Prions and the new molecular phenetics.

P rions were injected into the public consciousness earlier this year when the British Government’s Health Secretary, Stephen Dorrell, rose in the House of Commons to make his dramatic announcement that the ‘most likely’ explanation for ten cases of a Creutzfeldt-Jakob disease-like (CJD) illness in young people was exposure to British beef that had been infected with the agent causing bovine spongiform encephalopathy (BSE). The agent to which Mr Dorrell referred was, of course, the prion. Prions are implicated in a number of neurodegenerative disorders including the human diseases Kuru and CJD, scrapie in sheep, and most recently, BSE. The cause of disease in each case is thought to be accumulation of an abnormal form of the prion protein in the brains of affected individuals. Now, two research groups have isolated prions in the cytoplasm of yeast (Saccharomyces cerevisiae), opening up the possibility that prions and their effects are taxonomically more widespread than previously appreciatedl,2. What makes prions interesting evolutionarily is the way that they accumulate. Stanley Prusiner coined the term ‘priori’ to describe a proteinaceous infectious particles. The prions investigated thus far are abnormal isoforms of normal cellular proteins that have acquired the ability to convert normal ‘benign’ proteins to the altered infectious form. More generally, one can think of prions as proteins that have the ability to transmit their phenotypes to other cognate proteins. The mammalian prion gene codes for a protein (PrPc) that appears to lie poised between two energetic states, corresponding to two different three-dimensional protein structure&5. Normal or cellular PrPc has an unknown but judging from its high degree of conservation687 probably fundamental function in the nervous systems of mammals. This form flips to the altered or ‘scrapie’ (PrPsc) structure of the protein, which is resistant to catalysis by the normal proteolytic enzymes. Over time, abnormal prions accumulate and cause disease, but not because large numbers of normal PrPc spontaneously switch to the altered form. Rather, the altered or PrPsC form is able to transmit its phenotype within an individual to the normal PrPc protein by a process analogous to cultural evolution: when PrPSC make contact with normal PrPc they can induce the normal form to adopt the altered or PrPSC phenotype. Precisely how they do this is unknown. Genetic mu-