Two to watch

They are intellectually fearless and a bit unorthodox. They form a crazy quilt of undergraduate majors, birthplaces, interests, and experiences. They work across UCSF in “wet” labs fitted with benches and large metal fume hoods and in “dry” labs amid cubicles and work surfaces topped with computers and oversized monitors. They are mentored by senior UCSF faculty scientists and work alongside PhD postdoctoral scholars and staff researchers.

Who are they? Some might say the future. For the record, though, they carry the title doctoral candidates, or more colloquially, UCSF’s basic science “grad students” who are pursuing PhDs.

Matt Jacobson, PhD, faculty member in the School of Pharmacy’s Department of Pharmaceutical Chemistry and director of the Biophysics graduate program, knows them well. “We get a particular phenotype here at UCSF that’s different than our competitor institutions,” he says. “Our grad students tend to be risk takers, very creative. They take on the hardest problems and oftentimes succeed.”

The success of a graduate program can be measured in many ways—by the number of papers authored by students, by fellowships received, and awards won. “But it’s the intangibles that I think are most important,” adds Jacobson. “It’s the creativity of the research that they do. It’s how many of them wind up developing new research interests or combining research in different areas—these unexpected surprises.” The graduate students who spur that research eventually pursue faculty positions and start labs of their own, work in industry, or become entrepreneurs and continue to innovate.

There are more that 1,500 graduate students of all types at UCSF. The stories here are of two of the students within the five interdisciplinary PhD basic science graduate programs most closely affiliated with the UCSF School of Pharmacy.

Michael Keiser: Scientist completes mission impossible

Michael Keiser graduated from Stanford University in 2004 with two bachelor’s degrees—one in computer science and the other in Slavic languages and literature—and a master’s degree in Russian, Eastern European, and Eurasian Studies. It was the height of the dot-com boom, and many people he knew had taken jobs at places such as Google. Indeed, Keiser had a few interviews himself in the private sector, but he also applied to graduate school to see what would happen.

“The turning point for me was when I came to UCSF for interviews,” he says. “I just loved it. I was really excited about what it felt like here, the ideas I discussed with professors.” After his visit, he says, “it was pretty clear to me that this is what I wanted to do."

Last year, after five years of training, Keiser earned a doctorate from UCSF in Biological and Medical Informatics (BMI), and he started his own small company.

Both the BMI and Biophysics graduate programs, with the graduate program in Complex Biological Systems, are under a larger umbrella called the Integrative Program in Quantitative Biology (iPQB). The iPQB faculty encourages intellectual independence, explains Jacobson. As a result, he says, “our grad students are often people who push faculty into new areas."

The iPQB program gives students the freedom to pursue their goals by dissolving the artificial walls that divide disciplines, explains Thomas Ferrin, PhD, who is also a faculty member in the Department of Pharmaceutical Chemistry and the director of the BMI graduate program.

Keiser concurs. “Professors are, in fact, delighted to schedule meetings with grad students from other labs, or even have you drop by unannounced as ideas or questions came up,” he says.

iPQB also requires graduate students to rotate through three different labs during their first year.

Eric Davila

Keiser spent his second rotation in the lab of Brian Shoichet, PhD, Department of Pharmaceutical Chemistry faculty member. There he tackled two complicated questions, both of which centered on proteins associated with disease for which no drugs have yet been found. By implication, the answers could be tremendously important to drug development and ultimately to patients.

• Could a protein be characterized by the “hit list” of small molecules that were predicted to plug into it and thereby stop its action from occurring?

• Could these hit lists reveal which proteins should have functions similar to those of proteins about which we already know?

When Keiser eventually joined the Shoichet lab, his initial challenges as a first-year graduate student turned into the focus of his PhD—a grand multiyear project to calculate the side effects of all known drugs. In collaboration with UCSF colleagues he developed a computer model that calculates and maps, in seconds, new “off-target” effects of drugs.

The model was then tested by scientists at the University of North Carolina, Chapel Hill. While drugs are designed to be selective, some bind to several sites, which explains why a drug can have both a beneficial effect and a side effect or effects. Keiser and co-authors concluded that it might be possible to predict the new drug uses and side effects of drugs by applying their computer model.

Their work was published in the November 1, 2009 issue of Nature in the paper “Predicting new molecular targets for known drugs.“ And, Wired Science selected the work as one of the top scientific breakthroughs of 2009.

“The basic idea behind our research is to use small molecules—like drugs such as aspirin, Prozac, or Viagra—grouped into “fingerprints” for human proteins. But why do we care about such protein fingerprints? We care because if we can identify a fingerprint for a human drug target, it means we might be able to find more drugs for that target,” explains Keiser. “Also, we can use these ideas to discover cases where drugs that people take everyday, like Prozac, are hitting targets in the human body that nobody ever suspected before."

Keiser and colleagues, along with UCSF PharmD student Kelan Thomas, found that Prozac hits and might plug the same target as many beta-blocker anti-anxiety drugs, which explains some of Prozac’s cardiovascular side effects. This insight suggested one way that researchers might be able to make a Prozac-like drug without these side effects; they presented these ideas in the Nature paper.

“Only years after Brian first brought up the idea of a computational model, which we ultimately developed, did he cheerfully remark during my exit seminar that ‘this was, in fact, impossible,’ and he was glad I hadn’t known that at the time. Because, by serendipity or great good fortune, we found a way to do it,” comments Keiser with a smile.

UCSF is a place to try grand new projects and explore broad-reaching ideas that many would dismiss as too risky, adds Keiser. “But there’s a reason this works here. It’s because professors and mentors here approach ambitious scientific ideas rigorously and demand that you follow through in your thinking on all potential outcomes of your project. UCSF provides the resources, guidance, and critical interactions to help you do this."

Keiser is now finishing work as a postdoctoral scholar in the Shoichet lab. His research company, SeaChange Pharmaceuticals, is an outgrowth of his PhD research. The company looks at existing drugs to see if they can be repositioned to treat other diseases. For example, Keiser and his colleagues have found that Claritin, a common over-the-counter antihistamine, also stops a protein in cancer cells from moving to its place at the cell membrane and can thereby interfere with the cancer’s growth.

SeaChange is focusing on drugs for orphan diseases, which do not draw much attention from pharmaceutical companies because they affect small or underserved patient populations.

Dan Widmaier: Genetic engineer spins silk from bacteria

Dan Widmaier, who is currently a PhD graduate student in UCSF’s Chemistry and Chemical Biology (CCB) graduate program, also homed in on his PhD project during a lab rotation his first year. He arrived at UCSF in 2004 with a bachelor’s degree in biochemistry from the University of Washington and a lot of diverse research experience from having worked in three different labs as an undergraduate. Widmaier’s projects not only indulged his passions for organic chemistry and biochemistry, but also for computer programming.

Eric Davila

One of those undergraduate lab experiences had focused on structure-based drug design, which is an approach to creating a drug that requires knowledge of the three-dimensional structure of a biological target. Knowing this structure, candidate drugs can be designed to plug into and inhibit the action of the biological target. Widmaier came to UCSF prepared to pursue his interest in the field. “UCSF has a lot of great crystallographers, a lot of great structure people, and they’re trying to bring in chemists to build chemical probes for use in structure-based drug design,” he says.

He spent his first two lab rotations focusing on structure-based design before moving into his third rotation with Christopher Voigt, PhD, another faculty member in the School of Pharmacy’s Department of Pharmaceutical Chemistry. Voigt’s interest is in synthetic biology, which uses genetic engineering to design and build new biological systems.

“My fundamental driving force was to build things, either doing organic chemistry and building molecules or building genetic systems from scratch. The activities are analogous while very different in practice,” explains Widmaier. “Also it was quite by accident that Chris was on the CCB admissions committee the year I interviewed, and I was scheduled to talk with him."

Beyond this, Widmaier points to two key factors in his decision to switch fields. First was the diversity of the CCB students and the CCB faculty research, which spans the biological sciences. “That aspect of UCSF took me back a bit,” he says. “Chemists were spanning neuroscience, to organic methodology, to synthetic biology."

The second factor was a comment during the interview process by Charles S. Craik, PhD, Department of Pharmaceutical Chemistry faculty member and CCB graduate program director. “Charly told me during the interview that you can do science with anyone here on whatever you’re interested in and they would fit it into the graduate program,” Widmaier adds.

Widmaier joined the Voigt lab, and now, five years later, is writing his PhD thesis on a bacterial secretion system called T3SS. Infectious bacteria, such as Salmonella and Shigella use this system, which structurally looks like a hypodermic needle, explains Voigt, to inject proteins into mammalian cells. But instead of using the system for its intended purpose, Widmaier has genetically engineered it to shoot proteins out of the bacteria and into the surrounding culture. This function would be helpful in the biotechnology industry, which uses bacteria to synthesize proteins in large quantities and needs a way to get them out of the cell where they can be collected.

Widmaier engineered Salmonella to produce spider silk, which is made primarily of protein and is tougher than Kevlar and stronger than steel. Spider silk would have myriad commercial uses, but scientists have had difficulty manufacturing spider silk proteins on an industrial scale. Proteins that are produced inside engineered microbes quickly tangle up into insoluble fibers, making them impossible to extract.

Widmaier’s breakthrough was to make the bacteria into efficient little factories that produce the spider silk proteins at just the right time. While the bacteria are synthesizing the proteins, the secretion system is getting ready to pump them out of the cell. Only after the proteins get tagged with a signaling molecule do they get secreted. “Dan created the toolbox of circuits and the parts needed to make the whole system work,” Voigt says.

Widmaier’s paper on this work, entitled “Engineering the Salmonella type III secretion system to export spider silk monomers,” was published September 15, 2009, in Molecular Systems Biology. He was the first author.

“My colleagues on the paper spanned an incredible array of backgrounds that helped challenge the assumptions during the work and led to more rigorous science,” explains Widmaier. To the project, co-authors Danielle Tullmann-Erck brought formal training in chemical engineering; Ethan Mirsky brought his experience in electrical engineering; and Rena Hill brought experience in molecular biology. “Each of them contributed a different skill set in doing some of the experiments, as well as helping to ask additional questions and design control experiments,” explains Widmaier. He also collaborated with the DNA synthesis company DNA2, without which the project would not have been possible.

“And, as anyone who has worked in a science lab should know, in addition to the co-authors, your colleagues in a lab environment are critical to thinking through ideas. In the case of most labs at UCSF you span an even broader group. For example the Voigt lab has chemists, chemical engineers, physicists, bioengineers, molecular biologists, electrical engineers, and biochemists amongst other disciplines."

Like Keiser, Widmaier has also begun a company, Refactored Materials, with the goal of commercializing the manufacture of spider silk.

“The environment at UCSF affected my long-standing interest in entrepreneurship and my decision to start a company. Some of my colleagues had come to graduate school after working in industry or even after starting companies. I had experience all around me. Plus the entrepreneurship infrastructure here at UCSF made it almost impossible not to learn about starting companies."