Bioenergetic Origins of Complexity and Disease

It was assumed that if we sequenced the human genome, defined all of the common single-nucleotide polymorphisms (SNPs) and their haplotype associations, and performed genome-wide association studies (GWAS) between the SNPs and the various “complex” diseases, we would identify the responsible genes, understand the causes, and find the cures. However, after enormous effort, we have yet to explain more than 20% of common disease risk. Thomas Kuhn, in his book The Structure of Scientific Revolutions (Kuhn 1996), argued that when a scientific endeavor invests increasing effort in a problem with diminishing returns, the difficulty may lie with the core assumptions (paradigms) on which the work was based. Assuming that this argument is valid in the current circumstance, what are the basic assumptions upon which Western biomedical science and these efforts were based? There are three: that evolution occurs through natural selection of variant forms, that organ-specific symptoms are the result of organ-specific defects, and that genes are located on the chromosomal DNA and inherited according to the laws of Mendel. All three of these paradigms are rooted in observations on the structure of organisms, thus generating an anatomical perspective on biology and medicine. However, recent discoveries on the role of bioenergetics in human evolution and disease suggest that these classical paradigms are incomplete. Life requires not only anatomy but also the vital force that animates anatomy. Therefore, life is the interplay among structure (anatomy), energy (the vital force), and information to encode the structural and energetic systems. Anatomical observations (i.e., the beaks of Darwin's finches) were the basis on which the theory of evolution by natural selection was derived. Whereas this can explain how different forms can exploit adjacent niches, it cannot explain the evolution of complex forms. The Second Law of Thermodynamics requires that complex forms decay because entropy increases. Hence, simple forms—viruses and bacteria—should destroy complex forms: humans. Yet humans exist and persist. We persist because we counter entropy by maintaining a constant flow of energy through our bodies. That is, life is in a state of nonequilibrium thermodynamics, not equilibrium thermodynamics as required by the Second Law (Morowitz 1968). Energy flow has the inherent property of generating structure in matter, for example the formation of convection currents in heated liquids. For terrestrial life, high-energy photons emanating from the sun are absorbed by the biosphere, the energy is used to build and maintain structures, and the spent energy is radiated out into space as near-infrared photons. For humans, we eat food that contains reducing equivalents, breathe oxygen, and react to the reducing equivalents and the oxygen within our mitochondria to generate the energy necessary to build, maintain, and animate our structures. Whereas energy flow explains the maintenance of complexity, it does not explain the origin of complexity. For this, we need a new biological principle. This can be derived from the inherent feature of carbon-based molecules to form nucleic acids when they are exposed to energy flow (Ricardo and Szostak 2009). Nucleic acids, in turn, are digital systems that can encode information. Hence, each year energy flow through the biosphere creates more nucleic acids that add more information to the system. The more information, the greater the complexity that can be encoded. Therefore, after 3.5 billion years of energy flow, sufficient information has accumulated to encode the complex structures of higher organisms and the defense systems they use to combat entropy. Natural selection's function, then, is to compare similar systems and, through competition, choose the most energy efficient of the alternatives. Therefore, in biology the sum of energy flow is proportional to the sum of organismal information, which adds up to complexity (Wallace 2010). The anatomical perspective also dominates Western medical thought and hasdone sosince the seminal description of human anatomy by Vesalius 450 years ago. Following Vesalius's example, subsequent physicians and medical investigators have specialized in subregions of the human body, leading to today's organ-based clinical subspecialists: neurologists, ophthalmologists, cardiologists, nephrologists, and so on. This organ specialization has led to an unstated corollary that organ-specific symptoms are the result of organ-specific problems. However, in the past 20 years, we have observed many patients with organ-based symptoms who have been found to have systemic mitochondrial defects. Therefore, systemic energetic defects can also cause organ-specific symptoms (Wallace 2005, 2007). The anatomical perspective also solidified our confidence in the predominance of Mendel's laws of inheritance. Mendel observed that certain traits showed a deterministic pattern of transmission correctly interpreted as individuals having two copies of each hereditary factor, one contributed from each parent in their sex cells. Early 20th-century Drosophila geneticists studying the inheritance of fly morphological traits realized that Mendel's laws coincided with the inheritance patterns they observed. Subsequently, the chromosomes were also shown to follow the same hereditary pattern. These observations led to a powerful synthesis. Morphological traits are encoded by genes that are located on chromosomes that are inherited according to the laws of Mendel. Because all of the anatomical genes are encoded by the chromosomal genes, this paradigm was completely internally consistent. However, deterministic genetics became increasingly problematic when it was applied to humans. Many familial traits do not exactly conform to Mendel's laws. Deviations were then given terms such as “variable penetrance and expressivity” and “delayed-onset-and-progressive-course,” which had no mechanistic explanation. The problems became unresolvable when the prevailing paradigms were applied to the causes of the age-related maladies such as neuropsychiatric disorders (Alzheimer disease [AD] and Parkinson disease [PD]), metabolic disorders (Type II diabetes and obesity), and autoimmune diseases (multiple sclerosis and Type I diabetes). To cope with the inadequacy of Mendel's laws for these diseases, they were declared to be “complex,” the result of the interaction of multiple genes and a variable environment. However, the number of genes was not defined and the nature of the “environment” was not specified, making this hypothesis impossible to disprove. Our perception of complex diseases began to change when it was discovered that there are genes that are not inherited according to Mendel's laws. These non-Mendelian genes are encoded by the mitochondrial DNA (mtDNA), and the mtDNA encodes the core genes for bioenergetics. Moreover, non-DNA sequence changes were found to be maintained during cell division and even transmitted across generations, leading to the concept that the epigenome contributed to complex diseases. This concept came together with bioenergetics when it was realized that all reactions that changed the epigenome were mediated by energy-rich mitochondrial intermediates (Wallace 2005, 2007; Wallace and Fan 2010; Wallace et al. 2010). Consequently, it is now clear that the anatomical perspective of biomedical science has a complement, the bio-energetic perspective of biology and medicine (Fig. 1). In the realm of evolutionary theory, the origin of species by natural selection is complemented by the origin of complexity through the information-generating capacity of energy flow. In medicine, the concept that organ-specific defects cause organ-specific symptoms is complemented by the concept that systemic energy defects can also result in organ-specific symptoms. Finally, in the domain of genetics, the deterministic laws of Mendelian anatomical genetics are complemented by the stochastic rules of mtDNA bioenergetic genetics and epigenomics modulated by energy flow. Figure 1 The anatomical and bioenergetic complementarities in evolution, medicine, and genetics. Comparison of the three pairs of complementary paradigms derived from the anatomical perspective and the bioenergetic perspective.