CDC racing to map smallpox genome

New tests, therapies a critical priority

When Dr. Inger Damon dresses for work, it takes a while.

First comes a doctor's scrub suit, followed by socks and gloves that are taped to stay put. She pulls an air hose from the ceiling to inflate her one-piece "space suit," checking for leaks before sliding into its heat-sealed gloves and booties. She settles its hood and face shield on her head, steps into a second pair of boots and walks to a heavy sealed door.

On the other side of the door lies the environment that demands such protection: the Bio-Safety Level 4 suite at the Centers for Disease Control and Prevention. It is one of the only labs in the world that works with smallpox.

"There are so many rituals going into the lab that it gives you a great deal of respect for the virus," said Damon, a leader of CDC's smallpox research effort.

Smallpox virus has been stored at the CDC since the disease was eradicated in the 1970s. CDC scientists took the virus from the freezer several years ago, racing to learn as much as possible about it before the World Health Organization destroyed the stockpile at the end of this year. On Thursday, the virus and the CDC got a reprieve: The WHO's Executive Board voted to postpone destruction indefinitely.

Terrorist threat

The stay of execution is based on fears that terrorists have the virus and might use it as a weapon: Most vaccinations against smallpox ended 20 years ago, and much of the world's population is vulnerable to it. The possibility of terrorism gives fresh urgency to a CDC research program that already has been working at a rapid pace.

"This started well before September 11," said Dr. James LeDuc, director of the smallpox research program. "I think its value is just now being appreciated."

The CDC is one of two institutions in the world where samples of the virus, called variola, were preserved by WHO. The other is in Novosibirsk, Russia. The collections -- 461 isolates here, and 161 in the Russian lab -- hold samples from dozens of countries: CDC's freezer contains varieties from Bangladesh, South Africa, Somalia and Britain, among others.

The WHO intended for both collections to be destroyed. Twice, variola has been reprieved. Its first execution date was mid-1999, until the WHO realized that new lab science methods could yield more information about the virus and pushed final destruction to the end of 2002. That launched the CDC's orthopox group -- 13 scientists who work with smallpox and its genetic cousins -- on an all-out effort to glean as much knowledge as possible before the deadline.

"It is a seven-days-a-week schedule," said Damon, chief of the poxvirus section. "I don't see that it can get much faster than it is already and still make sure experiments are done well and we are asking the appropriate questions."

The smallpox research includes scientists from the National Institutes of Health and the Department of Defense, but all work takes place at the CDC's headquarters, in the biosafety suites at the heart of the Clifton Road campus. That presumably is the home of the frozen virus collection: The CDC will not discuss its location nor allow the lab or freezer to be photographed.

The smallpox research has several goals: mapping the variola genome, creating lab diagnostic tests for smallpox and finding drugs for treatment if the disease returns. Those would all be achievements in basic science, but in the new era, they represent practical defenses as well.

"The defensive mode was always in people's minds, but it was never the real justification for this," LeDuc said. "Today that has all changed. The intelligence community is very much interested in the work we are doing."

Mapping the variola genome, for instance, adds new knowledge to smallpox science. But it also allows the CDC to build a detailed database of variola's genetic fingerprints, a tool that could help identify the strain being used if the virus were deployed as a weapon or pinpoint whether it had been genetically altered to be more virulent.

The genetic map also allows the CDC to check the integrity of its virus collection. The stockpile includes dried scabs that fall from smallpox lesions. Other sections of it contain multiple generations of the virus grown in culture, a process that can allow errors to creep in.

New techniques

Knowing which strains are pure serves the CDC's other research goals. Smallpox diagnosis and treatment did not change for more than 20 years, because they did not have to -- but laboratory science did. Techniques now exist that could allow the disease to be rapidly diagnosed by both genetic analysis of the virus and examination of a patient's immune reaction.

There have been similar changes in treatment. Antibiotics are useless against smallpox because it is a viral disease, so treatment for victims before eradication consisted mostly of making patients comfortable and protecting others from them. But the advent of AIDS after smallpox was eradicated spurred the rapid development of anti-viral drugs.

So far, one anti-AIDS drug, cidofovir, appears to be useful against variola. But it can be toxic and would be difficult to administer to large numbers of patients at once, so the CDC is looking for additional candidates.

"The goal is to have two fully licensed anti-virals so that resistance against the drugs would not evolve biologically and would be difficult to engineer," LeDuc said.

The search for smallpox diagnostic techniques and treatments has faced one significant obstacle: There are no cases of the disease to test them against. That leaves researchers with only virus grown in culture as a testing ground -- unsatisfying, because drugs must be successfully tested in humans to pass regulation by the Food and Drug Administration.

The solution has been a scientific achievement, although it is likely to prove controversial. CDC scientists have created what is called an "animal model" of the disease by infecting rhesus macaque monkeys housed in the high-biosafety suites with smallpox.

"It is not completely analogous to human disease," LeDuc said. "We need to refine it over the next course of experiments. But it is an important tool that allows us to evaluate in a living animal whether these drugs work."

The animal research should allow the CDC to test new smallpox vaccines as well. Health and Human Services Secretary Tommy Thompson has committed the Bush administration to acquiring 300 million doses of vaccine. Only 15.4 million now exist, although they could be used to protect 77 million people if research on dilution proves successful. But the current vaccine is dangerous for those with AIDS, cancer and organ transplants. There were few such patients in the population in the 1970s, but there are many now.

Beyond specific scientific goals, the CDC smallpox research program has a larger agenda: to spread reassurance about the disease.