Evidence For Early Diagnosis; Tracing proteins linked to mad cow disease may help in screening and understanding brain deterioration

Evidence For Early Diagnosis;
Tracing proteins linked to mad cow disease may help in screening and understanding brain deterioration

August 21, 2001 Newsday (New York, NY) by Robert Cooke

NEW EVIDENCE suggests the tiny proteins causing mad cow disease are detectable in the urine of infected animals and people, even before they're sick with devastating brain diseases, an Israeli research team reports.

The discovery, announced recently in the Journal of Biological Chemistry, may lead to a simple urine test that can spot infections early. It also raises what the study called "the alarming possibility" that such diseases can be transmitted via contaminated urine. Other scientists were not convinced there's danger from that, however.

The discovery of these abnormal protein particles, called prions, in urine samples was announced by neurologist Ruth Gabizon and her colleagues at Hadassah University Hospital in Jerusalem. Other researchers pursuing prion studies said it was an interesting and important discovery, one that may prove to be extraordinarily useful. The new findings address an especially worrisome set of diseases that involve deterioration of the brain. In the various prion diseases, an abnormal protein, acting rather like a virus, gets into the brain, triggers related proteins to also become abnormal and kills off nerve cells. As brain cells die, symptoms include declining mental capacity, loss of muscular control and, eventually, death. There are no known treatments.

Mad cow disease, as seen in Europe, apparently entered people via prion- contaminated beef. It's suspected that the cows got infected by eating the rendered remains of sheep that had scrapie, a prion disease.

Gabizon and her five colleagues had been searching for various substances in the urine of hamsters that had been experimentally infected with prions from sheep. After the scientists found prion materials in the rodents' urine, further tests yielded similar prions in urine from cattle, and in urine from humans who had the prion-based brain disorder called Creutzfeldt-Jakob disease. This is very similar to mad cow disease, which is also known as bovine spongiform encephalopathy, or BSE. The human version of BSE is called variant Creutzfeld-Jakob disease.

Although early diagnosis may someday help with treatment, at present there is no therapy to prevent the deterioration and death caused by mad cow disease or the very similar brain disorders. Nonetheless, early diagnosis could help in studying and understanding the diseases. Also, being able to spot infections early may provide a way to screen animals before they are slaughtered for food.

Meanwhile, researchers at the University of California at San Francisco report that two old drugs - one used for malaria, the other for schizophrenia - are showing interesting signs of effectiveness against prion-infected cells growing in laboratory dishes. While this does not say that a treatment for the prion diseases will come soon, it opens a door that may yet lead to treatments.

In fact, the UCSF scientists are planning a clinical trial within a year to see if the two drugs - quinacrine (malaria) and chlorpromazine (schizophrenia) - do any good in humans. Last month, the San Francisco team won permission from the U.S. Food and Drug Administration for the trial to treat patients suffering with advanced disease.

Two patients have already been getting "compassionate use" doses of quinacrine for the prion-based disease thought to be variant Creutzfeldt- Jakob disease. According to the university, one patient has shown no response. For the other, a woman from England, "it is too soon to say," a university representative said. Still, the patient's father, quoted in a London tabloid newspaper, was claiming she's cured. There was no further comment from UCSF.

Another research group, led by immunologist Dennis Burton at the Scripps Research Institute in La Jolla, Calif., also reports that disease- fighting antibodies - created artificially in laboratory experiments - can clear prion infections from nerve cells growing in culture dishes. This raises the possibility that the relatively new technology, making "monoclonal antibodies," may offer a route toward treatment of prion-based diseases - someday.

One reason for surprise about prion materials showing up in urine was that, until now, it was believed that prions could not get into urine, that they should be filtered out by the kidneys. Their route to urine is a mystery, but the Israeli researchers hypothesized that prions shed from some other organ, such as the brain, may find their way into the blood without going through the kidneys.

According to biophysicist Fred Cohen, a prion disease researcher at UCSF, "if a urine test could be a useful diagnostic ... it might provide you with faster detection, or a more clinically useful detection strategy."

He added, however, "I don't think there's ... [prion] transmission in urine" from one animal to another, because in the tests run by Gabizon and her colleagues, actual disease could not be transmitted via urine. "I think it's possible you can see fragments of degraded proteins that are part of the prion," Cohen said, but the fragments aren't necessarily dangerous.

At present, prions are detectable in people only by taking biopsies of brain tissue, Cohen said.

Mad cow disease is one of several types of the prion disorders now known. Although there is still debate over how it happened, scientists suspect that scrapie's prions moved from sheep into cattle in the United Kingdom, perhaps in the 1980s. Apparently, the prion particles from the brain and spinal cord tissue of sheep were mixed in the cooked and processed remains that were used to supplement cattle feed. It has not been shown exactly how the fatal disease got transmitted from cattle to humans, although the variant form of Creutzfeldt-Jakob disease did arise in some of the humans who consumed infected meat.

Scrapie is a relatively well known prion-based disorder that has been studied for years. It was named scrapie because the sick animals tend to rub themselves raw by scraping against rocks and trees before dying of the disease. Diseases similar to scrapie are also seen in deer, elk and mink.

Creutzfeldt-Jakob disease (CJD) has also been known for years as a rare brain ailment, striking about one in a million persons. It can be transmitted on the instruments used in brain surgery, and also into children treated with human growth hormone extracted from cadavers. CJD can also be inherited.

As infectious particles, the prions are stranger than strange. Unlike true microbes - fungi, bacteria and viruses - the prions are pure protein; they contain no genetic material, no DNA or RNA, of their own. That's why some scientists still resist the idea that prions actually cause these diseases.

The word "prion" was coined by a leading neurological researcher, Stanley Prusiner, at the University of California at San Francisco. He was awarded the Nobel Prize in 1997 for his discoveries. Gabizon did some of her research in Prusiner's laboratory.

In the past decade, the small set of prion diseases has become especially notorious, in part because of mad cow disease, and also because they are exceedingly strange. In addition to CJD and variant CJD, the list of human prion diseases includes kuru, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia. Incidentally, kuru, seen in New Guinea, is passed from person to person via ritual cannibalism.

Such disorders were once known as "slow virus" diseases, but rather firm evidence now shows they are caused by prions. The prions themselves are apparently normal bodily proteins that have gone haywire. The problem seems to be misfolding; the prion particles occur in abnormal shapes that cause serious damage, including the death of nerve cells.

The badly folded proteins do their damage by inducing the normal prion proteins found in cells to also misfold, and eventually enough abnormal proteins accumulate, clump together and cause brain cells to die. And as the nerve cells die off, a progressive and fatal disease ensues.

Prion diseases are difficult to diagnose in people, because the symptoms resemble other neurological disorders such as Alzheimer's disease. The signs include rapidly progressive dementia and seizures, followed by death.

Prion diseases had remained relatively obscure until the mid-1980s, when mad cow disease erupted in England and subsequently spread to humans. By 2000, more than 100 people in England and elsewhere in Europe had been killed by the disease, and more victims were expected to die from infections that haven't yet been recognized.

Because of the likely source of infection, British beef was widely banned in Europe, while Britain's farmers and health authorities struggled to ensure that beef was again safe. Even so, there were also a few cases of mad cow disease reported from infected animals in other European countries, despite the ban of British beef. The disease may have entered the cattle from the same source - rendered sheep carcasses.

In the research in Israel, Gabizon's team also tried to see whether the prion particles in urine are infectious, but no cases of prion-induced disease were seen in the hamsters. But there were signs that the prion particles - perhaps incomplete or altered prion particles - got into the animals' brains. So the Hadassah team concluded that "the clinical and epidemiological implications" of its findings are yet to be determined.

Commenting on the Israeli team's work, neuroscientist Huntington Potter, of the University of South Florida College of Medicine, said, "The finding of scrapie-like protein in the urine before clinical symptoms is going to be very helpful for both the veterinary and medical diagnosis of these diseases." But he also questioned whether prion-based diseases can be transmitted via urine. The Israeli researchers, he said, gave "no data addressing that question." And he called their raising the "alarming possibility" of such transmission a "hyper-scare paragraph" that he found confusing.

Nonetheless, Potter said, this idea of disease transmissibility via urine "is definitely worth following up. It has been a mystery in scrapie about how the animals infect each other in the field, and this is as good a hypothesis as any."

For now, however, the most important part of the report comes from the finding that "the detection of [prions in urine] can be used to diagnose humans and animal incubating prion diseases," Gabizon and her five colleagues wrote, "as well to increase our understanding of the metabolism" of prions in the body.

The Israeli researchers also wrote that "it is conceivable that urine can contaminate the living areas of [infected] animals."

The prion's proper function - if it has one - remains unknown, and it is only through analysis of symptoms and detection of prions in brain tissue that diagnosis can be made. So the discovery that prions can be detected in urine could be a landmark achievement. And, in fact, the researchers in Israel say their findings "pave the way for development of a simple test for prion diseases."

GRAPHIC: 1) Getty Images Photo / David Silverman - Israeli neurologist Ruth Gabizon is the head of a team at Hadassah University Hospital in Jerusalem that has discovered a potential method of testing for bovine spongiform encephalopathy (BSE), also called mad cow disease, in the urine of infected animals. 2) AP Photo, 1996 - Cattle throughout Britain were sent to slaughterhouses in 1996 under a government program to curb the spread of mad cow diesease, but animals elsewhere in Europe contracted it as well.

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