The cells of multi-cellular organisms die through numerous distinct mechanisms. For example, apoptosis and necrosis are clearly distinct biological entities that have different morphological manifestations and biochemical programs. Most importantly, apoptosis has been found to be genetically programmed to occur at specific times during development hence it is often referred to as "programmed cell death". My basic assumption is that there are yet-to-be-discovered programmed cell death pathways and phenotypes; my goal is to identify them. My suspicion stems from several lines of evidence. First, there are other cell destruction mechanisms, such as an active form of axonal degeneration (Wallerian degeneration), which is biochemically and morphologically distinct from apoptosis and autophagic death; there are similarities between Wallerian degeneration and the normal process of axonal pruning that occurs during early development. Second, even canonical death pathways are multi-faceted: it is possible to induce apoptotic-like death without caspase activation, mixed aponecrototic death or a form of necrotic cell death, termed necroptosis, in response to death receptor signaling in the absence of caspase activation; this type of hybrid cell death (necroptosis) involves autophagy and can be distinguished from necrosis, apoptosis and autophagic death. Finally, olfactory sensory neurons from mice die in culture, and perhaps in vivo, through a mechanism that is distinct from apoptosis; Stuart Firestein and I have shown this death process is distinct from known types of cell death (unpublished data). With two graduate students, I have developed a systematic chemical biological method of discovering novel cell death phenotypes. To do this, we developed a cocktail of small molecule suppressors of cell death that can be used to block known cell death mechanisms. We have screened tens of thousands of small organic molecules for their ability to kill cells in the presence of this cocktail. We used a secondary test to ensure that any identified compounds act through a mechanism requiring new protein or RNA synthesis to eliminate "detergent-like" compounds. We have identified two compounds that are active in this system and appear to activate novel cell death pathways. Morphological and molecular characterization of these and other such compounds will illuminate their mode of action and define one or more novel types of programmed cell death. Given the major biological implications of the already elucidated cell death mechanisms, the ability to uncover novel cell death pathways and phenotypes would have wide repercussions in the understanding of basic biological mechanisms and pathological states.
Arnold O. Beckman exemplifies the meaning of the word humanitarian. Combined with his unwavering enthusiasm for life, his keen sense of humor and his strong moral and ethical principles, he is a national icon.