Proc. Natl. Acad. Sci. USAVol. 95, pp. 13363–13383, November 1998Nobel LecturePrionsSTANLEY B. PRUSINER†Departments of Neurology and of Biochemistry and Biophysics, University of California, San Francisco, CA 94143ABSTRACT Prions are unprecedented infectious patho-gens that cause a group of invariably fatal neurodegenerativediseases by an entirely novel mechanism. Prion diseases maypresent as genetic, infectious, or sporadic disorders, all ofwhich involve modification of the prion protein (PrP). Bovinespongiform encephalopathy (BSE), scrapie of sheep, andCreutzfeldt–Jakob disease (CJD) of humans are among themost notable prion diseases. Prions are transmissible parti-cles that are devoid of nucleic acid and seem to be composedexclusively of a modified protein (PrPSc). The normal, cellularPrP (PrPC) is converted into PrPScthrough a posttransla-tional process during which it acquires a highb-sheet content.The species of a particular prion is encoded by the sequenceof the chromosomal PrP gene of the mammals in which it lastreplicated. In contrast to pathogens carrying a nucleic acidgenome, prions appear to encipher strain-specific propertiesin the tertiary structure of PrPSc. Transgenetic studies arguethat PrPScacts as a template upon which PrPCis refolded intoa nascent PrPScmolecule through a process facilitated byanother protein. Miniprions generated in transgenic miceexpressing PrP, in which nearly half of the residues weredeleted, exhibit unique biological properties and should fa-cilitate structural studies of PrPSc. While knowledge aboutprions has profound implications for studies of the structuralplasticity of proteins, investigations of prion diseases suggestthat new strategies for the prevention and treatment of thesedisorders may also find application in the more commondegenerative diseases.The torturous path of the scientific investigation that led to anunderstanding of familial Creutzfeldt–Jakob disease (CJD)chronicles a remarkable scientific odyssey. By 1930, the highincidence of familial (f) CJD in some families was known (1,2). Almost 60 years were to pass before the significance of thisfinding could be appreciated (3–5). CJD remained a curious,rare neurodegenerative disease of unknown etiology through-out this period of three score years (6). Only with transmissionof disease to apes after inoculation of brain extracts preparedfrom patients who died of CJD did the story begin to unravel(7).Once CJD was shown to be an infectious disease, relativelylittle attention was paid to the familial form of the disease sincemost cases were not found in families. It is interesting tospeculate how the course of scientific investigation might haveproceeded had transmission studies not been performed untilafter the molecular genetic lesion had been identified. Hadthat sequence of events transpired, then the prion concept,which readily explains how a single disease can have a geneticor infectious etiology, might have been greeted with much lessskepticism (8).Epidemiologic studies designed to identify the source of theCJD infection were unable to identify any predisposing riskfactors, although some geographic clusters were found (9–12).Libyan Jews living in Israel developed CJD about 30 timesmore frequently than other Israelis (13). This findingprompted some investigators to propose that the Libyan Jewshad contracted CJD by eating lightly cooked brain fromscrapie-infected sheep when they lived in Tripoli prior toemigration. Subsequently, the Libyan Jewish patients were allfound to carry a mutation at codon 200 in their prion protein(PrP) gene (14–16).My own interest in the subject began with a patient dying ofCJD in the fall of 1972. At that time, I was beginning aresidency in neurology and was most impressed by a diseaseprocess that could kill my patient in 2 months by destroying herbrain while her body remained unaffected by this process. Nofebrile response, no leukocytosis or pleocytosis, no humoralimmune response, and yet I was told that she was infected witha ‘‘slow virus.’’Slow Viruses. The term ‘‘slow virus’’ had been coined byBjorn Sigurdsson in 1954 while he was working in Iceland onscrapie and visna of sheep (17). Five years later, WilliamHadlow had suggested that kuru, a disease of New Guineahighlanders, was similar to scrapie and thus, it, too, was causedby a slow virus (18). Seven more years were to pass before thetransmissibility of kuru was established by passaging thedisease to chimpanzees inoculated intracerebrally (19). Just asHadlow had made the intellectual leap between scrapie andkuru, Igor Klatzo made a similar connection between kuru andCJD (20). In both instances, these neuropathologists werestruck by the similarities in light microscopic pathology of thecentral nervous system (CNS) that kuru exhibited with scrapieor CJD. In 1968, the transmission of CJD to chimpanzees afterintracerebral inoculation was reported (7).In scrapie, kuru, CJD, and all of the other disorders nowreferred to as prion diseases (Table 1), spongiform degener-ation and astrocytic gliosis is found upon microscopic exam-ination of the CNS (Fig. 1) (21). The degree of spongiformThe publication costs of this article were defrayed in part by page chargepayment. This article must therefore be hereby marked ‘‘advertisement’’ inaccordance with 18 U.S.C. §1734 solely to indicate this fact.Adapted from Les Prix Nobel, 1997. © 1997 by The Nobel FoundationPNAS is available online at http:yywww.pnas.org.Editor’s Note: This article is an abbreviated version of Stanley B.Prusiner’s Nobel Lecture, “Prions.” The 1997 Nobel Prize in Physi-ology or Medicine was awarded to Dr. Prusiner for his discovery ofprions, an entirely new genre of disease-causing agents, and forelucidating the fascinating principles that underline their mode ofaction. The Nobel Foundation graciously has granted us permission toreprint this article. The Nobel Lectures provide examples of successfulapproaches to major scientific problems as well as authoritativereviews. However, in recent years, these lectures have rarely been read,perhaps because of the difficulty in obtaining the collections. Byreprinting this lecture we hope to broaden their exposure.Abbreviations: Bo, bovine; BSE, bovine spongiform encephalopathy;CJD, Creutzfeldt–Jakob disease; sCJD, sporadic CJD; fCJD, familialCJD; iCJD, iatrogenic CJD; vCJD, (new) variant CJD; CNS, centralnervous system; CWD, chronic wasting