Metabolism and Medicine

The Physics of Biological Engines (Volume 1)

Brian Fertig

• Publisher: CRC Press
• Year: 2022
• ISBN:
  9781000472158
• Edition: 1
• Topic: Biowissenschaften
• Subtopic: Biophysik

Chronic disease states of aging should be viewed through the prism of metabolism and biophysical processes at all levels of physiological organization present in the human body. This book describes the building blocks of understanding from a reasonable but not high-level technical language viewpoint, employing the perspective of a clinical physician. It brings together concepts from five specific branches of physics relevant to biology and medicine, namely, biophysics, classical electromagnetism, thermodynamics, systems biology and quantum mechanics.

Key Features:

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• Broad and up-to-date overview of the field of metabolism, especially connecting the spectrum of topics that range from modern physical underpinnings with cell biology to clinical practice.

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• Provides a deeper basic science and interdisciplinary understanding of biological systems that broaden the perspectives and therapeutic problem solving.

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• Introduces the concept of the Physiological Fitness Landscape, which is inspired by the physics of phase transitions

This first volume in a two-volume set, primarily targets an audience of clinical and science students, biomedical researchers and physicians who would benefit from understanding each other's language.

Preface to Volume One

Dear reader,

First of all, I wish to express my appreciation to you for deciding to invest your time and money to read my book. The potential audience to which you belong spans a wide range of backgrounds from clinical physicians and other health care providers, to medical students and experts from a diversity of basic scientific disciplines as well as laypersons interested in biomedical research. Being aware of this, I made a concerted effort to meet increased demands for clarity and wherever possible simplicity, without compromising precision. Due to the interdisciplinary nature of this work, it covers many fields of natural and life sciences that have a profound impact on our current and future understanding of health and disease. I do hope that each reader will learn something new and exciting in these two volumes covering both basic and applied aspects of metabolism.

As you embark on this intellectual journey with me, it is important that I explain to you the compelling motivation that inspired me to write this book series. The reason has to do with the question of what motivates one to become a physician in the first place. There are three major drives that affect our decision-making: autonomy, mastery, and purpose. Autonomy allows one to decide within meaningful limits what, when, how, and with whom we engage to do things together. Mastery is a drive that equates to the motivation to improve. Mastery of skills has an asymptotic learning curve based on the notion that perfection is only hypothetical but improvement is our constant objective. For example, with each patient experience, as an endocrinologist, I learn something new every day, no matter how subtle, about reading between lines to better understand both fears and expectations. This progressively enhances the fulfilling nature of patient care for both the patient and the provider. However, no matter how many patients one sees over a career, there is always more to learn. As eloquently stated by Daniel Pink, “autonomous people working toward mastery perform at very high levels”.¹ Further, Pink beautifully goes on to describe purpose stating that, “those who do so in service of some greater objective can achieve even more. The most deeply motivated people—not to mention those who are most productive and satisfied—hitch their desires to a cause larger than themselves”. The more of these elements of autonomy, mastery, and purpose a physician has, the more engaged they become, which is tantamount to performance. One final and crucial quote of Pink paints an accurate picture, “when it comes to motivation, there’s a gap between what science knows and what business does. Our current operating system is built around external carrot-and-stick motivators that don’t work, and often do harm. We need an upgrade”. Lastly, Charles Black powerfully states “big vision and small daily steps = unexpected success”.² These are the quotes that resonated with me as I made efforts toward the completion of this work.

The two books Metabolism and Medicine: The Physics of Biological Engines and Metabolism and Medicine: The Metabolic Landscape of Health and Disease can be viewed as a primer for a scientific foundation that is aimed to guide students, physicians, and other healthcare professionals (applied scientists), as well as the larger family of basic interdisciplinary and computer scientists, and to serve as a resource for the pursuit of these three basic drives.

Ten years ago, at the age of 50 and having practiced medicine for over 20 years, my feelings of fulfilment were ambivalent. While the kinship, beautiful memories, and real privilege to serve patients and their families over the years was intrinsically rewarding, there was also an unspoken void I experienced practicing medicine. The modus operandi of medicine can be briefly summarized as based on differential diagnosis through the use of pattern recognition, which is algorithmic, and to a large extent still intuitive. I felt disheartened about this state of affairs on two fronts. First, in order to truly help people live healthier and longer lives, we needed to know more about both the individual patient and the mechanism behind the disease. The prototypical process of patient care fundamentally is too generic, failing to invoke Big Data that includes metabolomics, proteomics, microbiomics, genetic uniqueness, and its epigenetic expression. Integrating Big Data and performing the necessary analytic tools is the next level of complexity that still awaits full implementation in medical practice. Perhaps most importantly, we need a quantitative model guiding our decision making; a model that integrates and maps out this vast amount of individualized data, and the patient’s changing trajectory of the state of health over time. Additionally, essential in this process is to know more about our patients in order to understand the background to the disease they succumbed to. Included in the inadequacies is also the amount of time allocated to each patient, which is insufficient to delve into patient history beyond a few superficial questions. Next, in order to answer “the why”, i.e. the root cause of the patient’s state of health, we also need to know more both in terms of etiology and science. This is indeed the most important challenge facing medicine in the near future.

While the quest on each front is different, their solutions are intricately entwined and interdependent. Unlike any other area of human activity, health care is inherently complex and requires a multitude of fields of knowledge beyond any single individual’s intellectual capabilities. Therefore, implementing new ideas in medical practice will require a much broader health care team of interdisciplinary contributors than is currently the case. A major inadequacy in the way healthcare is administered and delivered today is the fragmentation of medical disciplines. A multitude of specialists in each subfield of medicine practice their craft in what can metaphorically be described as “splendid isolation”. This means that interactions between specialists are often limited to one-directional referrals and even proper patient data transfer, let alone data integration, is not commonplace. Instead, one would like to see a deeply interwoven network of multi-disciplinary interactions with other fields of medicine and interdisciplinary collaboration with fields outside medicine. In my opinion, this is one of the key aspects that can be successfully addressed by providing a comprehensive model of the patient’s physiological state using a precision personalized scale of medicine. This faces the basic and redoubtable challenge of modeling the virtually infinite complexity of the fabric of biological systems such as the human body. This approach is still very nebulous and to progress it to the next stage we need major conceptual advances, which in my opinion are within our reach.

Therefore, I am very optimistic that the answers to these questions are available and can be implemented in medical practice within a reasonable time frame. In fact, the Physiological Fitness Landscape (PFL) model proposed in this book provides a tangible framework and vision on which to build a new horizon of transformative potential for the future of medicine. In this connection, deep interdisciplinary perspectives of both basic and applied sciences are integral to understanding the parameters of the PFL. There is a robust number of these model parameters and even more data points (hundreds of thousands to a million) that need to be introduced into basic “rules” to simplify the sheer complexity of the system and to be integrated into a PFL. Additional guidance gained from the use of artificial intelligence models such as IBM’s Watson Oncology can trim down the numbers of essential parameters to a manageable few. To accomplish these goals, we’ll require a very large basic interdisciplinary scientific team of physicists (specializing in biological thermodynamics, electromagnetism, complexity theory, biophysics including quantum biology, and mathematical and computer physics), biological chemists, molecular and cell biologists, physiologists, stress experts, and metabolic biologists. We will also require multidisciplinary sub-specialties of clinical medicine that include endocrinologists, cardiologists, etc. Finally, teams of scientific administrators will be necessary to collate, steer and attach all the information into each individual PFL. In order to maintain cost efficiency for delivering individualized care on a wide public health scale, it will be essential to organize a huge number of “data assembly lines” that can accommodate demand with minimal waste. All of this can be done because if there is a will, there is always a way.

I hope that this two-part series of books can provide the broad outlines of what needs to be integrated in the future of medicine as a more rigorous discipline of applied science with enormous importance to the knowledge- and information-driven society of tomorrow. Volume 1 introduces each of the major scientific disciplines in the context of medicine while Volume 2 is more focused on translational medicine in the context of metabolic physiology. The combined information of the two volumes attempts to answer the questions of etiology, “the why”, and the sequence of physiology that allows the generation of optimally conducted PFLs. The latter can ultimately give the answers to which interventions, in a time-dependent fashion, can prevent and possibly even reverse disease, and accordingly allow maximum health span and longevity of each individual patient. For the sake of simplicity, we illustrate the concept of the physiological fitness landscape where control parameters of health and disease are represented as horizontal axes and the vertical axis maps the physiological (or metabolic) fitness function measured in response to them. Valleys in the stress response plots correspond to stability regions while peaks and ridges delineate boundaries of these physiological stability zones. Since almost all chronic diseases of aging share the same control parameters, a common framework offered by the PFL model proposed here is more appropriate than a fragmented approach prevalent today. Additionally, three critical aspects on the periphery of modern medical interventions: chronophysiology, microbiota, and prolonged stress, are entering the mainstream of medical research thanks to advances in understanding how they affect our health. Their inclusion within the physiological fitness landscape, whose methodology is elaborated on in the second volume of this series, offers a practical approach to finding optimal solutions for healthy aging and precision-medicine therapies for age-related diseases.

I believe the solutions emerging from the integration of the new advances in science and technology into health care will have an enormously positive impact not only on chronic diseases but also on genetic diseases, developmental disorders such as cerebral palsy, and indeed all aspects of medical care and prevention. The trajectory of health and disease as well as the intricate contextual nature of pharmacologic and other therapeutic interventions on metabolism and physiology is part and parcel of the approach advocated here. We live at a time of an unprecedented pace of change in all aspects of our lives. What was unimaginable a decade ago is a new normal today. Using smartphones, almost everybody on the planet can store and access reams of information accumulated over centuries by humanity. This information revolution will undoubtedly transform health care sooner than we think. It is my belief that real-time, precise, and personalized monitoring and optimization of our state of health will be the new normal in our lifetime. Many of the building blocks of this transformation are discussed in these two volumes.

My hope is that this book series represents a small step toward opening the curtain to fill the two major voids stated above for future generations of professionals engaged in the practice of medicine. If this effort is not in vain, I will consider my mission to have been worthwhile. Indeed, there is no greater magnanimous way to dedicate motivation and purpose than the goal of helping humankind live without the burden of helplessness against premature diseases of physiology. Moreover, reaching out to present and future medical students is particularly important to me since they are most likely to embrace positive change and carry the torch of progress. However, medical education and educators must not stagnate but, in tandem with students, evolve, embrace new ideas, and be open to cross-fertilization with other fields of science and technology. As this is always a collective endeavor, feedback from readers like you will undoubtedly result in future improvements. Since this series of books is firmly grounded in several academic disciplines requiring some intellectual investment on your part, dear Reader, I’d like to encourage you to persevere on this journey by remembering the words of wisdom Theodore Roosevelt wrote:

Nothing in the world is worth having or worth doing unless it means effort, pain, difficulty … I have never in my life envied a human being who led an easy life. I have envied a great many people who led difficult lives and led them well.

For me personally, the process of research, collaboration, discussions with numerous scientists, students, colleagues, and lay people, learning, and writing has been very gratifying. It amounted to an investment of more than ten years of my life. For my wife, Eileen, and my son, Matthew, it was their ultimate sacrifice, which is the only part of this endeavor whose cost I can never reclaim and which will leave me with lasting regrets. The endless support and the beauty in the souls of my loved ones allowed me to persevere during the ups and downs of working on this opus magnum. Life choices are often made but not voluntarily, on both my part and theirs. With ten years gone like the blink of an eye, my conscience will always be challenged as to whether this achievement of enduring “effort, pain and difficulty” balances the real-life sacrifices of my two rocks, to whom these books must be dedicated. As a member of the noble profession of physicians, the guiding light of helping humanity through our work has allowed me to continue this task, overcoming challenges along the way.

I invite you to join me on this exciting and fulfilling exploration of the new horizons where multidisciplinary science meets the future of medicine. It’s a bright future whose outlines we can already see and it makes the expectation of things to come so thrilling.

Respectfully yours,

Brian J. Fertig, M.D.

Piscataway, NJ

References

1. 1. Pink, Daniel. (2011). Drive: The Surprising Truth About What Motivates Us. Riverhead Books.
2. 2. Black, C. (2020, May 21). The Pursuit of Autonomy, Mastery, and Purpose in Medicine. Op-Med. https://opmed.doximity.com/articles/the-pursuit-of-autonomy-mastery-and-purpose-in-medicine

Prologue

How can one explain the rich interconnectedness, which defines the amazing organizational complexity at many hierarchical scales of a living system, and especially the human being? Looking beyond the awe-inspiring structural architecture 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 thermodynamics 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 living 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 biological energy production. Although it is a fundamental quantum phenomenon underpinning the deeply entangled healthy state of physiology and psychophysiology, it is likely not the only one. The interdisciplinary perspective which views “biology as really chemistry” and “chemistry as really physics” underscores the unavoidable recognition that the first and second 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 fundamentally 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 interconnectedness defining complexity. The greater that complexity, the greater in parallel the metabolic health capable of providing ...