Stanley Prusiner (born 1942) won the Nobel Prize in Physiology for Medicine in 1997 for his discovery of the prion, originally described as a disease-producing agent in animals and humans that, unlike any other known pathogen, contains no RNA or DNA. The prize was widely seen as a vindication of Prusiner's research and methods.
Prusiner was born on May 28, 1942, in Des Moines, Iowa, to Lawrence and Miriam Prusiner and named for his father's younger brother who died of Hodgkin's disease at age 24. In those World War II years, his father was drafted into the Navy shortly after Prusiner was born. The family moved to Boston so his father could attend officer training school. When he left for the South Pacific, his wife and son moved to Cincinnati, Ohio, to live near her mother. In his autobiography for the Nobel Foundation, Prusiner wrote fondly of his maternal grandmother and paternal grandfather, Ben Prusiner, who as a child immigrated to the United States from Moscow in 1896 and grew up in Sioux City, Iowa. At the end of the war, the reunited Prusiner family moved back to Des Moines.
In 1952, the family moved back to Cincinnati, where Prusiner's father worked as an architect for the next 25 years. Prusiner attended Walnut Street High School and studied Latin for five years. "I found high school rather uninteresting," he wrote in his autobiography for the Nobel Prize committee. He felt, however, that college was a different matter. "The intellectual environment of the University of Pennsylvania was extraordinary," he said, recalling how surprisingly willing the faculty members were to take time for undergraduates. He studied science, philosophy, history of architecture, economics, and Russian history. In the summer of 1963, he began a research project with Sidney Wolfson that continued through Prusiner's senior year, and he decided to stay at the university for medical school "largely because of the wonderful experience of doing research with Sidney Wolfson." Prusiner received his bachelor's degree in 1964.
In his second year of medical school, Prusiner began a study of fluorescence and brown fat that led to spending much of his fourth year at the Wenner-Gren Institute in Stockholm working on a related topic. That "exciting time" helped him choose to pursue a career in biomedical research.
In 1968 Prusiner returned to Philadelphia and received his M.D. He began a medical internship at the University of California, San Francisco (UCSF), as a prerequisite to a post in the U.S. Public Health Service at the National Institutes of Health (NIH). While in San Francisco, he met and married Sandy Turk, a high school math teacher. They subsequently had two children, Helen and Leah.
Once at the NIH, Prusiner spent three years studying glutaminases in E. coli. He called the period "critical in my scientific education" and said, "I learned an immense amount about the research process." Following the NIH post, he chose a residency in neurology rather than postdoctoral fellowships in neurobiology as "a better route to developing a rewarding career in research."
A key event in his career came about in September 1972, while he was serving his residency in neurology at UCSF. He admitted a patient dying from Creutzfeldt-Jacob disease (CJD), a rare, fatal condition in which the brain deteriorates. Prusiner learned that CJD did not elicit the body's usual immune response and behaved in ways un-characteristic of viral pathogens. He was fascinated and over the next two years read "every paper that I could find" on the CJD family of diseases, known then as "slow virus" diseases because they appeared relatively late in life.
In 1974, as an assistant professor of neurology at UCSF, Prusiner set up a lab to study scrapie, the "slow virus" disease that affects sheep. He secured funds for the project from the Howard Hughes Medical Institute (HHMI) and eventually the NIH. A temporary career crisis arose when (1) his research into scrapie failed to yield the viral pathogen he expected, (2) the HHMI ended its funding, and (3) UCSF denied him tenure. The crisis was short-lived. He streamlined some of his methods and found two new funding organizations, R. J. Reynolds Company and Sherman Fairchild Foundation, which he credits with buying the enormous number of mice and hamsters he used. His tenure denial was also reversed. NIH funding continued, amounting to $56 million between 1975 and 1997, according to one source.
Over the next eight years, Prusiner pursued the pathogen responsible for the so-called slow virus diseases and also became a professor of neurology and biochemistry at UCSF. In the spring of 1982, Science magazine published his first article on his research, which, in Prusiner's words, "set off a firestorm." He broke with scientific orthodoxy, announcing that his years of work had identified not a virus but a protein as the agent causing a set of diseases known as transmissible spongiform encephalopathies (TSEs) (the same group formerly known as the "slow viruses"). He also coined the term "prion," derived from "proteinaceous infectious particle," for his discovery. (Gary Taubes, writing in Discover magazine, says Prusiner tinkered with the spelling of his coinage for euphony's sake. Prion rhymes with Leon.)
The TSEs include Bovine Spongiform Encephalopathy (BSE), also known as Mad Cow Disease because of the way infected cattle behave; scrapie, documented in the eighteenth century in Iceland and in the 1940s in Scotland, where shepherds named it for the way infected sheep scrape their wool against fence posts; several other forms affecting animals; and the forms found in humans, including CJD, Gerstmann-Straussler-Scheinker (GSS) disease and fatal familial insomnia, each of which affects a very small number of related individuals, and kuru, a disease of indigenous people on New Guinea and now virtually extinct. All are fatal. All end in degeneration of brain tissue into a mass riddled with holes, like a sponge-accounting for the "spongiform" part of their collective name. The ones affecting humans threaten only a very small number of people, perhaps one in one million (the number in the United States with CJD has been put at some 225), but in the 1980s and 1990s, a new threat arose when BSE "broke the species barrier": Infected cattle apparently transmitted something that caused a form of CJD in humans who ate infected beef. Some 100 people, mostly in the United Kingdom, were thought to have contracted the disease in this fashion, and at least 130,000 British cattle were affected. Many were destroyed to avoid further spread of the disease. The specter of an unchecked spread panicked Europeans who consumed British beef.
Prusiner's work sparked controversy immediately. "His findings go against the central dogma of biology, which is that you can transmit information only with DNA and RNA," said Michael Shelanski, chairman of the department of pathology at Columbia-Presbyterian Medical Center. Infectious agents recognized in orthodox science include bacteria, viruses, fungi, and parasites, all of which contain DNA or RNA. While efforts to prove and disprove Prusiner's prion theory are ongoing, it has achieved a wide acceptance, especially the idea that prion proteins are involved in some way in the diseases like CJD. The theory itself has evolved since 1982. Regardless of the theory that achieves consensus in the end, Prusiner's work and the work of his critics have enriched the science associated with these diseases. In 2001, for example, WebMD reported that Prusiner's lab had identified at least two drugs, chlorpromazine and quinacrine, that may be effective against CJD contracted from BSE-infected beef.
Based on his work with mice and hamsters infected with scrapie, Prusiner concluded that prion protein (PrP) occurs naturally in white blood cells and brain cells. Its function is not understood, but ordinarily it is harmless. PrPs can be altered, however, so that their normal helical, or spiral, shape becomes flat and rigid. Collections of these flat, rigid prions form rods that group together into sheets or plaques that kill nerve cells, producing porous, spongy brain texture, dementia, and death.
The agent causing normal prions to change conformation is novel: As Prusiner explained to Rae Frey of Australian Radio National, "the abnormal protein is capable of recruiting the normal one into the abnormal form…. [O]nce the abnormal form of the prion protein is in the body, it then grabs on to the normal form and co-opts it and turns it into a rogue, or an abnormal form… . It becomes a chain reaction and more and more of the abnormal form accumulates … and eventually kills the host." The process is very slow. Prusiner says experiments in his lab confirmed the ability of scrapie-infected prion protein (PrPSc) to cause normal, helical PrP to change conformation.
Prion diseases arise in three ways: by infection (1 percent of human cases), by heredity (5-15 percent), and by no known cause, said to be sporadic (all the rest). Sporadic cases are thought to be genetic. The particular gene that carries the instructions for the amino acid sequence that makes up the prion protein has been pinpointed, and Prusiner has found a mutation that produces the "rogue" protein—provided the mutant gene is present on both "halves" of its chromosome.
Prusiner concluded the "villain" in scrapie and the other prion diseases was not viral but protein on the basis of several pieces of evidence. For instance, procedures that normally kill viruses did not destroy the ability of the material he extracted from infected laboratory animals to infect others in turn; the agent works very slowly-behavior uncharacteristic of viruses; it does not trigger the immune system to produce antibodies (a virus does); enzymes that destroy nucleic acids (the building blocks of DNA and RNA, which all viruses contain) do not kill it; and scientists have been unable to find a viral agent in more than thirty years of searching. Several other pieces of evidence support Prusiner's claim of a protein agent: Protein-destroying enzymes destroy its infectivity, and when the gene that encodes the prion protein is removed from laboratory animals, exposure to PrPSc does not lead to the disease; no PrP means no possibility of PrPSc, so therefore PrP must be present for the disease to occur.
Prusiner's theory is controversial not only because it is unorthodox, scientists have also accused him of claiming his lab work proves things it does not (perhaps the stunning degree to which the best-trained scientific minds can disagree on the design, conduct, and interpretation of scientific experiments reflects how very complicated the area is) and of failing to credit earlier workers, for instance researcher Pat Merz, who identified rigid protein plaques in the brains of mice with scrapie in 1978 and published her findings in 1981. Prusiner is said to have ignored her work in his 1982 paper, in which he claimed to have discovered prion rods. Others have alleged Prusiner rushed to the press early on with the suggestion that Alzheimer's and other diseases of brain-riddling amyloid protein plaque might be related to prion diseases. "It is an astounding finding," Prusiner told the New York Times in 1983 that, "we never would have dreamed that amyloid and prions are the same. The implications of the findings may be enormous." Alzheimer's expert George Glenner said there was no proof at the time that Alzheimer's amyloids and scrapie proteins were the same (and their difference has since been confirmed). Glenner explained in Discover, "I have the greatest respect for Stanley, but he wanted to get in the press fast. I do not think it should have been released at all." Prusiner as recently as 1999 still expressed optimism that his discoveries would link up with Alzheimer's, which affects far more people than does CJD and related diseases and therefore attracts more research dollars. He told an interviewer in Australia that once drugs for treating prion diseases are discovered, "The blueprint for going after drugs, for producing drugs that will stop Alzheimer's Disease, will stop Parkinson's Disease will be laid out… . Once you have one success, then many other successes will follow much more quickly."
Prusiner's Nobel Prize was unusual in several ways. First, the annual prize in physiology or medicine is usually shared by more than one person. Prusiner was the first single winner in ten years and one of only six singletons in the preceding 40 years. Moreover, the Nobel is usually awarded after major controversies have been resolved, but one member of the Nobel award committee, Dr. Lars Edstrom, suggested the committee may have taken a side. In a New York Times article, Dr. Edstrom noted: "There are still people who don't believe that a protein can cause these diseases, but we believe it." Prusiner's prize was also unusual because he was the second person to win for work on TSEs. Dr. Carleton Gajdusek won in 1976 for his work with kuru. With two awards in the area, the committee would be unlikely to award a third, which could dampen the enthusiasm of other researchers in the area; the clout, the glory, and the $1 million that go with the Nobel are mighty incentives in science.
Lately it seems that prions alone may not explain how PrPSc forces PrP (or PrPC, the normal, "cellular" PrP) to trim rigid, clump together, and kill brain cells after all. In his research summary on his UCSF Web page, Prusiner says an additional agent now seems to be involved. He calls it "an as yet to be identified factor that we have provisionally designated protein X." Protein X "binds to PrPC. The PrPC/ protein X complex then binds PrPSc; by an unknown process, PrPC is transformed into a second molecule of PrPSc. We are attempting to isolate protein X."
One or two of Prusiner's critics have suggested his protein X sounds suspiciously like a viral agent proposed in the 1970s by three scientists of the British Neuro-pathogenesis Unit in Edinburgh, Scotland. They were trying to isolate the agent causing scrapie and hypothesized it was "a small piece of nucleic acid protected by a protein made by genes in the host, rather than genes in the agent." They called it a "virino." Will it turn out to be Prusiner's protein X, or will protein X reveal itself as virus X? The end of the story has yet to be written. Perhaps some words of Francis Bacon are apt to the issue. "He that will not apply new remedies must expect new evils; for time is the greatest innovator."
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