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Science & Technology: RESEARCH
MAD COWS--AND HUMANS
A Nobel prize hasn't quelled the controversy over the diseases' cause
Clare Tomkins has been engaged to Andrew Beale for three years, but it is unlikely they will ever marry. Bedridden and fed through a tube in her stomach, the 24-year-old Englishwoman rolls her eyes from side to side and barely recognizes her family. The disease that is killing her is a new, human version of bovine spongiform encephalopathy (BSE), or mad-cow disease (below). "We are pushing like mad for a public inquiry," says an angry Roger Tomkins, Clare's father. "At 24, our daughter's life will be cut short, and we want answers."
On Dec. 10, American biochemist Stanley B. Prusiner was handed a Nobel prize for research that could provide those answers. The Nobel Assembly hailed Prusiner, a professor at the University of California at San Francisco (UCSF), for his research on "prions"--proteins found in brain cells that, under rare circumstances, assume an abnormal shape. These malformed prions are associated with brain-rotting illnesses such as mad-cow disease, a cluster of rare human ailments, and similar scourges in sheep and deer.
Some scientists say, however, that Prusiner's Nobel prize was premature. Nobody yet understands what normal prions do in cells, why they turn deadly, how they jump from beast to human, or why some individuals are vulnerable. How many people are infected is also unknown. There are no fast or certain diagnostic tests for prion-linked diseases, short of brain biopsies after death, and no cures.
Indeed, some scientists even question the core discovery attributed to Prusiner: that prions cause disease. "This whole field is hugely controversial," says Byron Caughey, a biochemist at Rocky Mountain Laboratories in Hamilton, Mont. "Many of us in the field don't feel that the nature of the disease-causing agents is solved."
CAPSULES, TOO. That uncertainty has spawned fierce battles over policies in the U.S. and Europe to protect people and livestock--such as restrictions on cattle feed and bans on gelatin made from cows. Gelatin can harbor malformed prions and is used in everything from desserts to drug and vitamin capsules. Some say the measures are too weak. Others say they're draconian. Lacking sure knowledge, scientists have no means to mediate the dispute.
Britain is ground zero for the new prion-linked diseases. It offers a chilling preview of what may soon confront other countries. Experts think BSE arose there in about 1981, when meat renderers altered their processing techniques, unwittingly exposing cattle to infected brains and nerves in feed protein supplements.
Britain has halted such "cross-feeding," but the damage is done. To date, 1.4 million cows have been destroyed, and the disease has cropped up in Switzerland, Belgium, and other parts of the Continent. Worse, since the early 1990s, 23 people in Britain and one in France have taken ill. Health authorities now fret that Britain's blood supply may be contaminated. And the European Union has threatened to ban sales of medicines containing suspect gelatin.
Prusiner was not the first to speculate that rogue proteins, unaided by viruses or other familiar infectious agents, might cause sheep scrapie and several rare human diseases. But in 1982, he became the first to isolate the suspected agents, christening them prions--short for proteinaCEOus infectious particles. Since then, his lab has demonstrated that normal prions can convert to the bad variety, which the body can't break down--and which don't degenerate even when exposed to organic solvents, heat, or radiation.
Prusiner and others have also shown that at least some prion-linked diseases can be inherited because of mutations of the gene that makes the protein. And in 1992, with biologist Charles Weissmann at the University of Zurich, he showed that laboratory mice stripped of the prion gene became immune to prion-linked diseases.
But these experiments don't prove that prions actually cause disease. Prusiner has never managed to convert a pure test-tube preparation of normal prion proteins into abnormal ones that are capable of causing infection in a lab animal.
As a result, a small group of respected scientists continues to hunt for more conventional infectious agents, such as viruses or bits of viral DNA or other nucleic acids. If present, these might explain why there are various strains of disease-causing agents, as there are in hepatitis or flu. Prusiner debunks viral theories; and yet, to explain why prions suddenly deform themselves, even he must invoke an additional nonprion agent--as yet unidentified--which he calls "protein X."
Critics say Prusiner is uncooperative. His lab "is not checking properly for [viral] nucleic acid and is not willing to exchange material," complains Heino Diringer, a professor and specialist in unconventional viruses at the Robert Koch Institute in Berlin.
LAB STRAINS. American scientists, including Laura Manuelidis at Yale University, voice similar reservations. "The narrow focus on prions is a terrible mistake," she says, adding that she also has had trouble obtaining Prusiner's preparations. Colleagues at other institutions, however, are quick to defend the scientist. "Any time I've requested materials from Dr. Prusiner, he has given them to me," says Clarence J. Gibbs, a top expert in prion-associated disease at the National Institutes of Health (NIH) in Maryland.
Prusiner rarely talks to reporters and declined to speak with business week. But his colleague and co-author at UCSF, Fred Cohen, dismisses Prusiner's critics. "There is a group that no amount of data could ever persuade," he says. Despite lingering questions, Cohen argues, scientists are pursuing more sensitive tests and even potential treatments. He notes, for example, that variations in the genes that make the prion protein give some individuals relative immunity to prion-linked diseases. There's a chance, he says, "of breeding a strain of animal that's relatively resistant" and of developing drugs and gene therapies for people.
PROGRESS. At the NIH and the California Institute of Technology, scientists have already developed a test around a family of proteins that appears in the spinal fluid of patients with prion-linked diseases. And in Switzerland, a team of scientists has announced a monoclonal antibody that homes in on only malformed prion proteins.
No test or treatment, however, can compensate for weak surveillance and regulation. On this score, the U.S. may come up short. Most European Union countries have banned the use of mammalian protein in ruminant feed. But U.S. measures are weaker. They allow cow-derived protein to be fed to pigs, whose remains can then be fed back to cows. That could lead to animal-feedback loops, with potential risks. Nonetheless, the congressional committee that pushed the Food & Drug Administration to take action earlier this year says the agency's safeguards are more than adequate.
Critics are not convinced. According to Michael Hansen of Consumers Union in Yonkers, N.Y., farmers are permitted to feed "spray-dried" slaughterhouse blood to weaning calves--despite proof that it can contain infectious agents. So far, no cases of BSE have been reported in U.S. herds. But similar diseases have turned up in mink, deer, and elk, whose carcasses are sometimes delivered to rendering plants. Sporadic cases can also crop up spontaneously in cattle populations. Animal-feedback loops can amplify even a single, freak occurrence into an epidemic.
Despite Prusiner's Nobel prize, people are getting sick and farmers are suffering devastating losses. Resolving the scientific controversy over prions is essential. The Nobel, which so often marks a triumphant conclusion, should in this case signal a new beginning.By Neil Gross in New York, with Heidi Dawley in London, John Carey in Washington, Mia Trinephi in Paris, and Karen Lowry Miller in FrankfurtReturn to top