Detecting this particular agent is difficult, and so far neither Rubenstein nor any other scientist has been able to find it. Many have given up the hunt, concluding that the virus cannot be found because it does not exist. Among these is Stanley Prusiner, a professor of neurology at the School of Medicine of the University of California at San Francisco. It was Prusiner who, in 1982, coined the term "prion," to describe what he believed was the probable agent of scrapie: not a virus but Griffith's long-abandoned infectious protein. Eventually—most notably in a 1995 paper in Scientific American—Prusiner went so far as to assert that prions are the cause of TSE. Prusiner's is a powerful and convincing voice, and the prion theory of TSE transmission has come to dominate the field. Last year Prusiner was awarded the Nobel Prize in medicine for discovering prions.
"Some of us are reluctant to use the term 'prion' for the infectious agent, because it presupposes that the agent is protein only," Caughey told me. "But so far most of the evidence points in that direction." Caughey explained that unlike most viruses, the TSE agent is undeterred by exposure to radiation and resistant (up to a point) to destruction by heat—both indications that it lacks nucleic acid. Peter Lansbury, Caughey's frequent collaborator, says that the agent "has the chemistry of a protein." David Bolton, a scientist at the Institute for Basic Research, who got his start in Prusiner's lab at UCSF, agrees. Bolton says, "Every aspect of this disease is best explained by the protein-only model." But Bruce Chesebro, a virologist, an immunologist, a physician, and Caughey's boss at Rocky Mountain, is not so sure. Considered by many to be the "voice of reason" in what has become a rancorous debate, Chesebro believes that the abnormal prion protein is a result of TSE infection rather than the cause of it.
"Viruses are very small, and sometimes they take decades to find," he explained to me. "We haven't found one yet, but that doesn't mean it's not there." Chesebro also said that TSE agent is not uniquely invincible, as some have implied. "Most of the infectious agent dies under exposure to prolonged high heat and detergents," he said. "You can get rid of ninety-nine-point-nine percent of it simply by heating the stuff at a high temperature for thirty minutes." To buttress his point that viruses can be very hardy creatures indeed—perhaps as tough as TSE infectious agent—Chesebro reminded me that viruses recently discovered in the geysers of Yellowstone National Park live near or at the boiling point.
Laura Manuelidis, the head of neuropathology at Yale Medical School, is perhaps the harshest critic of the protein-only hypothesis. She contends that the public mistakenly believes that Prusiner (who rarely gives interviews) has proved his case, and that this has made it difficult for scientists with an opposing view to get recognized, or even heard. "The prion has taken on a mythical component—it's become magical," she says. "But to me, TSE shares all the signs of a slow viral disease. In sheep it is found in the classic places viruses go: the spleen, the lymph nodes, the central nervous system. In cows it's in the central nervous system—where many slow viruses can hide." Despite arguments to the contrary, Manuelidis contends that the prion protein itself does not infect animals, and that the true infectious agent is still unknown. "It would be a shame," she says, "if we followed the wrong trail while an infectious epidemic was incubating."
For now, the infectious agent remains a mystery, and perhaps an academic one. Whether or not abnormal prion proteins are the cause of TSE, they are certainly among its results; and by the time the protein conversion has started, the case is beyond treatment. A more immediate question, then, is how the agent made its way into so many British cows. One theory has it that several cows with spontaneous BSE were rendered, made into feed, and fed to a large number of other cows, who were themselves rendered and served. A few cycles of this could infect a large number of cows. But many experts are dubious of this theory because spontaneous BSE, if indeed it exists, is probably rare, whereas the infection in British cows became widespread. Another possibility is that BSE got its start not in cows but in sheep infected with scrapie—the ovine TSE. What is particularly unnerving about this idea is that scrapie is not at all a rare disease.
Jumping the Species Barrier
ENGLAND has struggled with scrapie since the mid-1700s. In July the British government took the highly dramatic step of requiring all sheep and goats even suspected of being infected with the disease to be slaughtered and their carcasses disposed of by the Ministry of Agriculture, Fisheries and Food.