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SARS Stars

First published May 2003

When Joe DeRisi got word in late March 2003 that the Centers for Disease Control and Prevention (CDC) was trying to identify the cause of the mystery called SARS, or severe acute respiratory syndrome, his heart leapt. He'd been preparing for such a moment for two years.

Preliminary evidence from labs in Hong Kong and elsewhere around the world had suggested that the likely cause of the disease was a virus -- perhaps a coronavirus or a paramyxovirus. Studies under the electron microscope had revealed a crown- or corona- like halo of spikes surrounding a globular core, and studies in the culture dish revealed antibodies known to respond to coronaviruses. Likewise, studies involving polymerase chain reaction detected coronavirus DNA or RNA. But other studies under the electron microscope indicated the presence of paramyxovirus. The CDC needed more information. DeRisi and his postdoctoral fellow David Wang were ready. Weeks earlier they had put the finishing touches on a tool that would enable them to detect all known viruses -- and even those never seen before -- using their custom-built form of microarray, a technology in which gene activity is revealed on a glass slide.

While the technology draws on the latest in computer chip technology, computation and bioinformatics, the essence of the tool is a simple 3- by 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.

In their case, the team had bonded onto a slide DNA and RNA sequences from each of the 1,000 known viruses in bacteria, plants, animals and humans. In fact, they'd bonded 10 to 12 sequence samples from each of these viruses, for a total of 12,000 different nucleic acid "spots" on the slide. The strategy, with which the team reported success using a prototype (see the November 2002 issue of the Proceedings of the National Academy of Science , vol. 99, no. 24), was that the lit-up sections would reveal the type of virus present in the sample, whether known or unknown.

And that's exactly what happened in March. On a sunny Saturday morning, just weeks after the boxes had been unpacked in DeRisi's new labs at Genentech Hall, the first building to rise at the UCSF Mission Bay campus, DeRisi and Wang received several samples of nucleic acid made from tissue culture from the CDC and went to work. They washed the sample over the slide and by Sunday noon had their answer.

As they looked at the computer representation of the microscopic activity on the glass slide, they saw a field of brightly lit spots -- spots representing numerous forms of coronavirus, including bovine coronavirus, avian coronavirus and human coronavirus.

"This was a Eureka moment," says DeRisi, 33, assistant professor of microbiology and immunology and Tomkins chair. "We knew we'd found something totally new."

There are dozens of known coronaviruses found in a variety of species, but only two that have been found in humans. These cause the common cold. This new form of the virus contained an amalgamation of sources and had clearly jumped species.

Now it was up to the CDC and other labs to determine whether the virus was simply present in the tissue or actually the cause of, or a partial player in the pneumonia syndrome. The validation process would include infecting animals and determining whether they developed the disease. Subsequent research confirmed their results At a news conference on March 24, 2003 CDC Director Julie Gerberding called DeRisi's technology "the absolute state-of-the-art probe for viral genes."

DeRisi suspects this is just the beginning for the viral hunting microarray and ones like it. New viruses (HIV, hanta and Ebola being the most notorious recent examples) arise and evolve frequently, their strategy for staying a step ahead of immune system efforts to kill them -- and with the dramatic increase in international air travel there is a heightened need to detect and contain diseases quickly.

But the self-described "viral hunter" is also applying the microarray to studies of diseases that, while less sensational in their debut, also wreak havoc on people's lives. In collaboration with infectious disease specialist Don Ganem and pulmonologist Homer Boushey, DeRisi is studying the viruses that may cause or exacerbate respiratory illnesses, including asthma. (Currently, scientists are only able to determine the specific virus causing respiratory disease in 20 percent of cases.) He also has begun working with Ganem and neurologist Jorge Oksenberg to examine multiple sclerosis, a severe neurological disease in which a viral component is believed to sometimes cause or exacerbate flare-ups.

"We want to be viral hunters," says DeRisi, whose funding for developing the microarray and carrying out the ongoing respiratory studies is provided by an award from the Sandler Program for Asthma Research.

He also wants to cure malaria, which he points out kills millions of people in the Third World but is not the focus of attention by pharmaceutical companies. In fact, this goal is the overriding passion of his lab. Using another microarray he developed, DeRisi's team is studying the life cycle of the malaria parasite, in order to find weak links in its metabolism. The ultimate goal is to identify drugs, such as chemotherapies, that would kill the organism.

"If you have an infectious disease like malaria, you're out of luck if don't have a credit card," says DeRisi -- unless, one surmises, he comes up with the answer.

Joe DeRisi. Photo by Robert Footorap.

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