A mouse to remember

Transmissible spongiform encephalopathies (TSEs or priori diseases) such as Creutzfeldt-Jakob disease and kuru in man or scrapie in sheep presented and still present major challenges to biomedical research. The first phase of investigation of these diseases was dominated by experiments at the biological level and led to the discovery of transmissibility, the existence of strains, as well as the peculiar properties of the transmissible agent, such as lack of immunogenicity and very long incubation times. The unusual resistance to radiation led to the proposal that the agent, or prion, might be devoid of nucleic acid (in this paper we will use the term prion to signify infectious TSE agent, regardless of its composition or structure). The next phase, in which we and our colleagues at the Institute of Molecular Biology of Z0rich University participated, initially in collaboration with Stan Prusiner and his colleagues, saw the isolation and biochemical characterization of PrP s~ and PrP c (Oesch et al., 1985), followed by the cloning of the PrP gene (Basler et al., 1986), and the establishment of genetic linkage between it and familial prion disease (Hsiao et al., 1989). In the third phase, transgenic experimentation strengthened the link between the PrP gene and susceptibility to prion disease by showing that the socalled species barrier could be overcome, at least in some cases, by introducing the PrP gene of the donor into the recipient (Prusiner et al., 1990). It also became clear that mice expressing PrP transgenes with particular mutations acquired neurodegenerative diseases; however, with a possible exception (Telling et al., 1996), these were not transmissible. Since the mid 1960s, the nature of the transmissible agent has being continuously debated. Inasmuch as a virus is understood to consist of a protein-encased nucleic acid encoding some or all of its constituent proteins, the concept of a "slow" or "unconventional" virus lost support as intense efforts in many laboratories failed to identify a TSE-specific nucleic acid or even a nucleic acid long enough to encode a small protein (Riesner et al., 1993). Nonetheless, a valiant rear guard still clings to the idea that a virus, perhaps an endogenous virus whose nucleic acid would not score as extraneous, is responsible for TSEs (Chesebro, 1999; Manuelidis, 2003). The virino hypothesis, which holds that the infectious agent consisted of an agent-specific nucleic acid