Domaradskij, a foremost expert on the plague germ, insists that despite advances in synthetic biology, the real bioweapons threats have not changed. In his view, they remain smallpox, anthrax and plague. Decades of work in the Soviet bioweapons system convinced Domaradskij that these agents are unparalleled, supremely dangerous pathogens. Anthrax and plague are extraordinarily lethal bacteria. Untreated inhalational anthrax and pneumonic plague kill close to 100% of their victims. Except for rabies and untreated HIV, no other pathogens are as deadly. Anthrax also is amazingly durable in the external environment. When buried in soil, its spores remain viable and infectious for decades, perhaps even centuries. Anthrax contamination can make a large area virtually uninhabitable.

From a bioterrorist’s point of view, it’s highly desirable for a disease to spread quickly. Contagion is a chief virtue of smallpox, which kills an estimated 30% of those infected and leaves many of the rest scarred or blinded. Officially deemed eradicated from nature in 1979, smallpox is a highly adapted human pathogen; plague (one form of which is contagious) and anthrax are both animal diseases that are deadly to humans.

If terrorists wanted to go beyond these three, there are plenty of other less formidable but still dangerous natural germs—tularemia, brucellosis, Q fever, glanders and the reconstituted 1918 flu virus, among others. All are so-called select agents, kept under tight constraints by the government to limit possible misuse, accidental or otherwise, by researchers with access to them.
But some scientists contend that the whole idea of a long select-agent list, with the attendant tortuous restrictions, background checks and reams of paperwork, is rendered meaningless by the threat of synthetic biology. What’s the point of curbing access to particular agents if you can just produce endless new forms of life in the laboratory?

Roger Brent, president and research director of the Molecular Science Institute, an independent, nonprofit research organization in Berkeley, thinks we face a future of numberless synthetic microbes, the products of what he terms a revolution in biological competence. “It’s inevitable that somebody will deploy an infectious organism that has been hacked,” Brent says. He points out that scientists already routinely use altered agents—viruses as vectors for vaccines, for example. Like a designer pathogen, Brent says, vaccine vector viruses are constructed to infect human tissue and replicate, and he doesn’t see any qualitative difference between a virus altered to vaccinate a patient and a bug created to make people sick.

Steven Block, a biophysicist and biodefense expert at Stanford University, also sees a threat from synthetic agents. “Nature is creating pathogens all the time,” Block says. “If someone is bent on destruction, it should become possible to synthesize whole new genes, to create chimeras through mix and match. These germs don’t have to work at all well. They don’t even have to be very successful in the wild. They just have to kill a lot of people.”

Yet so far, there have been only a few instances in which altered microbes have been produced, and none gives much support to the idea that such an approach would be a bioterrorist’s dream. For example, there’s evidence that the Soviet Union’s bioweapons program created antibiotic-resistant strains of the plague germ Yersinia pestis. Scientists did this by adding genetic information conferring antibiotic resistance from E. coli, a distant relative of Yersinia pestis, to the plague germ, via tiny rings of DNA called plasmids. But Domaradskij, who originated these engineered plague strains, points out that altering bacteria even in this straightforward way is problematic: The plasmid can fall out, and the germ will lose its resistance. Moreover, though quite basic as genetic modifications go, engineering antibiotic resistance requires considerable scientific sophistication. It’s hard to imagine anyone making antibiotic-resistant plague germs in a cave in Waziristan.

Another data point: An Australian team reported in 2001 that while it was trying to develop fertility control for mice, it introduced into mousepox virus DNA a gene that codes for interleukin 4 (IL-4), a protein that stimulates the immune system. Sixty percent of mice that got the gene died, including those that had been vaccinated against mousepox or were normally immune. The experiment caused an uproar, primarily because mousepox is related to smallpox, and experts feared introducing IL-4 into the smallpox genome could likewise override human immunity.
Strict World Health Organization oversight on all smallpox work ensures that no American scientists will be “heating up” the closely restricted smallpox virus to see whether IL-4 might make it deadlier. But Mark Buller of Saint Louis University replicated the Australian mousepox experiment with a few enhancements of his own, and his modified IL-4 virus achieved a 100% kill rate. When he tried to get his chimeric mousepox to spread from mouse to mouse, however, Buller found that the infected mice generally died too quickly to pass on the disease. And although mousepox normally spreads quite easily, the few IL-4 mice that lived long enough to infect others seemed to transmit the disease less effectively than do mice infected with naturally occurring mousepox.

All of that suggests a serious flaw in any plan to use IL-4 to make smallpox a more efficient killer. Engineered smallpox might improve on the typical 30% fatality rate of natural smallpox strains, but it likely wouldn’t cause an epidemic—and if not reliably contagious, it would be no better as a bioterror agent than, say, anthrax.