On Metabolism

Metabolism is the set of life-sustaining chemical reactions in organisms. The three main purposes of metabolism are: the conversion of food to energy to run cellular processes; the conversion of food/fuel into building blocks for proteins, lipids, nucleic acids, and some carbohydrates; and the elimination of nitrogenous wastes.

Properties of metabolism - type of nutrients processed, type of metabolites produced, metabolic rate (or ins, outs, and how fast they go) - are indicative of cell types, activities, and, often, pathologies. A better understanding of metabolic processes can enable our ability to address a number of pathologies such as cancer, diabetes, inflammation, and aging.

While a lot of research has been focused on understanding the genetic causes of disorders in the hope to fix problems at the gene level, a number of disorders cannot be solved using this method alone — whether because they are multigenic or of unknown genetic cause. As a response, a growing trend has been to characterize pathologies according to their metabolic phenotypes. New techniques have allowed clinicians and researchers to measure more accurately a wider array of metabolites and nutrients, shedding new light on biology and disease.

Several clear themes have begun to emerge from this metabolic-centric work:

1/ Obesity and Metabolic Disorders have “come of age.”
There is a growing consensus that reprogramming the molecular physiology of Obesity (and related metabolic disorders and co-morbidities) demands more than simple lifestyle modifications. Prior to the American Medical Association’s drive to classify the condition as a “disease” in 2013, no anti-obesity therapies had been approved by the FDA from 1999 to mid-2012 and most major pharmaceutical companies had abandoned the space entirely after high-profile failures in the early 2000s. In the years since, new insights into metabolic and genetic parameters of the disease—many invariant to diet and exercise—have enabled a number of new drug programs, and we believe that we are in the early stages of a new era of pharmacological, diagnostic, and behavioral innovations to combat the medical problem of Obesity. We believe that many of the same trends that have transformed other disease areas over the past 20 years—including ‘omics-enabled precision medicine, biomarker-driven clinical trials, and new therapeutic modalities—are now shaping diseases of metabolism.

2/ Metabolic insights will continue to accelerate the development of therapeutics in areas outside Obesity.
As our understanding of the centrality of metabolism in health and disease has grown, so too has our appreciation of the nuanced metabolic differences among cells, tissues, and organ systems within and across humans. The FDA’s approval of enasidenib in 2017 validated the idea that targeted modulation of cellular metabolism could arrest cancer cell progression, unleashing a growing wave of innovation in the field. We are now seeing similar strategies to address conditions beyond cancer—including “immuno-metabolism” approaches to immunology and autoimmune disorders, as well as diseases of aging more broadly.

3/ Human health is animal health.
Metabolic insights—more so than in many other areas of biology—are shared among humans, companion animals, and livestock, creating opportunities to de-risk expensive human development of relevant products.

4/ Pharmaceuticals come first, but non-pharmaceutical products follow closely.
In the experimental sciences, we often seek to understand systems by perturbing them. In biology, these perturbations typically take the form of various diseases that pharmaceutical companies seek to correct with targeted therapies. The insights gleaned from these targeted strategies have increasingly laid the groundwork for non-pharmaceutical interventions—behavioral changes and nutritional products foremost among them—that are relevant in combination with targeted therapies and more broadly across wider segments of the population.

5/ Promising new business models are emerging on top of these novel therapies.
The success of emerging therapies—pharmacological, nutritional, behavioral—will hinge on our ability to deliver them to the right patient at the right time. Thus, novel diagnostics and telemedicine-enabled platforms are beginning to emerge that will support more targeted and effective access to treatment for metabolic conditions.

– Jonathan Friedlander, PhD & Geoffrey W. Smith



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