Smallpox Extermination Proposal Stirs Scientists

Eminent virologists from around the world are reacting strongly--both for and against--a recommendation made in September by a World Health Organization (WHO) committee to destroy all remaining stores of the smallpox virus. At a September 9 meeting in Geneva, the 10-member WHO Ad Hoc Committee on Orthopoxvirus Infections unanimously agreed that the potential costs to humanity from biological warfare or inadvertent outbreaks of the disease outweigh its research benefits to Science--especially when there are alternatives to using the live virus for scientific investigations. Advocates of preserving the viral stores argue, however, that given the powerful microbiological tools that have been devised in the recent past, it is short-sighted and foolish to get rid of the live virus just yet. They contend that information that is likely to be discovered in the smallpox genome could help fight other deadly viral pathogens, most notably HIV. "To me, on a scientific basis, we're taking an extremely precious resource and destroying it," asserts Bernard Fields, chairman of the microbiology and molecular genetics department at Harvard Medical School in Boston. While he does not advocate that researchers "immediately start doing experiments with the virus," Fields stresses that "destroying it ends the whole issue of possibly understanding it in the future." On the other hand, David Baltimore, Ivan R. Cottrell Professor of Molecular Biology and Immunology at the Massachusetts Institute of Technology in Cambridge, maintains that "we can get a lot of information from a variety of other routes, which I think scientists will be prepared to take because they're safe." He adds, referring to concerns that terrorists might use the virus in biological warfare: "Balance [these alternative methods] against the fact that there are nuts in the world, and I would just as soon get rid of it." If the recommendation to exterminate the stores by June 30 is carried out, it also means that the smallpox virus--more specifically, the variola strain, which is deadly to humans -would have the distinction of being the first species to be intentionally eliminated. Before the remaining stocks are autoclaved and incinerated, health ministers from around the world will vote on the ad hoc committee's recommendation at the annual meeting of the World Health Assembly--the decision-making body of WHO-next May in Geneva. Currently, live viral stocks are held in freezers in high-containment laboratories at the Centers for Disease Control and Prevention (CDC) in Atlanta and the Institute for Viral Preparations in Moscow. Smallpox was once the scourge of almost every inhabited continent on Earth, with hundreds of cases appearing in the former Yugoslavia as late as the early 1970s. In 1967, WHO launched an aggressive vaccination campaign to eradicate the disease. Ten years later, a man from Somalia was the last known person in the general populace to die of smallpox. In 1979, WHO announced that the Earth was smallpox-free, making the virus the only contagious pathogen ever to be eradicated. WHO first suggested that the virus be destroyed in 1986. According to Frank Fenner, chairman of the current WHO committee, there were no strong objections from the scientific community. But, he adds, in the interests of detente, a United States-Soviet Union collaboration was proposed in 1990 to sequence the virus, thus giving smallpox a reprieve until December 1993. "The U.S. Na-tional Academy of Sciences and the Russian Academy of Sciences got together and thought a way of softening Cold War attitudes might be to set up a collaborative enterprise of sequencing the genome of the variola virus," notes Fenner, who is also a professor, emeritus, at the John Curtin School of Medical Research of the Australian National University in Canberra. To date, two strains have been totally sequenced along with portions of five others. Another strain is currently being collaboratively sequenced by CDC and the Moscow institute, says Joseph Esposito, director of the WHO Collaborating Center for Smallpox and Other Pox Virus Infections at CDC. Should the virus be destroyed, the collaborating laboratories in Moscow and Atlanta will remain open, says Esposito. Among other responsibilities, he reports, the CDC center will continue working with other poxviruses. The WHO committee also recommended that CDC and the Moscow institute become repositories for cloned smallpox DNA stored in recombinant plasmids. But in mid-1993, Fenner says, a "small minority" of mostly U.S. scientists whose "words carry a lot of weight" expressed reservations about the standing directive to eliminate the virus after it was sequenced. These scientists voiced their hesitation despite the endorsement of the WHO committee's recommendation by several groups, including the American Society for Microbiology and the Council of the International Union of Microbiological Societies. Although the committee listened to the pleas from the scientific community to save the virus, Fenner says, the committee represents 156 nations and couldn't justify keeping the virus on hand because of a few vocal, yet eminent, virologists. "It was a small minority, and I think that weighed in the consideration of the committee," he remarks. To the WHO committee, the most compelling argument to get rid of the smallpox stores is the potential for the virus to be used by terrorists for biological warfare (B.W.J. Mahy et al., "The remaining stocks of smallpox virus should be destroyed," Science, 262:1223-4, 1993). "Political stability is a relative thing," Baltimore observes. "In a perfect world we would have a perfect repository where we could keep it just in case we were wrong [about destroying the smallpox virus], but I don't think that makes any sense now, since all of its information is decoded." But Fields views this reasoning as political rhetoric, not a scientific dilemma at all. Moreover, he says, this objection can be addressed through concomitant political solutions: "There are political ways to deal with that. Remove it from CDC and Moscow and put it in a neutral country under extremely safe conditions." Nonetheless, Fenner maintains, the committee's responsibility to the people it represents is justification for destroying the virus: "There are more countries in the world experimenting with bacterial warfare than there were a few years ago, and many countries feel more comfortable if there weren't these 600-odd strains of virus just [kept] in a deep freezer." Advocates of saving the virus, however, contend that, in any case, eliminating lab-controlled stocks doesn't mean that the threat of a smallpox outbreak is gone forever. Three potential sources, they say, exist: possible stocks unwittingly or intentionally stored in non-WHO laboratories; possible preservation of the virus in the tissues of smallpox victims buried in the Russian permafrost region; and possible re-emergence through a monkeypox variant. Given these circumstances, they ask, why not maintain the stores for study? Committee chairman Fenner counters that the likelihood that a vial of smallpox virus would be found in storage somewhere unbeknownst to WHO "gets more and more remote as time goes on" and if someone is keeping it secretly, there's "no way of knowing that, anyway." He also calls the chances that an epidemic would be initiated from permafrost cadavers "remote" and points out that easy transmission of the monkeypox virus in humans "hasn't happened in the whole human occupation of the rainforests of western, central Africa." In that unlikely event, WHO officials add, they have about 500,000 doses of vaccine readily available, with more capable of being produced in a matter of weeks. On the other hand, the possibility of accidental release from the lab is significantly less remote, according to the committee and its backers. "It can get out; it's proven its ability to get out," says Baltimore, referring to a 1978 isolated case that stoked early debates of what to do with the remaining stores. One year after the "last" death in Somalia, Janet Parker, a British photographer, became accidentally infected while taking pictures in a Birmingham University Medical School lab in which some samples were stored. Hers was the last recorded death by smallpox. This incident is the "practical example [of accidental infection] that everyone points to," he observes. "Even if that wasn't the case, we know that containment is never perfect. That's the problem with human beings--they're fallible." Supporters of retaining the virus, however, claim that the Birmingham incident couldn't happen in today's highly secure facilities in which the remaining smallpox stocks are stored. Opponents of the committee's recommendation maintain that biomedical researchers would forever lose unique scientific knowledge if the virus is destroyed, especially at a time when molecular biological techniques are just beginning to reveal so much about viral pathogens (W.K. Joklik et al., "Why the remaining stocks should not be destroyed," Science, 262:1225-6, 1993; L.S. Sandakhchiev, "We'd Better Think Twice Before Eradicating All Smallpox Virus Stocks," The Scientist, Aug. 23, 1993, page 11). They say that preserving the variola virus--at least for the next five to 10 years-for future study will aid in understanding the way other such other deadly viral pathogens as HIV operate and also in developing antiviral drugs. "Twenty years ago we didn't know anything about [smallpox] proteins," Wolfgang Joklik, James B. Duke Professor of Microbiology at Duke University in Durham, N.C., points out. "Twenty years ago we thought all the information present in a [human] viral genome was only to enable the virus to multiply. Now we know that half the information is to defeat the human defense mechanism." The smallpox virus infects humans exclusively. However, proponents of destruction say that genetic studies can be done without the live virus because the base-pair sequence of smallpox DNA has been mapped and that cloned smallpox viral DNA is being kept in recombinant plasmids. (As a precautionary measure, WHO also urged that no more than 20 percent of the plasmid fragments be housed in any one laboratory--with the exception of CDC and the Moscow institute--and that no studies be performed in labs where other poxviruses are kept.) But, Joklik counters: "To study smallpox pathogenesis, the complete virus is required, not just plasmid clones and a sequence. How viruses cause disease at a biochemical and molecular level is little understood, and in smallpox, viral proteins mimic or interfere with host immune and regulatory functions. Clones don't suffice for study because encoding regions of the smallpox DNA are separated from regions that control expression." Fields concurs: "Anyone who says the sequence is enough doesn't understand virology, and that includes some famous virologists. We have to understand holistic parts of this virus and how these work together. There are many other poxviruses [to work on], but not this one. This one is the key pathogenic virus in its family. It's qualitatively different." Even if the virus is destroyed, current pox research will proceed apace, according to Fenner: "Pox virologists are now working primarily with vaccinia [an avirulent strain of smallpox] and other pox viruses as vectors for novel vaccines" against diseases unrelated to poxviruses. Currently, the live smallpox virus is being used only in the sequencing project. One issue that does seem to trouble both camps in the debate is that, if the recommendation is carried out, smallpox will be the first species to be deliberately wiped out by humans. "I think that makes everybody a little unhappy," remarks Baltimore. "I do think that biological diversity is one of the great positive aspects of our planet and that we should be maximizing it rather than destroying it, so I think that that's a real concern. "On the other hand, it's very hard to find a positive side of viruses. As a virologist, that's always bothered me. If [eradicating] any species can be justified it's a species that has no obvious positive side to it, either aesthetic or any other." For the champions of sparing the virus, of course, this aspect of the smallpox debate is also of concern. "I don't mind containing things," Joklik says, "but I don't think we should destroy them. With the variola virus, obviously it's taken millions of years for nature to make it, and why should 10 guys sitting around a table say, 'Let's destroy it'? "It just doesn't make any sense to me because it's just such an admission of defeat to say we can't keep it safe."

Smallpox Extermination Proposal Stirs Scientists

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