Metabolism and Medicine: The Physics of Biological Engines

Book Preface

How can one explain the rich interconnectedness, which defines the amazing organizational complexity at many hier-archical scales of a living system, and especially the human being? Looking beyond the awe-inspiring structural architec-ture of biological systems, we see an even more impressive functional efficiency. To fully appreciate the latter, one must use the conceptual tools of physics because of the importance of concepts such as energy and force in analyzing metabolic processes. The second law of thermodynamics essentially states that energy dissipates as heat uniformly over time, with associated randomness or diffusion of particles. It is almost magical that the second law is abrogated in living systems, and that alone was the reason why the famous physicist Erwin
Schrödinger devoted an entire book entitled What Is Life to the elucidation of this scientific puzzle.
One aspect of this explanation speaks to the manifestations of quantum physics in living systems that occur at many levels of biological organization. While the second law of thermody-namics is empirical and embodies the tendency of all closed physical systems toward maximum disorder, the first law of thermodynamics is an expression of the fundamental principle of the indestructibility of energy in all physical processes. In the context of physiology, it accounts for the source of a calorie, rooted in Einstein’s famous equation E = mc2, whose practical consequence is that solar nuclear fusion and fission processes release energy that is captured on Earth within the chemical bonds of nutrients of plants. This universal solar energy source is converted into the chemistry of food contained in plants, and then undergoes another quantum transformation in liv-ing cells, becoming the biological currency of ATP, efficiently produced in the process of oxidative phosphorylation along the electron transport chain of mitochondria.
Furthermore, the phenomenon of quantum metabolism shows that our metabolism is a quantum manifestation of bio-logical energy production. Although it is a fundamental quan-tum phenomenon underpinning the deeply entangled healthy state of physiology and psychophysiology, it is likely not the only one. The interdisciplinary perspective which views “biol-ogy as really chemistry” and “chemistry as really physics” underscores the unavoidable recognition that the first and sec-ond laws of classical thermodynamics alone cannot explain the beautiful and exquisite design and potential that is intrinsic in human physiology. This entanglement of human physiology is rooted in metabolism and metabolic pathways that fundamen-tally distinguish living states from nonliving physical matter. The further any biological system can be moved away from the nonliving state—that is, separating it from death—the greater the metabolic entanglement which represents the intercon-nectedness defining complexity. The greater that complexity, the greater in parallel the metabolic health capable of pro-viding the necessary bioenergetic resources with maximum efficiency. Conversely, the loss of ATP-producing capacity achieved in the process of oxidative phosphorylation parallels mitochondrial dysfunction, and generates the excess heat from the chemistry of the rich organizational complexity. This latter effect is the manifestation of the breakdown of organization and often the beginning of metabolic disease and an associ-ated pathology. Hence, mitochondrial dysfunction parallels senescence and age-related disease states. This is a deteriorat-ing feed-forward, positive feedback destabilizing process that accelerates biological aging.
This forms the metaphorical basis for the application to the biology of physical ideas encapsulated in special theory of relativity, systems biology, chaos theory, and the theory of phase transitions. In addition to purely intellectual insights, this interdisciplinary cross-fertilization offers a promise of potential therapeutic advances with an ultimate goal of achieving phase transitions from diseased to healthy attrac-tor states and prolonging longevity characterized by dilating time. This can be accomplished, in practical terms, by reduc-ing the inflammatory and redox disturbance. An additional illustrative physical metaphor for a better understanding of biology is that aging and disease states are manifestations of an incinerating process, which degrades the quality of meta-bolic energy in the entropy-generating process conforming to the second law of thermodynamics. In particular, the energy that is locked in the chemistry underlying the organizationally complex biological structure can be viewed as representing negative entropy (or information). This state is highly func-tional, physiologically adaptive, and often coupled to deep levels of consciousness. However, it ultimately succumbs to the destructive force of nature that seeks the maximum entro-pic state that is characterized by loss of structure, function, and hence information.
It is hoped that the implications of this new way of think-ing for the field of medicine will be transformative. First and foremost, it should be acknowledged that the field of physics is not only the most fundamental branch of science from which biological systems derive, but also a far more mature scientific discipline, rooted in mathematics as its language and logic as its modus operandi. Physics has a centuries-old history and a time-tested methodology that is a foundation of the scientific method in general. The very nature of the hypothesis in phys-ics is consistent with the goal of asymptotically approximating the truth. Fundamentally, it involves searching for flaws and counter-examples to falsify the starting hypothesis, rather than validation—the latter having the aim of proving that the origi-nator of the hypothesis was right while the former is attempt-ing to bring one closer to the truth. The latter may be the way the legal profession or the political class operates, while the former is the first rule of scientific methodology. The objective of this method is to evolve the hypothesis, by gradually remov-ing incorrect assumptions, and bringing our state of knowl-edge ever closer to objective truth.

The understanding of biological systems using insights from physics is, therefore, hoped to provide new models for find-ing solutions to healthcare problems. The goal, in general, is to slow the rate at which the aging process advances, i.e. causing an effective dilation of time invoking the metaphor of special relativity to medicine. The phenomenon of quan-tum metabolism exemplifies a mathematically validated pro-cess highlighting the correlated nature of energy production in a maximally efficient, organized, reduced-entropy state. It is worth stressing that all disease is rooted in dysfunction of the metabolic pathways. Expertise in the area of metabolism is central to clinical decision-making throughout the spectrum of susceptibility or chronic disease states.
There are many ways in which insights from physics can allow medicine to evolve. The dynamic model of a fitness landscape is a general framework for integrating insights from all disciplines—a Nobel Prize–worthy mathematical model that will be shown in this book to be applicable to physiology. We refer to it as the Physiological Fitness Landscape (PFL). However, to date, it has not yet been utilized for either biomed-ical research or clinical medicine. Physicians specialize in the application of science to the clinical setting of patient care, but this application typically involves an art that sits on top of the science, and uncertainty is inherent in the application of broad algorithms of care to a given patient. Improving the applica-tion of science to reduce uncertainty is the goal. Therefore, it must be recognized as a barrier that physicians—and certainly clinicians—speak a different language than the non-applied basic scientists. Bridging this divide is a very challenging but meritorious pursuit in the interest of public health. The science and the tools exist to shift the direction of clinical healthcare towards empowerment, but this goal requires an interdisciplin-ary assimilation from diverse areas of expertise, functionally related in such a way that the integration of the parts provides a greater whole.
This book describes the building blocks of understand-ing from a reasonable but not high-level technical language viewpoint, employing the perspective of a clinical physician. It attempts to assimilate concepts from five specific branches of physics relevant to biology and medicine, namely, biophys-ics, classical electromagnetism, thermodynamics, systems biology, and quantum mechanics. This framework includes the knowledge base afforded by molecular biology and bio-chemistry, integrated into an accessible model that invokes the dynamical fitness landscape. This endeavor is expected to provide a broader therapeutic perspective on a clinical scale, useful for biomedical research and ultimately helpful in the improved execution of patient care medicine. Hopefully, it does not lose the fidelity of meaning of the concepts described, so that it engages the interest of basic scientists seeking a per-spective to clinical medicine. These physical concepts are pre-sented in an accessible way in the first four chapters of the book. The final chapter is less technical and more clinically oriented, and highlights the fitness landscape concept applied for understanding susceptibility and disease states in the con-text of the stress response, allostatic and homeostatic param-eters, and pathological states of disease. Importantly, insulin resistance/endogenous hyperinsulinemia appear to be inextri-cably linked to the stress response, underpinning a unifying model of chronic disease integrated into the framework of the fitness landscape. Identifying extrinsic and intrinsic control parameters to susceptibility states, as well as to disease states, provides the landscape to which therapeutic strategies can be applied. This is a highly dynamic construct whereby the strat-egy changes according to the stage and trajectory of the sus-ceptibility or disease state, that is, the attractor state.
Also important is the concept of criticality and the thresh-old at which a disease becomes irreversible. Conversely, the Physiological Fitness Landscape approach also allows us to analyze, qualitatively and quantitatively, the existence of a potential phase transition toward a normal state, and the opti-mal path to achieve it. Crucially, irreversibility depends on the available intervention. For example, diabetes that was consid-ered irreversible long-term, based on lifestyle and pharmaco-logically available interventions due to insulinopenia relative to the degree of peripheral insulin resistance, became revers-ible in the sense of achieving remission with the emergence of bariatric surgery. Application of the concepts of intrinsic and extrinsic control parameters, order parameters, susceptibility states, and the notion of criticality are relevant in the context of bariatric surgery for metabolic disease, providing insights that stem from the analysis of the associated fitness landscape.
A combination of lifestyle, existing polypharmacy, and metabolic surgery should be capable, including in refractory cases, of promoting phase transition of the manifestations of metabolic diseases such as central obesity, metabolic syn-drome, diabetes, and even prediabetes states. Discussions of traditional pharmacologic therapy of metabolic disease are well-described in existing endocrinology and other literature and are promulgated by the American Association of Clinical Endocrinologists (AACE), the Endocrine Society, and the American Diabetes Association (ADA). A purpose of this book’s content is to show a limited number of novel thera-peutic strategies to fundamental targets of metabolic disease. These targets are control parameters to the order or fitness of human physiology or pathophysiology. They are discussed (and some are illustrated) in the multidimensional and dynam-ical (changing with time) fitness landscape model, which we are espousing as a clinical tool and even as a paradigm shift in medicine. These targets include the machinery of oxidative metabolism carried in mitochondria and insulin signaling. There is an emphasis on the stress response that orchestrates allostatic neuroendocrine and autonomic nervous system changes enlisted to preserve organismic health by maintain-ing biochemical parameters within tight homeostatic ranges. Higher-order control parameters, such as those that maintain or threaten the resilience of the stress response, are described, too. Also discussed are the limited number of truly extrinsic control parameters, as well as intrinsic control parameters (called secondary order parameters) defined with reference to a particular disease state. We also discuss in this book how the primary order parameters characterize the state of human health or disease, alternately stated as the state of biological aging compared to chronological aging. Within the framework of the stress response, allostatic swings of the CNS-mediated neuroendocrine and autonomic nervous system are acutely adaptive for calibrating bioenergetic priorities and immune function, and ultimately preserving homeostatic parameters Prologue
and vital organ system function. There is an emphasis cen-trally on abnormal perceptions that drive the chronic and exaggerated stress response, and ultimately, pathophysiology. Peripherally, the importance of the gut microbiome and how it affects the gut endocrine system and bile acid metabolism in terms of metabolic health and chronic disease should be stressed. These are control parameters that also can be studied vigorously and dynamically in the model of the Physiological Fitness Landscape, on the basis of susceptibility to accelerated aging or a given chronic disease, as well as the reversibility of the susceptibility state or the chronic disease.
The Physiological Fitness Landscape model is highly appli-cable to precision-based medicine, and invokes available data from computational-based bioinformatics, which in turn uti-lizes genomic, proteomic, metabolomic, microbiomic data, and so on. The role of computers in medicine undoubtedly will shape the direction of the practice of medicine. The fit-ness landscape model is a mathematical one that will naturally emerge with the evolution of computers in medicine. Thus, it is historically timely to invoke the model of the Physiological Fitness Landscape, which demands an interdisciplinary coor-dination of computer scientists, mathematician physicists, bio-physicists, and clinicians.
It is also critical that while connecting patient care to basic science, the intuitive non-algorithmic personal connection and the decision-making that recognizes patient fears, expecta-tions, biases, and belief systems are not lost. The patient–phy-sician relationship is powerful and must be prioritized to avoid losing this necessary therapeutic and traditional perspective of clinical healthcare with the Watson IBM computer already being utilized for diagnostic purposes with some success in the free market. Furthermore, medical training of physicians is increasingly channeling students towards either basic or clinical tracks, which reduces the number of years of training, and highlights the risk of the applied science of the medical profession being replaced by computers and essentially tech-nicians. This risk is real and threatens the quality of health-care delivery. There are advantages to computational medicine with the application of precision care, however, the high-level expertise and personal connection of physicians needs to be preserved as foundational to the expectations and therapeu-tic nature of healthcare. The Physiological Fitness Landscape provides a proactive model, and a framework capable of inte-grating valuable contributions in an interdisciplinary assimila-tion, while preserving the integrity of the skills and expertise of the clinical physician.