In a surprising and unexpected discovery, researchers in Israel have found a form of prion in urine that can indicate the presence of disease caused by the mysterious protein even before symptoms appear.

	GABIZON PHOTO BY DAVID SILVERMAN/GETTY IMAGES

The findings suggest that a urine test could be developed to identify cows with mad cow disease, people with Creutzfeldt-Jakob disease (CJD), sheep with scrapie, and animals with other forms of prion diseases--transmissible spongiform encephalopathies, or TSEs.

The discovery is surprising because dozens of companies, academic research teams, and government groups have been in active competition to devise diagnostic tests for TSEs, but none had detected diagnostic prions or prion-related metabolites in urine before. Urine samples are relatively easy to obtain, whereas current TSE tests must be carried out on brain tissue samples obtained with great difficulty from postmortem autopsies.

The discovery was made by graduate student Gideon M. Shaked, senior lecturer Ruth Gabizon, and coworkers at the department of neurology of Hadassah University Hospital, Jerusalem [J. Biol. Chem., published June 21, Papers in Press, (http://www.jbc.org/cgi/reprint/C100278200v1.pdf)]. Gabizon is hardly a newcomer to prion research. A decade ago, she worked for neurology professor Stanley B. Prusiner of the University of California, San Francisco, who won the 1997 Nobel Prize in Physiology or Medicine for discovering that prions cause TSEs.

While looking for other substances in hamster urine, she and her coworkers found an isoform (tissue-specific form) of protease-resistant prion protein in the urine of prion-infected hamsters, and subsequently also in the urine of cattle and humans with prion diseases. Few researchers had looked for prions in urine before, Gabizon notes, because they generally believed prions would not pass through the kidneys in substantially intact form.

Using Western blotting (electrophoresis and immunological detection), the Hadassah group detected the prion isoform in hamster urine before disease symptoms appeared--a hopeful sign for diagnostic purposes. They found a prion isoform in CJD patients as well. And in a blind test they were able to distinguish cows with mad cow disease from those without it.

Steve Dealler, a consultant medical microbiologist at Burnley General Hospital, in the U.K., who follows TSE diagnostic developments closely (http://sparc.airtime.co.uk/bse/adco.

htm), comments that the discovery of a diagnostic form of prions in urine "is bound to be an exciting twist, and this method ... may well turn out to be the final answer" to the problem of TSE diagnosis.

Research chemist Mary Jo Schmerr of USDA's National Animal Disease Center,, Ames, Iowa--who is developing an antibody-binding assay to detect low levels of prions in blood--says the new study "has potential." Despite "a few unanswered questions" in the study that still need to be addressed, she believes prion isoforms in urine "could very well prove to be a valid diagnostic marker for TSEs."

A potentially troubling implication of the study is "the alarming possibility that urine from prion-infected individuals, either ill or as yet incubating the disease, can somehow transmit prion diseases," Gabizon and coworkers note. "This prospect is especially disturbing in the case of [TSE-infected] cattle as well as in natural scrapie in sheep. Since the mechanism by which these diseases are transmitted among animals within the herd was never elucidated, it is conceivable that urine can contaminate the living areas of these animals" and thus spread the diseases to other members of herds.

Gabizon and her team are in the process of establishing a Jerusalem start-up company, sponsored by Hadassit (Hadassah's R&D arm), to produce a commercial kit for using animal and human urine samples to diagnose mad cow disease, CJD, and other TSEs.

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