotional structure and function creates the opportunity for personalization of an intervention
program that is focused on treating the root causes of a condition rather than managing symptoms.

Structure-Function: Back to the Future

Let’s return—for a moment—to the past. In 1928, as Archibald Garrod’s medical career was coming to an end,
he delivered an address at the Middlesex Hospital that was titled “The Place for Biochemistry in
Medicine.”26 He reflected on the evolution of medicine and the importance of biochemistry in helping to
understand the etiology of disease. He suggested that biochemistry should not restrict itself solely to the
diagnosis of disease, but also to the physiochemical aspects of function that relate to prognosis as well as
diagnosis. He pointed out that a better appreciation of the structure of an individual’s diet and its constituents
are needed to understand the relationship between their lifestyle and their function. As he was bringing his
presentation to a close, he made the following comment: “I, for one, believe that the liabilities of certain
individuals to, or their immunity from, certain maladies—what may be called their diathesis—have chemical
origins.” This was a powerful insight from a wise and senior member of the scientific community who had spent
decades examining the structural and functional aspects of genetic metabolism disorders.

Medicine is now at a turning point. The important role of a broader application of the structure-function model in
health care is gaining recognition and it may, in fact, be a defining principle that can guide the development of
future health care systems. This concept can be applied to the search for solutions to complex health-related
issues that span across multiple domains: molecules, cells, tissues, organs, and organ systems. I believe it can
equally be applied to a search for solutions to the social issues of our modern era: individual empowerment,
relationships between and among people, relationships between and among nations, and population-based
global concerns.