In the struggle of human against virus, it pays to be prepared.
In early June, after months of press conferences and university lectures stressing vigilance to the emerging global SARS epidemic, North Carolina’s state epidemiologists and UNC Hospitals staff had reason to mobilize. A contract UNC-Chapel Hill employee, having visited a sick relative in a tainted Toronto hospital, came down with severe acute respiratory syndrome while on the job. State health officials quarantined the man’s coworkers, caregivers, and family in a successful effort to control the infection.
At the same moment, though, Ralph Baric, professor of epidemiology and microbiology and immunology, was doing the opposite. He was figuring out ways to make more of the deadly virus by rebuilding it from the bottom up.
But he’s no rogue scientist.
Baric was attempting to create an infectious clone of the urbani strain of the SARS coronavirus. By July he had successfully tested — at the Army’s top bio-level three labs in Maryland — his cloning approach, which could lead to a SARS vaccine and less of the deadly disease.
“It is nice to be positioned to respond to a potentially important human problem,” Baric says. His SARS clone will allow other researchers around the world to produce other mutated SARS coronaviruses in an attempt to find one that the human body could tolerate enough to produce antibodies. (Baric is also an expert in Norwalk viruses, the pathogen that has caused widespread illness among cruise-ship passengers.)
For twenty-one years Baric has studied coronaviridae, a family of viruses that causes 15 to 30 percent of our common colds and devastates swine, cattle, cats, and lab rats with severe illnesses. Coronaviruses, with their protein envelope and halo of spikes, are the most complex of the positive-stranded RNA viruses. RNA viruses replicate in the cytoplasm of the host cell independent of the cell’s nucleus.
The coronavirus replication strategy is unique, Baric says, and in 1982 he thought it would become an exciting field of virology. But a year later, HIV emerged, and the world’s attention turned to the human immunodeficiency virus. Even so, Baric kept his focus.
Normally jocular, Baric now has more reason to smile — he was right all along. “A lot of my research pointed to the fact that new coronaviruses had the high potential to emerge and cause significant disease,” Baric says. He published a paper in 1995 suggesting that danger.
“His predictions came true in remarkably short time,” says Mark Denison, a physician at Vanderbilt University Medical Center who has known Baric for fifteen years and is currently collaborating with him on two coronavirus studies.
What makes a coronavirus so serious, Baric says, is its high rate of recombination and mutation, a constant genome shifting that gives viruses abilities to efficiently replicate and to evade animal immune defenses. With increasing population densities and ecological change, we’re becoming exposed to more exotic animals and the viruses they harbor. The civet cat and other species found in the live-animal markets of China have been implicated in the transmission of the SARS coronavirus to humans.
Baric is an expert in the study of cross-species transmission. As he studied the way coronaviruses move from one species to another, he found that the viruses become more prolific. “They become generalists,” adapting to multiple species at the same time, he says. Mouse hepatitis virus, for example, adapts to humans just as easily as it does to hamsters and primates.
Then, once a virus is comfortable in a particular species, he says, it probably evolves into a specialist, developing a more efficient replication and transmission strategy for that specific animal. Over the past decade, several new coronavirus pathogens emerged in pigs and cows. These viruses spread globally and within a few years of emergence caused considerable economic loss in the United States and elsewhere.
Baric is the only U.S. researcher who’s been able to clone any of the coronaviruses, which had eluded laboratory manipulation for many years. He and his students, including Boyd Yount and Kristopher Curtis, developed a method to reproduce multiple viruses, break their genomes into fragments that could be genetically manipulated, and then patch pieces of each into a full-length clone from which molecularly cloned viruses could be recreated in the laboratory.
It was a profound approach, Denison says, and one that has dramatic implications for how scientists study coronaviruses. Susan Baker, a virologist at Loyola University Chicago, agrees.
“Ralph’s work on the systematic assembly of a full-length infectious cDNA of coronaviruses — first for the porcine coronavirus and then for the murine coronavirus — produced landmark studies,” Baker says. She praises Baric for sharing the clones with other researchers, who use his creations to put specific mutations back into the genetic information of the virus to learn if the mutations have any effect on virus replication.
The global focus on SARS, and the scientific community’s interest in Baric’s work, meant he was able to persuade university officials to convert an unused bio-level three laboratory into a coronavirus lab. And this summer, the National Institutes of Health shoved money Baric’s way to support his efforts to produce the infectious SARS coronavirus clone. Within a few years, this clone could lead to an attenuated virus — a live SARS virus that has been tweaked so it’s no longer deadly. That, in turn, could be used to create an effective vaccine.
Baric’s dedication to understanding the minute details of coronaviruses has made him a “go-to guy” that other virologists respect, says Curtis, a recent doctoral student mentored by Baric.
“There’s nobody in the field that I respect more,” Denison says. “Ralph deserves a tremendous amount of credit for his work.” Indeed, Baric was quickly invited to participate in the important weekly SARS teleconferences convened by the Centers for Disease Control and Prevention in May and June.
By August the world health community had beaten back SARS and learned a valuable lesson.
“The SARS coronavirus illustrates that even supposedly benign viral pathogens have considerable potential to evolve and cause significant disease,” Baric says. “And really what that means is basic research in all virus families — even those that don’t seem to be important pathogens — has the potential to have big payoffs.”