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A marker for mad cow disease may be found in urine

A marker for mad cow disease may be found in urine

July 17, 2001 The New York Times by Sandra Blakeslee

In a discovery that is capturing the attention of experts on mad cow disease, an Israeli scientist has reported finding a unique substance in the urine of people and animals afflicted with various forms of the malady.

The substance -- a small, never-before-seen protein molecule -- may be a clear marker for mad cow disease and related ailments, a group of illnesses called prion diseases. Its presence in urine could lead to a simple test for mad cow disease and its human form, called variant Creutzfeldt-Jakob disease. The only definitive test now is a brain biopsy, which is rarely done; most cases are verified only after death.

Because the protein is found in urine well before symptoms appear, the test could be used to identify people who had been infected but did not know it and, thus, prevent them from donating blood. Moreover, the test could be used to screen live animals for mad cow disease; current tests can be carried out only on dead animals.

Several prion experts said a screening test in people would raise ethical issues. The incubation period for the human disease may be more than 30 years. The disease is untreatable and fatal, but people who test positive may live for decades -- with a death warrant in hand. Thus, many people may refuse to be tested.

Researchers stress that the finding needs to be validated by other laboratories. A number of promising tests have not worked out in the past. But in the meantime, many experts are excited by the possibility of a diagnostic test based on urine, which is easy to obtain and analyze.

The marker was discovered by Dr. Ruth Gabizon, a scientist in the department of neurology at Hadassah University Hospital in Jerusalem. The Journal of Biological Chemistry published an electronic version of her research paper on June 21 and will publish the printed version in September.

"Every prion laboratory in the world is rushing to see if they can validate the discovery," said Dr. Adriano Aguzzi, a neuropathologist at the University Hospital of Zurich in Switzerland. "We're certainly doing it."

He continued: "We don't know its predictive value or if it will lead to a test. But if this holds water, it may revolutionize the way the disease is handled."

Dr. Neil Cashman, a professor of neurology at the University of Toronto, said: "Scientists have sought infectious prions in urine for 20 years. They never found them. Today, everyone is looking for prions in blood, but Ruth Gabizon took a second look at urine."

The American Red Cross will not accept blood from anyone who spent three months in the United Kingdom or six months in Europe in the last two decades. At least 107 people, most of them from Britain, have died or are dying from the disease, which has been linked to infected beef.

To combat the epidemic in cattle, the European Union now requires that all animals over 30 months old be tested for mad cow disease upon slaughter. The premise is that these older animals are likely to have the more advanced infections that pose the greatest danger to people.

This testing requirement has led to a race among more than 20 companies in the United States and Europe to develop a screening and diagnostic test for mad cow disease, a market potentially worth billions of dollars.

It is no easy task. If prions are in blood, they occur in such minuscule amounts that no current technology can find them. Scientists are searching for surrogate prion markers in blood or are developing ways to increase the small amount found in blood so they can be detected.

Prion diseases occur when a normal protein called a cellular prion misfolds into an abnormal shape that cannot be broken down by enzymes. The misfolded, or rogue, protein acts like a template, forcing other healthy prions to fold into the abnormal shape. At first, these rogue prions can accumulate in the lymph nodes, spleen and other organs. Eventually, the proteins build up in the brain and produce holes that destroy brain function.

If the rogue proteins are in lymph nodes, Dr. Gabizon said, it stands to reason that they will end up in the bloodstream. Because the abnormal proteins cannot be broken down by enzymes in blood, she said, it also stands to reason that they will be cleared from the body by the kidneys.

The rogue proteins are small enough to pass through the kidneys' filtration system, she said, so they should turn up in urine.

To find the rogue proteins in urine, Dr. Gabizon and her assistant, Gideon Shaked, came up with a purification scheme. The kidneys contain urea, a compound that disrupts protein folding but does not destroy the proteins. The researchers suspected that the rogue proteins might be altered by urea and excreted in urine as particles that would not be recognized as prions.

To test that idea, the researchers took urine samples from hamsters, humans and cattle infected with known prion diseases, and from healthy controls. The urine was put into a machine that removes urea, a process that allows proteins to fold back into their original shapes. These refolded proteins were then exposed to enzymes that broke down normal proteins, but not prions.

In healthy controls, all proteins were destroyed. But in animals and people with prion diseases, one protein could not be broken down. Dr. Gabizon called that enzyme-resistant protein a urinary prion and said it was new. The presence of such a protein is the diagnostic hallmark of prion diseases, she said.

Tests show that the urinary prion is not overtly infectious, although it may have some low level of infectivity, Dr. Gabizon said. Hamsters injected with the particles have not developed any signs of disease after 300 days but are still under observation. Other rodents have been shown to harbor infectious proteins without showing signs of disease, she said, and yet as carriers they can pass on the disease.

The urinary prion seems to be an excellent marker for the progression of prion diseases, Dr. Gabizon said. For example, hamsters were injected with the classic rogue prion that causes scrapie, a sheep disease. For one week, the hamsters excreted the urinary prion, then stopped. Sixty days later, the urinary prion reappeared in increasing amounts. Dr. Gabizon said this suggested that as the infection built up in the body and brain, the amount of urinary prion increased.

"It is as if the urine was a mirror to the brain," she said.

The people in Dr. Gabizon's experiment had a genetic form of Creutzfeldt-Jakob disease. People with variant C.J.D., most likely contracted from cattle, have not yet been tested with the new method.

If other laboratories confirm the usefulness of urinary prions, the testing process could be automated for screening purposes, Dr. Gabizon said. The Hadassah hospital has a patent on the process and is seeking partners to develop the technology.

The urinary prion may shed light on an unsolved mystery regarding how prion diseases spread among deer, elk and other wild animals. Fresh urine may be noninfectious because it contains urea, which may alter the prions and inactivate them. But over time, soil can absorb the urea, which may allow the prions left behind to refold and become reactivated, Dr. Gabizon said. If animals grazed in fields where sick animals had urinated, they might become infected.

Because many laboratories are now running Dr. Gabizon's experiment, the verdict on urinary prions may be known in a month or two.


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