"It’s a privilege to pursue compelling scientific questions within the Genentech Research community, motivated by the opportunity to enable groundbreaking therapeutics."
Following academic training with a research focus on RNA biochemistry, I made the big decision to decline academic opportunities, switch fields, and begin a career in biotech. After negotiating the ups and downs at a couple of early-stage companies, I embraced the chance in 2005 to join Genentech and lead a collaborative effort to target the Notch signaling pathway. Contributing to a research community that combines the philosophy of “following the science” with a stellar track record of converting discoveries into medicines has proven extremely motivating. Genentech continues to feel like an exciting, rewarding and collaborative professional home.
Many factors combine to make Genentech a fantastic place to pursue postdoctoral research. The postdoc program is central to the intellectual vitality of Genentech Research, providing license to pursue compelling basic research questions and actively engage at the cutting edge of the larger scientific community. The program can boast of a longstanding tradition of top-notch science supported by close-knit connections and a collaborative culture. I feel grateful to be a postdoc mentor, knowing that the mentor-trainee interaction not only leads to scientific breakthroughs but also brings fresh enthusiasm to my research group and challenges me to grow as a scientist.
Our overarching goal is to develop therapeutic antibodies that selectively perturb function of individual ligands and receptors of the Notch signaling pathway. Such precise manipulation of the pathway not only shows promise in disease indications such as cancer, regenerative medicine and immunology but also enables discoveries of how Notch functions in adult mammalian biology.
Historically, Notch has been most thoroughly studied as an arbiter of cell-to-cell communication that mediates binary cell fate decisions of dividing progenitors. Classic paradigms hold that such Notch activity pertains to development or tissue regeneration, contexts characterized by abundant cell proliferation. Our recent studies, however, have revealed that Notch profoundly affects cell fate in adult tissue under homeostasis. Using novel antibodies that selectively inhibit the Notch ligands Jag1 or Jag2, we discovered that Jag blockade dramatically alters cell fate in the epithelial layer of mouse lung airways. Acute Jag blockade induced a rapid and near-complete loss of secretory club cells, with a concomitant gain in ciliated cells, under homeostatic conditions. Lineage-trace analyses revealed a direct conversion of club cells to ciliated cells without proliferation, indicating direct transdifferentiation. These studies have thus uncovered an inherent requirement for Notch activity in club cells to maintain their cell fate in an adult homeostatic tissue.
This discovery raises a myriad of questions that form the foundation of ongoing studies. Is the Notch-controlled club-ciliated cell relationship the tip of the iceberg, and what other cells and tissues may Notch control in this manner? We are particularly interested in the skin, liver and intestine. What are the molecular mechanisms underlying such Notch control of plasticity, and how does the Notch signal integrate with the chromatin landscape? Can we exploit the ability to quickly modulate cell fate for therapeutic benefit? Diseases characterized by excess mucus secretion provide a compelling entrée but we suspect that there may be broader implications.