Evolutionary origin of disease and complexity: A nonequilibrium thermodynamic solution

Abstract

Our long-term goal was to develop realistic animal models of complex disease that are underwritten by fundamental principles. Along this path we noted a literature demonstrating that low exercise capacity is a stronger predictor of death relative to all other clinical conditions including diabetes and smoking. From this linkage we formulated the Energy Transfer Hypothesis (ETH): Variation in capacity for energy transfer is the central mechanistic determinant of the divide between disease and health. As an unbiased test of the ETH we reasoned that: divergent artificial selection of rats based on low and high intrinsic treadmill running capacity would yield contrasting models of capacity for energy transfer that also divide for disease risks. Thirty-five generations of selection produced Low Capacity Runners (LCR) and High Capacity Runners (HCR) that differ in running capacity by over 8-fold. Selection failed to disprove the ETH: disease risks segregate in the LCR, and the HCR demonstrate resistance to disease. For mechanistic explanation of the ETH we postulate that evolution, life, and thus disease follow the same entropic path of the other atoms and molecules of the universe. That is, 1) all systems tend towards Maximal Entropy Production, 2) entropy can temporarily decrease locally and form order such as life, 3) life developed with a genome as a path for coding for replication of energy metabolism units, and 4) evolution selects, in a constantly changing environment, for features that enhance lifes capacity for energy transfer. That is, Maximal Entropy Production is the driving force mediating evolution. Thus, for each species, consider that there is phenotypic variation for this capacity that underlies the divide between health and disease. One goal of this paper is to stimulate new cross-disciplinary tests of the ETH of disease.