The Connecting Link Between Volumes 1 and 2

This book’s main objective is to provide a new perspective on human health and disease combining recent advances in biology, physiology and physics. Volume 1 gives an overview of several branches of physics, such as biological thermodynamics, quantum biology, phase transition, complexity and chaos theories, needed to better grasp modern biology. Volume 2 provides physiological perspectives on the stress response, circadian biology, insulin signaling, mitochondrial function and microbiota.

The metabolic parameters of human health and chronic diseases of aging are best profiled, studied and understood by invoking the modern principles of physics. The conceptual centerpiece linking together the two volumes is the Physiological Fitness Landscape (PFL), a novel measure of metabolic fitness combining patient data and artificial intelligence (AI). The existing AI algorithms are in the early stages of development in clinical healthcare and represent bottom-up approaches seeking patterns within -omic Big Data homogenized over large cohorts of patients sharing a clinical disease presentation. The PFL is applicable on an individual patient scale in both bottom-up and top-down approaches. The latter optimize treatment over time depending on the patient’s response. The patient’s metabolic parameters determine a trajectory of disease, and identify interventions can favorably alter that trajectory. The notion of fitness combines the physics-based quantity called Gibbs free energy and the physiological concept of stress resilience.

Sophisticated AI algorithms can discern simple rules from omics data and uncover patterns for both physiological and pathophysiological conditions. This can reveal nuances that dependon the unique dataset and predict emergent behavior in both adaptive healthy and maladaptive trajectories of disease.Applications include, for example, the patho-biogenesis of diabetes, Alzheimer’s, cardiomyopathy or particular cancer types on a personalized scale. Relevant parameters of biological thermodynamics describe neuroendocrine hormonal systems, insulin signaling and other growth promoter pathways, components of oxidative phosphorylation, glycolysis and its parallel (e.g.PPP, AGEsand PKC) pathways.

Quantum biology is an emerging area, which bridges modern physics and molecular biology. One of its advances is the explanation of the allometric scaling laws of physiology obtained by using the quantum theory of solids.It concludes that the high efficiency in the quantum regime correlates with oxidative phosphorylation in optimal health while low efficiency in the classical regime correlates with glycolysis and signifies the onset of pathology. Powerful illustrations of these correlations can be found in cancer and neurodegenerative diseases such as Alzheimer’s. The uncontrolled cell proliferation that gives rise to cancer occurs when cells switch from oxidative phosphorylation to the inefficient process of glycolysis.

The PFL exploits the concepts developed not only in quantum biology and biological thermodynamics but also in chaos and complexity theories. Chaos theory describes the behavior of nonlinear dynamical systems such as the weather and also numerous physiological processes including heart rate variability and the brain’s electrical activity. Chaotic dynamics may enable an efficient search in the phase space of dynamical behaviors. This may lead to theidentification of optimal physiological parameters to maintain homeostasis. Seemingly chaotic systems that  adapt to changes in environmental conditions are necessary for optimal health. When this innate physiological potential is lost, the onset of disease appears, manifested as a decline in the amplitude within the PFL terrain. Ultimately, attaining thermodynamic equilibrium is equivalent to death in a living system.

An important application of thePFL is the cardiac autonomic conduction system, which responds to changes in body position (e.g. sitting, standing and lying) and breathing (inspiration and expiration), resulting in heart rate variability required to maintain the function of vital organs. Conversely, the state of insulin resistance correlated with mitochondrial dysfunction, impaired bioenergetics and redox disturbance, is associated with cardiac autonomic neuropathy. Hence, loss of heart rate variability corresponds to the body’s inability to maintain homeostasis, which increases the risk of ventricular tachycardia and ventricular fibrillation. Another example is the loss of the healthy chaotic neuronal EEG patterns, indicative of a decrease in the normal brain complexity, which might lead to seizures. The PFL approach also applies to metabolic disorders. Metabolic transformations are fundamental features of neurodegenerative and cardiovascular diseases, and all chronic diseases of aging.

Unfortunately,physics-based principles in the study of medicine are still sorely lacking, hence the need for this book. This book discusses the exquisite organizational perfection of biological systems understood from perspectives of physics (Volume 1) and physiology (Volume 2). It is the author’s conviction that this approach has a foundationally-transformative potential for the future of Medicine.