Imagine a place where every child wants to grow up to be a physicist. For Hao Li, that place was his homeland of China in the late 1970s, following the Cultural Revolution and the demise of Mao Zedong. "Physics was the number-one choice in China as a major. The best students would go into that. People were fed up with politics." Li says the return of role models helped to fuel the nation's interest in science. "Once China was open to the Western world, a lot of famous scientists came back," he recalls. Among those who returned as heroes were Chen Ning Yang and Tsung Dao Lee, winners of the 1957 Nobel Prize in physics. "There was a great emphasis on science. In that environment, a lot of students got very excited."

Li — who says that even as a child he wondered how the universe worked — was so inspired that he studied theoretical physics as an undergraduate at Beijing University and, later, as a graduate student at the Massachusetts Institute of Technology. But, today Li has shifted his focus from outer space to the inner workings of the human genome. "Most everything in the world of physics can be explained by the same theory. Biology is different. It's going through a revolution. The underlying theoretical framework is still lacking."

Li is at the forefront of that revolution and a driving force behind efforts to make sense of the immense amount of data generated by the human genome project. He is an assistant professor of biochemistry and biophysics at UCSF and a faculty member in the newly created QB3, or the Institute for Quantitative Biomedical Research. A multi-campus partnership, the institute is funded by both state and private funds and will be headquartered at UCSF's new Mission Bay campus. It was established to accelerate the integration of biology with physical, mathematical and engineering sciences so as to tackle highly complex biological problems.

Li says he is "quite excited" about his upcoming move to Mission Bay. "Everyone is excited . One obvious reason is that everyone is going to get much more space." Li says he is particularly happy that he will be sharing space with experimental biologists. In that environment, both his research and that of others will thrive, he says. "I think it will have a big impact. Modeling biological systems requires a lot of feedback from experiments. The data has to come from experiments, we have to be able to try to extract principles from this data." Working together, Li's models can guide experiments while the data from these experiments allows him to refine old models as well as develop new ones. "Theoretical models can give predictions about what will happen. Experiments can challenge the theoretical model. That's unique."

Li began working in genomics while he was an independent research fellow at Rockefeller University in New York City. He found himself fascinated with the problem of how to make sense of the billions of letter-code generated by the effort to sequence the entire human genome. He took on the challenge of trying to figure out how a genome codes information that determines when and where to turn on or off genes. "If you think of the genome as very long text, only a small fraction of DNA codes for genes. In the vast non-coding regions, there are portions of the sequence that are involved in gene regulation."

Li's idea was to design a computer program that could identify patterns, such as the short DNA sequences recognized by regulatory proteins, from the vast sea of noncoding sequences. Before testing this on genetic data, however, Li tested his theory by using the program to identify words by looking for patterns in Herman Melville's Moby Dick once all of the punctuation and spaces had been removed and junk letters added in between words. And, it worked.

The idea now is to apply that sort of approach to the genome one portion at a time. Li and his UCSF collaborators have begun to do just that. Peter Walter, chair and professor of biochemistry, says Li's approach "has worked fantastically," adding that their results are now being prepared for publication.

Walter says Li is the kind of scientist and collaborator he and other campus leaders envisioned when they began planning for Mission Bay and QB3. "Now that we know the complete genome for many organisms we have the blueprint and we have to figure out ways of reading it." The "tool kit" Li is building is one that will not only be useful to many UCSF researchers, but one that will advance the field, Walter says. "It's a tremendous contribution."

Walter says Li is just as eager to learn from his colleagues as he is to teach them the subtleties of theoretical work. "He has a wonderful way of speaking the language so that it's understandable to us mere mortals." Li does this in a quiet way, Walter says. "He makes a living out of understatement."

Because Li's work is about applying theory to real data, he has numerous collaborators. In addition to Walter, Li's collaborators include Carol Gross, professor of microbiology and immunology, Christine Guthrie and Cynthia Kenyon, both professors in biochemistry and biophysics, and Cori Bargmann, professor and vice chair of anatomy. Li says he relishes the collaborative spirit he finds among his colleagues. "This is unique about UCSF," Li says.

When he's not working, Li enjoys spending time with his wife and two young daughters in Golden Gate Park, which he calls "the most beautiful park in the world." Li also makes time once a year to return to Southern China's Szechuan Province, where his parents still live and the place where, as a boy, he dreamed of being a scientist.

Source: Camille Mojica Rey

Last updated January 28, 2005

Hao Li

Hao Li has developed a "novel" method for studying gene regulation, thanks in part to Herman Melville's Moby Dick. Photo by Robert Foothorap.