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after oral ingestion of the kuru agent (14). In contrast, goats fed scrapie-infected tissue frequentlydevelop disease (15). Recently, we have taken advantage of the naturalcannibalisticactivities of hamsters to develop an experimental model of scrapie transmittedby cannibalism (16). Oral transmission of the scrapie agent appears to be extremely Stanley B. Prusiner inefficient.Cannibalismrequiresa dose of agent 109times greaterthanthat needed to produce scrapie by intracerebral injection.These results provide compelA major,unansweredquestion in mo- senile dementia, was shown by Gibbs, ling evidence for oral transmissionof the lecular biology concerns the chemical Gajdusek,and co-workers to be caused scrapieagent and may offer new insights structureof the scrapie agent. Until re- by atransmissibleagent (6, 7). into the spread of kuru by cannibalism the A recent study suggeststhat there may amongthe Fore people and their neighcently, mysteries surrounding scrapie agent were so commonplace that be similaritiesbetween the agents caus- boringtribes. investigatorshad come to accept rather ing scrapieand CJD (8). Goats inoculatthan question its enigmatic properties. ed with brain tissuefrom demented paThe scrapieagent causes a degenerative tients dying of CJD developed a neuro- Bioassay of the Scrapie Agent disorder of the central nervous system logicaldisorder3 to 4 years afterinoculation (Fig. 1). Five out of ten CJDinocula Studies on the scrapie, kuru, and CJD (CNS) in sheep and goats (1). The extraordinaryresistance of the have produceddisease in goats (9). Ex- agents havebeen greatly limited by the CJD in goats is indistinguish- slow, tedious, and costly bioassays used scrapieagent to Formalinwas responsi- perimental ble for the inadvertent inoculation of able both clinically and neuropathologi- to detect these agents. Since tissue culsheep in Scotland. Eighteen thousand cally from natural scrapie. Monkeys ture systems are not available for the and replicationassay of these agents and they appearto be nonantigenicin their Summary.After infection and a prolonged incubationperiod, the scrapie agent native forms, animalbioassays must be causes a degenerativedisease of the centralnervoussystem in sheep and goats. Six used. For many years all assays for the lines of evidence includingsensitivity to proteases demonstrate that this agent scrapie agent wereperformedin sheep contains a protein that is requiredfor infectivity.Althoughthe scrapie agent is and goats (17). In 1961, transmissionof inactivatedby alkali,five procedureswith more specificityfor modifying the scrapie agent to mice transformed irreversibly nucleicacids failedto cause inactivation. agent shows heterogeneitywithrespect research (18), but the murine end-point The to size, apparentlyaresult of its hydrophobicity; smallest form may have a titrationassay was still heroic. Quantifythe molecular of weightof 50,000 or less. Because the novel properties the scrapie agent ing a single sample requiredeight to ten is distinguishit fromviruses, plasmids, and viroids,a new term "prion" proposed to serial tenfold dilutions and injection of denote a small proteinaceousinfectiousparticlewhich is resistantto inactivation by each dilutioninto six mice (19). Then 50 most proceduresthat modifynucleicacids. Knowledgeof the scrapie agent structure to 60 mice were held for 1 year and may have significance for understandingthe causes of several degenerative dis- examined weekly for signs of scrapie. eases. The number of animals developing scrapie at the highest dilutionwas used to calculatean end point. The time reanimalswere vaccinatedagainstlouping have been used as a commonexperimen- quiredfor titrationof a sample was reill virus with a formalin-treated suspen- tal host for scrapie and CJD; curiously, duced to 200 days when a more rapid sion of ovine brain and spleen that, as chimpanzeesare susceptibleto CJD but form of the disease in hamsters was was shown subsequently,had...
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