Medicine 1997

The Nobel Prize in The Nobel Prize in Physiology or Medicine Physiology or Medicine 1997 1997 Press Release "for his discovery of Prions - a new biological principle of infection" Presentation Speech Illustrated Presentation

Stanley B. Prusiner Autobiography Curriculum Vitae Banquet Speech Nobel Diploma Prize Award Photo Other Resources

Stanley B. Prusiner 1996 1998 USA The 1997 Prize in: University of California School of Medicine Physics San Francisco, CA, USA Chemistry b. 1942 Physiology or Medicine Literature Peace Economic Sciences Find a Laureate:

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Press Release: The 1997 Nobel Prize in Physiology or Medicine

NOBELFÖRSAMLINGEN KAROLINSKA INSTITUTET THE NOBEL ASSEMBLY AT THE KAROLINSKA INSTITUTE

6 October 1997 The Nobel Assembly at the Karolinska Institute has today decided to award the Nobel Prize in Physiology or Medicine for 1997 to

Stanley B. Prusiner

for his discovery of "Prions - a new biological principle of infection". Summary The 1997 Nobel Prize in Physiology or Medicine is awarded to the American Stanley Prusiner for his pioneering discovery of an entirely new genre of disease-causing agents and the elucidation of the underlying priciples of their mode of action. Stanley Prusiner has added prions to the list of well known infectious agents including bacteria, viruses, fungi and parasites. Prions exist normally as innocuous cellular proteins, however, prions possess an innate capacity to convert their structures into highly stabile conformations that ultimately result in the formation of harmful particles, the causative agents of several deadly brain diseases of the dementia type in humans and animals. Prion diseases may be inherited, laterally transmitted, or occur spontaneously. Regions within diseased brains have a characteristic porous and spongy appearance, evidence of extensive nerve cell death, and affected individuals exhibit neurological

http://www.nobel.se/medicine/laureates/1997/press.html (1 of 5) [7/15/2003 2:30:13 PM] Physiology or Medicine for 1997 - Press Release symptoms including impaired muscle control, loss of mental acuity, memory loss and insomnia. Stanley Prusiner's discovery provides important insights that may furnish the basis to understand the biological mechanisms underlying other types of dementia-related diseases, for example Alzheimer's disease, and establishes a foundation for drug development and new types of medical treatment strategies. The prize winning research was initiated 25 years ago In 1972 Stanley Prusiner began his work after one of his patients died of dementia resulting from Creutzfeldt-Jakob disease (CJD). It had previously been shown that CJD, kuru, and scrapie, a similar disease affecting sheep, could be transmitted through extracts of diseased brains. There were many theories regarding the nature of the infectious agent, including one that postulated that the infectious agent lacked nucleic acid, a sensational hypothesis since at the time all known infectious agents contained the hereditary material DNA or RNA. Prusiner took up the challenge to precisely identify the infectious agent and ten years later in 1982 he and his colleagues successfully produced a preparation derived from diseased hamster brains that contained a single infectious agent. All experimental evidence indicated that the infectious agent was comprised of a single protein, and Prusiner named this protein a prion, an acronym derived from "proteinaceous infectious particle." It should be noted that the scientific community greeted this discovery with great skepticism, however, an unwavering Prusiner continued the arduous task to define the precise nature of this novel infectious agent. The infectious prion particle forms within the body Where was the gene encoding the prion, the piece of DNA that determined the sequence of the amino acids comprising the prion protein? Perhaps the gene was closely associated with the protein itself as in a small virus? The answers to these questions came in 1984 when Prusiner and colleagues isolated a gene probe and subsequently showed that the prion gene was found in all animals tested, including man. This startling finding raised even more questions. Could prions really be the causative agent of several dementia-type brain diseases when the gene was endogenous to all mammals? Prusiner must have made a mistake! The solution to this problem became evident with the sensational discovery that the prion protein, designated PrP, could fold into two distinct conformations, one that resulted in disease (scrapie PrP = PrPSc) and the other normal (PrP = PrPc). It was subsequently shown that the disease-causing prion protein had infectious properties and could initiate a chain reaction so that normal PrPc protein is converted into the more stabile PrPSc form. The PrPSc prion protein is extremely stabile and is resistant to proteolysis, organic solvents and high temperatures (even greater than 100o C). With time, non-symptomatic incubation periods vary from months to years, the disease-causing PrPSc can accumulate to levels that result in brain tissue damage. In analogy to a well known literary work, the normal PrPc can be compared to the friendly Dr. Jekyll and the disease causing PrPSc to the dangerous Mr. Hyde, the same entity but in two different manifestations.

http://www.nobel.se/medicine/laureates/1997/press.html (2 of 5) [7/15/2003 2:30:13 PM] Physiology or Medicine for 1997 - Press Release Mutations in the prion gene cause hereditary brain diseases The long incubation time for prion based disease hampered the initial efforts to purify the prion protein. In order to assess purification schemes Prusiner was forced to use scores of mice and in each experiment wait patiently for approximately 200 days for the appearance of disease symptoms. The purification efforts accelerated when it was demonstrated that scrapie could be transferred to hamsters, animals that exhibited markedly shortened incubation times. Together with other scientists, Prusiner cloned the prion gene and demonstrated that the normal prion protein was an ordinary component of white blood cells (lymphocytes) and was found in many other tissues as well. Normal prion proteins are particularly abundant on the surface of nerve cells in the brain. Prusiner found that the hereditary forms of prion diseases, CJD and GSS (see the last section), were due to mutations in the prion gene. Proof that these mutations caused disease was obtained when the mutant genes were introduced into the germline of mice. These transgenic mice came down with a scrapie-like disease. In 1992 prion researchers obtained conclusive evidence for the role of the prion protein in the pathogenesis of brain disease when they managed to abolish the gene encoding the prion protein in mice, creating so called prion knock-out mice. These prion knock-out mice were found to be completely resistant to infection when exposed to disease-causing prion protein preparations. Importantly, when the prion gene was reintroduced into these knock-out mice, they once again became susceptible to infection. Strangely enough, mice lacking the prion gene are apparently healthy, suggesting that the normal prion protein is not an essential protein in mice, its role in the nervous system remains a mystery. Structural variant disease-causing prions accumulate in different regions of the brain Specific mutations within the prion gene give rise to structurally variant disease-causing prion proteins. These structural prion variants accumulate in different regions of the brain. Dependent upon the region of the brain that becomes infected, different symptoms, typical for the particular type of disease are evident. When the cerebellum is infected the ability to coordinate body movements declines. Memory and mental acuity are affected if the cerebral cortex is infected. Thalamus specific prions disturb sleep leading to insomnia, and prions infecting the brain stem primarily affect body movement. Other dementias may have a similar background Prusiner's pioneering work has opened new avenues for understanding the pathogenesis of more common dementia-type illnesses. For example, there are indications that Alzheimer's disease is caused when certain, non-prion, proteins undergo a conformational change that leads to the formation of harmful deposits or plaques in the brain. Prusiner's work has also established a theoretical basis for the treatment of prion diseases. It may be possible to develop pharmacological agents that prevent the conversion of harmless normal prion proteins to the disease-causing prion conformation.

http://www.nobel.se/medicine/laureates/1997/press.html (3 of 5) [7/15/2003 2:30:13 PM] Physiology or Medicine for 1997 - Press Release Intrinsic defense mechanisms do not exist against prions Prions are much smaller than viruses. The immune response does not react to prions since they are present as natural proteins from birth. They are not poisonous, but rather become deleterious only by converting into a structure that enables disease causing prion proteins to interact with one another forming thread-like structures and aggregates that ultimately destroy nerve cells. The mechanistic basis underlying prion protein aggregation and their cummulative destructive mechanism is still not well understood. In contrast to other infectious agents, prion particles are proteins and lack nucleic acid. The ability to transmit a prion infection from one species to another varies considerably and is dependent upon what is known as a species barrier. This barrier reflects how structurally related the prions of different species are. Prion diseases in animals and man Without exception, all known prion diseases lead to the death of those affected. There are, however, great variations in pre-symptomatic incubation times and how aggressively the disease progresses. Scrapie, a prion disease of sheep, was first documented in Iceland during the 18th century. Scrapie was transferred to Scotland in the 1940s. Similar prion diseases are known to affect other animals, e.g., mink, cats, deer and moose. Bovine Spongiform Encephalopathy (BSE) - Mad cow disease is a prion disease that has recently received a great deal of publicity. In England BSE was transmitted to cows through feedstuff supplemented with offals from scrapie-infected sheep. The BSE epidemic first became evident in 1985. Due to the long incubation time the epidemic did not peak until 1992. In this year alone roughly 37,000 animals were affected. Kuru among the Fore-people in New Guinea was studied by Carleton Gajdusek (recipient of the the 1976 Nobel Prize in Physiology or Medicine). Kuru was shown to be transmitted in connection with certain cannibalistic rituals and was thought to be due to an unidentified "slow virus". The infectious agent has now been identified as a prion. Duration of illness from first symptoms to death: 3 to 12 months. Gertsmann-Sträussler-Scheinker (GSS) disease is a hereditary dementia resulting from a mutation in the gene encoding the human prion protein. Approximately 50 families with GSS mutations have been identified. Duration of illness from evidence of first symptoms to death: 2 to 6 years. Fatal Familial Insomnia (FFI) is due to another mutation in the gene encoding the human prion protein. Nine families have been found that carry the FFI mutation. Duration of illness from evidence of first symptoms to death: roughly one year. Creutzfeldt-Jakob Disease (CJD) affects about one in a million people. In 85-90% of the cases it has been shown that CJD occurs http://www.nobel.se/medicine/laureates/1997/press.html (4 of 5) [7/15/2003 2:30:13 PM] Physiology or Medicine for 1997 - Press Release spontaneously. Ten to fifteen per cent of the CJD cases are caused by mutations in the prion protein gene. In rare instances CJD is the consequence of infection. Previously infections were transmitted through growth hormone preparations prepared from the pituitary gland of infected individuals, or brain membrane transplants. About 100 families are known carriers of CJD mutations. Duration of illness from evidence of first symptoms to death: roughly one year. A new variant of CJD that may have arisen through BSE-transmission. Since 1995 about 20 patients have been identified that exhibit CJD-like symptoms. Psychological symptoms with depression have dominated, but involuntary muscle contractions and difficulties to walk are also common.

The Figure schematically illustrates how variants of disease causing prions affect different parts of the brain. In Bovine Spongiform Encephalitis (BSE), the brain stem is affected, in Fatal Familial Insomnia (FFI), the thalamus region, in Creutzfeldt-Jakob Disease (CJD), the cerebral cortex, while in KURU and Gerstmann-Sträussler-Scheinker (GSS) disease the cerebellum is damaged.

http://www.nobel.se/medicine/laureates/1997/press.html (5 of 5) [7/15/2003 2:30:13 PM] The Nobel Prize in Physiology or Medicine 1997 - Presentation Speech

The Nobel Prize in Physiology The Nobel Prize in Physiology or Medicine or Medicine 1997 1997 Press Release Presentation Speech by Professor Ralf F. Pettersson of the Presentation Speech Nobel Committee at The Karolinska Institute Illustrated Presentation Translation of the Swedish text Stanley B. Prusiner Your Majesties, Your Royal Highnesses, Ladies and Autobiography Gentlemen, Curriculum Vitae Banquet Speech This year's Nobel Prize in Physiology or Medicine has been Nobel Diploma awarded to Stanley B. Prusiner for his discovery of prions - a Prize Award Photo new biological principle of infection. What is a prion? It is a Other Resources small infectious protein capable of causing fatal dementia-like diseases in man and animals. It has been known for approximately a century that infectious diseases can be caused by bacteria, viruses, fungi and parasites. All these infectious 1996 1998 agents possess a genome, the hereditary material that provides The 1997 Prize in: the basis for their replication. The ability to replicate is essential Physics for the manifestation of the diseases they cause. The most Chemistry remarkable feature of prions is that they are able to replicate Physiology or Medicine themselves without possessing a genome; prions lack hereditary Literature material. Until prions were discovered, duplication without a Peace genome was considered impossible. This discovery was unexpected and provoked controversy. Economic Sciences Find a Laureate: Although the existence of prions was not known until the work of Stanley Prusiner, many prion diseases have been previously documented. On Iceland, scrapie, a disease affecting sheep was first described in the 18th century. In the 1920s, the neurologists Hans Creutzfeldt and Alfons Jakob discovered a similar disease in man. During the 1950s and 60s Carleton Gajdusek studied kuru, a disease that was spread through cannibalistic rituals practised by the Fore people in New Guinea. Presently attention is focused on mad cow disease, which has affected approximately 170,000 cows in Britain. These diseases exhibit common pathologies. They are inevitably fatal due to the destruction of the brains of infected individuals. The incubation times may last for several years, during which the affected regions of the brain become gradually spongy in appearance. Gajdusek discovered that kuru and Greutzfeldt-Jakob disease could be transmitted to monkeys

http://www.nobel.se/medicine/laureates/1997/presentation-speech.html (1 of 3) [7/15/2003 2:30:23 PM] The Nobel Prize in Physiology or Medicine 1997 - Presentation Speech demonstrating that these diseases are contagious. In 1976, when Gajdusek received his Nobel Prize, the nature of the infectious agent was completely unknown. At this time, these diseases were assumed to he caused by a new unidentified virus, termed a slow or unconventional virus. During the 1970s, no significant advances regarding the nature of the agent were made, that is, not until Stanley Prusiner took on the problem. Prusiner set out to purify the infectious agent, and after 10 years of hard work he obtained a pure preparation. To his great surprise, he found that the agent consisted only of a protein, which he named prion, a term derived from proteinaceous infections particle. Strangely enough, he found that the protein was present in equal amounts in the brains of both diseased and healthy individuals. This discovery was confusing and it was generally concluded that Prusiner must have arrived at the wrong conclusion. How could a protein cause disease if it was present both in diseased and healthy brains? The answer to this question came when Prusiner showed that the prion protein from diseased brains had a completely different three-dimensional conformation. This led Prusiner to propose a hypothesis for how a normal protein could become a disease-causing agent by changing its conformation. The process he proposed may be compared to the transformation of Dr Jekyll to Mr Hyde - the same entity, but in two manifestations, a kind innocuous one, and a vicious lethal one. But how can a protein replicate without a genome? Stanley Prusiner suggested that the harmful prion protein could replicate by forcing the normal protein to adopt the shape of the harmful protein in a chain reaction-like process. In other words, when a harmful protein encounters a normal protein, the normal protein is converted into the harmful form. A remarkable feature of prion diseases is that they can arise in three different ways. They can occur spontaneously, or be triggered by infection, or occur as a consequence of hereditary predisposition. The hypothesis that prions are able to replicate without a genome and to cause disease violated all conventional conceptions and during the 1980s was severely criticised. For more than 10 years, Stanley Prusiner fought an uneven battle against overwhelming opposition. Research during the 1990s has, however, rendered strong support for the correctness of Prusiner's prion hypothesis. The mystery behind scrapie, kuru, and mad cow disease has finally been unravelled. Additionally, the discovery of prions has opened up new avenues to better understand the pathogenesis of other more common dementias, such as Alzheimer's disease.

Stanley Prusiner,

http://www.nobel.se/medicine/laureates/1997/presentation-speech.html (2 of 3) [7/15/2003 2:30:23 PM] The Nobel Prize in Physiology or Medicine 1997 - Presentation Speech Your discovery of the prions has established a novel principle of infection and opened up a new and exciting area in medical research. On behalf of the Nobel Assembly at the Karolinska Institute I wish to convey to you my warmest congratulations and I now ask you to step forward to receive your Nobel Prize from the hands of His Majesty the King. From Les Prix Nobel 1997.

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The Nobel Prize in Physiology or

Medicine 1997 The Nobel Assembly at the Karolinska Institute in Stockholm, Sweden, has awarded the Nobel Prize in Physiology or Medicine for 1997 to Stanley B. Prusiner, for his discovery of "prions - a new biological principle of infection".

Stanley B. Prusiner was born in 1942 in Des Moines, Iowa, USA. Since 1968 he has been a professor in neurology, biochemistry, and virology at the University of California in San Francisco, and in Berkeley.

Contents: Introduction Prions - novel infectious agents differing from all other known pathogenic agents Prions infect animals and humans From Dr Jekyll to Mr Hyde Different prions affect different regions of the brain Prion disease arise in three different ways These pages are based on material from the 1997 Physiology or Medicine Nobel Poster. Credits and references for the poster

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Prions – novel infectious agents differing from all other known pathogenic agents

Prions are simple proteins that are much smaller than viruses. They are unique since they lack a genome. All other known infectious agents contain genetic material.

Bacteria are often Fungi may cause Parasites thrive on Viruses are small surrounded by a strong infections of the their host, often packages of genetic protective cell wall mouth, throat, lungs, causing longlasting material that can only and replicate through and skin. chronic infections. replicate inside a cell. simple cell division.

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Prions infect animals and humans

All known prion diseases are fatal. Since the immune system does not recognize prions as foreign, no natural protection develops. Scrapie in sheep was first described during the18th century. It has been transmitted to other animals such as mink and cats, and more recently to cows (mad cow disease or bovine spongiform encephalopathy, BSE) through contaminated feedstuff.

In New Guinea, the Fore-people contracted kuru by eating the brains of deceased people. Creutzfeldt-Jakob Disease (CJD) frequently arises spontaneously, while fatal familial insomnia (FFI) Gerstmann-Sträussler-Scheinker (GSS) disease, and 10-15% of CJD are caused by mutations in the gene encoding the prion protein. A new variant CJD, diagnosed in some 20 patients, may have arisen through transmission of BSE to humans.

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From Dr Jekyll to Mr Hyde PrPc The prion protein exists in two forms. The normal, innocuous protein (PrPc) can change its shape to a harmful, disease-causing form (PrPSc). The conversion from PrPc to PrPSc then proceeds via a chain-reaction. When enough PrPSc proteins have been made they form long filamentous PrPSc aggregates that gradually damage neuronal tissue. The harmful PrPSc form is very resistant to high temperatures, UV-irradiation and strong degradative enzymes.

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Different prions affect different regions of the brain Prions affect different regions of the brain. A sponge-like appearance results when nerve cells die. Symptoms depend on which region of the brain is affected. Cerebral cortex When the cerebral cortex is affected, the symptoms include loss of memory and mental acuity, and sometimes also visual imparement (CJD). Thalamus Damage to the thalamus may result in insomnia (FFI). Cerebellum Damage to the cerebellum results in problems to coordinate body movements and difficulties to walk (kuru, GSS). Brain stem In the mad cow disease (BSE), the brain stem is affected.

Mutations can result in different shapes of the prion protein that accumulates in different regions of the brain: In familial insomnia (FFI), mutated prions (violet squares) accumulate in the thalamus, with the result that the patients are unable to sleep. In Creutzfeldt-Jakob disease, the prion protein accumulates primarily in the cerebral cortex (red dots and area).

A precise diagnosis of a prion disease can only be made upon autopsy. The figures show thin sections of diseased brains. FFI, with typical proliferation of astrocytes, the support cells of the brain, is shown to the left (arrows). CJD, with the characteristic spongiform appearance with vacuoles (arrows) is shown to the right.

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Prion diseases arise in three different ways

1. Through horizontal transmission from e.g. a sheep to a cow (BSE). 2. In inherited forms, mutations in the prion gene are transmitted from parent to child. 3. They can arise spontaneously. Route of infection When cows are fed with offals prepared from infected sheep, prions are taken up from the gut and transported along nerve fibers to the brain stem. Here prions accumulate and convert normal prion proteins to the disease-causing form, PrPSc. Years later, BSE results when a sufficient number of nerve cells have become damaged, affecting the behaviour of the cows.

The kuru epidemic started a long time ago and has subsided since the 1950s. The mad cow disease epidemic started in 1985 affecting approximately 170,000 cows.

Kuru disease Mad cow disease

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The graph shows how kuru The graph shows the course of the BSE disappeared among the Fore-people epidemic. It reached its maximum in 1992 when they stopped their cannibalistic with 37,000 affected animals. When rituals. In children the disease feedstuff containing sheep offals was disappeared more rapidly, while adults banned, the incidence of BSE decreased continued to be affected. An rapidly. There is now a fear that humans incubation time of up to 30 years has might have been infected by eating been reported. products from BSE-affected cows giving rise to a new variant type of CJD.

http://www.nobel.se/medicine/laureates/1997/illpres/three-ways.html (2 of 2) [7/15/2003 2:32:31 PM] Stanley B. Prusiner - Autobiography

Stanley B. Prusiner – The Nobel Prize in Physiology or Medicine Autobiography 1997 Press Release My history is not atypical of many Presentation Speech Americans: born in the midwest, Illustrated Presentation educated in the East, and now living in the West. My early years Stanley B. Prusiner were shared between Des Moines, Autobiography Iowa and Cincinnati, Ohio. Shortly Curriculum Vitae after I was born on May 28, 1942 Banquet Speech in Des Moines, my father, Nobel Diploma Lawrence, was drafted into the Prize Award Photo United States Navy. I was named Other Resources for my father's younger brother who died of Hodgkin's disease at the age of 24. We moved to Boston briefly where my father enrolled in Naval officer training 1996 1998 school before being sent to the south Pacific. He served as a The 1997 Prize in: communications officer for the remainder of World War II on Physics an island called Eniwetok where the first hydrogen bomb was Chemistry detonated a decade later. Physiology or Medicine Literature During my father's absence, my mother, Miriam, and I lived in Peace Cincinnati where her mother, Mollie Spigel, also lived. Prior to moving to Cincinnati, Mollie had lived in Norfolk, Virginia, Economic Sciences where she raised three children after her husband Benjamin was Find a Laureate: killed at age 50 in a traffic accident. Besides many special memories of my maternal grandmother, I have many fond reminiscences of my paternal grandfather, Ben, who emigrated to the United States in 1896 as a young boy from Moscow. He grew up in Sioux City, Iowa, as did my father with many other Russian Jews. Shortly after the end of World War II, we returned to Des Moines where I attended primary school and my brother, Paul, was born. In 1952, we moved back to Cincinnati with the hope that my father would be able to find a much better job as an architect. In Cincinnati, he practiced architecture for the next 25 years, which enabled him to provide a very comfortable home for his family.

During my time at Walnut Hills High School, I studied Latin for five years, which was to help me immensely later in the writing of scientific papers. But I found high school rather

http://www.nobel.se/medicine/laureates/1997/prusiner-autobio.html (1 of 6) [7/15/2003 2:32:46 PM] Stanley B. Prusiner - Autobiography uninteresting and was most fortunate to be accepted by the University of Pennsylvania where I majored in Chemistry.

The intellectual environment of the University of Pennsylvania was extraordinary--there were so many internationally renowned scholars who were invariably receptive to the intrusions of undergraduate students even before the days of student evaluations of the faculty. The small size of the undergraduate student body undoubtedly contributed to the accessibility of the faculty. Besides numerous science courses, I had the opportunity to study philosophy, the history of architecture, economics, and Russian history in courses taught by extraordinarily knowledgeable professors. Although I was among the smallest of the heavyweight crew team members and thus had no chance of rowing in the varsity boat, I greatly enjoyed the many hours that I spent at this wonderful sport.

During the summer of 1963 between my junior and senior years, I began a research project on hypothermia in the Department of Surgery with Sidney Wolfson. I quickly became fascinated by the project and continued working on it throughout my senior year. I decided to remain at Penn for Medical School largely because of the wonderful experience of doing research with Sidney Wolfson. During the second year of medical school, I decided to ask Britton Chance if he would allow me to study the surface fluorescence of brown adipose tissue in Syrian golden hamsters as they arose from hibernation. Chance had reported that the surface fluorescence of other organs reflected the oxidation-reduction state of those tissues. As anticipated, large changes in the fluorescence of brown fat were found during non-shivering thermogenesis.

My research on brown fat allowed me to spend much of the fourth year of medical school at the Wenner-Gren Institute in Stockholm working with Olov Lindberg on the metabolism of isolated brown adipocytes. This was an exciting time and I began to consider seriously a career in biomedical research. Early in 1968, 1 returned to Philadelphia to complete my medical studies and to contemplate my options. The previous spring, I had been given a position at the NIH once I completed an internship in medicine. It was the height of the Vietnam war with 500,000 young Americans trying to control the spread of Communism in southeast Asia. But I was facing an internship at the University of California San Francisco (UCSF) that would require me to work every other night for an entire year, a prospect about which I was not enthusiastic. The privilege of serving in the US Public Health Service at the NIH clearly outweighed the unpleasant prospects of an internship. Although the workload was awesome, I managed to survive because San Francisco was such a nice place to live. During that year, I met my wife, Sandy Turk, who was teaching mathematics to high

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At the NIH, I worked in Earl Stadtman's laboratory where I studied glutaminases in E. coli. My three years at the NIH were critical in my scientific education. I learned an immense amount about the research process: developing assays, purifying macromolecules, documenting a discovery by many approaches, and writing clear manuscripts describing what is known and what remains to be investigated. As the end of my time at the NIH began to near, I examined postdoctoral fellowships in neurobiology but decided a residency in Neurology was a better route to developing a rewarding career in research. The residency offered me an opportunity to learn about both the normal and abnormal nervous system.

In July 1972, I began a residency at the University of California San Francisco in the Department of Neurology. Two months later, I admitted a female patient who was exhibiting progressive loss of memory and difficulty performing some routine tasks. I was surprised to learn that she was dying of a "slow virus" infection called Creutzfeldt-Jakob disease (CJD) which evoked no response from the body's defenses. Next, I learned that scientists were unsure if a virus was really the cause of CJD since the causative infectious agent had some unusual properties. The amazing properties of the presumed causative "slow virus" captivated my imagination and I began to think that defining the molecular structure of this elusive agent might be a wonderful research project. The more that I read about CJD and the seemingly related diseases--kuru of the Fore people of New Guinea and scrapie of sheep--the more captivated I became.

Over the next two years I completed an abbreviated residency while reading every paper that I could find about slow virus diseases. In time, I developed a passion for working on these disorders. As I plotted out a course of action, the task became more and more daunting. The tedious, slow, and very expensive assays in mice for the scrapie agent had restricted progress and I had no clever idea about how to circumvent the problem. I did think that after working with the scrapie agent for some time that I might eventually be able to develop such an assay.

Since both Sandy and I liked living in San Francisco, I accepted the offer of an assistant professor position from Robert Fishman, the Chair of Neurology, and began to set up a laboratory to study scrapie in July 1974. Although many people cautioned me about the high risk of studies on scrapie due to the assay problems, such warnings did not dull my enthusiasm. To gain a base of research support from the NIH, I initially wrote grant proposals on glutamate metabolism in the choroid plexus. Such proposals were dull but were readily funded

http://www.nobel.se/medicine/laureates/1997/prusiner-autobio.html (3 of 6) [7/15/2003 2:32:46 PM] Stanley B. Prusiner - Autobiography because I had worked on glutaminases earlier. Eventually, I managed to gain modest NIH support for my scrapie studies but this was not without considerable difficulty. To rebut the disapproval of my first NIH application on scrapie, I set up a collaboration with William Hadlow and Carl Eklund who were working at the Rocky Mountain Laboratory in Hamilton, Montana. They taught me an immense amount about scrapie and helped me initiate studies on the sedimentation behavior of the scrapie agent.

I had anticipated that the purified scrapie agent would turn out to be a small virus and was puzzled when the data kept telling me that our preparations contained protein but not nucleic acid. About this time, I was informed by the Howard Hughes Medical Institute (HHMI) that they would not renew their support and by UCSF that I would not be promoted to tenure. When everything seemed to be going wrong, including the conclusions of my research studies, it was the unwavering, enthusiastic support of a few of my closest colleagues that carried me through this very trying and difficult period. Fortunately, the tenure decision was reversed and I was able to continue my work. Although my work was never supported by HHMI again, I was extremely fortunate to receive much larger funding from the R. J. Reynolds Company through a program administered by Fred Seitz and Macyln McCarty and shortly thereafter from the Sherman Fairchild Foundation under the direction of Walter Burke. While the vast majority of my funding always came from the NIH, these private sources were crucial in providing funds for the infrastructure which was the thousands of mice and hamsters that were mandatory.

As the data for a protein and the absence of a nucleic acid in the scrapie agent accumulated, I grew more confident that my findings were not artifacts and decided to summarize that work in an article that was eventually published in the spring of 1982. Publication of this manuscript, in which I introduced the term "prion", set off a firestorm. Virologists were generally incredulous and some investigators working on scrapie and CJD were irate. The term prion derived from protein and infectious provided a challenge to find the nucleic acid of the putative "scrapie virus." Should such a nucleic acid be found, then the word prion would disappear! Despite the strong convictions of many, no nucleic acid was found; in fact, it is probably fair to state that Detlev Riesner and I looked more vigorously for the nucleic acid than anyone else.

While it is quite reasonable for scientists to be skeptical of new ideas that do not fit within the accepted realm of scientific knowledge, the best science often emerges from situations where results carefully obtained do not fit within the accepted paradigms. At times the press became involved since the media

http://www.nobel.se/medicine/laureates/1997/prusiner-autobio.html (4 of 6) [7/15/2003 2:32:46 PM] Stanley B. Prusiner - Autobiography provided the naysayers with a means to vent their frustration at not being able to find the cherished nucleic acid that they were so sure must exist. Since the press was usually unable to understand the scientific arguments and they are usually keen to write about any controversy, the personal attacks of the naysayers at times became very vicious. While such scorn caused Sandy considerable distress, she and my two daughters, Helen and Leah, provided a loving and warm respite from the torrent of criticism that the prion hypothesis engendered. During the winter of 1983, I herniated a disc in my lumbar spine while skiing and this slowed the pace of my work for much of the year. After a laminectomy, I began swimming regularly, which brought relaxation and a much needed quiet time to my life.

Just prior to my back problem, the protein of the prion was found in my laboratory and the following year, a portion of the amino acid sequence was determined by Leroy Hood. With that knowledge, molecular biological studies of the prions ensued and an explosion of new information followed. I collaborated with Charles Weissmann on the molecular cloning of the gene encoding the prion protein (PrP) and with George Carlson and David Kingsbury on linking the PrP gene to the control of scrapie incubation time in mice. About the same time, we succeeded in producing antibodies that provided an extremely valuable tool that allowed us to discover the normal form of PrP. In a very important series of studies, the antibodies were used by Stephen DeArmond to study the pathogenesis of prion disease in transgenic mice. Steve brought the much needed talents of an outstanding neuropathologist to these studies. As more data accumulated, an expanding edifice in support of the prion concept was constructed. Ruth Gabizon dispersed prions into liposomes and purified scrapie infectivity on columns with PrP antibodies. Karen Hsiao discovered a mutation in the PrP gene that caused familial disease and reproduced the disease in transgenic mice while Michael Scott produced transgenic mice abrogating the prion species barrier and later artificial prions from chimeric PrP transgenes. Indeed, no experimental findings that might overturn the prion concept were reported from any laboratory. By the early 1990s, the existence of prions was coming to be accepted in many quarters of the scientific community, but the mechanism by which normal PrP was converted into the disease-causing form was still obscure. When Fred Cohen and I began to collaborate on PrP structural studies, I was again extremely fortunate. Fred brought an extraordinary set of skills in protein chemistry and computational biology to investigations of PrP structures.

As prions gained wider acceptance among scientists, I received many scientific prizes. The first major recognition of my work was accorded by neurologists with many other awards coming

http://www.nobel.se/medicine/laureates/1997/prusiner-autobio.html (5 of 6) [7/15/2003 2:32:46 PM] Stanley B. Prusiner - Autobiography soon thereafter. But the most rewarding aspect of my work has been the numerous wonderful friends that I have made during an extensive series of collaborative studies. It has been a special privilege to work with so many talented scientists including numerous postdoctoral fellows and technical associates who have taught me so much. Besides the many collaborators who have contributed their scientific skills to advancing the study of prions, I have had many colleagues who have contributed indirectly to my work by being supportive of the special needs that such a project has demanded. From Les Prix Nobel 1997.

http://www.nobel.se/medicine/laureates/1997/prusiner-autobio.html (6 of 6) [7/15/2003 2:32:46 PM] Stanley B. Prusiner - Curriculum Vitae

Stanley B. Prusiner – The Nobel Prize in Physiology or Medicine Curriculum Vitae 1997 Press Release Stanley B. Prusiner, born May 28, 1942 Presentation Speech Address: Department of Neurology, HSE-781, University of Illustrated Presentation California, School of Medicine, San Francisco, CA

94143-0518, USA Stanley B. Prusiner Autobiography Academic Education Curriculum Vitae 1964 A.B. (cum laude), University of Pennsylvania, The Banquet Speech College Nobel Diploma 1968 M.D., University of Pennsylvania, School of Prize Award Photo Medicine, Philadelphia, PA Other Resources 1968-69 Internship in Medicine, University of California, San Francisco, CA 1972-74 Residency in Neurology, University of California, 1996 1998 San Francisco, CA The 1997 Prize in: Physics Appointments and Professional Activities Chemistry

1974-80 Assistant Professor of Neurology in Residence, Univ Physiology or Medicine of California, SF Literature 1976-88 Lecturer, Department of Biochemistry and Peace Biophysics, UCSF Economic Sciences 1979-83 Assistant Professor of Virology in Residence, UC, Find a Laureate: Berkeley 1980-81 Associate Professor of Neurology in Residence, UCSF 1981-84 Associate Professor of Neurology, UCSF 1983-84 Associate Professor of Virology in Residence, UC, Berkeley 1984- Professor of Neurology, UCSF 1984- Professor of Virology in Residence, UC, Berkeley 1988- Professor of Biochemistry, UCSF

Major Honors and Awards Potamkin Prize for Alzheimer's Disease Research, American Academy of Neurology, 1991

http://www.nobel.se/medicine/laureates/1997/prusiner-cv.html (1 of 2) [7/15/2003 2:32:54 PM] Stanley B. Prusiner - Curriculum Vitae Christopher Columbus Quincentennial Discovery Award in Biomedical Research, NIH, 1992 Metropolitan Life Foundation Award for Medical Research, 1992 Dickson Prize for Distinguished Scientific Accomplishments, University of Pittsburgh, 1992 Charles A. Dana Award for Pioneering Achievements in Health, 1992 Richard Lounsbery Award for Extraordinary Scientific Research, NAS, 1993 Gairdner Foundation Award for Outstanding Achievement in Medical Science, 1993 Bristol-Myers Squibb Award for Distinguished Achievement in Neuroscience Res., 1994 Albert Lasker Award for Basic Medical Research, Albert and Mary Lasker Foundation, 1994 Paul Ehrlich Prize, Paul Ehrlich Foundation and the Federal Republic of Germany, 1995 Wolf Prize in Medicine, Wolf Foundation and the State of Israel, 1996 Keio International Award for Medical Science, Keio University, Tokyo, Japan, 1996

http://www.nobel.se/medicine/laureates/1997/prusiner-cv.html (2 of 2) [7/15/2003 2:32:54 PM] Stanley B. Prusiner - Banquet Speech

Stanley B. Prusiner – Banquet The Nobel Prize in Physiology or Medicine Speech 1997 Press Release Stanley B. Prusiner's speech at the Nobel Banquet, December Presentation Speech 10, 1996 Illustrated Presentation King Carl Gustaf, Queen Silvia, Distinguished Guests, Stanley B. Prusiner Tonight's awarding of the Nobel Prizes and this elegant Autobiography Banquet are a grand celebration of science and culture. These Curriculum Vitae events honor the vision, courage, and wisdom of Alfred Nobel, Banquet Speech a superb scientist in his own right. Nobel Diploma And they honor the Swedish people's uncommon sense of Prize Award Photo commitment to fulfill the enlightened wishes of Alfred Nobel - Other Resources the Nobel Prizes have truly become important benchmarks in the history of science. 1996 1998 But the Nobel Prizes are much more than awards to scholars, they are a celebration of civilization, of mankind, and of what The 1997 Prize in: makes humans unique - that is their intellect from which Physics springs creativity. I continue to be delightfully surprised by the Chemistry joy, excitement, and happiness that so many of my friends and Physiology or Medicine colleagues have felt when they learned of this year's Nobel Literature Prize in Medicine; moreover, many of these friends are Peace nonscientists who hail from many parts of our planet. Economic Sciences People often ask me why I persisted in doing research on a Find a Laureate: subject that was so controversial. I frequently respond by telling them that only a few scientists are granted the great fortune to pursue topics that are so new and different that only a small number of people can grasp the meaning of such discoveries initially. I am one of those genuinely lucky scientists who was handed a special opportunity to work on such a problem - that of prions. Because our results were so novel, my colleagues and I had great difficulty convincing other scientists of the veracity of our findings and communicating to lay people the importance of work that seemed so esoteric! As more and more compelling data accumulated, many scientists became convinced. But it was the "mad cow" epidemic in Britain and the likely transmission of bovine prions to humans producing a fatal brain illness called Creutzfeldt-Jakob disease that introduced prions to the public. Yet the principles of prion biology are still so new

http://www.nobel.se/medicine/laureates/1997/prusiner-speech.html (1 of 2) [7/15/2003 2:32:59 PM] Stanley B. Prusiner - Banquet Speech that some scientists and most laymen, including the press, still have considerable difficulty grasping the most fundamental concepts. Being a scientist is a special privilege: for it brings the opportunity to be creative, the passionate quest for answers to nature's most precious secrets, and the warm friendships of many valued colleagues. Collaborations extend far beyond the scientific achievements, no matter how great the accomplishments might be, the rich friendships which have no national borders are treasured even more. Besides scientific achievement, the Nobel Prizes honor the scientific process. In science, each new result, sometimes quite surprising, heralds a step forward and allows one to discard some hypotheses, even though one or two of these might have been highly favored. No matter how new and revolutionary the findings may be, as data accumulates, even the skeptical scholars eventually become convinced except for a few who will always remain resistant. Indeed, the story of prions is truly an odyssey that has taken us from heresy to orthodoxy. Lastly, we celebrate on the occasion of these Nobel Prizes, the triumph of science over prejudice. The wondrous tools of modern science allowed my colleagues and me to demonstrate that prions exist and that they are responsible for an entirely new principle of infection. Tack så mycket! From Les Prix Nobel 1997.

http://www.nobel.se/medicine/laureates/1997/prusiner-speech.html (2 of 2) [7/15/2003 2:32:59 PM] Stanley B. Prusiner - Nobel Diploma

Stanley B. Prusiner – Nobel Diploma

Calligrapher: Susan Duvnäs

http://www.nobel.se/medicine/laureates/1997/prusiner-diploma.html [7/15/2003 2:33:04 PM] Stanley B. Prusiner - Prize Award Photo

Stanley B. Prusiner – Prize The Nobel Prize in Physiology or Medicine Award Photo 1997 Press Release Presentation Speech Illustrated Presentation Stanley B. Prusiner Autobiography Curriculum Vitae Banquet Speech Nobel Diploma Prize Award Photo Other Resources

1996 1998 The 1997 Prize in: Physics Chemistry Physiology or Medicine Literature Peace Economic Sciences Find a Laureate:

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http://www.nobel.se/medicine/laureates/1997/prusiner-award.html (1 of 2) [7/15/2003 2:33:12 PM] NEUROSCIENCE : Stanley Prusiner

Stanley Prusiner, MD Molecular Biological, Genetic and Protein Structural Studies of Prion Disease

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Research Summary | Current Projects Lab Personnel | Publications

My research is focused on infectious proteins called prions that cause neurodegenerative diseases. Nascent prions are created either spontaneously by mutation of a host protein or by exposure to an exogenous source. Prions are composed largely, if not entirely, of a modified form of the prion protein (PrP) designated PrPSc. Like other infectious pathogens, they multiply but prions do not have a nucleic acid genome to direct the synthesis of their progeny. A post-translational, conformational change features in the conversion of cellular PrP (PrPC) into PrPSc during which alpha-helices are transformed into beta-sheets. Since this structural transition in PrP underlies both the replication of prions and the pathogenesis of CNS degeneration, much of the effort in the laboratory is devoted to elucidating the molecular events responsible for this process. Indeed, prion diseases seem to be disorders of protein conformation. After demonstrating genetic linkage between the PrP gene and the control of scrapie incubation times, we established linkage between a point mutation in the human PrP gene and development of the fatal, familial disease Gerstmann-Straussler-Scheinker (GSS). Like humans with GSS, transgenic mice expressing mutant PrP develop neurodegeneration and produce prions de novo as demonstrated by transmission of disease to inoculated recipients. These studies argue that prion diseases can be both inherited and infectious. Investigations of prion strains led to the conclusions that variations in disease phenotype are determined by the conformation of PrPSc. Since prion strains replicate, this argues that PrPSc must act as a template for the refolding of PrPC into a second molecule of PrPSc. Recent investigations argue that the length of the incubation time

http://www.ucsf.edu/neurosc/faculty/neuro_prusiner.html (1 of 3) [7/15/2003 2:33:28 PM] NEUROSCIENCE : Stanley Prusiner specified by prion strains is determined by the rate of PrPSc clearance. This discovery is being extended using inducible transgenes that are regulated by tetracycline derivatives in bigenic mice. Several studies are directed at elucidating the structure of PrPSc: (1) synthetic PrP peptides carrying pathologic mutations, (2) small redacted PrP molecules supporting PrPSc formation, (3) EM image analysis of 2-D paracrystalline arrays of PrPSc, and (4) epitope mapping of PrPSc using numerous recombinant antibody fragments (Fab). During prion replication, an as yet to be identified factor that we have provisionally designated 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 in order to develop an in vitro system for studying the mechanism by which nascent PrPSc is formed. Since PrPC molecules carrying basic residues within the epitope that binds to protein X act as dominant negatives in preventing PrPSc formation, we are developing drugs based on these findings. From an examination of several hundred thousand compounds, we have identified several lead compounds that effectively block PrPSc formation in cultured cells. Once more effective analogs of these drugs are discovered, we plan to initiate studies in mice and hamsters.

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Prusiner, S.B.: Prions. In Les Prix Nobel 1997, pp. 262-323, 1998. Nobel Foundation, Stockholm, Sweden. Reprinted in Proc. Nat. Acad. Sci. USA 95:13363-13383, 1998.

Viles, J.H., Cohen, F.E., Prusiner, S.B., Goodin, D.B., Wright, P.E., Dyson, H.J.: Copper binding to the prion protein: structural implications of four identical cooperative binding sites. Proc. Natl.

http://www.ucsf.edu/neurosc/faculty/neuro_prusiner.html (2 of 3) [7/15/2003 2:33:28 PM] NEUROSCIENCE : Stanley Prusiner Acad. Sci. USA 96:2042-2047, 1999.

Supattapone, S., Bosque, P., Muramoto, T., Wille, H., Aagaard, C., Peretz, D., Nguyen, H.-O. B., Heinrich, C., Torchia, M., Safar, J., Cohen, F.E., DeArmond, S.J., Prusiner, S.B., Scott, M.: Prion protein of 106 residues creates an artificial transmission barrier for prion replication in transgenic mice. Cell 96:869-878, 1999.

Liu, H., Farr-Jones, S., Ulyanov, N.B., Llinas, M., Marqusee, S., Groth, D., Cohen, F.E., Prusiner, S.B., James, T.L.: Solution structure of Syrian hamster prion protein rPrP(90-231). Biochemistry 38:5362-5377, 1999.

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