Model systems in cell death-grand challenge

In 1929, the Nobel Prize winning physiologist August Krough observed that “For a large number of problems there will be some animal of choice, or a few such animals, on which it can be most conveniently studied.” (Krogh, 1929). Known as the Krough Principal, this appreciation of a “model systems” approach has been foundational for many aspects of basic biology, from the use of the squid giant axon to define the ionic basis of the action potential to the use of the fruit fly to unlock the molecular basis of biological clocks. While the ultimate goal for many researchers may be to gain a better understanding of human development and/or pathogenesis, the complexity of mammalian systems often makes direct analyses challenging. Invertebrates and other “simpler”model systems often display adaptations that exaggerate normal cellular processes that make them attractive vehicles for the analysis of specific traits. This approach has also proven to be foundational for the study of cell death. The term “programmed cell death” (PCD) (now commonly referred to as “regulated cell death” to distinguish it from “accidental cell death” (Galluzzi et al., 2018)) was coined by Lockshin andWilliams in 1965 to describe the precisely timed loss of the intersegmental muscles of Lepidoptera at the end of metamorphosis (Lockshin and Williams, 1965). These giant cells (each of which is ~5 mm long and up to 1 mm in diameter depending on the species) initiate PCD coincident with the emergence of the adult moth from the overlying pupal cuticle. Few other naturally occurring examples of PCD are so exquisitely timed or offer such prodigious amounts of clean cellular material for molecular and biochemical analyses (e.g., Tsuji et al., 2020). However, it was another invertebrate model, the nematode Caenorhabditis elegans, that propelled the field of cell death from a small cottage industry with a few dozen investigators in the 1970s and 1980s into a massive research enterprise that has produced more than 560,000 publications during the past 30 years. One of the unique features of C. elegans that make it such an attractive model is that it displays “cell consistency”, meaning that every individual has the same number of somatic cells. By performing detailed lineage analyses, the identity and fate of every single cell was described by Sulston and Horvitz (Sulston and Horvitz, 1977). For about 20% of the cells, their fate is to die, primarily via apoptosis. At the time this work was conducted it was not well understood if PCD during development reflected the simple wasting away of surplus/unnecessary cells, active murder by neighboring cells, or cell-autonomous suicide. Using a clever genetic trick that prevented dying cells from being phagocytosed and thus rapidly removed, the Horvitz lab demonstrated that the ability of cells to die required the activity of specific genes that acted in a cell autonomous manner, and thus represented OPEN ACCESS