Front Page

Previous Story

Next Story

NIH Record vertical blue bar column separator

MRC's Weissmann Discusses Prion Transmission

By Rich McManus

On the Front Page...

The name of the mysterious pathogen that causes the brain-rotting transmissable spongiform encephalopathies such as scrapie, "mad cow" disease and Creutzfeldt-Jakob disease sounds like it came from a bad 1950's sci-fi film — prions. And according to Dr. Charles Weissmann, professor and senior research scientist at the Medical Research Council prion unit at University College, London — who lectured here Apr. 7 — prions have devilish characteristics that wouldn't put them beyond the pale of an old Outer Limits rerun: though mercifully rare — striking only one person in a million yearly — the buggers are wildly infectious, capable of surviving withering attempts at cleansing and able to stick stubbornly to such surfaces as plastic and stainless steel.


Dr. Charles Weissmann
These diabolical characteristics might explain why Masur Auditorium was full by the time Weissmann began his Wednesday Afternoon Lecture with the understatement, "Prions are pretty different from any other disease agent." Weissmann, who will soon relocate to Florida, where he will be affiliated with the Scripps Research Institute, has studied prions since the early 1980's, and reviewed some of the pathogen's properties in a talk titled, "Propagation of Prions."

In humans, prion-associated disease usually strikes in people of advanced age (60-70), is lethal within a year of diagnosis, occurs only rarely, is transmissable and has a long incubation time, perhaps up to 40 years. Unlike other infectious agents, which cause an immune response of some kind, prions cause "no classical cellular or humoral immune reaction," Weissmann said.

The most common human prion disease is sporadic Creutzfeldt-Jakob disease (CJD), followed by familial CJD, then acquired CJD (including variant CJD, which strikes young people, mainly below the age of 30), kuru (a brain disease discovered by former NIH scientist and Nobel laureate Dr. Carleton Gajdusek) and "iatrogenic" CJD, or disease caused by growth hormone or transplants derived from donors suffering from unrecognized prion disease.

Weissmann paused to consider the controversy associated with tainted beef and mad cow disease. "Yes, I do eat beef," he admitted. "I'm at an age where the disease is not usually acquired." He further divulged that he doesn't proscribe beef-eating among his grown children, either.

What is now known as prion disease was first recognized in the mid-1930's, Weissmann said, when scrapie — then thought to be a "slow virus" — was found in sheep. The disease was characterized by unusually long incubation times during which no symptoms were evident for years. It was known even then, however, that even formaldehyde could not kill the scrapie agent.

American scientist Stanley Prusiner was the first to purify the scrapie agent, from diseased hamster brains; he called it PrP scrapie. To this day, no scrapie-specific nucleic acid has ever been identified. It is known, rather, by its qualities — it is resistant to protease digestion, and tends to aggregate, forming beta-sheet-rich clumps called amyloid.

Weissmann described how his laboratory found the messenger and the gene that encode PrP scrapie. A series of biological linkage tests established that PrP is the infectious agent causing prion disease. And because the familial form of CJD is associated with point mutations in human genes, there is now a genetic link to prion disorders. This finding was buttressed by later studies in knockout mice in which PrP was linked to disease.

The hypothesis that prions were a form of slow virus was discarded when scientists could find no nucleic acid associated with prions. This is also the drawback of the "virino" hypothesis, which posited a very small nucleic acid incapable of encoding a protein on its own, but able to recruit a host protein to form a capsid that could elude recognition by the immune system. Again, "There's no evidence of a nucleic acid," said Weissmann.

Then there's the "protein-only" hypothesis, advanced back in 1965, which attributed disease to abnormalities in protein conformation. "There is good evidence that conformational modification of PrP is involved in the disease, although the mechanism by which this occurs is still obscure," he said. "Recent studies positing a role for RNA in the process still need to be confirmed."

Of the two models proposed, the "refolding" and the "seeding" model, the latter has been "demonstrated convincingly in yeast."

From these theoretical heights, Weissmann then descended to what science knows in fact: there are many different strains of the scrapie agent that can be propagated in a single species, be it mouse or human. Different strains are characterized by lesion site and incubation time. And there are many types of abnormal configuration of PrP; the way PrP misfolds determines where it is susceptible to cleavage by certain proteases. In man, four strains of PrP are detectable by gel electrophoresis signatures, giving scientists a diagnostic tool. NIH's Dr. Reed Wickner, who introduced Weissmann, has shown that yeast contains elements that behave like prions.

"Different conformations of protein are associated with distinct, stable prion strains, which confirms the 'seeding' hypothesis," Weissmann said. "PrP is essential for multiplication of prions, their propagation through the organism and pathogenesis. But structure of the prion is still unknown."

To illustrate transmission of prion disease by surface-bound prions, Weissmann described an accidental transmission of CJD by an EEG brain electrode. After having been used on one infected patient, the electrode was treated with benzene, ethanol, and formaldehyde vapor for 48 hours in an attempt to disinfect it, yet was still able to transmit disease when reused in a second and even a third patient. NIH scientist Dr. Clarence Gibbs later showed that the same electrode was still capable of transmitting prion disease to a chimpanzee 3 years after the accidental human transmission.

Weissmann's studies established that steel surgical wire could carry prions whether left in animal brains permanently or merely dipped briefly into the brain. "Only a short time is sufficient to pass the infection from a wire to a mouse...and an enormously small amount of protein was the same [in terms of infectivity] as injecting concentrated brain homogenate [which teems with prions]. This may be because the surface-bound agent is stabilized against degradation in the host, Weissmann said.

It was no comfort to learn that prions appear to bind as tightly to plastic as they do to metal.

Weissmann said there are only half a dozen cell lines that can be successfully infected with PrP; unsurprisingly, given its penchant for infecting brain, a neuroblastoma line is one. New cell-based assays for prions promise to advance prion science faster than was possible in the slow and expensive mouse bioassay, he noted.

He concluded with a detailed analysis of how prions move around in the body, migrating typically from gut to brain with a stopover in the spleen and lymph nodes, where replication is amplified, before advancing to the peripheral nervous system, to spinal cord and finally the brain (although if the dosage is high enough, prions can go directly from gut to central nervous system). As to how and why prions arose in mammalian history, hypotheses are now wide open, Weissmann said.

To hear the full discussion of prion propagation, visit, where the talk is archived.

Up to Top