Human Heterogeneity and Survival of the Species: How Did It Arise and Being Sustained?—The Conundrum Facing Researchers

Abstract

Current humans, Homo sapiens, are genetically and epigenetically very heterogeneous, and subsequently also biologically and physiologically heterogeneous. Much of this heterogeneity likely arose during evolutionary processes, via various iterations of humanoid lineages, and interbreeding. While advantageous from a species perspective, the heterogeneity of humans poses serious challenges to researchers attempting to understand complex disease processes. While the use of inbred preclinical models makes the research effort more effective at some levels, the findings are often not translatable to the more heterogeneous human populations. This conundrum leads to considerable research activity with inbred preclinical models, but modest progress in understanding many complex human conditions and diseases. This article discusses several of the issues around human heterogeneity and the need to change some directions in preclinical model research. Using newer Artificial Intelligence and Machine Learning approaches can begin to deduce important elements from the complexity of human heterogeneity.

Immune dysfunction following severe trauma: A systems failure from the central nervous system to mitochondria

“…The heterogeneity of the human condition is a major variable when conducting animal experiments to solve a medical problem ( 149 ). Preclinical models typically use animals from relatively homogeneous breeding colonies whereas humans are genetically, epigenetically, biologically and physiologically heterogeneous ( 149 , 150 ).…”

“…The heterogeneity of the human condition is a major variable when conducting animal experiments to solve a medical problem ( 149 ). Preclinical models typically use animals from relatively homogeneous breeding colonies whereas humans are genetically, epigenetically, biologically and physiologically heterogeneous ( 149 , 150 ). Large animals, such as pigs and sheep, do have some advantages with similar physiologies and/or anatomies as humans, however, they are more costly than using rodents ( 149 , 150 ).…”

“…Preclinical models typically use animals from relatively homogeneous breeding colonies whereas humans are genetically, epigenetically, biologically and physiologically heterogeneous (149,150). Large animals, such as pigs and sheep, do have some advantages with similar physiologies and/or anatomies as humans, however, they are more costly than using rodents (149,150). A second confounding variable are poorly designed human trials that are either not sufficiently powered or recruit patients who do not adequately represent the wider population for which the drug therapy is intended (151)(152)(153).…”

Sex Determination in Homo sapiens as a Multi-Step Process: Potential for Development of Variants and Sex Differences in Disease Risk

“…Thus, while the initial sex determination is determined from whether the fetus derives an X or Y chromosome (the SRY gene specifically on the Y chromosome; discussed in 12] from the sperm donor and an X from the egg donor, subsequent events post-fertilization can also influence the survival of the fetus. This system, which appears to drive aspects of heterogeneity in humans [32] appears to operate with many species (i.e. humans, pigs], but not rodents such as mice which can be inbred and thus, such species are not representative of humans in this regard.…”

“…The evolution of cognition to the degree associated with Homo sapiens, the current humanoid dominating the planet, is not clear as to when and how various attributes evolved and were integrated into the current function level [discussed in [76][77][78][79][80][81]]. Furthermore, humans are very heterogenous at multiple levels [discussed in [32]], which is a survival strength, and this also likely extends to various cognitive abilities. In this regard, cognition in Homo sapiens is likely a "work in progress" and evolution of this attribute is not complete.…”