Because apoptosis is central to both development and tissue homeostasis, as well as intimately associated with a variety of human diseases including cancer, autoimmunity, AIDS, neurodegenerative disorders and liver diseases, an understanding of its regulatory mechanisms could be used to manipulate apoptosis for therapeutic benefits. Using both Drosophila and mice as model organisms, Dr. Steller’s work delves into how the regulation of many different signals, originating both from within the cell and from its environment, decides whether a particular cell lives or dies.

Apoptosis has been conserved in evolution from worms to insects to humans. Dr. Steller’s lab discovered and characterized a family of proteins (the Reaper proteins) that act as integrators of many different signaling pathways to ensure that the death program is activated in cells that are doomed to die. Reaper, Hid and Grim (now termed RHG proteins) activate apoptosis by binding to and inactivating inhibitor of apoptosis proteins (IAPs), which in turn directly inhibit caspases, the key executioners of apoptosis. In this way, Reaper and related proteins remove powerful “brakes on death.”

Developing tissues can often compensate for the massive loss of cells in response to injury and/or stress (such as radiation). Dr. Steller discovered that cells undergoing apoptosis can stimulate their own replacement by secreting mitogens to induce proliferation of adjacent progenitor cells. These secreted mitogens include Wingless (Wnt) and BMP/TGFb family proteins. Since these pathways have been highly conserved in evolution, similar phenomena may occur in mammals as well, and Dr. Steller is investigating this possibility. These findings have profound implications for cancer therapy, stem cell biology and regenerative medicine. Caspase activity is also responsible for an apoptosis-like process in sperm, as Dr. Steller’s lab has shown, and is necessary for the generation of mature sperm. As sperm develop, caspase activation is tightly regulated by the mitochondria organelle and the protein cytochrome C. To create the characteristic streamlined shape of a mature sperm, active caspase proteins remove the bulk of the cytoplasm from the head of the sperm. Mice that are mutant for a caspase-activating protein are unable to remove the extra cytoplasm and are infertile as a result.

Cells that are highly resistant to cell death, including terminally differentiated neurons in Drosophila, are also a subject of interest in the Steller lab. Using Drosophila photoreceptor development as a model system, Dr. Steller is researching the survival mechanisms that these cells employ to resist apoptosis. One such mechanism, recently described by Dr. Steller, involves the unfolded protein response, which has been linked to diabetes, cancer and neurodegenerative diseases. However, Dr. Steller’s lab has shown that in a Drosophila model of autosomal dominant retinitis pigmintosa, a disease that causes blindness, the unfolded protein response is initiated in the endoplasmic reticulum organelle, not the cytoplasm, and serves to protect the cells from apoptosis. This research has added another level of complexity to the role of unfolded proteins in cell death and disease.

While Dr. Steller uses Drosophila as the primary model to discover cell death genes and order them into pathways, his lab is also testing whether concepts originally developed in Drosophila can be applied to mammalian systems. For this purpose, they have generated mouse strains with mutations in select cell death genes. This work has provided the first direct evidence for a role of mammalian IAP antagonists in caspase regulation and tumor suppression in vivo.

CAREER

Born in Germany, Dr. Steller received his undergraduate degree in microbiology and molecular genetics from the University of Frankfurt in 1981. At the European Molecular Biology Laboratory and the University of Heidelberg, in Germany, he earned his Ph.D. in molecular biology in 1984. After a postdoc in molecular neurobiology at the University of California, Berkeley, Dr. Steller became assistant professor of neurobiology at the Massachusetts Institute of Technology in 1987. He became associate professor in 1993, received tenure in 1994 and became professor in 1996. Dr. Steller came to Rockefeller University in 2000.

In 2001, Dr. Steller received the Lady Davis Award from the Faculty of Medicine-Technion in Haifa, Israel. He was given the Pew Scholar award by the Pew Charitable Trusts in 1989 and the Searle Scholar Award from the Chicago Community Trust in 1988.