To Vanquish a Virus

The best defense against SARS, should it resurface, may be an understanding of its natural history

ARMED FORCES INSITUTE OF TECHNOLOGY Contributed by Charles Humphrey and Anthony Sanchez of the National Centers for Disease Control and Prevention
The global SARS panic has fizzled. In early July, the World Health Organization (WHO) deemed all known chains of person-to-person transmission broken and cautiously pronounced humans SARS-free. Quarantine and isolation seem to have snuffed out the flames for now. But where SARS still smolders is not known. As world health officials draft priorities for the long-term response to the new disease, evolutionary biologists warn against embarking on vaccine development without a fuller understanding of where the virus lurks and how many genetic variations it has. To do so, they fear, could lead health experts down an unnecessarily long and cumbersome trail to treatment and prevention¿or worse, to a more virulent form of the disease.

The first line of defense against emerging infectious disease is epidemiologists. They grapple with questions ranging from how long the virus incubates before transmitting to a new host to how many new cases come from each sick person. After their detective work is complete and the virus has been traced back to its origin, evolutionary biologists tackle what the virus is doing and how genetic changes affect its ability to infect humans. The questions they seek to answer push the limits of science: Not only do they probe how a particular virus came to harass humans in the first place, they also look to predict how it will change as it adapts to our species. But some evolutionary biologists complain that their know-how is underutilized, pointing to the abysmal failure of vaccines against HIV¿the virus responsible for AIDS¿and flattened hopes for a drug cure as an example of infectious disease management gone wrong, because of poor data on the evolution and genetic diversity of the virus.

At the first global conference on SARS held in Kuala Lumpur, Malaysia, in mid-June, the top two priorities set by the WHO were the development of an effective measure to stop SARS transmission¿ideally a vaccine¿and an inexpensive, easy-to-use diagnostic test. According to a June 18 WHO report, experts agreed that not enough is understood about the origins of the new virus. Failure to specifically address the ongoing evolution in the relationship between SARS and its new human host has some evolutionary biologists worrying that the rush for a cure could follow the same ill-fated path as the quest for a quick fix for HIV.

In recent years, international organizations and governments have begun to channel funds into understanding the full panoply of HIV variants on the loose in the population. But for decades, most of the money was spent searching for a drug cure for the disease. Subsequent efforts to develop a vaccine have borne no fruit; the most recent disappointment coming from the much anticipated VaxGen clinical trials, in which the company¿s HIV vaccine, AIDSVAX, did not lead to a statistically significant reduction in HIV infection. The study revealed the ignorance of the medical community to the high degree of variation in the HIV virus within the U.S., says Keith Crandall of Brigham Young University, a consultant on the VaxGen study.

"Failure to monitor how viruses are adapting to human hosts will continue to allow viral evolution to proceed haphazardly, favoring harmful strains in one setting and mild strains in another," comments Paul Ewald of the University of Louisville. Like HIV, the SARS virus contains only a single strand of RNA, and lacks the "zipper" feature seen in its double-stranded cousin, DNA, that ensures more accurate replication. Left to its own devices, RNA makes mistakes as it copies itself and thus mutates rapidly. When developing vaccines, scientists often use a live but benign strain of the virus. The strain used must be similar enough to the disease-causing forms to allow the immune system to build up defenses against the virulent variety but not so similar that it causes disease or could easily evolve virulence. For a rapidly mutating RNA virus, as SARS is believed to be, such a strategy would be difficult at best and doomed to fail without a clear picture of how a strain selected for a potential vaccine stacks up, not only in terms of the number of mutations from the generic strains but also in terms of the molecular function of those mutations.

Paul Turner of Yale University has studied how incorporating carefully calculated mutations that amplify the weaknesses of other mutations in a viral strain can best utilize researchers?understanding of evolutionary biology to prevent live vaccines from adapting to human hosts. Public health experts, he says, are not trained to understand the pitfalls of how a particular disease can change and how its relationship to the host can also morph over time. "What you¿re implementing today could be set up for failure only a few years from now," Turner warns. "The way you manage the disease could actually put more in favor of the pathogen changing to a more virulent form." Researchers could target only a subset of the gene pool and thus inadvertently hand unknown¿and potentially more lethal¿strains a selective advantage.

But hope is not lost, Turner asserts. He and others view SARS as an opportunity for evolutionary biologists to interact with public health officials to make great strides in combating the disease. "With recent outbreaks it¿s becoming more apparent that at least [public health experts are] thinking about evolution," Crandall says. An evolutionary tree showing the origin of the SARS virus even appeared in the May 30 issue of Science. Still, it wasn¿t up to snuff, he notes. "They¿re not using the information to its fullest advantage. They draw the tree and draw circles around different groups and say, ¿Look, here¿s our SARS virus and here are these other coronaviruses and somehow it must be related to these other things.? What they¿re missing, Crandall observes, is what each change in the genome means to the function of the virus.

For his part, Crandall is studying SARS from a bioinformatics standpoint, looking at variants of the disease and identifying those nucleotide sites that have mutated without affecting viral function and those that have conferred a selective advantage to the virus. This sort of analysis, he explains, is key to understanding how new forms arise and will enable scientists to think more creatively about combating those particular sites that dictate the disease-causing characteristics of SARS. "It lets you know where the important changes have happened to make this a distinct virus," he says. Drugs can then be developed to target the specific sites that have mutated to enable the virus to infect humans, or to create a vaccine based on specific regions of the genome that have clear and meaningful differences from other coronaviruses.

In a matter of weeks the global scientific community has sequenced and shared 21 strains of SARS on GenBank, the National Institutes of Health¿s Web-based database of genomic information. Considering the speed with which that was accomplished, evolutionary biologists believe a broader survey of the genetic diversity of SARS is feasible in the short term. At last count, the WHO reported 8,437 cases of SARS and 813 deaths. Crandall is inclined to believe that more than just the 21 known variants caused disease in those people. "If you took a month to collect 500 isolates and sent them off to genomics labs, they¿d crank them out and within a year¿it would take a while to analyze such an enormous amount of data¿you could expect to have a very nice picture of the global diversity of SARS," Crandall remarks.

If SARS does indeed turn out to be highly variable and it reestablishes itself in the human population, a full understanding of how different strains cause disease will be critical, Ewald says. He believes that provided diagnostic tests are developed, such knowledge will enable scientists to treat the disease selectively, in a way that focuses on preventing the transmission of the most disease-causing strains, thus steering the virus toward a more benign character. Even if our ability to treat the disease progresses no further than it is today, with a better grasp on what¿s out there we can still use quarantine and isolation to our fullest advantage.

Ewald, who has been refining this theory of virulence management for two decades, sees SARS as a test. Not everyone agrees with this approach. James Bull of the University of Texas at Austin is one of the most outspoken critics of virulence management. He notes that there is no evidence of how SARS has adapted and evolved in humans, or if it has changed at all, making virulence management impossible to apply. Bull does see merit in treating only those individuals who are sickest while allowing those with mild symptoms to go untreated, however, based on the notion that having the less virulent strain will be a natural way to immunize people against the nastier virus.

Bull is less hopeful about the immediate role that evolutionary biology can play in the management of SARS. He notes that epidemiologists must address fundamental questions before evolutionary folks can do their job to the fullest. The first priority should be "getting out there, figuring out if there¿s a whole group of people being infected that are asymptomatic," Bull contends. "What are the contacts between these people? What is the rate of transmission? These are the things that will then allow us to get in there and stop this."

Laura Wright is based in New York City.
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