When the World Health Organization's (WHO) external advisory committee on smallpox recommended last week that WHO allow the two research teams still possessing the virus to insert a green fluorescent marker gene into it to test the efficacy of potential anti-smallpox drugs, the committee also made at least six other research recommendations, according to a WHO spokesman, including at least two that some researchers find controversial.

The additional recommendations, which along with the green-marker proposal have yet to be approved by WHO, would allow labs around the world to work with fragments of the variola virus as large as 20% of the whole genome, according to Daniel Lavanchy, WHO's in-house smallpox expert. The proposals would also permit the two smallpox repository labs—one at the Centers for Disease Control and Prevention in Atlanta and the other at Novosibirsk in Russia—to insert variola genes one at a time into other viruses in the orthopox family, like monkey pox and cowpox, Lavanchy wrote in E-mail to The Scientist.

Two other recommendations would allow the Russian and American teams to share their smallpox samples with one another for the first time and to perform experiments on variola and other orthopox viruses simultaneously, provided the work is performed at the strictest biosafety containment level, BSL-4. Another two propose that other researchers elsewhere be permitted to synthesize smallpox fragments up to 500 base pairs in their labs but prohibited from synthesizing longer ones and, with microarrays, permitted to include the whole variola genome, just as long as individual array fragments are no longer than 80 base pairs. The six recommendations the committee approved last week were all proposed by its technical subcommittee in 2003.

C.J. Peters, director of the Center for Biodefense at the University of Texas Medical Branch in Galveston, said he has reservations about the proposal to allow individual labs to possess up to 20% of the entire variola genome. "If they're going to send out big chunks of genome, I think that's a problem," he said, because different labs with different chunks "would only have to link them together, and it would be a lot easier" to recreate the entire smallpox genome than it would be to synthesize it.

Lavanchy said this was a "theoretical possibility" because not all labs would receive exactly the same 20%. As a practical matter, however, he said, "this is a rare request from a few labs working on that, and it's absolutely manageable."

Richard Ebright, a professor at Rutgers University, said that a 10–15% threshold would be preferable because "the 20% threshold corresponds to about 37,000 base pairs," which he believes is too large a number.

The rationale for the recommendation to allow scientists to insert any single variola gene into any other orthopox virus is "to create a better model for drug screening," Lavanchy said. Because other orthopox viruses very similar to smallpox can be worked on at lower containment levels than the BSL-4 that smallpox requires, this proposal would allow faster and safer testing of candidate drugs to cure smallpox, he said. The proposal would require the two labs to ask WHO for permission separately for each variola-insertion experiment they want to conduct, Lavanchy said.

The committee also recommended that the two labs be required to perform the variola gene-insertion experiments at one higher biocontainment level than each orthopox virus normally requires, to guard against the possibility that a modified orthopox virus might be more virulent than the original one. The concern is always around when you manipulate," Lavanchy said. However, David Evans, a committee member from the University of Alberta, said there is no reason to think the modified virus would be more virulent.

Matthew Meselson, a professor at Harvard University, said he is unconvinced that the proposed increased containment requirement will be sufficient to contain any unexpectedly increased virulence. "You can't predict that," he told The Scientist. "There's always surprises."

Meselson said that the proposal to require a one-level increase in containment is an admission that the modified orthopox virus might be more risky than the original. "Once you admit that, how can you say that one level is right?" he asked. "Maybe half a level. Maybe two levels. Who's to say? That's not a scientifically addressable topic."

Although Ebright agreed that the single-gene insertion experiments may be somewhat controversial among scientists, he pointed out that if adopted, the recommendation would obligate WHO only to consider proposals for transfers, not to necessarily approve them. For Ebright, the most important point about the WHO committee's recommendations is to note the lack of similar international oversight for other select biowarfare agents, like anthrax or Ebola.