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.
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.
Scrapie was long thought to be a purely genetic disease, but by the mid-1930s French researchers had shown that it is infectious. The disease got a foothold in the United States in 1947, when an outbreak, traced to an import of purebred Suffolk sheep, was reported in Michigan. In 1952, when scrapie outbreaks were reported in California and Ohio, the USDA launched the first of two eradication programs, requiring the slaughter of entire herds infected with even a single case of scrapie. Not surprisingly, sheep farmers were reluctant to report suspected cases, and scrapie, as one scientist puts it, was "driven underground."
From the mid-1950s through the mid-1970s a scant one to twenty-two flocks a year were reported infected—numbers that many thought were too small to be credible. In 1978 the USDA instituted a program of reimbursing farmers two thirds of the appraised value of the sheep sacrificed in their flocks, up to $300 per animal. But in 1983 it was decided that farmers would be required to kill (and would be reimbursed for) not their entire flocks but only infected sheep and immediate relatives. At this point reports of scrapie increased. Since scrapie is known to spread through contact, the new rule made little sense—blood relations had a slightly elevated chance of carrying the disease but were certainly not the only sheep at risk. In 1992, for a combination of scientific and budgetary reasons, the scrapie-eradication program was essentially dismantled: farmers were given six months to report sick sheep for reimbursement, and then the coffers were closed. Today a voluntary system is in place, under which farmers can apply to have their sheep certified "scrapie-free." But as of this writing less than one percent of the country's flocks have joined the program. "No one knows the exact incidence of scrapie in the United States," Richard Race, of the Rocky Mountain Laboratories, says. "Surveillance in some states is so poor, and some vets tell me they don't do anything about it."
Known strains of the scrapie agent do not seem to be infectious to human beings: at any given time over the past couple of centuries as many as a third of British sheep have been infected with the disease, but they have not, apparently, conferred it on the people who ate them. However, American scientists have found that they are able to transmit scrapie from sheep to cows by injecting infectious material into their brains. Since scrapie is an old disease and BSE a new one, it seems that if the agent got boosted over the species barrier, it did so only in the past few decades.
Linda Detwiler, the senior staff veterinarian for the USDA, coordinates BSE surveillance and used to coordinate surveillance for scrapie. When we spoke, she reassured me that scrapie is "not rampant" in the United States—that thirty to sixty-five infected flocks a year are reported. But when I asked how many cases might go unreported, she responded, "We really don't know the amount of scrapie that there is in the United States. This is mostly due to the lack of a validated test—although one is being developed—that can detect scrapie in a live animal not yet showing signs of the disease. Some sheep producers are afraid, because the lack of a live-animal test has led to programs that have either destroyed animals without scrapie or have left producers with diseased animals." There is no telling how many herders quietly kill off their scrapie-infected sheep and bury them, burn them, or send them to a willing renderer to be converted into feed for other animals.
William Hadlow, a research veterinarian who devoted his career to the study of scrapie and other TSEs, is a world expert on them. Though he retired more than a decade ago, his house, just one block from the Rocky Mountain Labs, is piled kitchen to living room with texts on animal pathology and neurology. Hadlow explained to me when I visited him that the scrapie infectious agent appears in several strains—as might be expected if the agent is a virus, but not if it's a protein. "People who accept the idea that a protein is responsible for transmission of this disease probably haven't gotten within arm's length of a sheep," he told me, adding that he had worked with Stanley Prusiner and respected him, but that he had difficulty accepting the prion theory. And it is likely, Hadlow said, that each scrapie strain is tailored to the genetic makeup of the sheep it infects.
In 1979 two of Hadlow's colleagues injected the brains of ten cows with a strain of scrapie found in American sheep and goats. Hadlow later examined the brains and wrote up the case with his colleagues. The ensuing paper was rejected by three journals before being published in the American Journal of Veterinary Research, in May of 1995. The findings were alarming. Although Hadlow and his colleagues found only scant spongiform changes in the cattle's brains, they did find disease in three of the ten cows. "In all 3 affected cattle," they wrote, "the disease was expressed clinically as increasing difficulty in rising from recumbency, stilted gait of the pelvic limbs, disorientation, and terminal recumbency during a 6-to-10 week course." They concluded, "Pathologists should keep this variability in mind when looking for microscopic evidence of a scrapie-like encephalopathy in cattle." What Hadlow had found was that American cattle infected with American scrapie developed a very different disease from the BSE diagnosed in British cattle.
"My point is that there are a number of sheep-scrapie strains extant in the United States, and that these strains may not cause the same clinical signs in American cows as the British strain of scrapie caused in British cows," Hadlow said. "The changes in the brain we found in Texas were very subtle, and they might easily be overlooked if you're not looking for them."
Indirect evidence of just such an infectious agent in cows in the United States was uncovered by Richard Marsh, who, until he died last year, was a member of the Department of Animal Health and Biomedical Sciences at the University of Wisconsin at Madison. Marsh was an expert on transmissible mink encephalopathy. In 1985 he investigated a mysterious outbreak of TME on a Wisconsin mink ranch. Marsh was told by the rancher that the minks had been fed fish, cereal, poultry, and large amounts of butchered and ground "downer cattle." Although no one is tracking how many cows "go down" in the United States each year (that is, become too lame or too ill to stand on their feet), a common estimate is 100,000. Downer cows are by law not admitted into the food supply without first being cleared by a veterinarian, but most enter the food chain through the rendering process.
Marsh found that he could pass the mink disease into healthy cows by injecting their brains with TME, and that he could pass the disease back into healthy minks by simply feeding them the brain tissue of infected cows. The permeability of the species barrier that this experiment demonstrated led Marsh to conclude that the United States may well have its own brand of BSE—one that is perhaps being disguised by the much broader problem of downer cows.
Chronic wasting disease, another TSE, was diagnosed more than a decade ago in mule deer and elk in Colorado and Wyoming, and it is said to be spreading. Whether outbreaks of the disease have anything to do with scrapie or cattle feed is uncertain. What is known is that these and other diseased animals can be recycled back into the food chain through the rendering process. If TSE in elk or minks is capable of jumping the species barrier, it is being given every opportunity to do so in the rendering vat. And although the FDA's recent feed ban will limit the amount of rendered beef and lamb that is fed to cattle and sheep, it is almost certainly increasing the amount of rendered beef that is fed to other domestic and farm animals, notably poultry and pigs. The FDA estimates that the cost of the ban to the rendering industry is about $200 million a year, because lessened demand from the cattle industry is bringing down the price for animal feed made from beef and lamb. But if the FDA is right, this can only make the feed more attractive to farmers of other animals.
Pigs are a particular worry. Although they do not seem to get a TSE spontaneously, a recent study in England showed that one of ten pigs inoculated with BSE came down with an analogous disease. Several consumer groups have voiced concern that TSE in pigs may have appeared in this country. In 1979 the USDA sponsored a study of 106 pigs that showed symptoms of central-nervous-system disease on their arrival at a packing plant in upstate New York. The brains of seventy of the pigs were examined, and one was found to have evidence of the spongelike formations and lesions associated with scrapie and transmissible mink encephalopathy. The study was shelved until 1996, when the USDA, alarmed by the British mad-cow outbreak, sent a single slide of the pig's brain to William Hadlow. Hadlow examined the slide but could find nothing conclusive. "It was a bum slide," he recalled. "There was no evidence to make any diagnosis." Four months later the USDA sent him seven additional slides. Again, the slides were not well prepared, and Hadlow could draw no solid conclusions. But, Hadlow cautioned in a report to the USDA, "should neurologic disease occur in swine exposed to [TSE], conceivably it could be expressed microscopically, as is scrapie in some sheep and as is the encephalopathy in cattle experimentally infected with scrapie agent from American sheep." In other words, if the disease exists in pigs, it could be in a form researchers don't recognize. Meanwhile, no public agency is screening for TSE in pigs.
Last summer the Yale researcher Laura Manuelidis showed that CJD can evolve into more virulent strains by being passed from human beings to mice, from there to hamsters, and finally to rats. Her paper, published in the July 4, 1997, issue of the journal Science, concluded that when the agent changed, it provoked a variant disease, and warned that public-health agencies should be on the watch for diverse signs of brain pathology in human beings—not only those symptoms known to be associated with the new variant of CJD. Manuelidis's concern is that if a new variant of CJD has appeared in the United States, we will be slow to realize it, because we are looking for the variant that appeared in Great Britain.
"Fewer than ten percent of all deaths are investigated with an autopsy, and even a smaller percentage of victims of dementia," Manuelidis said. "Alzheimer's disease was rarely diagnosed prior to 1940, but now we diagnose all sorts of people with the disease. But Alzheimer's is a heterogeneous disease with many different causes. One cause for some people could be an infectious agent. And we really have no idea how much CJD there is. The one-in-a-million figure may be an underestimate."
From the look of it, CJD, too, is a heterogeneous disease. Some victims have plaques in their brains, whereas others don't. Some suffer with evident symptoms of the disease for years before dying, some only for months. What made the new variant of the disease particularly noticeable in Great Britain was that the victims were young, and it has not gone unmentioned that other, older victims may well be overlooked, presumed to be afflicted with another form of dementia.
Jeffrey Almond, a British scientist, is a member of the Spongiform Encephalopathy Advisory Committee, a body of scientists and physicians appointed in 1989 to advise the British government on BSE and other TSEs. When we met, at an infectious-disease meeting at the Harvard School of Public Health last year, he looked haunted. He had recently received a heartrending letter from the family of a twenty-one-year-old man who had died of the new variant of CJD. This family, he said, simply pleaded to learn the underlying cause of the young man's death, but others might have reacted differently. He said to me, "If there is an epidemic of this disease—and there might be—and you lost your son or your wife to CJD, you might wish to blame someone, wouldn't you?" He said that he regrets that Britain did not make greater efforts to control its meat industry before the outbreak. "Every bit of the carcass is used—it's all valuable, isn't it?" he murmured over a lunch of vegetarian lasagna. "They cut off what they can; then they use solvents and sprays to get off the last bits to make into mince and pâté, gravies and sauces. And they put the bones—including the vertebrae—into gelatin. It's a messy business, hard to control. And as recently as 1995 we were, I regret to say, still allowing mechanical recovery of meat off the vertebrae. We finally put a stop to that—but too late." In the United States, of course, this practice is to date unchanged.
Much in the scientific picture of CJD today is hazy. What is clear is that protecting the population from the most obvious potential source of the disease—TSE from animals—would be a relatively straightforward affair. And yet regulatory agencies in the United States have not taken up the challenge. The veterinary epidemiologist Will Hueston, who is the only American member of Britain's Spongiform Encephalopathy Advisory Committee, has witnessed firsthand the terror, chaos, and agony that mad-cow disease brought to Britain. A cautious man, he is concerned lest the public overreact. When I spoke to him not long ago, he argued that the rendering industry performs an invaluable service: to some extent it sanitizes waste products that might otherwise be dumped into landfills or, worse yet, left to fester. But he warned that we can't be certain that any current processing method will sterilize rendered products. In a better world, he said, no diseased animals or central-nervous-system tissue of any kind would go into the food chain. Daniel McChesney, a microbiologist at the Animal Feed Safety Branch of the FDA, told me that such steps would become a priority if an outbreak of BSE were to occur in this country, but for now there is simply no need. "The measures that we're taking are proactive," he said. "Great Britain has the problem; we do not." When I mentioned this to Hueston, he was not impressed. "I, for one, have no interest in eating brain," he said.
Stephen Morse, the director of the Program in Emerging Diseases at the Columbia University School of Public Health, worked with Richard Marsh on his studies of TSE agent in minks. In a letter to the journal Nature in March of 1990 he said that he did not believe that what was then generally called scrapie agent would ever find its way through the food chain and into human beings. But he has changed his mind. "Many were wrong about it, including me," he told me recently. "We didn't imagine it could pass from cows into humans. But now we think it can, and it has the potential to be terrifying. Perhaps the best analogy is to the AIDS epidemic. Although it's almost certain that TSE doesn't transmit as readily as HIV, it's similar in a number of other ways. It can remain in the body for long periods without obvious symptoms, and it is fatal. But what I'm thinking about is how we regarded AIDS in the early days, before we really understood it. We underestimated the threat. Perhaps we should avoid making that mistake again."