Guy Salvesen

It is indeed a pleasure to have the opportunity to honor Guy Salvesen in the land of his birth. Guy worked his way from South Africa by way of Cambridge, England, where he studied with the then dean of proteases, Alan Barrett, before moving to the US and successively to the University of Georgia, Duke University, and finally to the Sanford Burnham Institute at La Jolla, California, where he is currently Dean of the Graduate School of Biomedical Sciences and Professor in the Cell and Molecular Biology of Cancer Program.

His research exemplifies the adage that Science is an Onion: You peel off one layer only to find a deeper and richer layer underneath. First we understood that the death of a cell, like its birth, could be biologically, even genetically, controlled and regulated. Then we learned that this death most commonly followed a ritualized collapse that Wyllie, Kerr, and Currie named apoptosis, syllogizing its role as the other end of the life cycle that began with mitosis. Next, Horvitz, Sulston, and Brenner identified the first genes regulating cell death, and they and colleagues recognized that these genes controlled proteases. The next layer of the onion was to realize that apoptosis could be subdivided into apical or initiator caspases and effector caspases. The initiator caspases could be membrane bound and triggered by a ligand, or metabolically activated by factors from mitochondria or elsewhere. Ultimately leading to activation of effector caspases, most commonly caspases 3.and 7

Dean Salvesen, combining his considerable skills as a biochemist with the rapidly developing ability to determine, thorough molecular analysis, the control and function of molecules, asked the fundamental question of how apical and effector caspases worked. In his work he has determined the importance of dimerization of caspases, how the structures of the molecules determine what binds to them, to regulate what they can cleave or to inhibit them, and how the apical caspases control the activity of the effector caspases.

All this has given us a remarkably clear sense of the mechanics of caspase activity and is now pushing into the next layer of the onion: what metabolic mechanisms determine when and under what conditions these pathways are initiated or blocked. His research has given us a deep understanding of how the DAMP-activated caspases work and has expanded our insight into how the intrinsically activated caspases are controlled. These discoveries have led to better clinical management of inflammatory processes and are the basis for advanced clinical research into how to target apoptosis in cancer cells—which frequently have lost apoptosis-activating mechanisms or have increased apoptosis-inhibitory mechanisms—as well as research into how to identify and relieve the distress in cells such as neurons that are subject to inappropriate and devastating apoptosis. For peeling back so many layers of this onion, today we thank and honor a son of South Africa, Guy Salvesen.