BMJ No 7114 Volume 315
News Saturday 18 October 1997
The prion hypothesis is finally accepted by the establishment
Professor Stanley Prusiner has won this year's Nobel prize for medicine for his pioneering work on prions. Deborah Josefson examines his groundbreaking and frequently controversial research
| Stanley Prusiner, professor of neurology and biochemistry at the University of California, San Francisco, has won the 1997 Nobel prize for medicine for his work on prions. This new class of infectious agents are thought to underlie a variety of sporadic, transmissible, and hereditary neurodegenerative disorders including kuru, Gerstmann-Sträussler-Scheinker disease, fatal familial insomnia, Creutzfeldt-Jakob disease (CJD), scrapie, and bovine spongiform encephalopathy (BSE). |  | |
| Stanley Prusiner persisted with his radical theories on prions |
Professor Prusiner's work has long been controversial because it challenges conventional biomedical dogma which holds that an infectious agent must contain nucleic acid. The Nobel prize winner's revolutionary concept was that a deformed protein could serve as an infectious particle and propagate in the absence of genetic material. Professor Prusiner dubbed these proteins "prions" - short for proteinaceous infectious particles.
The Karolinska Institute, which bestowed the prize, said: "Stanley Prusiner has added prions to the list of well known infectious agents including bacteria, viruses, fungi, and parasites. Stanley Prusiner's discovery provides important insights that may furnish the basis of understanding the biological mechanisms underlying other types of dementia related illnesses - for example, Alzheimer's disease - and establishes a foundation for drug development and medical treatment strategies."
Professor Prusiner began his work on prions as a neurology resident in the 1970s after a patient died of CJD, a rare neurological disorder that affects one in a million people. In a review of the literature on the disease, he found that kuru (a disease of ritually cannibalistic people of Papua New Guinea, who ingested the brains of infected people), scrapie, and CJD had all been shown to be transmissible by the injection of diseased brain extracts into healthy animals. The infectious agent was thought to be a slow acting virus, yet numerous attempts to isolate this virus were fruitless. Moreover, several procedures known to denature nucleic acids and inactivate viruses failed to eradicate the infectious principle in these extracts. When the extracts were exposed to protein denaturing agents, however, they were rendered uninfectious.
Agent isolated
Intrigued, Dr Prusiner and his colleagues set out to isolate the infectious agent of scrapie, a disease of sheep so named because the afflicted animal incessantly scratches and scrapes off its skin. As suspected from previous work, no virus was isolated. The team did, however, find a protein, dubbed PrP, which transmitted the infection. Amino acid sequencing of this protein led to the identification of the gene specifying it. Further analysis showed that the gene was highly conserved and resided on the chromosomes of all mammals studied - from mice to men.
It seemed, then, that having a prion protein was normal. So how did it cause disease? Professor Prusiner speculated that an isoform of the protein might exist that could be responsible. Further work showed this to be the case. The prion protein was present in at least two forms - a normal form that does not cause disease (designated PrPC) and another form that does (PrPSC). The proteins differ in their tertiary structure, with the normal protein exhibiting a tightly coiled alpha helical configuration while the PrPSC form is in unwound ß pleated sheets.
Professor Prusiner found that the prion diseases are due to abnormal protein conformations, which occur when the normal tightly coiled * helical structure unwinds to form the unwieldy, but more stable, PrPSC form. The therapeutic implication of these observations is that anything which could stabilise the native * helical structure could prevent the progression of prion diseases.
Accordingly, Professor Prusiner and his colleagues are working on developing drugs which bind to the alpha helical form and stabilise it. A further therapeutic avenue relies on breeding sheep and cattle that lack the prion protein. Preliminary work with transgenic "knock out" mice, in which the gene for PrPC is entirely eliminated, have shown that these mice are resistant to contracting scrapie, even when inoculated with the prion that causes disease. Interestingly, these mice - lacking the PrPC gene - appeared entirely normal. Thus, although it is unknown what the function of the normal prion protein is, at least in mice, it does not seem to be essential for life.
The BSE epidemic in Britain is thought to be secondary to the practice, outlawed in 1988, of supplementing cattle feed with sheep offal. The prion that causes scrapie is believed to have been transmitted from sheep to cattle and thence to humans as new variant CJD. So far, 20 cases of new variant CJD have been identified, and they differ from conventional CJD in having a younger age of onset and shorter course. Professor Prusiner has proposed that the breeding of prion resistant domestic animals might be one way of preventing prion transmission to humans (Science 1997;278:245-50).
Awarding the Nobel prize to Professor Prusiner represents official acceptance of the prion hypothesis. None the less, sceptics remain. Dr Robert Rohwer, director of neurovirology at the Veterans Affairs Medical Center in Baltimore, calls prions the "cold fusion of infectious disease." Dr Laura Maneulidis of Yale University thinks that a virus will eventually be found to have caused prion-type diseases and worries that the Nobel prize will prevent further inquiry. "That's the problem with Nobel prizes. If people think that everything is decided, you can't possibly risk going against the grain," she said.
Heretical hypothesis
The irony is that Professor Prusiner did go against the grain, and he endured decades of ridicule for persisting in his notions. Dr Zachary Hall of the National Institute of Neurological Disorders and Stroke said: "It's a very, very well deserved prize. The ideas were bold and the hypothesis was heretical. But he pushed unrelentingly and was unfazed." Dr David Baltimore, himself a Nobel laureate and former director of the Whitehead Institute and Rockefeller University, said, "These are the mythological stories of science - people who have really kept their own faith for so many years and lived through a period of opprobrium and finally are discovered to be right."
In an interview after learning he had won the prize, Professor Prusiner said that scientists were right to doubt him: "I think that scientists should be very reticent to accept new ideas - 99% of new ideas are wrong. We have to be very tough on our colleagues."
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