‘Nothing makes sense in biology, but in the light of evolution’ wrote Theodosius Dobzhansky, one of the founders of the New Synthesis that led to the unification of evolutionary theory and genetics in the midst of the 20th century. During the last 3 years, the Nobel Committee has provided strong support to this view by highlighting the importance of seminal discoveries identifying in various, early diverging model organisms, ancestral evolutionary conserved molecular mechanisms of crucial importance for our own survival and fitness. In 2000, the Nobel prize for physiology and medicine recognized the contribution of the Aplysia model to the deciphering of the molecular processes allowing the emergence and maintenance of long-term memory. In 2001, it highlighted the contribution of the Yeast model to the identification of the basic, conserved, machinery driving the cell cycle. And last but not least, in 2002, the Nobel prize awarded to Sydney Brenner, John Sulston and Bob Horvitz singled out the extraordinary scientific adventure that led in the Caenorhabditis elegans model to the elucidation of cell fate during embryonic development, and in particular to the first identification of the existence of a genetic control of developmental cell death.1,2,3,4,5 The latter provided the first proof of concept that the term and idea of programmed cell death (PCD)6 had indeed a genetic correlate, in the form of a basic genetic module operating in most – if not all – cells during the development of at least one living organism. It also provided support to the hope – raised by the previous discovery of the often conserved phenotype of PCD, apoptosis7 – that a search for a similar form of genetic control might one day prove fruitful in other animal species more closely related to us. Because genetically regulated PCD has today become textbook knowledge, it is difficult to recapture and convey the feeling of substance, coherence and simplicity that these findings conveyed at the beginning of the 1980s to the fascinating but somehow fleeting notions of developmentally regulated cell death, PCD, cell suicide, self-destruction or apoptosis.6,7,8,9,10 ‘What is true for the bacteria is true for the elephant’ had written Jacques Monod. But could it be that what was true for PCD in C. elegans might also be true for PCD in us? This was far from being a predominant idea.

Between 1992 and 1994, Bob Horvitz and his students JunYing Yuan and Michael Hengartner reported the sequence of the three major components – ced3, ced4 and ced9 – of the genetic module involved in the control of PCD in C. elegans. This led to the surprising finding that the core machinery of PCD in C. elegans had evolutionary conserved counterparts in mammals,11,12,13,14 including humans, in drosophila,15 and in other animal species.16 Such a striking conservation across a phylogenetic divergence range of around 700 million years reinforced the view that PCD may have been essential for animal survival. However, consistent with the notion that evolution of crucial molecular pathways usually involves both genetic conservation and diversification, at least 14 homologues of the Ced3 executioner – the caspases – were progressively identified in mammals, together with at least 20 homologues of the Ced9 protector – the antagonistic Bcl2/Bax family,11,12,14 whose first members had already been discovered in humans13,17 prior to the C. elegans Ced9 sequencing. For the last 10 years, C. elegans has provided a blueprint for the identification and ordering of the complex and diverse PCD pathways operating in our cells, while at the same time research performed on our cells, and then on drosophila cells, revealed the involvement in mammals and insects of several molecular actors, signaling pathways and intracellular organelles whose implication had not been predicted by the C. elegans studies. These included the tumor necrosis factor (TNF) superfamily of death ligands and receptors,18 the inhibitors of apoptosis (IAPs),19 the IAP inhibitors, such as Reaper in drosophila15 and Smac/Diablo in mammals,19 the mitochondria and their intermembrane proteins, such as Cytochrome c in mammals,20,21 and more recently, in drosophila cells, small noncoding micro RNAs (miRNA) sharing similarities with the interfering RNAs (RNAi).22 Moreover, during the last 5 years, mammalian research and C. elegans research have begun to cross-fertilize in more intricate ways. This turn began in 1998 with the identification by Bob Horvitz's group of the Egl1 homologue of the mammalian proapoptotic BH3-only members of the Bcl2/Bax family,23 and of its important role in C. elegans PCD induction. More recently, a new molecular effector of PCD, the mitochondrial protein Endonuclease G, has been simultaneously identified in C. elegans24 and mammalian cells,25 and a C. elegans homologue of the mammalian effector of PCD, the mitochondrial apoptosis-inducing factor (AIF) has been found to participate to C. elegans PCD,26 suggesting that mitochondria, which play a crucial role in mammalian PCD, might also participate, in a still poorly understood way, in the regulation of C. elegans PCD.

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