Bioterror Researchers Build a More Lethal Mousepox

November 1, 2003

By WILLIAM J. BROAD

Scientists have created a highly lethal virus in an effort to develop stronger protections against supervirulent forms of smallpox that terrorists might turn on humans, researchers said yesterday.

The genetic engineering involved a virus known as mousepox, which infects mice but is not known to hurt people. Into that virus the scientists spliced a single gene that made it superlethal, then tested it on mice treated with different combinations of a smallpox vaccine and drugs.

The scientists said the results showed that the best defenses proved quite effective in preventing deadly disease not only in mice, but probably in humans exposed to customized smallpox of similar design.

This type of research has been debated for years, with critics arguing again yesterday that superviruses created in laboratories could inspire terrorists to create their own deadly diseases. The mousepox scientists countered that the research could help deter terrorism by demonstrating the emergence of more potent medical defenses.

The mousepox research was done at St. Louis University as a project financed by the National Institute of Allergy and Infectious Diseases meant to find new protections against smallpox, which kills one in three victims.

The leaders of the research said that the lethal mouse virus would have no effect on humans even if it somehow escaped from the laboratory, which they said was safeguarded at biosafety level three, the second-highest degree of security.

"To my knowledge, there's no scientific evidence to suggest that this kind of research poses any sort of human health risk," said Mark Buller, a professor of molecular microbiology at St. Louis University who directed the mousepox research. Many experiments have shown that mousepox does not cause disease in humans, he said.

It goes beyond similar research on mousepox that Australian scientists reported in early 2001. They warned that their genetic technique, which they said they stumbled onto, could overpower existing vaccinations and produce deadlier kinds of biological weapons. The news prompted heated scientific debate internationally.

Yesterday, Dr. Buller said the St. Louis researchers had also made a designer form of cowpox, another cousin of smallpox, to better understand how easy or difficult it would be to apply the same kind of genetic engineering to the human smallpox virus and make it more lethal.

Experts said both the threat of such developments and the federal response seemed part of a theoretical debate, not something to worry about for now. They split over whether the research was prudent. Some argued that, given the accelerating pace of advances in genetic engineering, it was wise to investigate worst cases and responses.

"If we do not act across a wide range of areas we will be failing in our responsibilities as global citizens," said Ken Alibek, a former leader of the Soviet Union's germ weapons program.

Other experts called such research a slippery slope that could aid terrorists, and argued that the research should have had the kind of rigorous peer review that a National Academy of Sciences panel called for last month in new recommendations.

"This is bigger than the original Australian work," said Elisa D. Harris, a Clinton administration arms control official now at the University of Maryland. "They knew the mousepox results and deliberately set out to build upon that work in a way to create a more deadly virus."

"There was a need here," she added, "for consequential research to be reviewed to weigh the potential risks and benefits before the work proceeded, and that apparently didn't happen here."

Dr. Lawrence D. Kerr, a senior official at the White House Office of Science and Technology Policy, agreed, noting that the research began before the recommendations were issued and would have undergone such scrutiny if begun now.

"This is the exactly the kind of scenario" that federal officials worry about, he said in an interview.

Eradicated two decades ago, smallpox no longer exists in nature or human populations. Officially, only the United States and Russia have stocks of the virus, under tight security. But federal experts suspect that clandestine supplies of the virus exist or could be fabricated.

The mousepox research was first reported in the current issue of New Scientist, a British magazine.

It involved inserting into the mousepox virus a mouse gene that controls interleukin-4, a primary chemical in the immune system's response to invaders. In the Australian case, the designer virus so crippled mice's immune system with extra production of interleukin-4 that the microbe reproduced wildly, killing mice that had been vaccinated and leaving others permanently disabled.

Yesterday, Dr. Buller said the St. Louis research made the killer germ more lethal by inserting the interleukin-4 gene into an unimportant region of the virus's DNA, unlike the central part of the genome that the Australians chose. That allowed the virus to multiply even faster, he said.

"It can't affect humans," he emphasized repeatedly.

The human smallpox vaccine offered no protection to mice exposed to the superlethal virus. "They all died," Dr. Buller said.

The antiviral drug cidofovir similarly failed to give protection. But a combination of the drug and vaccine, he added, saved some mice. The researchers found that the best protection was a combination of cidofovir with a monoclonial antibody drug that fought the effects of interleukin-4. "We protected all the mice from a very high dose" of the virus, he said.

He added that he planned to submit the research for publication and had no qualms about disclosing the exact location of the gene transfer. "It's irrelevant" to the design of a human weapon, he said.

Dr. Buller said that colleagues at the Army's biodefense institute at Fort Detrick, Md., were planning to test the superlethal cowpox virus on mice. Yesterday, neither the White House nor Fort Detrick would comment on whether those plans had been approved.

The cowpox virus can infect humans, though the resulting disease is usually mild. Still, critics worry about the ramifications of such research, for safety and for precedent. "The issue here," Dr. Harris said, "is the potential of this research being misapplied for destructive purposes."