[Selective "death programs" or pleiotropic"life programs"? Looking for programmed cell death in the light of evolution].

Abstract

"Nothing in biology makes sense except in the light of evolution", wrote Theodosius Dobzhansky, one of the founders of the Modern Synthesis that led to the unification of evolutionary theory and genetics in the midst of the 20th century. Programmed cell death is a genetically regulated process of cell suicide that is central to the development, homeostasis and integrity of multicellular organisms. Conversely, the dysregulation of mechanisms controlling cell suicide plays a role in the pathogenesis of a wide range of diseases. While great progress has been achieved in the unveiling of the molecular mechanisms of programmed cell death, a new, and somehow puzzling level of complexity has recently begun to emerge, suggesting i) that several different self destruction pathways may exist and operate in parallel in our cells, and ii) that molecular effectors of cell suicide might also perform other functions unrelated to cell death induction and crucial to cell survival, such as cell differentiation, metabolism, and the regulation of the cell cycle. These new findings, with important physiopathological and therapeutic implications, seem at odds with the paradigm of programmed cell death derived from the studies of Caenorhabditis elegans, which led to the concept of the existence of selective, bona fide death genes that emerged and became selected for their sole capacity to execute or repress cell death. In this review, I will argue that this new level of complexity might only make sense and be understood when considered in a broader evolutionary context than that of our phylogenetic divergence from C. elegans. A new view of the regulated cell death pathways emerges when one attempts to ask the question of when and how they may have become selected during a timeline of 4 billion years, at the level of ancestral single-celled organisms, including the bacteria. I will argue that there may be no such thing as a bona fide genetic cell death program. Rather, in the framework of a model that I have termed the "original sin" hypothesis, I have proposed the existence of an initial pleiotropy of the molecular tools involved in the control and execution of self-destruction--an ancestral involvement in both pro-life and pro-death activities. I will discuss how this hypothesis may be reconciled with the C. elegans paradigm of programmed cell death. Finally I will discuss how an ancestral level of pleiotropic functions of the molecular tools involved in the control of cell death, aging and genetic diversification might have favored their initial selection, their constant availability for de novo selection, and their progressive propagation in most--if not all--species during the course of evolution.