Proof Positive

In 1982, a neurologist named Stanley Prusiner made a highly unorthodox proposal about a group of mysterious and devastating human and animal brain diseases known as “transmissible spongiform encephalopathies” (TSEs). Prusiner claimed that the TSEs—including mad cow disease, the sheep disease known as scrapie, and kuru, a degenerative brain disorder found among the Foré people of New Guinea—moved from victim to victim in a fundamentally different way than all other known contagious diseases. Instead of being carried by bacteria or viruses, he said, they were spread by what he called “prions,” tiny malformed proteins with the ability to convert healthy brain proteins into copies of themselves.

Initially quite controversial, Prusiner’s “prion hypothesis” gradually gained traction as researchers piled up evidence in its favor. It spilled into public awareness when the brain-destroying ailment known as new-variant Creutzfeldt-Jakob Disease (nvCJD) suddenly appeared in Britain and was blamed on the consumption of beef tainted with mad cow prions. In 1997, Prusiner received the Nobel Prize in Medicine for his work. But one small hitch remained: no one had been able to completely confirm the prion hypothesis by causing a TSE in normal lab animals with prions created entirely in a test tube.

In April 2005, though, UTMB professor of neurology Claudio Soto announced in a paper published in the journal Cell that his team had done just that. Using a method they call “protein misfolding cyclic amplification” (PMCA), Soto’s group—including assistant professor Joaquín Castilla and research assistant Paula Saá— rapidly multiplied a small number of prions taken from infected hamsters and placed them in test tubes containing healthy brain proteins. When the healthy proteins had been largely transformed into prions, the samples were diluted over and over again and the process repeated, until the only remaining prions were those that had been generated in the test tubes. These were then injected into the brains of healthy hamsters, which began showing TSE symptoms within four months and, on average, died less than six months after inoculation.

“For many years, people have tried to make these infectious prions in test tubes, to rule out the presence of a virus,” Soto says. “The evidence in favor of the prion hypothesis was strong, but the final proof was still missing. Now we have supplied this proof.”

According to Soto, his group’s success in dramatically increasing the efficiency of PMCA made the breakthrough possible. That achievement enabled them to multiply prion concentrations by as much as a million times. The same enhancement, Soto says, should also soon make possible a much-needed blood test for prions, which would greatly improve surveillance techniques for mad cow disease and nvCJD.
—Jim Kelly