IN his excellent Plagues and Peoples (1977), William H. McNeill pointed out that many of the distinctive infectious diseases of human beings got their start in animals, particularly domestic animals. Measles is probably related to canine distemper, and influenza to a disease in hogs. Clinical and experimental evidence has led many scientists to suspect that mad-cow disease has made the jump as well. The infectious agent responsible for the British mad-cow epidemic was given ample opportunity to mutate into a human pathogen. It is thought that stricken cows ground up, processed into feed, and fed to other cows created a cycle of intense infection that eventually landed on people's dinner plates; after repeated exposure to this infected meat, a group of human beings, especially susceptible for genetic or other as yet unknown reasons, developed a human form of the illness, a variant of Creutzfeldt-Jakob disease.
CJD in its natural form was first described in the 1920s by the German physicians Hans Gerhard Creutzfeldt and Alfons Jakob. Symptoms vary, but may include loss of coordination, personality changes, mania, and dementia; death inevitably follows. It is generally said that about nine people a year in 10 million contract CJD "spontaneously"—that is, by a means unknown—and one in 10 million does so through inheritance. Still more rarely CJD has been contracted through the transplantation of infected tissues, such as corneas, through contaminated surgical instruments, or through the injection of growth hormones derived from CJD-infected pituitary extracts. Though it has not been shown to be transmissible in blood outside the laboratory, dread of the disease is such that more than $100 million worth of blood products have been destroyed for fear of CJD contamination. In the United States about 250 cases occur each year. Although young people can and do acquire CJD, and the first case ever described was in a twenty-three-year-old woman, the average age of onset in the Western world is over sixty. The new variant of CJD associated with the mad-cow outbreak differs clinically from the traditional form in two significant ways, both of them cruel. The old form is quicker, mercifully. And whereas traditional CJD is a disease of the elderly, the new form seems to prey on the young: the median age of onset is twenty-eight.
All transmissible spongiform encephalopathies, including CJD, attack and destroy the nervous system of the host organism. No one knows precisely how the TSE agent infects an organism, but once it takes hold, it is unstoppable. Strains of TSE have been found in sheep, goats, elk, mule deer, white-tailed deer, mink, and cats. In sheep and goats TSE is called scrapie. Mad-cow disease is more properly called bovine spongiform encephalopathy, or BSE. In human beings CJD and two extremely rare syndromes, Gerstmann-Sträussler-Scheinker disease and fatal familial insomnia, have been identified as forms of TSE. Clarence Joseph Gibbs, who is the chief of the Laboratory of the Central Nervous System at the National Institutes of Health and an expert on TSE, says it's probable that most if not all mammalian species acquire TSE, but that this is difficult to prove, because "no one would notice a rabbit with dementia and bad balance."
Gibbs and other scientists I recently spoke with believe that all mammals that acquire TSE do so at the human rate—about one case per million. If this figure is accurate, then approximately a hundred U.S. cows come down with BSE spontaneously each year. But detecting isolated cases of BSE in American cattle herds is exceedingly difficult, in part because the cattle population is too widely dispersed for efficient surveillance. "We've had one reported case of BSE in North America—in Canada, in a cow imported from the United Kingdom," Gibbs told me. "That cow was found by a rancher who had gone out on the range to feed his herd because of a severe snowstorm. If there had been no storm, the rancher would have stayed home, the cow would have gone down, a coyote would have eaten it, and no one would have been any the wiser. Do we have BSE in the United States? The real question is, if we do, will we find it?"
The U.S. Department of Agriculture has examined the brains of only about 7,100 dead suspect cattle for signs of BSE, and about 2,000 have undergone an additional procedure required for a diagnosis of the illness. Tam Garland, a veterinarian and a research associate in the Department of Veterinary Physiology and Pharmacology at Texas A&M University, describes this number of tests as "phenomenally small." She also says that she is not surprised that no more suspect animals have been reported. "As a rancher, you're not going to haul a vet out onto the range to look at a dying animal, only to get fingered by your neighbors as the cause of plummeting beef prices," she told me.
TSE infectivity concentrates in the central nervous system, in the spinal cord and brain. And the more of the infectious material an animal is exposed to, the likelier it is to get sick. For this reason Britain has implemented a series of more and more restrictive bans from its food chain, starting with cattle brains, spinal cords, and other tissues that have been shown to contain infectious material, and now including some sheep and goat parts as well. The United States has not followed suit, and the heads and backbones of cows, pigs, and other animals continue to figure prominently in the rendering mix.
In fact, brain doesn't just enter our food chain but goes directly into the human food supply. Each year, according to the USDA's Food Safety and Inspection Service, which is charged with regulating the meat industry, about a million cow brains are sold for consumption in the United States, and others are exported. Generally these are whole brains taken from cows slaughtered in the kosher manner—that is, their throats are cut while they are still conscious. Most cows in the United States, though, are shot in the head with a stun gun before having their throats cut, a process perhaps more humane but also, at least when a pneumatic stun gun that injects air is used, more likely to contaminate other parts of the carcass with brain. This pneumatic gun can crack the cow's skull, causing the brain to leak out. And the force of the gun is such that it can blow pieces of brain into the bloodstream, where they can be carried to the animal's lungs or liver. Tam Garland has recovered chunks of brain as large as six inches across in the lungs of slaughtered cattle. Canadian researchers have spotted pieces of brain about two and a half inches wide lodged in cow livers.
There is no law against the addition of heart, liver, and other "variety meats" to hot dogs, sausages, and canned or bottled meat products, such as chili and spaghetti sauce (when present, variety meats are noted in the list of ingredients). Nor does any regulation mandate that spinal cords be removed before carcasses are processed, although some plants are said to follow this procedure nonetheless. Unless spinal cords are removed, "mechanically deboned" meats, which are found in products such as hamburger and bologna, can be contaminated with bits of central-nervous-system tissue when the spinal columns are mechanically plucked and squeezed to get off the last bits of flesh.
Will Hueston, a veterinary epidemiologist formerly with the USDA and now an associate dean at the Virginia-Maryland Regional College of Veterinary Medicine, says that the agency has not imposed a ban on spinal column and brain in the rendering process because to do so would be very expensive and basically unenforceable. As one rendering-plant employee told me, "Who would want the job of cutting out all those spinal columns and brains? You couldn't even get occasional workers to do it." But when asked why brain and spinal column are not banned from the human food supply in the United States, Hueston was circumspect, suggesting that I speak with someone at the Food Safety and Inspection Service.
Jacque Knight, a spokeswoman for the FSIS, was vague and seemed annoyed when asked whether brain or spinal cord was getting directly into sausage or other processed meats. "Since the Meat Act of 1906 we have never prohibited brain or spinal cord," she said. "It is part of the animal. However, it is not something people expect to find in meat. Therefore, as of May of last year, we have told our inspectors that if they suspect brain or spinal cord of getting into meat, they should report it." The inspectors' union expressed concern that it would be difficult for its members, already bogged down in other duties, to take on this additional task. The agency employs 7,535 inspectors in 6,200 meat and poultry slaughtering and processing plants. To date fifty-four reports have been filed and five plants have been found in violation of the rule.
TSE infectious material does not concentrate in muscle tissue, so steaks, chops, and roasts are probably fairly safe to eat. Though contamination of these cuts is possible (through, for example, splattering when the spinal cord is cut during processing), the amount of infectious material on them, if any, is likely to be low. More than one scientist told me that if I was concerned about my family's exposure to TSE agent, I would do well to steer clear of processed and reformed meats such as bologna and head cheese. Not being a head-cheese fan, I have not found it difficult to follow this advice. In addition, I avoid any ground meat that hasn't been ground in the store where I buy it. I get hamburger by asking the butcher in my supermarket to put a chuck roast through the mill. I no longer buy spaghetti sauce with meat (an old favorite), and my eight-year-old daughter has forsaken lunch meats for what she calls "vegetarian burgers," which consist of a slice of American cheese melted over two sandwich pickles on a bun. Though whether it is possible to acquire CJD from American beef is entirely unclear, making these small culinary adjustments seems well worth doing given the gravity of the disease and the government's hesitation to do all it can to avoid it.
THE Rocky Mountain Laboratories is an unassuming NIH outpost hunkered in the shadow of the magnificent snow-crested Bitterroot Mountains. Built on a residential street in Hamilton, Montana, the red-brick structure stands out like a Brooks Brothers suit on Casual Friday. The lab was set up by the state in 1928 to study Rocky Mountain spotted fever, a deadly tick-borne disease that plagued the region. The people of Hamilton were so nervous about ticks going AWOL from the lab that a moat—really, a puddle-deep trench—was dug around its perimeter. Over time the laboratory has branched out to consider a wide range of infectious diseases, and has attracted, among other notables, a world-renowned team of experts on TSE. One of these is Byron Caughey, a strapping, bearded biochemist who looks nothing like the poet whose name he shares.
For about the past decade Caughey has studied "prion" proteins, molecules of uncertain function that are found on the surface of nerve cells. The buildup of a distorted form of these proteins—called, simply enough, abnormal prion proteins—is the identifying characteristic of TSE. In a scientific paper published in 1995 Caughey and his co-author, Peter Lansbury, a protein chemist at the Harvard Medical School, likened abnormal prion proteins to ice-nine, the sinister agent that catalyzed the freezing of all water on earth in Kurt Vonnegut's classic novel Cat's Cradle. Like Vonnegut's ice crystals, abnormal prion proteins convert neighboring prion proteins to the abnormal form, contorting protein molecule after protein molecule in a demonic domino effect. The resulting prion-protein buildup kills brain cells and forms the characteristic spongelike holes, the "spongiform" encephalopathy, of TSE.
Whereas the symptoms of TSE are clear, the debate over what initiates the conversion of normal prion proteins to the virulent form—that is, over what constitutes the infectious agent in TSE—is one of the hottest and most contentious controversies in modern biology. One theory has it that the abnormal prion protein itself is the infectious agent. The British mathematician J. S. Griffith was the first to propose the idea that proteins could be infectious, in a paper published in 1967 in Nature. He suggested that proteins might self-replicate much the way crystals do, by building up around a central seed crystal. But crystals do not "grow" in the organic sense of the word. The notion that proteins, the building blocks of life, could replicate without the aid of genetic material, or the nucleic acids that make up that material, was heretical. Even the simplest microbes require nucleic acids to direct their growth. As one scientist puts it, the notion that a protein in and of itself could control life "defies basic Darwinian principles." Coming as it did from a mathematician rather than a life scientist, the crystal theory was regarded largely as a theoretical construct. In any case, Griffith never published on the subject again, and when he died, in 1972, his theory faded. It was assumed by virtually everyone at the time that TSE was caused by a virus.
Viruses are extremely basic creatures, each consisting of a single thread of genetic material enclosed in a protein sheath. Unlike bacteria, they lack the wherewithal to multiply on their own and rely on the largesse of the creatures they infect. Generally it takes a few hours or days for a virus to replicate in large numbers. The host recognizes this viral buildup as an alien onslaught and, unless weakened or old, usually marshals its immune system in order to ward off the attack. Unlike most viruses, the TSE agent does not attack within hours or days but bides its time, hiding out and multiplying in the host for years, even decades, before making its presence known. In the meantime, TSE does not elicit an immune response, and there is very little inflammation—indeed, no outward sign of infection at all until the disease has progressed beyond the body's ability to control it. For this reason some scientists assume that a TSE virus lurks cloaked in the host's own protein, disguised as a natural part of the host until it's ready to pounce.
"Whatever is causing this disease is unique; it falls out of the realm of all other disease agents," says Richard Rubenstein, the head of the molecular and biochemical neurovirology laboratory at the New York State Institute for Basic Research, in Staten Island. "We feel that it is probably a virino—a nucleic acid protected by a host protein that camouflages it so that the immune system doesn't pick it up. There is no antibody reaction to the agent at all. The body simply does not recognize it as foreign."
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."