UCSF scientist Joe DeRisi named MacArthur Fellow

By Jennifer O'Brien

Joseph DeRisi, PhD, of UCSF, has been named a 2004 MacArthur Fellow, one of the highest honors bestowed on an individual in the United States.

A molecular biologist, DeRisi has designed new tools for exploring the activity of genes, and used them to make major advances in understanding such infectious diseases as SARS (severe acute respiratory syndrome) and malaria. He is an associate professor of biochemistry and biophysics and Gordon M. Tomkins Chair at UCSF.

The honor, which includes $500,000 in support over the next five years, to be used at the recipient’s discretion, is intended to “celebrate the creative individual in our midst,” says Jonathan F. Fanton, president of the John D. and Catherine T. MacArthur Foundation, which bestows the honor. It is given in recognition of an individual’s “originality, creativity and the potential to do more in the future.”

It is the Foundation’s conviction, says Fanton, “that talented individuals, free to follow their insights and instincts, will make a difference in shaping the future.”

DeRisi, the only molecular biologist to be named in 2004, is one of 23 new fellows, who include such talents as a ragtime pianist, a novelist and an archaeological illustrator. The award is popularly referred to as the “genius award.”

“I’m very surprised and extremely honored,” says DeRisi, who learned about the award with a single phone call from the MacArthur Foundation last Tuesday, Sept. 21. “I feel like I’m in pretty extraordinary company.”

Candidates are nominated for the award, evaluated and selected through a rigorous and confidential process, according to the Foundation. No one can apply for the awards, and no interviews are conducted.

“I have not before experienced anything coming close to the degree of transformation that Joe has brought about in our community,” says Peter Walter, PhD, chairman and professor of the UCSF Department of Biochemistry and Biophysics. “He projects seemingly endless energy and infectious enthusiasm that, when combined with his outstanding science and generous, collaborative attitude, translates into new and wonderful things happening not just in his lab but in the whole community.”

“If the McArthur Award is for geniuses, then they have found the right person,” says UCSF Chancellor J. Michael Bishop.

Also named a 2004 MacArthur Fellow was Julie Theriot, PhD, formerly a UCSF Program in Biological Sciences (PIBS) graduate student in the laboratory of former UCSF scientist Tim Mitchison. Theriot, a microbiologist, cell biologist, and biophysicist, is focused on unraveling the secrets of bacterial infection.

In 1997, Eva Harris, PhD, formerly of the UCSF laboratory of Nina Agabian, PhD, in the UCSF Department of Stomatology, was named a MacArthur Fellow for her work in developing techniques to diagnose and treat disease in Central and South America.

DeRisi is the second member of the UCSF Department of Biochemistry and Biophysics to be named a MacArthur fellow. In 1987, the late Ira Herskowitz, PhD, a UCSF geneticist, received the honor. His studies on the yeast Saccharomyces cerevisiae yielded major insights into the fundamental aspects of cells. He was also a pioneer in pharmacogenetics—the study of the way natural variations in individuals’ genes affect their response to drugs.

DeRisi, who designs and builds microarrays—a technology in which gene activity is revealed on a glass slide—to carry out his studies on infectious diseases, says he plans to use the MacArthur funding to “drill deeper into malaria.”

“I want to try new research directions in the field that would probably be too risky to be supported with traditional funding mechanisms,” he says. “I want to learn more about the life cycle and internal regulatory mechanisms of the parasite, and how it avoids the immune system of the organisms it invades, with an eye toward drug development.”

DeRisi, a faculty affiliate with the California Institute for Quantitative Biomedical Research (QB3), headquartered at UCSF’s Mission Bay Campus, has already made significant strides against the malaria parasite, Plasmodium falciparum, which infects 200 to 300 million people world wide each year, mostly in tropical climates, such as sub Saharan Africa, and kills 700,000 to 2.7 million people annually, mostly children under the age of four.

In August 2003, he and his team reported that they had identified the full breadth of genetic activity at a key stage of development in the parasite, revealing that an unusually high percentage of genes ? at least 60 percent—were “turned on,” or expressed, at the third and critical stage in the parasite’ s life cycle ? when it invades red blood cells and wreaks the havoc that causes the disease’s symptoms.

Their analysis showed that the pattern, or timing, of gene expression was unique, with most genes expressed only once during the stage, and in a certain order, for a simple, continuous cascade of gene expression, beginning with genes that correspond to normal cellular processes and ending with highly specialized functions for invading red blood cells.

The discovery of the pronounced level of activity, in which a gene is transcribed into messenger RNA on the path toward producing a protein, points to numerous new potential targets for drug and vaccine therapy.

DeRisi is acutely aware of the need for such therapies, noting that Third World diseases such as malaria have not been a prime focus of pharmaceutical companies. “If you have an infectious disease like malaria, you’re out of luck if don’t have a credit card,” he once said.

An outspoken advocate of making scientific findings freely accessible to scientists around the world, many of whom cannot afford to subscribe to scientific journals, DeRisi published his malaria finding in the new on-line, freely accessible science journal Public Library of Science Biology.

“Malaria is the number one killer in the Third World. But many scientists in countries like Brazil and India, who are carrying out very good science on malaria, don’t have first world budgets,” he said at the time.

DeRisi also focuses much of his energy on using his custom-built microarrays to move in on viruses that cause a variety of infectious diseases. In January 2003, he and his then-postdoctoral fellow David Wang used a microarray designed to detect all known viruses—and even those never seen before—to provide the confirming evidence that SARS was a novel form of a coronavirus. At the time, the head of the Centers for Disease Control and Prevention, Julie Gerberding, called his tool the “absolute state-of-the-art probe for viral genes.”

But the self-described “viral hunter” is also applying the microarray to studies of diseases that, while less sensational in their debut, wreak havoc on people’s lives. In collaboration with infectious disease specialist Don Ganem, MD, and pulmonologist Homer Boushey, MD, he is studying the viruses that may cause or exacerbate respiratory illnesses, including asthma. (Currently, scientists are only able to determine the specific viruses causing respiratory disease in 20 percent of cases.) He also is hoping to begin using the tool with neurologist Stephen Hauser, MD, to examine multiple sclerosis, which is believed to have a viral component in some cases.

Funding for developing this microarray and carrying out the ongoing respiratory studies is sponsored by an award from the Sandler Program for Asthma Research.

While microarray technology draws on the latest in computer chip technology, computation and bioinformatics, the essence of the tool is a simple 3 x 1 inch glass slide—the kind found in a high school science laboratory. Scientists bond DNA or RNA sequences to the slide, wash fluorescently tagged DNA or RNA sequences of interest over it and see where the two sets of nucleic acid match up, as indicated by the fluorescent light. The outcome reveals which, if any of the genes in the sample of interest are active.

Ever interested in providing free access to scientific information, DeRisi has made a point of posting instructions on his website for making microarrays, and has given several workshops on their construction at Cold Spring Harbor and UC Santa Cruz.

“Joe has made a monumental effort to improve technology, creatively applying it to exciting disease-oriented problems, and making it accessible and freely available. Already, dozens of laboratories and hundreds of students have directly benefited from the resources he has developed and made available to the scientific community,” says Walter.

“He is an outstanding researcher, a talented and dedicated teacher, an active participant in university and public service, and a wonderful human being. Joe’s impact to date has been well beyond our wildest expectation. Among the many lucrative projects that could be tackled with microarray technology, Joe has focused a significant fraction of his research on malaria, a disease primarily afflicting the Third World. This focus is motivated by his genuine desire to have a positive impact on the human condition.”