Systems Biology Meets Functional Medicine

Abstract

Through experiences gained over the past 3 decades, the development and application of the Functional Medicine model has demonstrated its ability to improve clinical decision making in the treatment of patients with complex chronic disease. The Functional Medicine model provides a system that effectively translates the emerging understanding of the gene-environment regulation of the structure and function of the individual into clinical practice.

The late 1980s was a remarkable time in the development of medicine. This was the era in which we witnessed advances in biometrics, genomics, informatics, and cellular biology. The exciting intersection of these diverse fields provided the world with mechanistic insights into many diseases that had previously been described but not fully understood. This intellectual environment, layered on top of decades of groundbreaking discoveries that marked the first half of the 20th century, was the impetus for many people in medicine to start thinking ahead to the next frontier and ask a singular question: what will healthcare become in the 21st century?

By 1989, I was eager to focus on the future, and I was not alone. Susan Bland, MA, had spent a decade organizing and hosting medical meetings, and she felt it was time to sponsor a collective gathering of innovative professionals who were connected through their interest in finding a better way to manage the complexity of chronic disease. This foundational meeting was attended by a dedicated group who had overlapping but diverse skills in bioscience and medicine. We came together in Victoria, British Columbia, Canada and from our efforts the concept of Functional Medicine was born. These are the colleagues I would like to honor and acknowledge for their participation and contributions:

• Jeffrey Bland, PhD, Program Chairman (Gig Harbor, Washington)

• Susan Bland, MA, Organizer (Gig Harbor, Washington)

• David Jones, MD (Oregon)

• Scott Rigden, MD (Arizona)

• Joseph E Pizzorno, Jr, ND (Seattle)

• Leo Galland, MD (New York, NY)

• Sidney Baker, MD (Sag Harbor, NY)

• Wayne Matson, PhD (Boston, Massachusetts)

• Graham Reedy, MD (Enumclaw, Washington)

• Peter Wilhelmsson, ND (Sweden)

• Darrell Medcalf, PhD (Gig Harbor, Washington)

• Jean Munro, MD (England)

• Alan Hadley, MD (Australia)

• J Alexander Bralley, PhD (Georgia)

• Peter Madill, MD (California)

• Hakeem Lewis, ND (Ohio)

• Jeff Katke (California)

• Martin Lee, PhD (North Carolina)

• Stephen Barrie, ND (North Carolina)

• Stephen Paul, PhD (California)

What did we look like in that room so long ago, having a whiteboard discussion about the ideal 21st-century healthcare system and how medicine might evolve? I recall that we focused initially on the history of molecular medicine, the promising future of systems biology thinking, and how both related to patient-centered care. We recognized the contributions of legendary figures like Archibald Garrod, who discovered alkaptonuria—the first genetic metabolism disease—at the turn of the 20th century, which led to recognition of the concept of chemical individuality.1 A few years before our Victoria meeting took place, I had completed a research sabbatical at the Linus Pauling Institute of Science and Medicine. The opportunity to work with Linus Pauling, PhD, for 2 years had been a transformational experience in my life. Dr Pauling coined the term molecular disease and published a landmark paper in Science in 1949 that was titled “Sickle Cell Anemia: A Molecular Disease.”² To this day, scientists and historians credit this paper with establishing our understanding of the relationship between the structure of a protein and its influence on the function of the individual.³

Roger Williams, PhD, was a colleague of Dr Pauling who had written about the important relationship between genetic structure and function in a 1948 paper also published in Science, “Biochemical Approach to Individuality.”⁴ Dr Williams and Dr Pauling shared certain life experiences and their respective work had a unique juxtaposition. At different times, each served as a faculty member of the Chemistry Department at Oregon State University. Dr Williams went on to develop the concept of genetotrophic disease, which he defined as a disease that occurred when the proper intake of specific nutrients required to meet a person’s unique genetic needs was absent.⁵ In 1968, Dr Pauling put forth the concept of orthomolecular medicine in a paper published that year in Science. He wrote: “Function of the brain is affected by the molecular concentrations of many substances that are normally present in the brain. The optimum concentrations of these substances for a person may differ greatly from the concentrations provided by his normal diet and genetic machinery.”⁶ In Victoria, these powerful concepts developed by Dr Linus Pauling and Dr Roger Williams guided our thinking. These brilliant pioneers—in spirit—contributed greatly to the development of principles that underpinned the conceptual framework of Functional Medicine and its relationship to systems biology.

Systems biology, as a field, is most closely linked to Leroy Hood, MD, PhD, and his work on predictive and preventative medicine. In 2004, Dr Hood proposed the following: “Systems approaches to disease are guided in the idea that disease-perturbed protein and gene regulatory networks differ from their normal counterparts.” He described his work as “pursuing the possibility that these differences may be reflected by multi-parameter measurements of constituents of the blood.”⁷ The concept of biochemical individuality, when amplified by advances made in elucidating the systems biology of disease, has not only led us to a better understanding of the origin of complex disease, but has also made clear the potential of more precise treatment based on emerging knowledge about the structure-function relationship.^8,9

Today it seems very clear that a scientific systems approach to medicine might bolster the development of a patient-centered focus on individualized wellness.¹⁰ The structure-function concept can now be applied to the understanding of a person’s disease from a systems biology perspective. Furthermore, this information can be combined with actionable clinical entry points to improve an individual’s function through personalization of their lifestyle, diet, and environmental interventions.^11,12

The Functional Medicine Concept: From Origins to Impact

Back in Victoria, our inaugural group of nascent thought leaders recognized that medicine was perched on the threshold of a major paradigm shift. We felt that the gene-environment connection to disease would become a driver for change in the personalization of assessment, prevention, and treatment of chronic disease. As it happens, we were ahead of our time as individuals and prescient as a collective. In 2004, Nabholz and von Overbeck, researchers with the Swiss Reinsurance Company in Switzerland, wrote the following: “In the assessment of mortality and morbidity risk, the ability of the family history and genetic test results to predict the age of occurrence, severity, and long-term prognosis of ‘genetic’ diseases is important. An increasing number of gene-gene and gene-environment interactions have been demonstrated in a number of monogenetic Mendelian diseases. These interactions can significantly modify the clinical presentation (disease phenotype) of diseases previously regarded as purely ‘genetic.’ As a result, ‘genetic’ diseases can be positioned in a continuum between classic Mendelian and complex disease where the extremes, pure genetic or solely nongenetic, do not exist. The position of any given disease in this continuum is defined by three components: the major gene(s) contributing to the phenotype, the variability added by modifier genes and the significance of environmental factors influencing the phenotype.”¹³

In 2018, I published a detailed article—“The Natural Roots of Functional Medicine”—that I feel could be characterized as the definitive origin story of Functional Medicine.¹⁴ I advocated for use of the word “function” in this field that I am credited with founding because function represents a process, while disease is simply a pathological descriptor of an endpoint. Function at any level, from the whole organism to the molecular components of the cell, can improve or decline depending on the interaction of the genetic machinery of the individual with their environment, lifestyle, and diet. The Functional Medicine model for health care is concerned less with what we call the dysfunction or disease, and is more about the dynamic processes that produced the dysfunction.¹⁵ Over the years, my thinking about function has continued to evolve. I have come to think about function in terms of four separate subgroups: physical, metabolic/physiological, cognitive, and behavioral/psychological function. Significantly, these subgroups can be quantified by using a Functional Medicine assessment of a patient’s antecedents, triggers, mediators, and signs/symptoms that relate to dysfunctions in each of the four categories.¹⁶

Functional Medicine can be viewed as an operating system for integrating systems biology approaches to health care into a system that can be clinically applied to the management of complex chronic disease.¹⁷ In 2016, Patrick Hanaway, MD, a respected leader in the Functional Medicine community, published an important editorial titled “Form Follows Function: A Functional Medicine Overview,” and he wrote the following: “Functional Medicine is 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. Functional Medicine uses a unique operating system and personalized therapeutic interventions to support individuals in achieving optimal wellness.”¹⁸

Over the years—the decades, really—it has been gratifying to watch the Functional Medicine movement grow. It’s sometimes hard to believe that the small conclave that assembled in Victoria has grown to have global reach and impact. But are we really innovators or are we simply curators of a concept so enduring that its roots stretch farther back than any of us ever imagined?

In recent years it has emerged that Willoughby F Wade, BA, MB, may have been the true first pioneer of Functional Medicine. Not long ago, while tracing the intellectual lineage of Functional Medicine, a colleague came upon an article titled “Clinical Lecture on Functional Medicine” that Dr Wade published in Lancet in 1871.¹⁹ Discovery of this early work reminded the founding members of The Institute for Functional Medicine (IFM) that there is very little that is truly new. Rather, it is more often the case that old concepts evolve with new discoveries. Here is a modern-day synopsis of Dr Wade’s 19th century insights:

• The general approach in medicine is that the practitioner attaches a greater importance to physical diagnosis, which seems to be an end in itself, than to treatment of its cause.

• The most successful practitioners of medicine often treat the symptoms of the patient as their principal objective, but this may ignore determination of the origin of the cause of the disease and preempt a focus on treatment of that cause.

• According to Dr Wade, whenever we come to treat a case “we should first of all consider what function of the body it is that is improperly performed.”

• He also said this: “Every symptom of a disease arises from the imperfect discharge of some function by its appropriate organ.”

• Also: Functional Medicine “leads us to anticipate disease, and so to forestall the enemy.”

• And finally: “What is a disease? In old times people used to think that a disease was some actual entity or thing which had got into the body in some way, and was there lying hidden and secreted, and was to be cast out. We know that there are a few instances of this kind of thing… Here, then, I say, is the highest justification for all treatment being based upon the principle of restoring disordered functions to order, and this it is which I have ventured to term Functional Medicine.”

It is remarkable to now recognize that the group that met in Victoria for meetings about the creation of a Functional Medicine operating system unknowingly reframed Willoughby Wade’s concept from more than 100 years earlier through the lens of advancements made in the biological sciences and medicine during the many decades that had transpired.

Functional Medicine and Clinical Decision Making

Applying the Functional Medicine operating system in clinical practice requires the development of new clinical decision-making skills based upon the gene-environment and systems biology concepts. Joseph E Pizzorno, Jr, ND, wrote an important article in 2012 about the need for a Functional Medicine practitioner not only to focus on the diagnosis of the patient, but also on what the patient’s underlying physiological dysfunctions are, as well as the underlying causes of those dysfunctions.²⁰ This is a complex process that requires advanced training and education, which has historically not been provided in traditional health-education curricula.

In 1991, IFM was founded to help fill this unmet need through its post-graduate medical education courses and research efforts. A number of organizations have taken up the Functional Medicine model over the past decade, including the Academy of Nutrition and Dietetics Section on Nutrition in Integrative and Functional Medicine.²¹ Significantly, case reports and clinical studies have demonstrated the value of the Functional Medicine model in the management of many complex chronic diseases such as osteoarthritis and rheumatoid arthritis, irritable bowel syndrome, and chronic fatigue syndrome.^22,23,24,25 Functional Medicine provides a systematic way of introducing personalized lifestyle intervention based upon evidence-based concepts derived from the advancing understanding of systems biology and genomically-targeted therapy.²⁶ Decisions that are made using the Functional Medicine model are built upon the evidence provided by properly designed randomized trials, nested case studies, and N-of-1 studies.²⁷

Functional Medicine: Standing on the Shoulders of Giants

Advancement of the Functional Medicine concept has been made possible through the support and intellectual contributions of many pioneering researchers and clinicians. In 1996, IFM established the Linus Pauling Functional Medicine Award to be given annually to an individual whose efforts have resulted in uniquely important advances in the development of Functional Medicine. Past award winners include:

• 1996: Glenn Doman, for his work in the development of improving function in brain-injured children

• 1997: David S Jones, MD, for his contributions to the development of the clinical application of Functional Medicine

• 1998: Sidney Baker, MD, for his contributions to the formalism and heuristic model of Functional Medicine

• 1999: Kilmer McCully, MD, for his development of the homocysteine theory of atherosclerosis as a molecular disease

• 2000: Leo Galland, MD, for his development of the patient-centered concept

• 2001: Gerald Reaven, MD, for his development of syndrome X/metabolic syndrome

• 2002: Abram Hoffer, MD, PhD, for his development of the concept of orthomolecular psychiatry

• 2002: David Perlmutter, MD, for his contributions to the development of functional neurology

• 2003: Walter Willett, MD, DrPH, for his contributions to the science of epidemiology and the understanding of lifestyle-related diseases

• 2004: Joseph E Pizzorno, Jr, ND, for his contributions to the development of the science and practice of natural medicine

• 2005: Catherine Willner, MD, for her contributions to the development of functional neurology therapeutics

• 2006: Eleanor Rogan, PhD, for her contributions to the understanding of the metabolism of estrogen and its relationship to dysfunction

• 2007: Michael Holick, MD, PhD, for his discovery of 25-hydroxyvitamin D and work on expanding the understanding of the pleiotropic effects of vitamin D

• 2008: Bethany Hays, MD, for her contributions to understanding unique aspects of women’s hormonal function

• 2009: Mark Hyman, MD, for his contributions to the development of the clinical application of Functional Medicine

• 2010: Dean Ornish, MD, for his pioneering work on the relationship between diet and lifestyle and the reversion of atherosclerosis

• 2011: Bruce Ames, PhD, for his contributions to molecular medicine and its application to the development of micronutrient therapy

• 2011: Jeffrey Bland, PhD (Lifetime Achievement Award), for his work in development of the Functional Medicine model and founding of IFM

• 2012: Mimi Guarneri, MD, for her work in the development of the institutional application of Functional Medicine

• 2013: Alessio Fasano, MD, for his pioneering work in the understanding of the role of gluten in the development of autoimmune disease

• 2014: Randy Jirtle, PhD, for his discovery of and contributions to the field of nutritional epigenetics

• 2015: Robert Rountree, MD, for his decades of contribution as an expert clinician, mentor, and teacher of the Functional Medicine clinical model

• 2016: Toby Cosgrove, MD, for his innovation in medicine and his advocacy for the development of the Center for Functional Medicine at the Cleveland Clinic

• 2017: Patrick Hanaway, MD, for his decades of contribution to the clinical application and teaching of Functional Medicine and its relationship to intestinal immune function

• 2018: Terry Wahls, MD, for her contribution to the development and research of a Functional Medicine approach to the management of multiple sclerosis

• 2019: P Michael Stone, MD, for his contributions to the application of Functional Medicine to the health of the unborn and children

Special acknowledgement and attribution are also very much due to the efforts of David Jones, MD, who contributed to the initial conceptual development of Functional Medicine and served as president of IFM for 10 years. Dr Jones pioneered the development of the clinical program for the implementation of Functional Medicine in collaboration with Laurie Hofmann, MPH. Ms Hofmann held a variety of leadership roles within IFM from its inception onward, first as member of the board of directors, then as a key consultant, moving on to chief executive officer during IFM’s period of unprecedented growth, and finally as chairperson of the board of directors. Under Ms Hofmann’s direction, IFM expanded its partner base, established important strategic relationships, and became recognized as the global leader in Functional Medicine education.

Through experiences gained over the past 3 decades, the development and application of the Functional Medicine model has demonstrated its ability to improve clinical decision making in the treatment of patients with complex chronic disease. The Functional Medicine model provides a system that effectively translates the emerging understanding of the gene-environment regulation of the structure and function of the individual into clinical practice. Functional Medicine has stood the test of time and its future is bright. It is recognized to be a potentially scalable approach to the management of complex chronic disease that is cost-effective. Widespread adoption of the Functional Medicine model will require both a different educational approach to medical therapy (one that is based on systems biology concepts), and a unique organizational and financial system for its application.²⁸

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.