Tests on Monkeys May Help Scientists Thwart Smallpox

By MARILYN CHASE, Staff Reporter of THE WALL STREET JOURNAL

Although smallpox is one of humankind's oldest scourges, "it's almost shocking how little we know" about it, says David Relman, a Stanford University microbiologist.

The World Health Organization eradicated smallpox in 1980, "before the advent of modern molecular biology," Dr. Relman notes. While stamping out the deadly disease with vaccinations was a triumph, it left a major gap in the collective understanding of how the virus works -- and how modern medicine could thwart a bioterrorist who chose it as a weapon. Currently, there is no approved treatment for smallpox .

Tests on monkeys infected with smallpox last month could help fill that gap. Dr. Relman, as an academic collaborator, is working with a team of governmental animal researchers, who are giving smallpox to macaque monkeys with the hope of finding ways to outmaneuver the contagious virus, using early diagnosis, antiviral drugs, and novel high-tech tools. The experiments, raising a furor among animal-rights activists and some public-health school deans, began last month in a high-security lab at the U.S. Centers for Disease Control and Prevention in Atlanta.

If the experiment is successful in mimicking human smallpox, researchers will begin to test potential treatments in a new crew of monkeys. Tests of the first candidate drug, cidofovir, could begin as early as September, says Peter Jahrling, lead researcher of animal-model studies.

Cidofovir, made by Gilead Sciences Inc. of Foster City, Calif., is marketed as Vistide for an AIDS-related eye infection. Cidofovir previously had shown promise against somewhat similar pox viruses in mouse studies. However, it has never been tested against an animal infected with actual smallpox virus, or variola. Dr. Jahrling, a senior research scientist at the U.S. Army Medical Research Institute of Infectious Diseases in Fort Detrick, Md., also hopes to test a new oral form of the drug created by University of California at San Diego researchers.

Skepticism over finding an effective smallpox drug stems from concerns that, once the telltale blisters break out, it may be too late to treat the disease. But the animal-model tests may lead doctors to a method of early diagnosis. Last summer, in a prelude to the current monkey experiment, Dr. Jahrling found he could recover virus from throat swabs and blood tests of monkeys several days before blisters broke out. This summer, the team confirmed early detection, by using PCR, or polymerase chain reaction.

In the event of a bioterror attack, early diagnosis would enable public-health officers to screen exposed persons and identify infected people before they develop full-blown disease. This could help limit transmission of smallpox to others, as well as enabling early treatment.

Dr. Relman's group at Stanford also is using data from the monkey blood tests to create new high-tech smallpox tools called microarrays. These are small glass microscope slides, dotted with 30,000 to 40,000 DNA probes. The probes can detect the ways the body responds to danger of an invading virus. When the body detects a virus, it reacts, and a host of genes are turned on or off to make antibodies and other defensive substances.

To measure this reaction, DNA from the blood of infected monkeys is labeled with fluorescent tags and put on the microarray slide. When the fluorescent tags light up, they illuminate which genes are activated as the animal fights back against the smallpox .

Using the probes, scientists will get a detailed view of the virus's attack strategy and how the victim responds. By studying the immune responses of monkeys who live or die, scientists may gain clues that help them to predict which new drugs or vaccines might work best. Scientists will get the equivalent of a molecular blueprint of smallpox -- "a previously unavailable, detailed picture of what happens during infection," Dr. Relman says.

James LeDuc, director of viral disease research at the CDC, concurs: "It will give us a database to be mined for years."

For safety and security reasons, Dr. Relman wasn't allowed to take virus -- or the blood of infected monkeys -- back to Stanford. The only two known repositories of smallpox virus are stored in freezers at the CDC in Atlanta, and at Vektor, a virologic institute in Russia. Dr. Relman and his colleague Patrick Brown sent graduate student Kate Rubins and research assistant Addie Whitney to Atlanta to collect data from the infected monkeys for use at the Stanford campus in Palo Alto, Calif.