Seminar

Darwinian evolution of prions in cell culture

PROF. CHARLES WEISSMANN

Ectopic Seminar

Prions, transmissible agents causing lethal spongiform encephalopathies, such as Creutzfeldt-Jakob and Mad Cow disease, consist mainly of PrPSc, a β sheet-rich conformer of the normal host protein PrPC and occur in the form of different strains. Strain identity is believed to be encoded by PrPSc conformation. We have found that biologically cloned prion populations become heterogeneous within 30 doublings by accumulating "mutants", and that selective pressure exerted by the cellular environment or a drug may result in the emergence of different mutants as major constituents of the evolving population. Thus, when transferred from brain to cultured cells, "cell-adapted" prions gradually outcompete their "brain-adapted" counterparts, and the opposite occurs when prions are returned from cells to brain. Similarly, when exposed to the inhibitor swainsonine, a novel substrain emerges that is resistant to the drug, while in its absence the susceptible substrain outgrows its resistant counterpart. Prions, albeit devoid of a nucleic acid genome, are thus subject to mutation and selective amplification, resulting in Darwinian deportment.