In 1859 a wealthy Australian grazier named Thomas Austin imported for sport thirteen wild English rabbits to his estate near Geelong, in Victoria. The rabbits did what rabbits do, and within three years 14,253 of them had been shot on Austin’s land. By 1869 more than two million had been killed on a neighbor’s property. Soon hundreds of millions of rabbits formed what became known as a “gray blanket” across the continent, destroying native plants, competing with native animals for food and shelter, and savaging grazing lands. In 1950 the government agreed to wage bio-warfare against them, and scientists released myxomatosis, a rabbit-specific pox virus from South America, into the wild. The virus quickly killed 99 percent of the country’s rabbits. During the next three years, however, the kill rate among the initial survivors and their descendants dropped to 95 percent; it continued to decline until, eventually, it leveled off at about 50 percent. “It was a classic example of the co-evolution of virus and host,” Frank Fenner told me recently. Fenner, a virologist at the John Curtin School of Medical Research, in Canberra, headed the studies analyzing why myxomatosis became less effective. In essence, he said, “you’ve got this arms race” in which the virus becomes weaker and the rabbit more resistant.
In 1988 a young virologist named Ron Jackson began working at what would later be called the Pest Animal Control division of the Cooperative Research Centre, in Canberra. His goal was to devise a solution that would sidestep those evolutionary forces and work indefinitely. Specifically, he hoped to produce a genetically altered virus that would sterilize rabbits. Jackson initially planned to use myxomatosis, but he couldn’t easily get the rabbit genes he needed to engineer the virus. So he switched to mice and a virus called mousepox, intending to perform a “proof-of-concept” experiment that would allow him subsequently to proceed with rabbits. When the project showed early signs of success, he realized that the strategy might also be applied to mice, which bedevil Australia almost as much as rabbits do.
Every four years or so Australian mouse populations explode, causing what is referred to as a plague of mice. Each mouse plague costs the grain industry roughly $75 million in lost production. “So we view it very much that we’re working on industry’s behalf,” Tony Peacock, the head of the Pest Animal Control division (essentially, Australia’s Minister of Pests), told me recently. Mouse plagues also affect the general population, causing annoyances large and small; for example, mice are expert at chewing through electrical wires in people’s homes.
And then there are rats, which cause widespread damage in Australia and destroy up to 20 percent of the world’s rice crop—$4.5 billion worth—each year, and which carry some sixty viruses that can infect human beings. Research into contraceptives for rabbits and mice might ultimately have the added benefit of pointing to an effective strategy for controlling rats. Back in 1988 there seemed no reason not to pursue it.
“What Have We Created Here?”
Ten years later, on January 27, 1998, Ron Jackson’s day began, like many of his days, with a drive along the winding roads of the Australian National University campus in Canberra. Eventually Jackson pulled up in front of the brick buildings of the John Curtin School, located across town from his own lab at the Cooperative Research Centre. The school is one of the few places in the world where researchers can work with mousepox. Although it is closely related to variola, the virus that causes smallpox in human beings, mousepox cannot harm people. It can, however, wipe out entire colonies of mice. An accidental release of mousepox among laboratory mice could ruin months’ or even years’ worth of experiments, so the school takes many precautions to ensure that the mousepox used there stays there.
Jackson came first to the outer door of the animal lab. Next to it a sign warns, in block red letters, NO ADMITTANCE. HIGHLY INFECTIOUS AREA. After swiping his key card, he walked down the hall and entered the “clean room,” a small vestibule lined with bright-green surgical gowns. He donned a gown and snapped on a pair of powder-blue polypropylene shoe covers. He then opened the door to the “dirty room,” a facility with negative pressure to prevent air from escaping. Inside the dirty room, amid the odors of mouse food and urine, he padded over to two metal cages, each of which held five mice of the strain known in lab shorthand as Black 6.
Jackson and his fellow researchers, who included Ian Ramshaw, an immunologist at the Curtin School, were working with a genetically engineered mousepox that should have caused no serious harm to Black 6, which can survive even the most lethal known strain of the virus. Ideally, female mice infected with Jackson and Ramshaw’s virus would become sterile and would also infect other females, sterilizing them as well. The virus would work like a vaccine, preventing pregnancy much as a vaccine prevents illness.
Mice, like human beings, coat their eggs in a jelly composed of several proteins. The jelly helps sperm to implant and protects the fertilized egg as it makes its way through the fallopian tube. Female mice normally do not mount an immune response to their own eggs; but Jackson and Ramshaw reasoned that if female mice became flooded with high doses of an egg-jelly protein, the mice’s immune systems would “break tolerance” for the protein: the protein would, in effect, look like foreign material, triggering an antibody attack against the eggs. Because the protein is neither infectious nor transmissible, it would have to be carried by another agent—a sort of Trojan horse. Genetically engineered mousepox would serve as the Trojan horse.
Earlier that month Jackson and Ramshaw had published a paper suggesting that their virus could work: in one strain of mice it had sterilized 70 percent of the females they had tried it on. There was a big catch, however: it failed to work in two other mouse strains. To reduce mouse populations significantly, a sterilizing vaccine would, of course, have to work in many strains. The researchers decided to tackle the problem head on, refocusing their efforts on the most recalcitrant of the other two strains—Black 6.
Jackson and Ramshaw theorized that the immune system in Black 6 was so effective against mousepox that it was destroying the Trojan horse before it could breach cellular walls and deliver the protein. They decided, therefore, to tweak the immune system in two ways, simultaneously boosting its attack on the protein and blunting its attack on the mousepox. The researchers were encouraged to pursue such seemingly contradictory aims by the fact that the immune system has a seesaw-like mechanism. On one end of the seesaw are Y-shaped antibodies, which latch onto proteins and render them inert. On the other end are so-called killer cells, which target and destroy cells infected by foreign invaders. Tilting the seesaw toward a greater antibody response should, theoretically, push it away from producing killer cells, allowing more mousepox to survive long enough to deliver the protein.
In an effort to tilt the seesaw in this way, Jackson and Ramshaw inserted a gene for interleukin-4 into their mousepox. IL-4 is a chemical, secreted by the immune system, that boosts the production of antibodies in both mice and human beings. On January 21 the team injected ten Black 6 mice with the new version of mousepox. Six days later, when Jackson checked on the mice, he found that the IL-4 had had a vastly different effect from what he’d expected. One mouse was dead, its tissues badly swollen—a classic symptom of mousepox. Several others were hunched up and quiet. Two days later three more mice died; by the end of the month all ten were dead.
Jackson and his colleagues immediately realized the implications with respect to smallpox and its potential as a biological weapon. “We’d come up with, at least with mousepox, a highly effective mechanism for increasing lethality of a virus for genetically resistant animals,” he explains. In short, they had stumbled on what might prove a relatively simple way to bolster the killing power of smallpox, already one of the most feared viruses of all time.
Soon the researchers would have data that were even more alarming. The mice, they realized, had died because the IL-4 had undermined their production of killer cells too well, leaving the animals vulnerable to a disease they were normally able to resist. What would happen, they wondered, if they vaccinated Black 6 mice against mousepox before injecting them with the IL-4 version of the sterilizing virus?
By November, Jackson had the results: even in vaccinated mice the mousepox with IL-4 was lethal 60 percent of the time. He immediately went upstairs to Ramshaw’s office to convey the news. “Oh, boy,” Ramshaw said. “What have we created here?”
Again, the implications regarding smallpox were inescapable. The vaccine against smallpox was so effective that the World Health Organization eradicated variola from the human population more than two decades ago, and routine vaccinations were halted. All stockpiles of the virus were destroyed, save for two: one in a laboratory in Atlanta, Georgia, the other in a lab in Koltsovo, Russia. Mass vaccination would be our most effective defense should terrorists (or “rogue nations”) obtain smallpox and use it as a weapon. But a version of variola containing IL-4 might render that defense useless.
Jackson and Ramshaw knew that the bio-weapon they had created to combat common pests—a weapon whose mechanism might be used to intensify a host of human diseases, not just smallpox—fundamentally altered the world’s terror equation, much as suicide hijackers did again three years later. What they did not know was how to handle their findings, or even whether to publish them at all—a quandary that molecular biologists will increasingly face. Their uncertainty would be borne out: when they did publish their results, in February of last year, they found themselves at the center of a media storm that distorted many of the details and implications of their work. People would soon begin imagining the worst: terrorists unleashing a virulent disease and public-health officials mounting enormous vaccination campaigns, only to see those vaccinated rapidly succumb; health-care workers dying by the hundreds; panic sweeping the populace, with some people blocking access to their communities and others taking to the backwoods with food and weapons in an effort to escape. Moreover, the media’s handling of the story would muddy a vital discussion about how to gauge the threats posed by natural and engineered bio-weapons and how to determine what steps scientists, policymakers, and the public should take.
The Perils of Playing Ostrich
The mousepox-IL-4 results surfaced at a time when the public had an unusually hearty appetite for such information. The late 1990s had brought startling revelations about bio-weapons programs in the former Soviet Union and Iraq, along with rising concerns about emerging viruses such as Ebola and West Nile. Some scientists had begun to discuss the potential of genetic engineering to create bugs that could cause mayhem. Steven Block, a biophysicist at Stanford University, quickly established himself as a leading oracle of doom, albeit one with a carefully reasoned argument based on cutting-edge science.
To Block, the mousepox- IL-4 data represented a vindication of sorts. “I was enormously relieved that someone did this,” Block told me when I visited him in his lab last winter. “We needed at least one example like this to galvanize our thinking and our actions. I believe on balance they’ve done us a service.”
Block came to bio-weapons through JASON, an elite, semi-secretive group of nearly fifty primarily academic scientists who provide independent advice about national-security issues to the U.S. government. (The group is named after the figure in Greek mythology who set out with the Argonauts to fetch the golden fleece.) In 1997 Block led a JASON study of the threats posed by recent advances in molecular biology. The results, published in a collection of essays called The New Terror (1999), in a chapter titled “Living Nightmares,” constitute a chilling overview of the ways in which new technologies might allow the creation of “designer bugs” that would be everything a terrorist could hope for: safer than conventional bugs to handle, easier to distribute, more contagious, deadlier, and better at dodging existing drugs and vaccines.
Cradling a cappuccino (brewed on his lab’s $5,000 Italian espresso maker) as we spoke, Block mixed rapid-fire discussion of “stealth viruses,” “binary weapons,” and “gene shuffling” with references to a fictional “Q” bomb (from The Mouse That Roared) and H. G. Wells’s warnings in The Outline of History (human beings more and more often find themselves in “a race between education and catastrophe”). A clock with a photo of Albert Einstein on its face hung on the wall, and a row of trophies that Block won in banjo-playing competitions adorned one shelf. “There have been a lot of criticisms of the JASON report that said, ‘Block, this is all good and well, but that stuff is so far out there, it’s so futuristic, it’s so weird, we shouldn’t devote any of our time to this sort of fictional nonsense—let’s worry about the real world here,'” Block told me. The mousepox experiment, he emphasized, shows that the threat of designer bio-weapons must now be considered part of the real world.