Building a prion? In a model of prion formation, misshapen PrP proteins (red) stack up into amyloid fibrils.

Debate Over Prion Infectivity Continues

A bold set of prion experiments in mice suggest that the misshapen proteins are, by themselves, infectious. If the work holds up, it will be a watershed in prion biology, validating the widely held belief that these proteins are the culprits in "mad cow disease" and similar illnesses. But many scientists express reservations about the study. It was led by Stanley Prusiner of the University of California, San Francisco, who won the Nobel Prize in 1997 for discovering prions.

For years, biologists have tried to prove that a protein called PrP becomes infectious when it misfolds. They've purified PrP clumps from diseased animal brains and injected them into healthy ones. But it hasn't been clear that PrP is the only thing being injected. Injecting misfolded PrP created in the lab, meanwhile, hasn't reliably triggered disease.

In their tests, Prusiner and colleagues used transgenic mice making 16 times the normal amount of PrP. To obtain prions free of brain tissue, Prusiner's team genetically altered Escherichia coli bacteria into producing PrP, which the team then misfolded into amyloid fibrils, which have been implicated in various brain diseases. But when they injected that into the transgenic mice, at first none of the animals got sick. But then, 380 days after being inoculated, one showed symptoms of a prionlike disease. Eventually, all seven inoculated mice showed neurological disease, the last one 660 days after injection. When brain tissue from one of these sick mice was injected into healthy mice, they showed neurologic symptoms 150 days later, the team reports in the 30 July issue of Science.

"This is the beginning of the end of all the objections about the prion hypothesis," says Neil Cashman, a neuroscientist at the University of Toronto. Not so fast, reply other experts. John Collinge, director of the Medical Research Council Prion Unit at University College London wonders whether Prusiner's mice with excess PrP get sick without prion injections, something Prusiner denies. Prusiner's mice, says Collinge, may be "poised" to become infectious; giving them a shot of synthetic, misfolded PrP may push them over the edge, but so might other stresses. In fact, Collinge's team gave up on experiments in rodents with 10 times the normal level of PrP after finding prionlike pathology in animals that hadn't been inoculated.

No one has yet accomplished the gold-standard experiment: infecting normal mice, not transgenic ones, with pure prions. Until then, one of biomedicine's longest-running controversies is likely to continue.

Related Sites
Prusiner and colleague's Science paper
Stanley Prusiner's home page
Imperial College of London Neurogenetics page