Science at UCSF Genetech Hall



UCSF Genentech Hall supports the largest concentration of chemists in any medical-pharmacy school building in the country. Chemists can subtly modify the structure of molecules active in cells, or create new molecules to determine, for example, the role specific proteins play in chemical signaling between and within cells. This detailed knowledge is needed to develop drugs that can counter malfunctions in the vital signaling process. 
More than 80 faculty scientists will direct laboratories at Genentech Hall, including:

Blocking Enzymes That Can Kill  
Charles Craik, PhD, professor of pharmaceutical chemistry, UCSF School of Pharmacy and professor of biochemistry and biophysics, UCSF School of Medicine, studies the chemical biology of proteolytic enzymes and their natural inhibitors. These enzymes, known as proteases, cut other proteins, an activity essential to nearly all life processes.

A particular emphasis of his work is identifying the roles and regulating the activity of proteases associated with infectious diseases, cancer and development.  These studies are providing a better understanding of both the chemical make-up and the biological importance of these critical proteins that constitute about two percent of the human genome.  This in turn is leading to the development of strategies for regulating proteolytic activity in medical treatment.

The laboratory has had success in developing protease inhibitors as anti-virals for AIDS and has isolated a key protease associated with the Kaposi’s Sarcoma Virus as well as a novel protease family associated with prostate and ovarian cancer. Further study of these proteins holds promise for better understanding, rapid detection and eventual control of infectious diseases, obesity and cancer.

Drugs Tailored to Your Genetic Make-up
Kathleen Giacomini, PhD, professor and chair of biopharmaceutical sciences,  UCSF School of Pharmacy, focuses on understanding the processes by which drugs enter cells.
As the sequencing of the human genome was nearing completion, Giacomini was among the first to take genomics to its next step: identifying how differences in genetic make-up affect drug response.

She is the principal investigator of an NIH-funded project studying how drug response is affected by small differences in genes that code for cellular “gatekeepers” called transporters, which determine whether a drug will get into the blood stream. The UCSF project focuses on variants in 25 transporter genes that underlie the response to many frequently used drugs, including antidepressants. The pioneering project first determines the amount of genetic variation in an ethnically diverse sample of about 250 people. Scientists then test the performance of these transporter variants in cell cultures, and finally, clinical researchers determine if people with those variants respond differently to drugs in a clinically significant way.

“Our ultimate goal is to be able to read someone’s DNA and know what drugs to use and at what doses, as well as which drugs to avoid,” Giacomini says. “At the same time, this early genomics study is offering us surprising insights into how genetic information is organized” - insights that were unattainable until scientists began to scrutinize genetic variation.

Dissecting Cellular Communication  
Kip Guy, PhD, assistant professor of pharmaceutical chemistry, UCSF School of Pharmacy, and cellular and molecular pharmacology, UCSF School of Medicine, applies a chemist’s skills to understand cellular signaling, particularly the signaling pathways involving estrogen receptors, thyroid hormone receptors and the regulation of the tumor suppressor gene, p53.

In this pursuit, he has brought a large-scale technique known as parallel synthesis into the university laboratory setting. His lab produces large “libraries” of potential inhibitors of protein-protein interactions involved in the signaling pathways and then screens the molecules for their different effects.

The approach can efficiently zero in on the key structural and chemical elements that allow a specific molecule to inhibit an interaction. This can lead to better understanding of the natural signaling process and also guide efforts to develop drugs that uniquely block a particular pathway.

Guy’s lab is also trying to synthesize phalloidin, one of the toxins produced by the “Green Deathcap” mushroom Amanita phalloides. Phalloidin acts by blocking the dynamics of actin in cells, a protein essential for cellular movement, and therefore important in cancer metastasis. Guy hopes the research will allow studies to determine if actin is a good target for anti-tumor drugs.

Genes and Aging
Cynthia Kenyon, PhD, Herbert Boyer Professor of Biochemistry and Biophysics,  UCSF School of Medicine, studies the genetics of aging.

She will direct the new Hillblom Center for the Biology of Aging based in UCSF Genentech Hall. The center supports research on the biology of aging as well as research program in diabetes, neurodegenerative diseases and eye disorders.

Ten years ago Kenyon made international news when she discovered that blocking the activity of a single gene in the roundworm C. elegans doubled the animal’s lifespan. The gene, known as daf-2, encodes a receptor for insulin as well as for a hormone called insulin-like growth factor. The same or related hormone pathways have since been shown to affect lifespan in fruit flies and mice, and therefore are likely to control lifespan in humans as well. The gene also affects reproduction, and many researchers had predicted that lifespan could not be extended without inhibiting reproduction.

Recently, Kenyon’s lab discovered that vigor and lifespan can be extended without dampening reproduction or causing any other serious side effects as long as the daf-2 gene is silenced only in adulthood. Kenyon hopes the research will lead to understanding how youthfulness and longevity can be extended in humans as well.

Pinpointing New Targets for Drugs
Kevan Shokat, PhD, professor of cellular and molecular pharmacology, UCSF School of Medicine, studies kinases—enzymes that are central to the complex communication pathways in cells.  Each human cell has 500 or so different kinases, and efforts to understand what these key players do has been hindered by the difficulty of studying one kinase without affecting many others.  Shokat developed a way to very selectively mutate kinases and then inactivate them so that one and only one kinase out of the 500 is shut down. The approach allows researchers to determine the normal role of the kinase and is also a boon to drug developers, since the ability to precisely inactivate specific proteins is what modern drug-making is all about. As Shokat says, “The ability to understand how a specific kinase regulates signaling pathways would permit the development of new drugs and new strategies to control almost all disorders including cancer, neurological disorders, autoimmunity and tissue rejection.”


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