For Cynthia J. Kenyon, the secret to a long, healthy life is in the genes. That's what she concluded after 10 arduous years spent isolating and analyzing some of the 19,000 genes of a microscopic roundworm. The University of California, San Francisco biochemist announced in early July that a single gene known as daf-2 dictates the behavior of other genes that control cellular-stress responses. When altered through a process of chemical mutation, that lone gene keeps the others functioning normally -- helping the body resist the wear and tear of aging. The worm's lifespan doubles, and by all appearances, it is healthier than other worms half its age.
Dorian Gray, the worm, is just the beginning. Scientists elsewhere have duplicated Kenyon's results in fruit flies and mice, shedding light on some of the fundamental questions about why and how living things age. Because humans share many genes and much basic biochemistry with lesser animals, such work may provide clues to creating a fountain-of-youth pill or injection. And even if 50-year-olds don't end up looking like college kids, this line of inquiry could spawn novel treatments for heart disease, Huntington's disease, and certain cancers associated with aging.
Kenyon credits the school that has backed her research. "There's a goodly amount of brains here," she says, "and the university provides the brawn." Indeed, if any team of researchers seems positioned to crack the mysteries of aging, it's the UCSF network of students, staff, and alums. Once little more than a good regional medical institution in an agriculture-focused state school system, UCSF has become a world-class showcase for biomedical innovation. Its achievements and culture have attracted both faculty and funding on a scale few other medical-research schools have been able to match.
The concentration of brainpower defies simple enumeration. Down one hall is the lab of Stanley B. Prusiner, the 1997 Nobel Prize winner who discovered prions, the infectious agents that cause mad cow disease. In an office across the street is J. Michael Bishop, who shared a 1989 Nobel Prize with UCSF alum and former faculty member Harold E. Varmus for the discovery of genes that cause normal cells to become cancerous. The faculty boasts 30 members of the prestigious National Academy of Sciences, and professors have been involved in upwards of 60 biotechnology spin-offs. These include industry pioneers Genentech, Chiron, Geron, and Scios, which Johnson & Johnson (JNJ) acquired this past April for $2.4 billion.
Step off the campus, and the stewardship of America's top scientific institutions seems to be in the hands of UCSF graduates and former faculty. A short list includes Julie Gerberding, director of the Centers for Disease Control and Prevention; Bruce Alberts, head of the National Academy of Sciences; Surgeon General Richard Carmona -- and, of course, Varmus, who ran the National Institutes of Health and is now president of the Memorial Sloan-Kettering Cancer Center in New York.
The UCSF medical mafia is just one manifestation of the institution's growing presence. The university has an uncanny ability to attract funds. For five years running, it has outshone most other universities in numbers of NIH research grants. With a $365 million tally last year, it surpassed every school nationwide except Johns Hopkins University, the University of Pennsylvania, and the University of Washington, exceeding rivals such as Harvard and Stanford in postgraduate grants.
Private donations, meanwhile, have topped $200 million every year since 1999. In the past year alone, the Bill & Melinda Gates Foundation awarded $28 million for research into AIDS prevention in Africa. And Intel Corp. Chairman Andrew S. Grove offered $1.5 million in donations and $5 million in matching grants for research in stem cells. UCSF is one of the few U.S. institutions pursuing work in these controversial cells, which are often harvested from embryos and can mature into any tissue of the body. "It's fitting to use some of the money that came from the previous tech revolution to help fund the next one," Grove says.
In some regards, UCSF's academic achievement seems almost accidental. Unlike Stanford or Harvard -- and not by any particular plan -- the institution has no undergraduate schools or athletic programs that compete for funding. So wealthy donors never have to listen to more than one fund-raising pitch. But sharp strategic thinking also helped turn the campus into a research powerhouse. Starting in 1968, administrators devised radical, collaborative approaches to research, and these methods quickly attracted some of the brightest minds.
That's not to say that UCSF outshines other distinguished research centers such as Harvard, Yale, or Johns Hopkins. "The Eastern institutions are doing just fine," says Varmus. Nevertheless, notes alum Marv Cassman, former head of General Medical Science at the NIH: "There are just a few institutions in the country that compete for top talent, and UCSF is one of them."
For the research staff at UCSF, the monumental goal is to churn out a scientific discovery a week across a variety of fields and disciplines. Administrators believe that will require a major upgrade of the physical environment. The institution is in the first phase of a 15-year, $1.5 billion building boom, the largest university expansion in the country. A 43-acre second campus called Mission Bay is rising south of downtown San Francisco, replacing old railyards and abandoned warehouses with state-of-the-art research facilities. Here, scientists will combine physical science and biology with intense computational research to study some of the most complex biological processes -- such as how the body's genes, hundreds of thousands of proteins, and chemical signals interact with one another and with pathogens in the genesis of disease. This work could lead to new drug-development strategies as well as insights on disease management and prevention.
For most of its history, UCSF seemed an unlikely place for creating radical change. As late as the 1960s, it was known mostly for competently providing clinical care to the public through San Francisco's general hospital. Fundamental research was little more than a dream. But the mission changed under the influence of Bill Rutter, who ran the department of biophysics and biochemistry. Hired in 1969 to head UCSF's modest chemistry department, Rutter institutionalized the practice of collaborative research on a grand scale. Eschewing the traditional department concept, Rutter believed the best way to encourage discovery was by grouping researchers who shared a common interest instead of lumping specialties together by department. These so-called neighborhoods might include chemists working side by side with mathematicians and biologists.
It was in Rutter's own lab that a hepatitis B viral gene was cloned and inserted into a bacterium, leading to the hepatitis B vaccine -- the first recombinant human vaccine ever produced. "For more than three decades, the university has invested unflinchingly in collaborative biomedical research," says David A. Kessler, former head of the Food & Drug Administration who in June was named UCSF's new dean of the School of Medicine.
The university's strength in genetic research has helped transform modern medicine. Scientist Herbert W. Boyer's 1973 work on techniques for altering DNA led directly to the synthesis of insulin, human growth hormones, and hemophilia medicine. The biotech revolution was under way, and Boyer went on to co-found Genentech Inc.
Three years later, Varmus and Bishop discovered that a gene that directs normal cell growth, if it mutates, can promote the uncontrolled growth of cancer. The discovery of these so-called oncogenes turned cancer research on its ear by establishing how the growth of cancerous cells can be triggered by exposure to a carcinogen, such as radiation or smoke. More than 100 oncogenes have since been identified, opening the door to a variety of cancer treatments aimed at activating or shutting them off at the right times. Bishop now serves as chancellor of UCSF, spearheading the Mission Bay expansion. "The reason we've been so successful is that there's open discussion and a totally unfettered exploration of the question 'what if?"' Bishop says.
The string of discoveries attracted powerful friends. Venture capitalists, many of them in the Bay Area, jumped at the chance to fund UCSF's many spin-offs. And when the landlocked university considered moving out of San Francisco in 1996 because researchers were working out of closets and reclaimed bathrooms, Gap Inc. Chairman Donald Fisher, investment banker Sanford Robertson, and the mayor's office struck a deal with the commercial developer that owned the 303-acre Mission Bay property to offer part of it -- worth $70 million -- for free. "These are enormously important research facilities, and we wanted to do everything we could to keep them here," says Rudolf Nothenberg, former chief administrative officer for the city.
The university also doubles as an incubator for promising scientists. Senior faculty scour the world for young researchers, graduate students, and postdoctoral candidates who might thrive in this cross-disciplinary hothouse. "The place is crawling with people who could be off on their own little ego adventures because they're that good, but they see the value of talking with each other," says Keith R. Yamamoto, chairman of the Cellular & Molecular Pharmacology Dept.
The can-do attitude helps win converts. For instance, when the CDC was struggling to classify the SARS virus, it turned to a young UCSF scientist, Joe DeRisi. Months earlier, DeRisi had imprinted samples of all 12,000 viral gene sequences known to science on a single slide. Called a DNA microarray, it relied on the laws of nature, meaning that any virus applied to the slide would gravitate toward a like virus. DeRisi and a research assistant took just 12 hours using a PC and fluorescent microscope to confirm that SARS was closely related to a bird virus but merited a new classification all its own. Discovering the AIDS virus, by contrast, took many years. "What we did obviously wasn't that novel, except we did it quickly," DeRisi says.
UCSF's newest challenge is marrying such technology with more basic research. Genomics, proteomics, nanotechnology, and other fields that probe the fundamental interaction of individual proteins -- and even atoms -- require intense utilization of databases and pattern-recognition tools. At the new Mission Bay campus, UCSF aims to attack these exact problems. In fall, 2004, the school plans to open the Institute for Quantitative Biomedical Research, headed by Cassman. It will serve as a clearinghouse for expertise and tools at the intersection of genetics, physics, chemistry, and computer science. The goal is to create the medical equivalent of industry-standard technology -- tools that can be quickly disseminated elsewhere, helping speed the creation and delivery of new medical treatments. Researchers at UCSF would not have it any other way.
Corrections and Clarifications
Marvin Cassman is misidentified as an alumnus of the University of California at San Francisco. His PhD is from the Albert Einstein College of Medicine in New York.
By Cliff Edwards in San Francisco