A SCIENTIST funded by the US government has deliberately created an extremely deadly form of mousepox, a relative of the smallpox virus, through genetic engineering. The new virus kills all mice even if they have been given antiviral drugs as well as a vaccine that would normally protect them. The work has not stopped there. The cowpox virus, which infects a range of animals including humans, has been genetically altered in a similar way. The new virus, which is about to be tested on animals, should be lethal only to mice, Mark Buller of the University of St Louis told New Scientist. He says his work is necessary to explore what bioterrorists might do.

But the research brings closer the prospect of pox viruses that cause only mild infections in humans being turned into diseases lethal even to people who have been vaccinated. And vaccines are currently our main defence against smallpox and its relatives, such as the monkeypox that reached the US this year. Some researchers think the latest research is risky and unnecessary. "I have great concern about doing this in a pox virus that can cross species," said Ian Ramshaw of the Australian National University in Canberra on being told of Buller's work.

Ramshaw was a member of the team that accidentally discovered how to make mousepox more deadly (New Scientist, 13 January 2001, p 4). But the modified mousepox his team created was not as deadly as Buller's.

Since then, Ramshaw told New Scientist, his team has also created more deadly forms of mousepox, and has used the same method to engineer a more deadly rabbitpox virus. But this research revealed that the modified pox viruses are not contagious, he says. That is good news in the sense that these viruses could not cause ecological havoc by wiping out mouse or rabbit populations around the world if they escaped from a lab.

However, this discovery also means some bioterrorists might be more tempted to use the same trick to modify a pox virus that infects humans. Such a disease, like anthrax, would infect only those directly exposed to it. It would not spread around the world and rebound on the attackers. But there is no guarantee that other pox viruses modified in a similar way would also be non-contagious. Ramshaw's team made its initial discovery while developing contraceptive vaccines for sterilising mice and rabbits without killing them. The researchers modified the mousepox virus by adding a gene for a natural immunosuppressant called IL-4, expecting this would boost antibody production. Instead, the modified mousepox virus was far more lethal, killing 60 per cent of vaccinated mice. The addition of IL-4 seems to switch off a key part of the immune system called the cell-mediated response.

Now Buller has engineered a mousepox strain that kills 100 per cent of vaccinated mice, even when they were also treated with the antiviral drug cidofovir. A monoclonal antibody that mops up IL-4 did save some, however. His team "optimised" the virus by placing the IL-4 gene in a different part of the viral genome and adding a promoter sequence to maximise production of the IL-4 protein, he told a biosecurity conference in Geneva last week.

Buller has also constructed a cowpox virus containing the mouse IL-4 gene, which is about to be tested on mice at the US Army Medical Research Institute of Infectious Diseases at Fort Detrick, Maryland. Cowpox infects people, but Buller says the IL-4 protein is species-specific and would not affect the human immune system. The experiments are being done at the second-highest level of biological containment.

Ramshaw says there is no reason to do the cowpox experiments, as his group's work on rabbits has already shown the method works for other pox viruses. While viruses containing mouse IL-4 should not be lethal to humans, recombinant viruses can have unexpected effects, he says. "You'd hope the combination remains mouse-specific."

Why his group's engineered viruses are not contagious is a mystery, he says. It is not, for instance, because the host dies faster than usual, taking the virus with it. But his findings could explain why pox viruses containing IL-4 have never evolved naturally, even though the viruses frequently pick up genes that affect their host's immunity.

Despite the concerns, work on lethal new pox viruses seems likely to continue in the US. When members of the audience in Geneva questioned the need for such experiments, an American voice in the back boomed out: "Nine-eleven". There were murmurs of agreement.


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