The epidemic of mad cow disease that erupted in British herds in 1986 has slowed down recently, probably because the country's meat industry changed its methods of recycling animal byproducts into cattle feed.

Yet an unknown number of apparently healthy people who ate infected meat in Britain long ago may be incubating a fatal brain disorder, new-variant Creutzfeldt-Jakob disease (vCJD), which seems to be caused by the same type of infectious proteins, or prions, as mad cow disease. At least 105 people have been infected, mostly in Britain, and 98 have already died.

Mad cow disease and vCJD kill so many brain cells that they leave holes in the victim's brain, making it look like a sponge—which is why these disorders are called "spongiform" diseases. In sheep, the equivalent disease has been known for about 300 years as scrapie, a fatal illness that makes its victims tremble and wobble frantically, often rubbing themselves raw against the fences of their pens as they try to stay upright. Their brains, too, are riddled with holes.

Was it scrapie that infected British cows? Maybe. But how could infectious prions overcome the usual barrier between species? Recent studies by Jonathan S. Weissman, an HHMI investigator at the University of California, San Francisco (UCSF), and graduate student Peter Chien provide a possible answer. Working with two different species of yeast, they showed that a yeast prion, Sup35, can misfold into several "dramatically different" infectious shapes; this property enables abnormal prions from one yeast strain to interact with normal prion proteins from other strains, inducing them to adopt similarly abnormal shapes. In yeast, abnormal prion proteins clump together and lose their normal activity. In mammals, clumps of abnormal prion proteins may damage the brain.

"Other aggregation diseases are either sporadic, like most cases of Alzheimer's, or inherited, like Huntington's," says Weissman. "What makes mad cow disease so frightening and unusual is that it's infectious. But that also gives you a chance to eliminate it."

All mammals, including humans, carry the prion gene PrP, which was discovered and named by Stanley Prusiner of UCSF in the 1980s. Prusiner and others showed that transgenic mice lacking the prion gene were totally resistant to infection with scrapie. "One of the keystone experiments in the prion hypothesis was to delete the prion gene from mice and show that now they weren't capable of acquiring the disease," comments Arthur L. Horwich, an HHMI investigator at Yale University. When these mice were given a normal prion gene, they became susceptible to scrapie again.

Several research teams have been looking for ways to eliminate PrP-scrapie aggregates or to prevent them from forming in the first place. "We work with molecules that denature PrP protein," says Fred Cohen, at UCSF, where he collaborates with Prusiner. "We learned that branched polyamines work well in cell culture. But they don't cross the blood-brain barrier and don't get into the brain, so they cannot be used on animals. However, they could still be quite useful as disinfectants." There are no good disinfectants against abnormal prions, and cases of people contracting Creutzfeldt-Jakob disease from surgical instruments or from corneal transplants have been reported.

"We also found that some antibodies actually clear prions from mouse cells infected with scrapie," Cohen says. "This argues that prion diseases may be treatable with antibodies." Most recently, Prusiner's team examined a large number of compounds that are known to cross the blood-brain barrier and discovered that two older drugs—chlorpromazine, an antipsychotic, and quinacrine, an antimalarial agent—prevent the formation of PrP scrapie. They are so encouraged by this finding that they suggest the drugs are "immediate candidates" for treating Creutzfeldt-Jakob disease and other prion diseases, and have begun testing them in people dying from CJD.

Still, the best approach would be prevention, Weissman points out. The new-variant CJD is "a very aggressive disease," he says. "Once you have the symptoms of vCJD, it will be difficult to treat." Because there's no blood test for the disease, the American Red Cross announced in May that it would stop accepting blood from anyone who has spent as little as three months in the United Kingdom or six months elsewhere in Europe during the past two decades.

Weissman would like to know what makes cows or people susceptible to these diseases. Since some sheep are naturally resistant to scrapie, it might be possible to find bulls that are naturally resistant to prion diseases and use them to breed more-resistant cattle herds. "If we can learn where mad cow disease came from and how it is transmitted," he says, "we may be able to ensure that the cattle supply is completely free of mad cow disease—and to prevent future outbreaks." —MP

Photo: Barbara Ries

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Reprinted from the HHMI Bulletin,
September 2001, pages 8-13.
©2001 Howard Hughes Medical Institute