Cell death as a life force

Cell death can be good or bad. Regardless of your point of view, the cell death field has grown exponentially in importance during the past three decades, in the context of both basic research and pharmaceutical discovery. This is reflected in the high frequency of scientific literature citations (Fig. 1) and in the number of pharmaceutical and biotechnology companies that are hoping to develop drugs that work by controlling cell death (Table 1). For a journal such as Drug Development Research, cell death has become particularly relevant, with many targets, assays, and therapeutic candidates emerging in essentially all fields of medicine. Indeed, much of the excitement in cell death research today is the potential to have an impact on so many disease states, including cardiovascular disease, infectious disease, central nervous system (CNS) disorders, cancer, and inflammation. Whether your interest is in caspases, kinases, mitochondria, or some other part of the cell death story (Table 2), one or more of the articles in this special issue should catch your attention. Cell death is indispensable for normal embryonic development and adult homeostasis, and insufficient or excessive cell death contributes to a wide variety of human diseases. Broadly speaking, cells die by either of two mechanisms, necrosis or apoptosis. In necrosis, noxious stimuli within or surrounding the cell overwhelm the cell’s homeostatic mechanisms, leading to a catastrophic and “messy” death, or lysis. In contrast, apoptosis, or programmed cell death, is a genetically controlled form of cell suicide effected by specific gene products acting within dying cells. Apoptosis results in the orderly and “tidy” removal of unwanted cells. A number of apoptosis pathways have recently been elucidated in human cells (Fig. 2). Key effectors of apoptosis include a set of unique cysteine proteases, the caspases, which are very efficient killers once unleashed inside cells. One of the early articles on “programmed cell death” was that by Lockshin and Williams [1965] at Harvard University, who studied the ability of cholinergic drugs such as the muscarinic agonist pilocarpine and the cholinesterase inhibitor physostigmine to inhibit the “programmed” death of the intersegmental muscles of silkworms. Fast-forward to our present understanding of the role of cell death in Alzheimer’s disease and marketed drugs such as the cholinesterase inhibitors donepezil and tacrine and perhaps there is a more scientific basis to the “use it or lose it” concept. The term “apoptosis” was first coined in an article by Kerr et al. [1972] at the University of Aberdeen, with credit given to James Cormack, a professor of Greek. As stated therein: “The word ‘apoptosis’ . is used in Greek to describe the ‘dropping off ’ or ‘falling off ’ of petals from flowers, or leaves from trees. ” The authors used this terminology to describe a morphologically unique form of cell death that included cell shrinkage, membrane blebbing, chromatin condensation, and nuclear fragmentation, with otherwise intact cell membranes and organelles. Knowing, it seems, how prevalent this terminology would become (see Fig. 1), the authors even gave instructions on the pronunciation of apoptosis, with the second “p” being silent, as in “ptosis,” a word already in use at that time to describe a drooping eyelid. As in many areas of biology, however, it was molecular genetic studies that dramatically enhanced progress in the cell death field. In the 1980s, studies on the etiology of human follicular lymphoma identified the upregulation of the bcl-2 gene (resulting from a chromosome translocation) as the causative “lesion” [see Tsujimoto et al., 1985]. Bcl-2 was later shown to be a powerful inhibitor of apoptosis in many cell types. In the same period, Horvitz and colleagues at the Massachusetts Institute of Technology (MIT) defined a genetic pathway controlling programmed cell death in the roundworm C. elegans [Ellis and Horvitz, 1986]. Mutations in three genes, ced-3, ced-4, and ced-9, prevented all of the 131 cell deaths that normally occur during worm development. Today, we know that ced-3, ced-4, and ced-9 are faithfully represented in human cells as the caspase family, apaf-1, and bcl-2 family, which collectively form a “core” apoptotic pathway (Fig. 2). Importantly, these genetic studies taught the scientific community that some forms of cell death are controlled by an autonomous biochemical path-