The rich interconnectedness and organizational complexity at many hierarchical scales of a living system leads to its unprecedented functional efficiency. Physical concepts such as energy and force are needed to analyze metabolic processes. While the second law of thermodynamics states that energy dissipates as heat uniformly over time, it is abrogated in living systems by their use of metabolic energy to overcome entropy generation. The universal source of energy on Earth is light emitted by the Sun and converted into the chemical bonds of food molecules contained in plants. It then undergoes a quantum transformation in living cells, becoming the biological currency of ATP, efficiently produced through oxidative phosphorylation in mitochondria. This is a manifestation of quantum physics in living systems. Metabolism represents a fundamental distinction between living states and nonliving physical matter. The further any biological system can be moved away from the nonliving state, the greater the metabolic entanglement in the system’s complexity. Conversely, the loss of ATP-producing capacity parallels mitochondrial dysfunction, and leads to excess heat, entropy production and compromised organizational perfection. Hence, mitochondrial dysfunction is at the core of senescence and age-related diseases. This is a deteriorating positive feedback destabilizing process that accelerates biological aging.
Analyzing physiology from the perspective of physical concepts requires metaphorical inspiration from Special Theory of Relativity, Systems Biology, Chaos Theory and the Theory of Phase Transitions. The resultant interdisciplinary cross-fertilization promises potential therapeutic advances with an ultimate goal of facilitating phase transitions from diseased to healthy attractor states and prolonging longevity. In practical terms, this can be achieved by reducing the inflammatory and redox disturbance involved in metabolic dysfunction. The understanding of biological systems using insights from physics offers new solutions to healthcare problems with the goal of slowing down the aging process. Quantum metabolism exemplifies an ideal state of energy production in a maximally-efficient manner corresponding to perfect health.
There are many ways in which insights from physics enable medicine to evolve. The dynamical model of the physiological fitness landscape (PFL) is a general framework for integrating insights from various disciplines. It is applicable to precision-based medicine and invokes available data from bioinformatics that utilizes genomic, proteomic, metabolomic and microbiomic data. Computers and computational algorithms will undoubtedly shape the practice of medicine. The PFL is a mathematical representation of the patient’s individual state of health that can be used to chart an optimal trajectory for disease treatment given the clinical data available and an evolving course of the underlying disease. This allows a better understanding of susceptibility and disease states in the context of stress response, allostatic and homeostatic parameters and pathological states. For example, insulin resistance/endogenous hyperinsulinemia are inextricably linked to the stress response, underpinning a unifying model of chronic disease. Identifying extrinsic and intrinsic control parameters to susceptibility and disease states provides the landscape to which therapeutic strategies can be applied. In this dynamical construct the strategy changes according to the stage and trajectory of the susceptibility or disease state.
The concept of criticality translates clinically into the threshold at which a disease becomes irreversible. The PFL approach allows us to determine the presence of a potential phase transition to the normal state and the optimal path to achieve it. Crucially, disease irreversibility depends on the available intervention. For example, diabetes was considered irreversible based on lifestyle and pharmacologically-available interventions due to insulinopenia relative to the degree of peripheral insulin resistance, but it became reversible with the emergence of bariatric surgery. A combination of lifestyle, existing polypharmacy, and metabolic surgery should be capable of promoting phase transition of the manifestations of metabolic diseases such as central obesity, metabolic syndrome, diabetes, and prediabetes states.
Novel therapeutic strategies emerge, which address fundamental targets of metabolic disease. These targets are control parameters for human physiology or pathophysiology. They can be represented in the multidimensional and dynamical fitness landscape model, which is proposed here as a clinical tool that represents a paradigm shift in medicine. The specific targets include the machinery of oxidative metabolism carried out 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 maintaining biochemical parameters within tight homeostatic ranges. Primary order parameters characterize the state of human health or disease, alternately stated as the state of biological aging compared to chronological aging. Higher-order control parameters, such as those that maintain or threaten the resilience of the stress response, are also identified. Within stress response, allostatic swings of the CNS-mediated neuroendocrine and autonomic nervous system are acutely adaptive for calibrating bioenergetic priorities and immune function, preserving homeostatic parameters and vital organ system function. Peripherally, the importance of the gut microbiome should also be stressed.
While connecting patient care to basic science, the intuitive non-algorithmic personal connection and decision-making that recognizes patient fears, expectations, biases, and belief systems must not lost. The patient-physician relationship is powerful, and must be prioritized to avoid losing this necessary therapeutic and traditional perspective of clinical healthcare. Furthermore, medical training is increasingly channeling students towards either basic or clinical tracks, reducing the number of years of training, but carrying the risk of the medical profession being replaced by computers and technicians. While advantages of computational medicine are tangible, the high-level expertise and personal connection offered by physicians is foundational to the therapeutic nature of healthcare. The PFL approach presents a framework integrating interdisciplinary science with the irreplaceable skills and expertise of the clinical physician.
Physicians specialize in the application of science to the clinical setting of patient care, however, a major barrier for physicians to implement the latest scientific insights is that they speak a different language than 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 interdisciplinary assimilation of diverse areas of expertise aiming for their seamless integration.
CHAPTER 1 Biological Thermodynamics: On Energy, Information and its Evil Twin, Entropy
The terms physicist and physician come from the same root word but the respective professions diverged over the centuries. Now may be a good time to shrink the gap between the two, especially with modern technology being such an integral part of health care delivery. Thermodynamics is a branch of physics that launched the first industrial revolution but it also directly links to the way our body works. In this chapter we presented an overview of the key concepts in thermodynamics, which is based on the static equilibrium of physical systems as well as on processes that take physical systems from one equilibrium state to the next. Energy conservation is the basis of the first law of thermodynamics while a tendency to reach a maximum entropy state is behind the second law. Both of them are important in the context of biology and medicine, although biological systems by definition are far from thermodynamic equilibrium, except at death. Thermodynamics teaches us about the irreversibility of processes that generate heat and human metabolism is one of such examples.
Paradoxically, living systems reduce entropy by utilizing energy coming from nutrients ingested by them. Nonetheless, with high but less than perfect efficiency, all living systems gradually succumb to the arrow of time and increase their entropy content bit by bit. Speaking of bits, information, which is of critical importance to all forms of life, is also referred to as negative entropy and it requires energy to be created or destroyed. Among the more recent applications of thermodynamics, the idea of phase transitions is of utmost importance to biology and medicine since a transition from health and disease can be understood as a phase transition between two states of living matter. Associated with it is another powerful concept, namely that of symmetry breaking and all life emerges as a broken symmetry, a new phase of matter, a living state. Phase transitions are well characterized by the use of quantities called order parameters and control parameters as well as the function, which depends on them that describes the state of the thermodynamic system, the free energy. In applications to living systems we have borrowed generously from this vocabulary of physics but renamed free energy, a physiological fitness function, which is a mathematical formulation of the state of health of the living system. Much of the rest of this chapter describes in substantial detail key metabolic processes of energy generation and energy transformations that form the basis of the biochemistry background needed to understand metabolic processes and metabolic diseases.
CHAPTER 2 Biological Engines and the Molecular Machinery of Life
Living systems use energy and generate mechanical force. Nutrition provides the fuel for all life processes. Cells can be viewed as information processing units but also as mechanical machines with many interlocking parts. Hence, physical forces and energy-transducing elements are important aspects of cell behaviour. In this chapter, we reviewed the key physical forces and their origin. Importantly, life is sustained by molecules present in food and the energy stored in their chemical bonds. Once again, metabolism is the central aspects of the living systems seen as complex machinery driven by interlocking cyclical biochemical transformations. Structural stability of a cell is provided by tensegrity, which relies on maintaining tension, which in turn requires energy input from the cell’s “power plants”, the mitochondria. Equally importantly, both active and passive transport in and out of the cell maintains a balance of material fluxes and electric potential gradients across the many membranes in its compartments and around the cell itself. While mitochondria produce the quanta of biochemical energy in the form of ATP molecules, the cytoskeleton uses this energy as input to perform the work of cellular “bones and muscles”, i.e. microtubules, actin filaments and their complexes with other proteins such as myosin. This molecular machinery of the cell includes both translational and rotational motors, some of which uncannily resemble man-made machines and even electrical engines. It is astounding that the efficiency of these biological machines surpasses that of man-made equivalents. Nature, through the eons of evolutionary refinement achieved the level of a nanotechnology master.
Although we now know a lot about the biological motors, many mysteries remain unsolved. One of them is how cells, tissues and organisms maintain functional coherence across all scales, facing constant thermal noise and various perturbations. Is it achieved by electromagnetic communication, quantum coherence or something completely different that we still do not know? This spectacularly well-organized coherent whole is perhaps best illustrated in the case of the human brain, one of the most complex systems found in Nature. However, when this exquisite functional integration is lost, pathological states ensue. In other words, we can summarize it by saying that coherence is a hallmark of health and decoherence correlates with disease states.
CHAPTER 3 From Quantum Biology to Quantum Medicine
There is a paradigm shift occurring across the scientific landscape. Linear reductionist thinking going back over three centuries to Rene Descartes and Isaac Newton seems to be running out of steam and is unable to provide a proper account of the functioning of complex systems that abound in biology. Physics has undergone several scientific revolutions and it seems that with the dawn of Big Data swamping medical researchers with enormous amounts of information about living systems, time has come to rethink the foundations of the research methodology appropriate for this field today. One of the key discoveries that changed the face of physics in 20th century was quantum mechanics, which shattered the myth of Cartesian certainty and replaced it with the world described by probabilities and strangely entangled particles, which are also behaving like waves. It took chemistry to embrace the quantum reality a few decades and biology now appears to be reluctantly accepting that at least some phenomena in the warm, wet, complex and heterogeneous hierarchical living systems need to be explained using quantum mechanical principles. The list of such effects is short but non-trivial and growing. Photosynthesis, vision, olfaction, bird navigation and perhaps even molecular recognition are all examples of quantum physics at work in the service of biology. It is not surprising that Mother Nature found uses for sophisticated quantum algorithms, perhaps even in driving gene mutations to favorable configurations in a self-propelled evolutionary race to never-ending optimization. After all, biology has had two billion years and countless replicates of its experiments to find best solutions for its problems. Importantly, strong evidence exists that metabolism, which is arguably, the most crucial attribute of biological systems, is itself a quantum phenomenon. It was mathematically demonstrated that the empirically discovered allometric scaling laws of physiology can be very well understood using the methods of the quantum theory of solids within the theory called quantum metabolism. This chapter presents the reader with a kaleidoscope of insights and elaborations on the theme of quantum physics informing biology and also on the potential of these advances making their way to the field of medicine. Once again, quantum coherent states achievable in such physical systems as lasers, if applicable to the living state, could shed light on the coherent unitary state of self in biology. This would be especially significant in the context of brain dynamics. Conversely, loss of coherence could be directly linked to pathologies and disease states, for example metabolic diseases when the human body’s energetics is disturbed or to mental diseases such bipolar disorder when the brain’s coherent state is perturbed beyond the range of stability.
CHAPTER 4 From Systems Biology to Systems Medicine
As argued in the previous chapter, reductionism in science has run its course. Complex systems, such as the various life forms, are nonlinear by design. They are, in fact, in almost all cases, constructed as systems of systems operating based on the principles of nonlinear response to external perturbations. One of the most interesting properties of such systems is the possibility of symmetry breaking, which allows for a change of state, also a dynamical state. This is a powerful concept, fully exploited in the physics of phase transitions where the same physical system can exist in different phases, say liquid water or solid ice. The same applies to the structure of elementary particles that are composed of quarks and quantum fields. We propose to use these ideas in the context of medicine where the same system can exist in different states, e.g. a state of health and various types of disease or pre-diseases states. Transitions between these states represent analogues of physical phase transitions and differences between these states highlight the associated broken symmetries. The ultimate phase transition in a living system is that from being alive to the state of death. The march toward this ultimate destiny of all living things is called aging and it is characterized by a gradual increase of entropy, hence loss of information and heat generation (manifested by inflammatory state of the body). All of the above can be quantified and parameterized enabling the construction of a personalized physiological fitness landscape. In the future, such a fitness landscape will be used to navigate the individual’s lifestyle and, if necessary, to design therapeutic interventions, in order to avoid treacherous valleys of pathological attractor states or to climb a “mountain” range separating a pathological valley from an area characterized by well-being. Luckily, the task of accomplishing such algorithmic analyses is not as daunting as even a decade ago. This is because of the explosive growth of the field of systems biology and now, systems medicine. These areas of biomedical research are building not only methodological framework for an engineering approach to the living system of systems, but also amassing reams of parametric data that feed the construction of predictive models, not only retrospective but also prospective. For now, most of this research is limited to either meta-analyses of population studies or to model animal systems (e.g. yeast, fruit fly, E.coli bacteria or C. elegans worms). However, with these model systems used as validation tools, in the future systems medicine approach will be applied to personalized precision medicine.
This chapter provides a broad-stroke painted canvas showing the reader the present-day foundation (e.g. chaos, fractals, solitons, cellular automata) for this type of approach and directions for explorations (e.g. artificial intelligence, big data analytics) and applications in the future.
CHAPTER 5 Introduction to The Roadmap of Future Medicine – The Physiological Fitness Landscape
We have attempted to construct a rich tapestry of elements, interconnections and relationships involving the most important aspects of metabolic health at all scales. It is tempting to say that the emerging picture shows a bottom-up hierarchy starting at the molecular level and concluding at the whole-organism representation of the metabolism’s hierarchy of coherence and synchrony. However, such a sweeping generalization is too simplistic since the hierarchy involves a flow of signals in both directions, from molecules to cells to tissues and the entire body as well as a reverse flow of signalling which, in fact, begins with our interactions with the outside world. As it turns out, the outside world cannot be cleanly separated from ourselves as we are social “animals” whole lives are tightly enmeshed with those of others close to us and with society in general. This is a source of both vitalizing stress and toxic stress, depending on the situation we are in, our individual sensitivities and the severity as well as duration of stresses. Another part of our “greater” selves is the microbiota, which is comprised of more genes and more cells than those that are an integral part of the human body. In a sense, we are indeed what we eat. Another important relationship between our body and the external world concerns the biology of time and how we synchronize our internal biological clocks with circadian cycles of the Earth revolving and orbiting around the Sun. It is becoming increasingly clear that not respecting the cycles of day, year and lifetime results in negative consequences for our health. How then do we integrate the many factors, both internal and external to our bodies in an internally consistent, logical and quantifiable framework that can guide us through life and also provide important information to the physicians in their diagnostic and therapeutic approaches aimed at maintaining optimal health and combating disease? In this chapter, we have provided an outline for a future methodology that does exactly this and does it at an individual level. This framework is inspired by physics and it is based on the identification of order and control parameters that are respectively response functions to external perturbations to the homeostatic equilibrium that living organisms tend to preserve. The response of our body to external perturbations, best exemplified by the stress test used to assess our cardiac health, is a measure of the system’s flexibility or resistance to change. In terms of a mathematical formulation of the resultant picture of our state of health (or disease), we proposed to use the so-called physiological fitness landscape. This is a close analogy with the free energy function commonly used in thermodynamics and in the physics of phase transitions. This general formula is indeed a function of many parameters and forms a multi-dimensional manifold that allows the navigation, akin to the use of GPS when we travel far and wide, but in this case the journey involves lifestyle choices and pharmacological interventions aimed at health risk avoidance and maximum possible fitness. The input data for the construction of the personal physiological fitness landscape, of course, depends on our access to genomic, proteomic, metabolomics as well as physiological information about the construction and functioning of our body. Hence, in the future, the entire battery of big data analytics can be brought to bear on the resultant construction of precision medicine algorithms that the fitness landscape platform will enable. An additional important element in the development of this methodology is the aspect of time, more specifically aging processes. The landscape will be periodically updated and its projections refined as new data become available. As always, the devil is in the details and we hope that this book has provided a sufficient amount of details to spawn future studies in the area of metabolism as both a branch of science and medicine. In Volume 2 of this book, we will delve deeply into the detailed descriptions of the key physiological aspects of human metabolism and its relationships to the state of optimum health, the onset of disease, disease progression, aging and eventual demise.