Secret Behind Mad-Cow PDF

Scientists have found some intriguing clues that could help shed light on how mysterious proteins called prions can jump between species and lead to brain-destroying disorders. The prion is a misshapen protein believed to be the cause of mad-cow disease and similar brain ailments in humans, sheep a...

Scientists have found some intriguing clues that could help shed light on how mysterious proteins called prions can jump between species and lead to brain-destroying disorders. The prion is a misshapen protein believed to be the cause of mad-cow disease and similar brain ailments in humans, sheep and other species. But the prion's origins, how it becomes infectious across species, and its role in the disease process still aren't fully understood. Neurologist Stanley Prusiner won the Nobel Prize in 1997 for his discovery of the prion, but Dr. Prusiner's prize marked just the beginning of a world-wide scientific effort to understand the prion. The answers slowly are emerging, as scientists begin to piece together clues that one day may fully explain the outbreak of bovine spongiform encephalopathy in European cattle, as well as the ailment's frightening leap into humans through the food supply. What is more, scientists say the answers also could shed light on far more common ailments, such as Alzheimer's disease and Type II diabetes. The reigning scientific theory behind mad cow and other "transmissible spongiform encephalopathies" is that they are caused by the prion protein adopting a pathogenic shape that causes it to build up into sticky, toxic aggregations. Although its normal role isn't known, prion proteins do occur normally in humans and other animals. Two mysteries of the prion hypothesis involve the way prions cross from one species to another and how prions can cause different strains of disease. Proteins, unlike the viruses and bacteria that cause most diseases, don't contain a genetic code made up of DNA that would allow them to mutate and pass along resulting changes to the next generation. For instance, scientists theorize that such genetic mutations allowed the AIDS-causing virus, HIV, to hop from chimpanzees to humans. Similarly, random mutations can lead to different strains of ordinary diseases, such as the many varieties of the common cold. Prions, however, are identical to normal proteins except for their shape, leaving scientists baffled as to how they could produce different strains of diseases. Complicating the task of researchers has been the fact that no one has yet managed to produce prion diseases in mammals simply by injecting them with a pure solution of prion proteins. Instead, laboratories produce the disease by using partially purified solutions derived from the brain matter of infected animals. While those solutions are highly infectious, some scientists argue that the remaining impurities may include other biological agents that could be responsible for the disease. The prion theory "has not been proven in an airtight way, but it is our working hypothesis," says Byron Caughey, a researcher with the National Institutes of Health's Rocky Mountain Laboratories in Hamilton, Montana. Recent research on yeast, of all things, may help to answer doubts. In work to be published Thursday in the journal Nature, molecular biologists Jonathan Weissman and Peter Chien of the University of California, San Francisco, have produced evidence of how a single protein can take on more than one infectious shape. The work helps explain both the existence of strains and the ability of prion diseases to jump between species. Ordinary baker's yeast, it turns out, sometimes suffers from a condition called psi-plus, in which a misfolded form of a protein known as Sup35 gums up the yeast's cellular machinery. Researchers previously observed that the abnormal prion-like proteins produced by baker's yeast, Saccharomyces cerevisiae, fail to infect another strain, Candida albicans. That often is seen in prion diseases of mammals; mice, for instance, are resistant to infection by brain matter from infected hamsters. To probe how prions from one species could infect another, Dr. Weissman and his student produced a "chimaeric" prion protein by fusing together parts of the prion-protein genes from the two types of yeast. "We thought one of three things would happen," Dr. Weissman says. Either the chimaeric protein would mimic the behavior of either of its two parents or it would do nothing at all. To the researchers' surprise, the chimaeric protein instead was "promiscuous" and able to bridge the species barrier, causing clumps of Sup35 protein to build up in either species of yeast. The upshot, Dr. Weissman says, is that the chimaeric protein strain appears capable of folding equally well into two different shapes. A similar effect may account for the way mad-cow disease crossed over to humans in the form of variant Creutzfeldt-Jakob Disease. "It doesn't prove that strains can cross the species barrier, but it supports the idea," says Susan Liebman, a molecular biologist at the University of Illinois at Chicago. Further evidence for the "protein-only" hypothesis comes from work that shows how under the right circumstances, nearly any protein is capable of producing potentially toxic buildups. In work that also appears in Nature Thursday, Christopher Dobson and colleagues of Oxford University in the United Kingdom have shown that even the ubiquitous muscle protein myoglobin can be coaxed to abandon its normal structure, in effect, an effect that loosely resembles what happens with prions. Dr. Dobson says evolution probably has favored proteins least likely to undergo such transformations. With aging, the body's ability to maintain order appears to be eroded, possibly by the accumulation of genetic mutations. A buildup of misshapen proteins is typical of some diseases of the elderly, including Alzheimer's disease, Parkinson's disease and even Type II diabetes.