Pruisner's Nobel prize:
NOBEL PRIZE:
Prusiner Recognized for Once-Heretical Prion Theory
Gretchen Vogel
The Nobel committee often honors scientists who spent years working against strong opposition on controversial ideas, but usually the prize arrives long after the
dust has settled. Not so this year for the prize in physiology or medicine. Stockholm's Karolinska Institute announced Monday that it had chosen to honor Stanley
Prusiner "for his discovery of prions--a new biological principle of infection." The University of California, San Francisco, professor of neurology, virology, and
biochemistry has championed the idea that infectious proteins can cause a range of degenerative brain diseases by misfolding and causing other proteins to do
likewise. The committee also departed from tradition by awarding the prize to a single researcher--the first time it has done so since 1987, and only the 10th time
in the last 50 years.
While many of Prusiner's colleagues have come to accept the once-heretical prion theory, most say it still faces some crucial unanswered questions. Many argue,
for example, that definitive proof that prions can cause disease by themselves is still lacking and that a cofactor such as a virus cannot be ruled out. Nevertheless,
they say, Prusiner's work so far in making his case is worthy of the prize. "The distance he has brought [the field] is unbelievable," says Peter Lansbury, a
biochemist at Brigham and Women's Hospital in Boston who studies the possible role of prion-type processes in Alzheimer's disease. In a statement, Charles
Weissmann of the University of Zurich--who some have argued should have shared the prize--called Prusiner "a true pioneer and iconoclast" who "has waged a
scientific battle for over 2 decades to convince his colleagues and the world that the infectious agent responsible for diseases such as scrapie, "mad cow
disease," and Creutzfeldt-Jakob disease [CJD] is an abnormal form of a protein ... and has accumulated the evidence which has convinced the vast majority of
scientists of the correctness of his view."
This year's prize is the second awarded for work with such degenerative brain diseases. D. Carleton Gajdusek won in 1976 for his work a decade earlier
demonstrating that kuru--a brain disease that affected highlanders in New Guinea who practiced ritualized cannibalism--was infectious. At the time, Gajdusek's
work led many to blame the malady on a slow-acting virus, but it is now widely considered to be a prion disease.
Prusiner coined the term in 1982 to describe the "proteinaceous infectious particles" he blamed for causing scrapie in sheep and hamsters. He suggested that
scrapie and a collection of other wasting brain diseases, some inherited, some infectious, and some sporadic, were all due to a common process: a misfolded
protein that propagates and kills brain cells.
In doing so, he was picking up on an idea proposed in the 1960s, when radiation biologist Tikvah Alper, of Hammersmith Hospital in London, and physicist J. S.
Griffith of Bedford College, London, suggested that an infectious agent that lacked nucleic acid could cause disease. Alper, studying scrapie in sheep, found that
brain tissue remained infectious even after she subjected it to radiation that would destroy any DNA or RNA. Griffith suggested in a separate paper that perhaps a
protein, which would usually prefer one folding pattern, could somehow misfold and then catalyze other proteins to do so. Such an idea seemed to threaten the
very foundations of molecular biology, which held that nucleic acids were the only way to transmit information from one generation to the next.
Inspired by a patient who died of the wasting brain condition CJD in 1972, Prusiner set out to determine the causative agent behind the disease, which resembles
both kuru and scrapie. He and his colleagues reported in Science in 1982 that they had found an unusual protein in the brains of scrapie-infected hamsters that
did not seem to be present in healthy animals. A year later, they identified the protein and called it PrP for prion protein.
In the next decade, a series of experiments, many led by Prusiner, demonstrated that PrP actually is present in healthy animals, but in a different form from the
one found in diseased brains. The studies also showed that mice lacking PrP are resistant to prion diseases. Taken together, the results have convinced many
scientists that the protein is indeed the agent behind CJD, scrapie, mad cow disease, and others.
Key questions remain, however. "The most important bit of information has yet to come forward: What triggers the normal cell protein to transform into the
[disease-causing] isotype of the protein?" says Clarence Gibbs, a virologist at the National Institute of Neurological Disorders and Stroke and a longtime colleague
of Gajdusek. (Prusiner addresses part of that question on page 245, where he suggests that a possible missing element, dubbed protein X, might help chaperone
the PrP protein into its infectious shape.) And no one has been able to inject a prion protein synthesized in the test tube--and therefore free of any possible
contaminating virus or other nucleic acid--into a healthy animal and make it sick. "I think it's speculation that the protein itself is infectious," says Laura Manuelidis,
a neuropathologist at Yale University who has argued that a virus or other particle is involved. Prusiner acknowledges that there are still many uncertainties.
"There are all these other experiments that should be done," he says. "I want to know more about all these details."
Although Prusiner had been mentioned frequently as a Nobel candidate, many expected the award would wait for some of those uncertainties to be resolved.
Byron Caughey, of the National Institutes of Health's Rocky Mountain Laboratories in Hamilton, Montana, said in a statement that the award is "somewhat
surprising in view of the incomplete resolution of these questions."
Ralf Pettersson, deputy chair of the Nobel Committee at the Karolinska Institute, says the panel was not bothered by the unanswered questions. The prize was
awarded, he says, for the discovery of the prion and its role in the disease process. "The committee is well aware of where the field stands," he says. "The details
have to be solved in the future. But no one can object to the essential role of the prion protein" in these brain diseases. Lansbury adds that Prusiner "is really a
trailblazer. ... He's captured the imagination of a huge segment of the scientific population." And those imaginations should in no way be limited by this week's
prize, Gibbs advises: "There's another Nobel Prize somewhere in this field."
http://www.sciencemag.org/feature/data/prusiner/214.shl
The Prion Diseases
Prions, once dismissed as an impossibility, have now gained wide recognition as extraordinary agents that cause a number of infectious, genetic and spontaneous
disorders
by Stanley B. Prusiner
http://www.nmia.com/~mdibble/prion.html
In Search of the Cause
I first became intrigued by the prion diseases in 1972, when as a resident in neurology at the University of California School of Medicine at San Francisco, I lost a
patient to Creutzfeldt-Jakob disease. As I reviewed the scientific literature on that and related conditions, I learned that scrapie, Creutzfeldt-Jakob disease and kuru
had all been shown to be transmissible by injecting extracts of diseased brains into the brains of healthy animals. The infections were thought to be caused by a
slow-acting virus, yet no one had managed to isolate the culprit. In the course of reading, I came across an astonishing report in which Tikvah Alper and her
colleagues at the Hammersmith Hospital in London suggested that the scrapie agent might lack nucleic acid, which usually can be degraded by ultraviolet or ionizing
radiation. When the nucleic acid in extracts of scrapie-infected brains was presumably destroyed by those treatments, the extracts retained their ability to transmit
scrapie. If the organism did lack DNA and RNA, the finding would mean that it was not a virus or any other known type of infectious agent, all of which contain genetic
material. What, then, was it? Investigators had many ideas--including, jokingly, linoleum and kryptonite--but no hard answers. I immediately began trying to solve this
mystery when I set up a laboratory at U.C.S.F. in 1974. The first step had to be a mechanical one--purifying the infectious material in scrapie-infected brains so that
its composition could be analyzed. The task was daunting; many investigators had tried and failed in the past. But with the optimism of youth, I forged ahead [see
"Prions," by Stanley B. Prusiner; SCIENTIFIC AMERICAN, October 1984]. By 1982 my colleagues and I had made good progress, producing extracts of hamster
brains consisting almost exclusively of infectious material. We had, furthermore, subjected the extracts to a range of tests designed to reveal the composition of the
disease-causing component.
Amazing Discovery
All our results pointed toward one startling conclusion: the infectious agent in scrapie (and presumably in the related diseases) did indeed lack nucleic acid and
consisted mainly, if not exclusively, of protein. We deduced that DNA and RNA were absent because, like Alper, we saw that procedures known to damage nucleic
acid did not reduce infectivity. And we knew protein was an essential component because procedures that denature (unfold) or degrade protein reduced infectivity. I
thus introduced the term "prion" to distinguish this class of disease conveyer from viruses, bacteria, fungi and other known pathogens. Not long afterward, we
determined that scrapie prions contained a single protein that we called PrP, for "prion protein." Now the major question became; Where did the instructions
specifying the sequence of amino acids in PrP reside? Were they carried by an undetected piece of DNA that traveled with PrP, or were they, perhaps, contained in
a gene housed in the chromosomes of cells? The key to this riddle was the identification in 1984 of some 15 amino acids at one end of the PrP protein. My group
identified this short amino acid sequence in collaboration with Leroy E. Hood and his co-workers at the California Institute of Technology. Knowledge of the
sequence allowed us and others to construct molecular probes, or detectors, able to indicate whether mammalian cells carried the PrP gene. With probes produced
by Hood's team, Bruno Oesch, working in the laboratory of Charles Weissmann at the University of Zurich, showed that hamster cells do contain a gene for PrP. At
about the same time, Bruce Cheseboro of the NIH Rocky Mountain Laboratories made his own probes and established that mouse cells harbor the gene as well.
That work made it possible to isolate the gene and to establish that it resides not in prions but in the chromosomes of hamsters, mice, humans and all other
mammals that have been examined. What is more, most of the time, these animals make PrP without getting sick. One interpretation of such findings was that we
had made a terrible mistake: PrP had nothing to do with prion diseases. Another possibility was that PrP could be produced in two forms, one that generated disease
and one that did not. We soon showed the latter interpretation to be correct. The critical clue was the fact that the PrP found in infected brains resisted breakdown
by cellular enzymes called proteases. Most proteins in cells are degraded fairly easily. I therefore suspected that if a normal, (3) nonthreatening form of PrP existed,
it too would be susceptible to degradation. Ronald A. Barry in my laboratory then identified this hypothetical protease-sensitive form. It thus became clear that
scrapie-causing PrP is a variant of a normal protein. We therefore called the normal protein "cellular PrP" and the infectious (protease-resistant) form "scrapie PrP."
The latter term is now used to refer to the protein molecules that constitute the prions causing all scrapie-like diseases of animals and humans.
same Prusiner article on scientific american's website:
http://www.sciam.com/0896issue/prion.html
