How the infectious proteins behind BSE (mad-cow disease) jumped a species barrier to cause the recent outbreak of variant Creutzfeld-Jakob disease is still something of a mystery. Now researchers have gleaned some clues from watching similar proteins in yeast flex their shapes enough to cross a species barrier1.

The infectious proteins involved in BSE are abnormal versions of common prion proteins. These somehow make normal prions mimic their shape so that, over time, all the normal prions in an animal's brain have the diseased shape. Disease is thought to result either from a build-up of infectious prions or a depletion of normal proteins.

Central to the question of how prions cross species barriers is whether infectious prions are flexible enough to adopt more than one pathogenic shape -- one to cause disease in their originating species and another to cause disease in a second species. Or whether additional factors, such as other, as yet undiscovered proteins, are also needed.

This question is difficult to address in mammals because creating infectious mammalian prions in the lab has proved impossible, and because samples of infectious tissue may contain other substances as well as the prions.

So Peter Chien and Jonathan Weissman of the University of California at San Francisco used two species of yeast (Candida albicans and Saccharomyces cerevisae) to investigate how prions jump the species barrier. "Yeast is technically much easier," says Weissman, not to mention much quicker and cheaper to study.

Yeast cells make a prion called sup35. Like most mammalian prions, normal yeast sup35 cannot influence the sup35 of another yeast species. But by creating a prion chimaera -- a fusion of portions of a prion from S. cerevisae and part of a prion from C. albicans -- the researchers saw how similar a prion from one species has to be to that of another to cause disease.

Chien and Weissman expected that if the chimaera could cause infection at all, it should only infect one species. This is because only one end of an infectious prion is believed to be involved in recognizing normal prions and so causing them to change shape. The researchers' chimaera contained only half of each original prion, so both of these crucial sequences could not be present.

But regardless of which yeast species it infected, the chimaera induced 'local' sup35 to adopt chimeric form. "This means a single prion protein can adopt more than one [disease-causing] conformation and subvert other proteins," says Weissman.

And this suggests that -- in yeast at least -- when prions are abnormally flexible they can infect other species, without help from other proteins.

"Working with simple model systems can be a very powerful way of looking at disease," Weissman says, "but in no way would it supplant mammalian work. Any mechanism we prove in yeast then has to be examined in mammals."

Byron Caughey of the National Institute for Allergy and Infectious Diseases in Hamilton, Montana, who studies mammalian prion diseases, concurs: "This research provides a convincing proof of principle." But, he cautions, "the proteins involved [in yeast and mammals] are completely different".