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Reading on Chronic Disease, an exceprt:


1. Introduction
Much of modern Western medicine is based on the principles of acute interventions for poisoning, physical injury, or infection. These principles trace to historical figures like Paracelsus (1493–1541), Ambroise Paré (1510–1590), and Louis Pasteur (1822–1895). These acute care interventions are now widely used in the modern fields of pharmacology, toxicology, urgent care, emergency medicine, and surgery. When caring for acute disruptions in health, the careful identification of the trigger, or cause of the problem, and the anatomical location of the defect, is an important part of good medical care. However, when dealing with chronic illness, treatments based on the rules of acute care medicine have proven less helpful, and can even cause harm by producing unwanted side-effects (Qato et al., 2018).

In chronic illness, the original triggering event is often remote, and may no longer be present. Emerging evidence shows that most chronic illness is caused by the biological reaction to an injury, and not the initial injury, or the agent of injury itself. For example, melanoma can be caused by sun exposure that occurred decades earlier, and post-traumatic stress disorder (PTSD) can occur months or years after a bullet wound has healed. If healing is incomplete between injuries, more severe disease is produced. If a new head injury is sustained before complete healing of an earlier concussion, the clinical severity of the second injury is amplified, and recovery is prolonged. This occurs even when the energy of the second impact was less than the first. Progressive dysfunction with recurrent injury after incomplete healing occurs in all organ systems, not just the brain. Chronic disease then results when cells are caught in a repeating loop of incomplete recovery and re-injury, unable to fully heal. This biology is at the root of virtually every chronic illness known, including susceptibility to sequential or recurrent infections, autoimmune diseases like rheumatoid arthritis, diabetic heart and kidney disease, asthma and chronic obstructive pulmonary disease (COPD), autism spectrum disorder (ASD), chronic fatigue syndrome (CFS), cancer, affective disorders, psychiatric illnesses, Alzheimer dementia, and many more.

Great strides have been made since the 1940s in the treatment of acute illness. This success has decreased infant mortality, lowered mortality from infections and trauma, and has improved survival after heart attacks, strokes, and cancer. However, this success has led to a sea change in medicine. Instead of spending the majority of time treating acute illness, physicians and health care workers in 2018 now spend the majority of time and effort caring for patients with chronic disease. Over $2.5 trillion is spent every year in the US to care for patients with chronic illness (Burke, 2015). While it has been tempting to treat this rising tide of chronic disease by using the principles that have proven so successful in acute care medicine, a growing literature supports the conclusion that every chronic disease is actually a whole body disease—a systems problem—that cannot be solved using the old paradigm. For example, autism, bipolar disorder, schizophrenia, Parkinson, and Alzheimer disease each affect the brain, but are also characterized by whole-body metabolic abnormalities that are measureable in the blood and urine (Gevi et al., 2016; Han et al., 2017; He et al., 2012; Varma et al., 2018; Yoshimi et al., 2016). Rheumatoid arthritis affects the joints, but also has metabolic abnormalities in the blood that show an activated cell danger response (CDR) (Naviaux, 2014) for several years before the onset of clinical joint disease (Surowiec et al., 2016). Coronary artery disease affects the heart, but is the result of long-standing abnormalities in metabolism called “the metabolic syndrome” (Mottillo et al., 2010).

All chronic diseases produce systems abnormalities that either block communication (signaling), or send alarm signals between cells and tissues. Cells that cannot communicate normally with neighboring or distant cells are stranded from the whole, cannot reintegrate back into normal tissue and organ function, and are functionally lost to the tissue, even when they are surrounded by a normal mosaic of differentiated cells. As this process continues, two different outcomes are produced, depending on age. If the block in cell-cell communication occurs in a child, then the normal trajectory of development can be changed, leading to alterations in brain structure and function, and changes in long-term metabolic adaptations of other organs like liver, kidney, microbiome, and immune system. If the communication block occurs in adults, then organ performance is degraded over time, more and more cells with disabled or dysfunctional signaling accumulate, and age-related deterioration of organ function, senescence, or cancer occurs.

Blocked communication and miscommunication inhibit progress through the healing cycle, and prevent normal energy-, information-, and resource-coordination with other organ systems (Wallace, 2010). This predisposes to additional damage and disease. When chronic disease is seen as a systems problem in which the healing system is blocked by key metabolites that function as signaling molecules—metabokines—new therapeutic approaches become apparent that were hidden before. What follows is a description of our best current model of the metabolic features of the healing cycle. Future research will be needed to flesh out additional details.

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3. Need for a systems biology of healing
The classical signs of inflammation that begin the process of wound healing have been known since before the time of Hippocrates (c. 460–370?BCE). Medical students today still learn the classical Latin terms for the signs of inflammation as rubor, tumor, calor, dolor, and functio laesa (redness, swelling, heat, pain, and loss of function). In United States, the curriculum at most medical schools does not yet include a specific course on the molecular systems biology of healing. The descriptive elements of injury and healing are taught in traditional courses like pathology, histology, and during clinical service on the surgical and burn wards. However, a dedicated systems biology course, describing our current understanding of the choreographed changes in cell metabolism, biochemistry, gene expression, cell structure, cell function, and pathophysiology that occur after injury and during healing, is missing. The rapidly growing fields of Integrative (Rakel, 2018), Functional (Baker et al., 2010), and Natural (Pizzorno and Murray, 2013) Medicine devote considerable attention to the broader, multi-dimensional study of whole-body healing as it applies to the treatment of chronic illness. However, a modern synthesis of functional and traditional medicine with state-of-the-art medical technology directed at the molecular aspects of healing has not yet been achieved.

4. Metabolomics—A new lens for chronic disease medicine
The newest “omics” technologies to be added to the systems biology toolbox are metabolomics (Jang et al., 2018) and lipidomics (Harkewicz and Dennis, 2011). Rapid advances in these emergent technologies were made possible by technological advancements in mass spectrometry that have occurred since about 2012. In 2018, we are still at least 10?years behind the technical sophistication of genomics, but a flood of new publications using metabolomics has revealed the first outlines of a missing link that connects the genes and disease. Whole-body chemistry appears to be this link (Fiehn, 2002).

5. Metabolites as both matter and information
Chemistry provides the link between genotype and phenotype in two ways: (1) cell metabolism is the direct result of gene-environment interactions (G?×?E?=?metabolism), and (2) chemicals (metabolites) made by and processed by the cell have a dual biology as both matter and information. Metabolites have a well-known function as matter; metabolites are the physical building blocks used for cell growth, structure, function, repair, and as energy and electron carriers. In ecosystem theory, this metabolic matter represents resources for system structure, function and growth, and for energy to support ecosystem connectivity and resilience to purturbation (Bernhardt and Leslie, 2013). Many metabolites also have a lesser-known function as information; they bind specific receptors to change behavior, regulate fetal and child development, shape the microbiome, activate neuroendocrine and immune systems, and regulate the autonomic and enteric nervous systems.

Metabolites like ATP, S-adenosylmethionine (SAMe), acetyl-CoA, NAD+, and others are used to modify DNA and histones directly to alter gene expression through epigenetics (Naviaux, 2008; Nieborak and Schneider, 2018; Wallace and Fan, 2010). Other metabolites like a-ketoglutarate, succinate, fumarate, iron, FAD, and oxygen act as essential cofactors for epigenetic modifications. These metabolites, and others like propionyl-CoA, butyryl-CoA, succinyl-CoA, myristoyl-CoA, farnesyl-diphosphate, and UDP-glucose, also alter the function of other proteins by post-translational modifications of nuclear transcription factors and enzymes throughout the cell as a function of real-time changes in metabolism. Finally, dozens of metabolites act as signaling molecules called metabokines, by binding to dedicated cell surface receptors.

6. The healing cycle
The healing process is a dynamic circle that starts with injury and ends with recovery. This process becomes less efficient as we age (Gosain and Dipietro, 2004), and reciprocally, incomplete healing results in cell senescence and accelerated aging (Valentijn et al., 2018). Reductions in mitochondrial oxidative phosphorylation and altered mitochondrial structure are fundamental features of aging (Kim et al., 2018). The changes in aging are similar to programmed changes that occur transiently during the stages of the cell danger response needed for healing (Naviaux, 2014) (Fig. 1). Although the circular nature of healing seems obvious from daily experience with cuts, scrapes, and the common cold, the extension of this notion to a unified theory to explain the pathophysiology of chronic complex disease has only recently become possible. Technological advancements in mass spectrometry and metabolomics have permitted the characterization of 4 discrete stages in the healing cycle (Fig. 1). The first of these is the health cycle, which requires wakeful activity alternating with periods of restorative sleep. The health cycle will be discussed after first reviewing the 3 stages of the cell danger response: CDR1, CDR2, and CDR3. Aspects of the CDR include the integrated stress response (ISR) (Lu et al., 2004) and the mitochondrial ISR (Khan et al., 2017; Nikkanen et al., 2016; Silva et al., 2009). While all aspects of the CDR are coordinated by nuclear-mitochondrial cross-talk, the precise controls of the transitions between the stages of the CDR are largely unknown.

Fig. 1. A metabolic model of the health and healing cycles. Health is a dynamic process that requires regular cycling of wakeful activity and restorative sleep. The healing or damage cycle is activated when the cellular stress exceeds the capacity of restorative sleep to repair damage and restore normal cell-cell communication. CDR1 is devoted to damage control, innate immunity, inflammation, and clean up. CDR2 supports cell proliferation for biomass replacement, and blastema formation in tissues with augmented regeneration capacity. CDR3 begins when cell proliferation and migration have stopped, and recently mitotic cells can begin to differentiate and take on organ-specific functions. Abbreviations: eATP; extracelllular ATP; CP1–3: checkpoints 1–3; DAMPs: damage-associated molecular patterns; DARMs: damage-associated reactive metabolites.

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