9 Transgenetic Investigations of the Species Barrier and Prion Strains

Abstract

The history of prion strains begins in 1936 with the first reported claim by Cuillé and Chelle (1939) of the successful transmission of scrapie by intraocular injection of healthy sheep with spinal cord from an afflicted sheep. This milestone event provided the first evidence that the disease was transmissible and led inevitably to a search for the infectious agent responsible. At first, the logical conclusion was that it must be a virus. Because of the extended incubation times, these diseases were often referred to as either slow virus diseases or unconventional viral diseases (Sigurdsson 1954; Gajdusek 1977, 1985). As detailed in other chapters in this volume, considerable effort was expended searching for the “scrapie virus”; yet nothing was found either with respect to a virus-like particle or a genome composed of RNA or DNA. Over the ensuing period of more than 60 years, it has become clear that scrapie is only one of a growing number of diseases known to be caused by prions and that prions comprise a unique class of pathogens that multiply by an entirely novel mechanism (Prusiner 1982a). In this chapter, we focus on the mechanisms that determine susceptibility to prions, that support prion diversity, and that govern the emergence of distinct prion strains during serial transmission.

EVIDENCE AGAINST A CONVENTIONAL GENOME
Aficionados of the virus hypothesis were challenged by a large body of evidence showing that the agent had properties unlike any known virus. The infectious agent showed a remarkable resistance to treatments, such as...