"I believe that the most important purpose of science is to advance human knowledge toward practical applications that can transform or save human lives."
I came to Genentech to pursue postdoctoral training because I valued the company’s scientific excellence and its foundational philosophy of integrating basic research and medical translation. My postdoc studies on neurotransmitter receptors led to papers in Science, Nature and Cell, and earned the 1988 Boeringer Ingelheim Award. I joined the department of Molecular Biology as Scientist in 1989, and my lab helped establish a technology to fuse biologically important proteins to antibody molecules. This approach is now widely implemented in biological research and biotech drugs.
In the 1990’s, the Human Genome Project inspired my team to discover several novel members of the TNF cytokine superfamily, most notably, Apo2L/TRAIL and its "death" and "decoy" receptors. This led us to investigate a cell-suicide process called Apoptosis—which has important roles in normal physiology as well as in disease. Our contributions to elucidating the mechanisms of apoptosis led to clinical investigation of a novel class of molecules called Pro-Apoptotic Receptor Agonists, and aided in the advancement of apoptosis-promoting cancer medicines such as venclexta. In separate work, my team identified a set of secreted proteins overexpressed in the tumor microenvironment, and developed antibodies to block their cognate receptors for therapeutic gain.
More recently, we’ve turned our attention to an intracellular signaling network dubbed the unfolded protein response (UPR). The UPR normally helps secretory cells to resolve issues with 3D shaping of newly synthesized proteins. UPR dysregulation can promote diseases such as cancer, autoimmunity and neurodegeneration. We have discovered that the key UPR enzyme IRE1 is hijacked by certain cancer cells to avert apoptosis and resist proteotoxic stress. Our research further revealed that inhibiting IRE1 activity in cancer-surveilling dendritic cells augments anti-tumor immunity. These studies identify IRE1 as a potential therapeutic target for cancer.
To date I have mentored over 25 postdoctoral fellows, who made many key contributions to our lab’s success. Most have gone on to obtain competitive scientific positions in industry or academia. Our postdocs enjoy significant autonomy: They learn how to (1) identify, define and address key biological questions with scientific rigor and elegance; (2) unite intellectual independence with collaborative teamwork; and (3) integrate basic and translational science to discover and develop transformative new medicines. Over the years our lab has had many scientific collaborations with academic groups, most recently, Peter Walter’s lab at UCSF.
Science, 2014, ISSN: 0036-8075
We are currently developing strategies that aim to kill cancer cells by disrupting their inherent stress- adaptation mechanisms. We are approaching this by identifying key molecular sensors of biological stress and related signaling mechanisms that enable cancer cells to circumvent activation of their built-in apoptotic suicide program.