These studies and observations generated a groundswell of interest in discovering the nature of the infectious agent or agents that caused scrapie and kuru. Many hypotheses on the nature of the agent surfaced between 1962 and 1981, ranging from a small DNA virus to a replicating polysaccharide to naked nucleic acid similar to plant viroids (Prusiner, 1982). None of these explanations gained widespread acceptance, however, and the cause of scrapie remained an enigma.

In 1982, neurologist Stanley Prusiner asserted that the infectious agent in scrapie was either a protein or a small nucleic acid surrounded by a tightly packed protein (Prusiner, 1982, 1999). He called this infectious agent a "prion," which stands for "small, proteinaceous infectious particles that are resistant to inactivation by most procedures that modify nucleic acids" (Prusiner, 1982, p. 141).

At the time, replication of microorganisms and viruses was thought to require nucleic acids. Several investigators had proposed that the infectious agent of scrapie might not require nucleic acids and could be a replicating protein (Alper et al., 1967; Griffith 1967; Lewin, 1972; Pattison and Jones, 1967). Until Prusiner's entry into the field, however, no other investigator had provided compelling data to support his hypothesis.

Applying advanced biochemical techniques, Prusiner generated a purified infectious scrapie preparation that yielded a peptide fragment. By determining the nucleic acid sequence that encoded the peptide, he located the gene where the sequence for the peptide was embedded, allowing him to decipher the full-length protein PrP (the prion protein) (Brown and Bradley, 1998). He then demonstrated that the scrapie agent resisted six different procedures known to attack nucleic acids and was susceptible to six methods of protein inactivation (Prusiner, 1982). (It was later established that prions and PrPSc [a protease-resistant protein associated with prion disease] were resistant to limited digestion by one of those methods, proteinase K digestion.) Like some investigators whose theoretical work preceded him, Prusiner correctly suggested that a prion might act as "an inducer or template for its own synthesis" (Prusiner, 1982, p. 139).

Two decades of research have borne out the prion hypothesis, leading most TSE experts to accept this theory. Prusiner won the Nobel Prize in Physiology or Medicine in 1997 for his groundbreaking work. But because Koch's postulates2 have not been demonstrated for prions,

2  

Koch's postulates: Criteria for proving that a specific type of microorganism causes a specific disease. 1) The organism should be constantly present in the animal suffering from the disease and should not be present in healthy individuals. 2) The organ-



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