March 26, 2002 Newsday (New York, NY) by Jamie TalanABNORMAL proteins linked to mad cow disease grow wildly in the skeletal muscle of laboratory mice, a new finding that has prompted calls to ensure food safety by testing to see if this occurs in other animals such as cattle, deer and elk.
Because it was thought that the deadly proteins called prions infected only brain, spinal cord and lympathic tissue, only these tissues are routinely tested for evidence of prion disease in an attempt to keep the disease out of the human food chain.
The new research was led by Nobel Prize winner Dr. Stanley B. Prusiner, the first scientist to describe the protein and its ability to turn infectious and deadly. The study appears in the latest issue of the Proceedings of the National Academy of Sciences. "Whether prions accumulate in the skeletal muscle of other animals remains to be established," said Prusiner, director of the Institute for Neurodegenerative Diseases at the University of California in San Francisco. "But our findings [in mice] indicate the need to carry out a comprehensive and systematic investigation of the distribution of prions in the skeletal muscle of other animals."
Since 1995, 125 people have died, the majority in England, of the human form of mad cow disease, called new variant Creutzfeldt-Jakob disease. The disease is linked to animal meat consumed years, maybe decades, earlier. The animals had bovine spongiform encephalopathy, or BSE, a disease that has been kept at bay since the epidemic of the mid-'80s killed more than 100,000 cows. More than a million have since been slaughtered.
In the human form of mad cow disease, the infectious protein ultimately damages brain cells, causing a rapid dementia, behavior problems and abnormal movements. It is fatal, with 90 percent of patients dying within the first year of symptoms.
If it does infect skeletal muscle, said Dr. Patrick Bosque, a co-investigator in the study who has since moved to the University of Colorado Health Sciences Center in Denver, the infectious agent could be getting into the human food supply and putting people at risk for the disease.
While much has been unearthed about the prion protein, it still remains a mystery. How does its normal form become abnormal? This question has kept scientists busy for two decades.
Prusiner and his colleagues wanted to know whether prions could replicate in tissues other than the brain and spinal cord. Of course, others have looked for evidence in many animal tissues, but the lab tools weren't precise enough to yield answers until now.
The scientists created two mouse models for this purpose. One model made the normal prion protein only in the skeletal muscle, and another only in the liver. Then both groups of animals were inoculated with the infectious prion protein. After many months, and even in some cases as long as a year, the scientists sacrificed the animals and looked for signs that the infectious protein had given the signal to the normal prion protein to alter its structure into an abnormal, diseased form. Indeed, in the skeletal muscle it had. But not in the liver. The same study was carried out in normal mice as well, with similar findings.
"We were very surprised," Bosque said. "These levels are far higher in skeletal muscle than we imagined. There needs to be a careful look in cattle, deer and elk." He added, however, that the brain has significantly more infectious protein than the muscle.
In England and throughout much of Europe, only the brains of cattle are tested for evidence of infection. But what if the abnormal prions begin accumulating in muscle before it enters the brain? The animal remains could be given the green light and enter the food chain. Other unanswered questions remain:Are people exposed to unsafe levels of abnormal prion? And what are the effects of chronic, low-level exposure?
BSE has not been found in America. But in the West, primarily in northeastern Colorado and southwestern Wyoming, about 15 percent of some elk and deer herds suffer from chronic wasting disease, thought to be related to abnormal prion protein. While no cases of CJD have been directly linked to eating venison, at least three people diagnosed with CJD have had some history of consuming deer or elk meat, according to Dr. Pierluigi Gambetti of Case Western Reserve University in Ohio.
Sporadic CJD also remains a mystery, with about 300 new victims a year. Gambetti is the country's CJD gatekeeper, studying tissues each year from hundreds of people who are thought to have died of the devastating neurodegenerative disorder.
Prusiner and his California colleagues are working to find a treatment to stop the abnormal prion in its tracks. One of the most powerful drugs that did just that in a test tube is the antimalarial drug quinacrine. Also being tested is chlorpromazine and methylene blue. Many victims of the new variant CJD in England are using these medicines, which have been approved for other diseases. The first young patient to receive the antimalarial drug had a dramatic improvement, but liver complications led Prusiner to stop the medicine. She died last December.
Experimental trials of these medicines for CJD are under way.
The hope is to find medicines to prevent normal prions from changing their shape or to reverse the abnormal disease process.