24 July 2003 12:00 GMT

by Bea Perks

If prion proteins really are the infectious agents of so-called prion diseases, the risk of cross-species transmission may be even greater than feared, warns the first researcher to pin down a prion's structure.

Much of the evidence for the 'protein-only hypothesis' of prion disease, in which misfolded prion proteins are able to trigger the misfolding of sibling and offspring prions without instruction from nucleic acids, comes from research on yeast prions.

But yeast and other invertebrate prions have little to teach investigators of vertebrate prion disease, says Kurt Wüthrich, professor of biophysics at the Federal Institute of Technology in Zurich, Switzerland.

The structures of prion proteins from yeast, fungi, cattle, sheep, humans, elk, and chickens have been resolved, and the picture is clear. "There is no obvious relation, for the structural biologist, between the prion proteins in any of these vertebrates and the prions that have been described in yeast and in fungi," said Wüthrich, who won the 2002 Nobel Prize in Chemistry for his development of nuclear magnetic resonance (NMR) spectroscopy.

"It may actually be more confusing than useful to place too much emphasis on work with yeast and fungi in the hope of getting new information on the problem with mammalian prion proteins," he said.

This is sharply in contrast to comparisons made between prion proteins of different vertebrate species, he says. The more structures that are resolved, the more it becomes clear that there is little variation between the prions of different vertebrates, mammals or not.

"Birds have the same type of prion protein as humans," said Wüthrich. There are some slight differences in the tail region of the molecule, he says, but overall they are identical. The same is true of the turtle prion. Although he concedes that there are no reports of prion disease in non-mammals like turtles or chickens, such species could act as a prion reservoir, he says.

"If the presence of a mammalian-type prion protein in the organism is sufficient for infection, then we have to presume that these species can act as silent carriers," said Wüthrich, who was speaking at a meeting in London organized by the Swiss Science Forum. That might not raise alarm bells in the case of turtles, he says, but there could be a threat posed by chickens because of their place in the human food chain.

"It then becomes more of a dilemma," said Wüthrich. There is evidence, he claims, that chickens in China have been fed on beef offal from Great Britain, for example. But these fears are not shared by all in the prion field.

"I wouldn't be all that nervous," said prion expert Adriano Aguzzi, professor of neuropathology at the University of Zurich in Switzerland. Despite numerous studies, he says, there is no evidence for the cross-species transmission of misfolded, or scrapie prions (PrPSc) from chickens.

Mechanisms governing the species barrier are not well understood, so the possibility cannot by completely ruled out, he admits. However, he told BioMedNet News, "I think one has to keep things in proportion."

Aguzzi agrees with Wüthrich that the structure, function, and topology of yeast prions has nothing - "I mean nothing" - in common with their vertebrate counterparts. "But that's not really the point," he said.

"This by no mean detracts from the interest in yeast prions. The irony is that the prion hypothesis in mammals is still not yet confirmed, whereas in the yeast prion field it's very obvious what is going on - there is no question whatsoever."

Aguzzi is a supporter of the protein-only hypothesis for mammalian prions, but it is still only a hypothesis. "One has to honestly admit that the evidence in favor of the protein-only hypothesis [in mammals] continues to be simply circumstantial," he concluded.