The hegemony of empiricism: the opportunity for theoretical science in medicine.

Partly spurred by the rapid emergence of discovery tools, empirical science founded on experimental validation now dominates academic funding, publishing, and recognition while forums for theoretical science have been marginalized. Although this hegemony of empiricism instills useful discipline to the scientific process, it also limits the pace of science to sensor innovation and renders the ontogeny of scientific knowledge path-dependent, concealing potential discontinuities in intellectual trajectories. Theoretical science, founded on intuition, inspiration, and abstraction, can complement empirical science by creating disruptive paradigms that facilitate detection of spurious results and frame new hypotheses. For example, framing the compendium of human diseases as varying manifestations of buffer dysfunctions - insufficient or maladaptive responses to stress - portends new insights into disease mechanisms and treatments. As a specific incarnation of this theory, the "trauma hypothesis" suggests that the coordinated regulation of inflammation, coagulation, vasoconstriction, and fluid retention that evolved as a prehistoric adaptation to predatory stress and environmental injury conspires in modern times to produce acute coronary syndromes, heart failure, renal dysfunction, stroke, and pulmonary embolism. The theory also exposes the paradigmatic flaw behind the half-century detour perfecting balloon-deployed endovascular interventions. As the basis of buffer acquisition shifts from genetic to cognitive, phenoptosis - the theory that adaptive programmed death of organisms yields opportunity to successors - is rendered maladaptive, as an extended lifespan permits more efficient trait acquisition compared with life-death recycling. While forestalling death is a largely unfruitful medical game of "whack-a-mole" today, the recognition that aging and death may be programmed adaptations suggests they may also be amenable to systemic reprogramming. Epitomizing this opportunity are tumor cells, which reprogram themselves to escape their apoptotic fate and assume indefinite persistence. The prevalence and resilience of these cancer cells, and their ability to withstand the protean assaults of toxins, poisons, radiation, and host defenses, presage the potential robustness of life when appropriately programmed. Paradoxical medicine and dynamic range management may represent initial strategies to reprogram the neuroendocrine stress axes to modulate lifespan at the organism level, and many other strategies are anticipated. The key to theoretical science is original insight, but the prevailing pressure to conform to medicine's educational and practice standards dis-incentivizes independent thinking. A scientific future is envisioned when the commoditization of experimental science will enable its outsourcing, liberating health scientists from the tyranny of empiricism to engage in a more balanced process of discovery infused with theoretical considerations.

Negative pressure ventilation via diaphragmatic pacing: a potential gateway for treating systemic dysfunctions.

Programmed diaphragmatic pacing using implanted neuromodulators represents an emerging method for providing pulmonary support using negative pressure ventilation. The implantable, rechargeable, programmable and miniaturized nature of diaphragmatic pacers may obviate many of the management issues associated with noninvasive positive pressure ventilation devices. Closed loop systems may facilitate the implementation of diaphragmatic pacing for the treatment of many indications. They may allow for wider adoption of ventilatory support in central sleep apnea and improve quality of life in diseases of chronic hypoventilation, such as amyotrophic lateral sclerosis. In addition, it might alleviate subclinical hypoventilation--a condition that may affect a significant proportion of the aging population. Diaphragmatic pacing could also reduce sympathetic bias, which may contribute to a wide range of diseases associated with autonomic dysfunction.

Is atherosclerosis a neurogenic phenomenon?

Identified risk factors for atherosclerosis include diet, age, gender, family history, stress, lifestyle, smoking, diabetes, dyslipidemias, hypertension, and HIV. The mechanistic rationale to explain these associations remains poorly understood. We believe that these seemingly unrelated entities may promote atherosclerosis through a common pathway by inducing adventitial autonomic dysfunction, specifically as an adventitial stress dysfunction of neurogenic origin. Atherosclerosis may represent a local vascular manifestation of the global autonomic dysfunction induced by age, smoking, hypertension, HIV, and diabetes. Atherosclerosis may also participate in a feed-forward cycle as aging, diabetes, dyslipidemia, and hypertension may also represent independent downstream consequences of global sympathetic bias. Chronic physiologic stress and behavioral stress can shift the autonomic balance towards a state of sympathetic predominance. The highly communicable nature of behavioral stress may partially implicate the familial association of atherosclerosis as an epigenetic phenomenon, independent of putative genetic mechanisms. Host stress, global autonomic dysfunction, and sympathetic bias may also arise from chronic maladaptive consumption of stressed foods, as organisms detect and assimilate the stress phenotypes of their dietary constituents through a process called xenohormesis. The benefits of exercise may operate through reduction of chronic physiologic stress associated with global sympathetic bias. The neurogenic adventitial stress response may explain the local tissue remodeling seen in atherosclerosis, including adventitial adipose dysfunction, inflammation, adventitial angiogenesis, thrombosis, and endothelial dysfunction. We believe that the locations of atherosclerotic lesions correspond to regions of neurogenic adventitial autonomic dysfunction, in similar fashion to the segmental patterns of involvement found in inflammatory bowel disease. The diffuse atherosclerosis exhibited in transplanted hearts may reflect a diffuse sympathetic bias of the donor heart, since tissues and organs exhibit an intrinsic sympathetic bias in the absence of an extrinsic source of autonomic hegemony. Once we regard atherosclerosis as a neurogenic phenomenon manifested in adventitial autonomic dysfunction, novel diagnostic and therapeutic paradigms become evident.

Unhappy meal: how our need to detect stress may have shaped our preferences for taste.

Conventional wisdom says that our preferences for particular tastes evolved to ensure an adequate instinctual intake of metabolic resources. Yet we discern scant taste in many vital dietary components, such as vitamins, minerals, co-factors, essential fatty acids and amino acids. We propose that taste preferences evolved to serve a secondary function--that of xenohormesis. Stress causes organisms to convert complex sugars to simple sugars, as seen during fruit ripening, and to increase the proportion of high-energy saturated fats relative to unsaturated fats, as seen among farmed livestock. The presence of dietary simple sugars, saturated fats, and salt within an organism may echo its stress experience--an experience assimilated by others when consumed. As each successive consumer in the food chain incorporates the stress phenotypes of its dietary components, cues for stress may accumulate in a game of "you-are-what-you-eat". Detection of environmental stress embedded in diet may promote adaptive phenotype remodeling such as caloric hoarding to contend with potential ecologic challenges. The phenotype remodeling may be the result of direct stress signaling properties of fats, sugars, and salt. Since food ecosystems typically exhibit seasonality in composition, early detection of cues of ecologic stress during autumn, such as dehydration, lowered ambient temperatures, and impending resource scarcity, likely confers advantages in fitness. Taste preferences may represent a form of "Darwinian rubbernecking. Much like paying attention to vignettes of violence and trauma, recognizing proxies of ecologic stress and adapting accordingly may yield fitness advantages. Many aspects of agricultural modernization may increase the level of stress embedded in the food chain, catering to pre-existing taste preferences in a form of illegitimate signaling. Globalization and technology have transformed the dietary experience of autumn--when the food chain undergoes stress and therefore tastes the best--into a year-round bacchanal. Instead of experiencing ecologic stress through their diet in a seasonal pattern, modern humans have become creatures of chronic stress. Many human conditions related to stress dysfunctions may partly arise from maladaptive consumption of stressed foods. We anticipate that low-stress and stress-free food may have therapeutic potential in the treatment of diseases and the promotion of health.

Environmental discontinuity hypothesis: Buffer dysfunctions as a source of human disease.

Adaptive physiologic buffers enable organisms to respond to environmental variation with appropriate plasticity. Modern humans have substantially remodeled their environment such that many interactions with the environment have become relatively discontinuous functions compared to the past. Examples include sunlight, temperature, and altitude. We propose that environmental discontinuity represents a Darwinian maladaptation and may promote disease by inducing buffer dysfunctions. Skin pigmentation is an adaptive, dynamic buffer that normalizes sunlight exposure to balance the potential harm of damaging rays with the importance of sunlight in driving systemic biologic functions such as melatonin and vitamin D. Due to lifestyle characteristics such as indoor-outdoor living, well-intended sun-avoidance campaigns, and inhomogeneous use of apparel and sunblock techniques, modern humans increasingly experience sunlight variation as a discontinuous function. The resulting skin pigmentation buffer dysfunction may promote diseases associated with over- or under-exposure to sunlight, the most striking example being melanoma. In addition to promoting discontinuity of sunlight exposure, sun-avoidance campaigns may undermine sun-dependent biologic pathways such as melatonin and vitamin D that appear to protect against cancer. These issues may partly explain the rise in melanoma rates despite the implementation of sun-avoidance campaigns. Also discussed is the potential role that discontinuous temperature variation associated with modern lifestyles plays in diseases such as viral infection, heart failure, and acute coronary syndromes. Acute discontinuous changes in pressure and oxygen levels related to air travel may contribute to autonomic dysfunction, venous thromboembolism, and viral infections. Therapeutic implications are discussed.

Brewing controversies: Darwinian perspective on the adaptive and maladaptive effects of caffeine and ethanol as dietary autonomic modulators.

Ethanol and caffeine are two of the oldest human drugs. Their pervasive integration into the modern human diet may reflect behavioral attempts to correct maladaptations induced by evolutionary displacement of the autonomic system. The dietary adoption of caffeine may parallel the emergence of cognition as an independent basis of competition. Enhancement of the cognitive ability to gather and process information likely evolved as a valuable adjunct to physical behavior in prehistoric fight-or-flight encounters. Caffeine effectively exploits this pre-existing association between adrenergic activity and cognitive readiness, leading to its use in the modern environment where success in competition increasingly depends on cognitive, rather than physical, prowess. Ethanol may have emerged as a dietary means to buffer the maladaptive chronic sympathetic activation and fear response associated with stressful lifestyles and the social phobias associated with the dissolution of kin networks. We explore the health implications of ethanol and caffeine use, with particular attention to their acute and chronic effects on the autonomic axis. The putative protective effects of ethanol in surviving major trauma or reducing inflammation and heart disease may relate to tempering the behavioral and cardiovascular consequences of catastrophic or chronic sympathetic activation. Acute or chronic abuse of ethanol manifests paradoxical pro-adrenergic effects such as tremors and insomnia that may partly represent compensatory responses. Compensatory remodeling may also explain why confirmation of detrimental effects related to caffeine-induced sympathetic activation has proven elusive; indeed, paradoxical pro-vagal benefits may eventually be recognized. Ethanol and caffeine are potential agents that may beneficially expand the dynamic range of the autonomic system. In an environment where the Darwinian value of knowledge has increasingly supplanted that of physical traits, the consumption of caffeine and alcohol may represent both a cause and an effect of modern human evolution.

Stress dysfunctions as a unifying paradigm for illness: repairing relationships instead of individuals as a new gateway for medicine.

Stress has been implicated as a risk factor for most diseases, but a mechanistic explanation behind such associations remains elusive. As emergent responses to stress, adaptations range from acute responses where extant system capabilities mitigate current stress, to longer-term responses where system plasticity buffers against future stress. The long compendium of human ailments manifests through a much shorter set of symptoms that may operate through the stress axis. We propose a unifying ontology for human illnesses that classifies stress dysfunctions according to types of Darwinian dysfunction - inadequate response with adequate adaptation, inadequate adaptation, inappropriate adaptation, and epiphenomena of adaptation. Examples include cancer as a bystander effect of increased biologic plasticity in response to stress, and infectious illness as a manifestation of mutually escalating stress in an otherwise commensal relationship between hosts and microbes. We explore the contributing role of man-made stresses that have emerged as humans increasingly remodel their environment. Examples include biologic decompensation associated with reliance on technology to buffer stress, and behavioral stress caused by the dislocation of kin networks that promotes illegitimate signaling. Dysfunctional relationships engender stress not only among humans, but also among individual organs; heart failure, renal failure, and carotid stenosis may represent examples of such conditions. If stress dysfunction is the Occam's razor of human illnesses, and derangements in biologic relationships induce stress dysfunctions, then the study of relationships - an incarnation of systems biology - may represent a new gateway for medicine.

A new wrinkle: skin manifestations of aging may relate to autonomic dysfunction.

Various mechanisms have been argued for skin wrinkling, one of the hallmarks of aging. We hypothesize that chronic sympathetic bias is a previously unrecognized mechanism for wrinkling. In the acute setting of water immersion, reversible skin wrinkling is a well-known reflex mediated by the autonomic nervous system. We postulate that skin wrinkling results as a local maladaptive manifestation of a global chronic sympathetic bias that emerges during aging. The persistence of such changes may induce additional compensatory remodeling to cause permanent alteration of the skin. Sympatholytic agents may prove beneficial for arresting or ameliorating the development of wrinkles. Conditions that amplify sympathetic bias such as stress, smoking, amphetamine abuse, HIV, heart failure, and transplantation may accelerate wrinkling. Other common diseases of the skin may also arise as particular manifestations of aberrant autonomic activity through induction of vascular and immune dysfunctions. The temporal and spatial distribution of these dermatologic conditions may reflect variation of autonomic balance, which also regulates T helper immune balance. For all of these dermatologic conditions, local and systemic administration of drugs and medical devices that pharmacologically or electrically modulate autonomic nervous system activity may yield benefits as well.

Peripheral arterial disease: a manifestation of evolutionary dislocation and feed-forward dysfunction.

Peripheral arterial disease in the legs represents a subset of atherosclerosis that manifests a particularly sinister profile. A predominance of sympathetic activity in the periphery favors the development of neurogenic atherosclerosis. Atherosclerosis may then produce flow derangements and decreased physical activity that serves to escalate sympathetic bias in a vicious cycle. Restoration of normal flow in peripheral arterial disease may not only produce local benefit due to improved perfusion, but also represent a gateway to correcting many systemic conditions that may at first glance appear unrelated but share a common etiology of autonomic dysfunction, such as gout, acute coronary syndromes, stroke, sleep apnea, arrhythmias, depression, erectile dysfunction, inflammation, hypercoagulability, sleep disorders, bowel dysfunction, renal failure, and aging.

Osteoarthritis: an example of phenoptosis through autonomic dysfunction?

Phenoptosis, the programmed death of organisms akin to cellular apoptosis, constitutes a type of Darwinian selection that enhances inclusive fitness. It provides a means by which senescent and pre-senescent members can self-terminate if they have incurred sufficient cumulative stress such that their continued survival detracts from inclusive fitness. Sepsis, vascular disease, menopause, cancer, and aging all represent examples of phenoptosis at work. We previously proposed that feed-forward autonomic dysfunction fundamentally drives phenoptosis in all its guises. Accordingly, we now postulate that osteoarthritis defines a type of biomechanical phenoptosis, mediated by feed-forward autonomic dysfunction, and manifested through joint destruction associated with fitness disadvantages. Biomechanical capability plays a significant role in evolutionary fitness, and sustained joint insults such as immobility or undue biomechanical stress may serve as proxies for inferior fitness. By both hindering an individual's ability to compete for energy and increasing that individual's vulnerability to predation, feed-forward joint destruction may facilitate adaptive phenoptosis among impaired or senile members. Empirical data suggests that contrary to common belief, heavy joint use does not necessarily cause osteoarthritis, whereas immobility and neuropathy can predispose to the condition. From a Darwinian perspective, another process mediated by sympathetic activity, the alarm cry of attacked prey, simultaneously promotes the escape of kin while attracting predators and scavengers. By effectively enabling the martyrdom of biomechanically-challenged individuals, osteoarthritis may serve to optimize system energy efficiency in a similar fashion. This framework may generalize to other situations where regenerative capacity dissipates in conjunction with maturation, typically leading to fibrosis. By allowing environmental pressure to sort the phenotypes, imperfect repair mechanisms may accelerate adaptation and optimize long-term inclusive fitness for all individuals. As the basis of competition shifts from biomechanical to cognitive skills, and as novel triggers for physical stress emerge, osteoarthritis may now represent a modern maladaptation.

A paradigm for viewing biologic systems as scale-free networks based on energy efficiency: implications for present therapies and the future of evolution.

A network constitutes an abstract description of the relationships among entities, respectively termed links and nodes. If a power law describes the probability distribution of the number of links per node, the network is said to be scale-free. Scale-free networks feature link clustering around certain hubs based on preferential attachments that emerge due either to merit or legacy. Biologic systems ranging from sub-atomic to ecosystems represent scale-free networks in which energy efficiency forms the basis of preferential attachments. This paradigm engenders a novel scale-free network theory of evolution based on energy efficiency. As environmental flux induces fitness dislocations and compels a new meritocracy, new merit-based hubs emerge, previously merit-based hubs become legacy hubs, and network recalibration occurs to achieve system optimization. To date, Darwinian evolution, characterized by innovation sampling, variation, and selection through filtered termination, has enabled biologic progress through optimization of energy efficiency. However, as humans remodel their environment, increasing the level of unanticipated fitness dislocations and inducing evolutionary stress, the tendency of networks to exhibit inertia and retain legacy hubs engender maladaptations. Many modern diseases may fundamentally derive from these evolutionary displacements. Death itself may constitute a programmed adaptation, terminating individuals who represent legacy hubs and recalibrating the network. As memes replace genes as the basis of innovation, death itself has become a legacy hub. Post-Darwinian evolution may favor indefinite persistence to optimize energy efficiency. We describe strategies to reprogram or decommission legacy hubs that participate in human disease and death.

Efficient inefficiency: biochemical "junk" may represent molecular bridesmaids awaiting emergent function as a buffer against environmental fluctuation.

The biochemical function of many parts of the genome, transcriptome, proteome, and interactome remain largely unknown. We propose that portions of these fundamental building blocks of life have no current biochemical function per se. Rather, sections of these "omes" may contribute to an inventory of biochemical parts and circuits that participate in the development of emergent functions. Low fidelity deoxyribonucleic acid replication, transcription, translation, and post-translational modification all represent potential mechanisms to produce an inventory of parts. Stochastic processes that influence the conformations of ribonucleic acid molecules and proteins may also contribute to potential biochemical inventory. Some components of the biochemical inventory may enable future adaptations, some may produce disease, and some may remain useless. The function of many of these components await discovery, not by science, but by evolution. While carrying such purposeless biochemical units may appear to dilute fitness by exacting a thermodynamic cost, we argue that net fitness becomes enhanced when considering the value for potential future innovations. One can envision components that intermingle, interact, and act out mock pathways, but in most cases remain molecular bridesmaids. Given sufficiently low thermodynamic cost, such stochastic cycling may persist until a markedly advantageous or cataclysmically disadvantageous trait emerges. Maladaptive screening and utilization of inventory content can lead to disease phenotypes, a process buffered and regulated in part by the heat shock protein and stress response network. Whereas failure of the ubiquitin pathway to recycle misfolded proteins has become increasingly recognized as a source of disease, protein misfolding may itself represent one step in a process that maximizes functional innovation through increasing proteomic diversity. Fractal correlates of these processes occur at the organizational level of cells and organisms. That the abnormal accumulation of units induces local collapse may serve to limit the extension of damage to the greater system at large. The immune and cognitive systems that selectively sample and prune environmental content may serve as additional portals for innovation.

Integrating systems biology and medical imaging: understanding disease distribution in the lung model.

OBJECTIVE: Many chronic diseases exhibit characteristic pulmonary distribution patterns, but the underlying biologic explanations remain elusive. On the basis of emerging evidence from systems biology, we propose that gradients of T helper immune function exist as an epiphenomenon of the hypoxic pulmonary vasoconstriction response. Regional variation of immune function may contribute to preferential distribution patterning of lung diseases. CONCLUSION: The lungs represent but one example in which the distribution of immune function throughout the body may explain disease location. This hypothetic framework can apply to diseases outside the realm of pulmonary biology and illustrates the potential benefit of integrating advances in systems biology and medical imaging.

Are we eating more than we think? Illegitimate signaling and xenohormesis as participants in the pathogenesis of obesity.

Resource utilization may represent a central force driving evolution. A tight link between sensing energy availability and managing energy acquisition and utilization constitutes a common feature among all organisms. While such a link was likely adaptive during prehistoric evolution, modern lifestyles may decouple perceived cues from actual energy availability so as to promote obesity in humans. A particular illegitimate signal is chronic stress, which may shift body phenotype to suit a more conservative state of energy management. In prehistoric times, such a response likely aided survival during periods of low resource availability. However, new sources of chronic stress have emerged that bear little relationship to contextual energy, which is generally abundant in the modern world. In addition, modern techniques of husbandry and agriculture can produce stress in the food chain, such that food itself can act as an illegitimate signal of chronic stress. Obese livestock and unusual fat profiles in farmed fish, meat, and eggs may reflect stress phenotypes. Consumers of stressed foods may sense those signals--a phenomenon known as xenohormesis--and assume the stressed phenotype. This maladaptive process may promote obesity by erroneously biasing hosts towards caloric accumulation in the context of energy abundance. Regional tissue accumulation of fat may indicate local tissue stress. Atherosclerosis may result from stress signals that induce sympathetic bias and regional fat accumulation in vessel adventitia. Medications such as neuroleptics and foods such as diet drinks may generate illegitimate signals by mimicking molecules used for energy management. Implications for the prevention and treatment of dysfunctions related to these derangements are discussed. New strategies for manufacturing biologics by manipulating stress conditions or controlling fatty acid attachments to proteins are envisioned.

When normal is not: the dilemma of interpreting laboratory averages of bioactive molecules subject to heterogeneous regulatory feedback and epigenetic mosaicism.

Complex regulatory systems control the levels of many bioactive molecules in the serum. These systems involve the integration of feedback responses from numerous tissues. End-organs and tissues can manifest epigenetic mosaicism, particularly with aging or disease states. We propose that an isolated lab value may reflect a blended average of inhomogeneous feedback responses from target tissues in various states of dysfunction. Reliance on such data may underestimate the state of systemic dysfunction. Yet in clinical practice, normal serum levels of a given molecule and its associated regulatory machinery are often assumed to reflect normal body homeostasis and tissue function. Organism-wide integration of abnormally high and low levels of bioactivity of a molecule in different tissues may yield apparently normal serum values of the bioactive molecule and known components of its regulatory system. We specifically discuss thyroid hormone regulation and function as a case example. Epigenetic reprogramming of either regulatory loops or tissue responses represents another way in which normal serum levels of the molecule may obscure target-organ dysfunction. The proposed idea has broad implications for disease pathogenesis, diagnosis, and therapies. A model where individual tissues employ illegitimate signaling to subvert the concerns of the organism as a whole is also proposed.

Opening the floodgates: benign prostatic hyperplasia may represent another disease in the compendium of ailments caused by the global sympathetic bias that emerges with aging.

We have previously posited that the global sympathetic bias that emerges with aging may constitute the common etiologic thread that links a myriad of ailments associated with aging. Recent data suggests that benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) may also be caused by sympathetic bias as an independent etiology from androgen dysfunction. The association of BPH with heart disease, independent of other variables, supports the view that both entities represent downstream manifestations of global sympathetic bias. The risk for development of BPH increases with caffeine intake and decreases with alcohol consumption, factors which wield opposing effects on autonomic balance. Heavy smoking, which induces chronic sympathetic bias, also increases the risk of BPH, a link also previously attributed to hormonal alterations. Sympathetic dysfunction appears to have a mitogenic effect on the prostate. The high prevalence of prostate cancer, a condition detected in the autopsy of many elderly men, may arise from this activity combined with a Th2 shift induced by sympathetic bias, leading to decreased cancer surveillance by the immune system. Exercise may improve BPH by restoring autonomic balance and normalizing the sympathovagal ratio. The benefits of alpha-adrenergic blockers on BPH, generally felt to achieve symptomatic relief afforded by bladder wall and sphincter remodeling, may independently exert a direct effect on prostate growth and enlargement. Sympathetic bias may play a role in adaptive enlargement of other organs such as the salivary glands, heart, liver, spleen, and skeletal muscles in response to stress. We envision novel pharmacologic and device-based neuromodulation therapies for BPH and related urologic dysfunctions based on these principles.

Obesity and ADHD may represent different manifestations of a common environmental oversampling syndrome: a model for revealing mechanistic overlap among cognitive, metabolic, and inflammatory disorders.

Obesity and attention-deficit hyperactivity disorder (ADHD) are both increasing in prevalence. Childhood exposure to television has shown linkage to both ADHD and obesity with the former ascribed to dysfunctional cognitive hyperstimulation and the latter to altered patterns of diet and exercise. Empirical evidence has contradicted prior presumptions that the hyperactivity of ADHD would decrease the risk of obesity. Instead, obesity and ADHD demonstrate significant comorbidity. We propose that obesity and ADHD represent different manifestations of the same underlying dysfunction, a phenomenon we term environmental oversampling syndrome. Oversupply of information in the form of nutritional content and sensory content may independently predispose to both obesity and ADHD. Moreover, the pathogenic mechanisms of these conditions may overlap such that nutritional excess contributes to ADHD and cognitive hyperstimulation contributes to obesity. The overlapping effects of medications provide further evidence towards the existence of shared etiologic pathways. Metabolism and cognition may represent parallel systems of intelligence, and oversampling of content may constitute the source of parallel dysfunctions. The emerging association between psychiatric and metabolic disorders suggests a fundamental biologic link between these two systems. In addition, the immune system may represent yet another form of intelligence. The designation of syndrome X subsumes seemingly unrelated metabolic and inflammatory entities. Environmental oversampling syndrome may represent an even more inclusive concept that encompasses various metabolic, inflammatory, and behavioral conditions. Apparently disparate conditions such as insulin resistance, diabetes, hypertension, syndrome X, obesity, ADHD, depression, psychosis, sleep apnea, inflammation, autism, and schizophrenia may operate through common pathways, and treatments used exclusively for one of these conditions may prove beneficial for the others.

A general theory of evolution based on energy efficiency: its implications for diseases.

We propose a general theory of evolution based on energy efficiency. Life represents an emergent property of energy. The earth receives energy from cosmic sources such as the sun. Biologic life can be characterized by the conversion of available energy into complex systems. Direct energy converters such as photosynthetic microorganisms and plants transform light energy into high-energy phosphate bonds that fuel biochemical work. Indirect converters such as herbivores and carnivores predominantly feed off the food chain supplied by these direct converters. Improving energy efficiency confers competitive advantage in the contest among organisms for energy. We introduce a term, return on energy (ROE), as a measure of energy efficiency. We define ROE as a ratio of the amount of energy acquired by a system to the amount of energy consumed to generate that gain. Life-death cycling represents a tactic to sample the environment for innovations that allow increases in ROE to develop over generations rather than an individual lifespan. However, the variation-selection strategem of Darwinian evolution may define a particular tactic rather than an overarching biological paradigm. A theory of evolution based on competition for energy and driven by improvements in ROE both encompasses prior notions of evolution and portends post-Darwinian mechanisms. Such processes may involve the exchange of non-genetic traits that improve ROE, as exemplified by cognitive adaptations or memes. Under these circumstances, indefinite persistence may become favored over life-death cycling, as increases in ROE may then occur more efficiently within a single lifespan rather than over multiple generations. The key to this transition may involve novel methods to address the promotion of health and cognitive plasticity. We describe the implications of this theory for human diseases.