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Using an advanced type of electron microscopy to investigate cellular suicide

Apoptosis, or programmed cell death, is a mechanism by which cells commit suicide to control cell proliferation or in response to DNA damage. Understanding in detail how cells undergo apoptosis has been crucial to improve cancer therapy. Over the last 20 years, important research from many groups, including Dr. Newmeyer’s team, have laid the foundation for the development of a new class of anti-cancer drugs that directly target the core cell death machinery. One of these drugs, Venetoclax, is now being used successfully to treat one type of leukemia and also is being tested actively for the treatment of several other forms of cancer.

The development of Venetoclax and other drugs in this category was made possible by research on the role of mitochondria, special structures within cells. In 1994, Dr. Newmeyer was the first to show that mitochondria are essential for the most common form of cell death, or apoptosis. This apoptotic function of mitochondria has proven to be an important target for cancer therapy.

Our most recent studies have made use of an advanced technique known as cryo-electron microscopy (a.k.a. cryo-EM). Cryo-EM has allowed us to observe in fine detail the effects of the pro-apoptotic Bax protein on biological and artificial membranes. Using cryo-EM, we were the first to show that Bax forms very large pores in the mitochondrial outer membrane that are responsible for cell death. However, precisely how Bax does this is not well understood.

In this project, we now propose to delve deeper into this central part of the apoptotic cell death process. In particular, we will use cryo-EM, as well as parallel biochemical approaches, to investigate the action of both normal Bax and also mutant forms of Bax that have shown unexpected and interesting behavior in our experiments. We expect that the highly advanced technique of cryo-EM will reveal the function of Bax in unprecedented detail, which will facilitate the development of new therapeutic strategies for cancer.