Rehovot, Israel, 2017: David Wallach

DAVID WALLACH has always been curious. As he says, “..from the day I crawled on the sand and saw something next to me.  It never stopped interesting me. It never changed…I want to thank my parents, of blessed memory…” That characteristic served him well. Throughout his life, David has sought mechanisms, how things worked. Training under Michael Schramm and Ira Pastan, his curiosity led him to the question of what drove inflammation, leading him to the elucidation of the mechanism of action of tumor necrosis factor. His work with TNF led to several important advances, including the development of drugs against several severe chronic inflammatory diseases. This basic research has eased considerable pain in this world.

Realizing that TNF was a cytokine that bound to specific cell-surface receptors, Dr. Wallach expanded these observations to elucidate the extrinsic cell death pathway. He identified the “death domain,” a region in the TNF and other cell death receptors that, upon self-association, triggers cell death. This observation established for cell death cascades a means of enzyme activation different from phosphorylation, cleavage, or ion change.  He cloned caspase-8 (the protease that, in the extrinsic pathway ultimately activates caspase-3) and its adapter protein FADD/MORT1. This work was crucial in establishing the importance of a caspase cascade to effect apoptosis.

He also recognized cFLIP/CASH as a natural antagonist of caspase-8, and thus a means of keeping apoptosis under control. This inhibition revealed that caspase-8 had activities that could not be directly tied to apoptosis:  differentiation of the hematopoietic system including the yolk vasculature and differentiation of macrophages; and binding to the cell membrane and translocation to the nucleus of the pseudokinase MLKL (mixed lineage kinase domain-like), leading to the controlled necrosis-like form of death called necroptosis. A third surprising function of Caspase-8 is to prevent escaping nucleic acid oligomers from activating inflammatory responses as keratinocytes terminally differentiate.  We look forward to his wide-ranging curiosity producing many more such surprises in the coming years.

It is therefore a pleasure to join many others in celebrating the achievements of David Wallach. David has already won many prestigious prizes including the Teva Founders Prize (1997), Rappaport Prize in Biomedical Sciences (2012), Merck-Serono Prize (2012), and Emet Prize (2014). He was Councilor (2007) and President (2011) of International Cytokine Society, and has served on the editorial boards of a dozen journals. He is currently the Joseph and Bessie Feinberg Chair of the Department of Biological Chemistry here at the Weizmann. An outstanding scientist, he is also a modest and wonderful and gentle human being. It is an honor to present one of our 2017 prizes for Lifetime Achievement to David Wallach.