Understanding Structure and Function as a Model for 21st-Century Health Care

Abstract

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.

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.^9,10

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.^13,14

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.^16,17

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.¹⁸

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.^20-26 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.^20,21 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.^22-23

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.”²⁴ 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.²⁵

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.

Biography

Jeffrey S. Bland, PhD, FACN, FACB, is the president and founder of the Personalized Lifestyle Medicine Institute in Seattle, Washington. He has been an internationally recognized leader in nutrition medicine for more than 25 years. Dr Bland is the cofounder of the Institute for Functional Medicine (IFM) and is chairman emeritus of IFM’s Board of Directors. He is the author of the 2014 book The Disease Delusion: Conquering the Causes of Chronic Illness for a Healthier, Longer, and Happier Life.