Prions are probably the strangest infectious agents because they lack DNA, and therefore are not considered alive. Yet they do interact with each other and combine in numbers to cause spongiform encephalopathies and other central nervous system disorders. Now researchers at Scripps Research Institute have shown that prions actually undergo Darwinian evolution even though this happens without any genetic involvement. So it seems that now we have an example of evolution without life.
In the first part of the study, Weissmann and his colleagues transferred prion populations from infected brain cells to culture cells. When transplanted, cell-adapted prions developed and out-competed their brain-adapted counterparts, confirming prions’ ability to adapt to new surroundings, a hallmark of Darwinian evolution. When returned to brain, brain-adapted prions again took over the population.
To confirm the findings and to explore the issue of evolution of drug resistance, Weissmann and his colleagues used the drug swainsonine or swa, which is found in plants and fungi, and has been shown to inhibit certain prion strains. In cultures where the drug was present, the team found that a drug-resistant sub-strain of prion evolved to become predominant. When the drug was withdrawn, the sub-strain that was susceptible to swainsonine again grew to become the major component of the population.
Weissmann notes that the findings have implications for the development of therapeutic targets for prion disease. Instead of developing drugs to target abnormal proteins, it could be more efficient to try to limit the supply of normally produced prions – in essence, reducing the amount of fuel being fed into the fire. Weissmann and his colleagues have shown some 15 years ago that genetically engineered mice devoid of the normal prion protein develop and function quite normally (and are resistant to prion disease!).
Another implication of the findings, according to the study, is that drug-resistant variants either exist in the prion population at a low level prior to exposure or are generated during exposure to the drug. Indeed, the researchers found some prions secreted by infected cells were resistant to the drug before exposure, but only at levels less than one percent.
The scientists show that prion variants constantly arise in a particular population. These variants, or "mutants", are believed to differ in the way the prion protein is folded. As a consequence, prion populations are, in fact, comprised of multiple sub-strains.
Press release: Scripps Florida scientists show ‘lifeless’ prions capable of evolutionary change and adaptation…
Abstract in Science Express: Darwinian Evolution of Prions in Cell Culture
Image: Colour-enhanced image of prion proteins (PrPSc) from an animal infected with scrapie. The orange prion protein particles are associated with lipoprotein ‘rafts’ (red) through glycosylphosphatidylinositol (GPI) linkages. The rafts are specialised microdomains of the membrane rich in cholesterol and sphingolipids. Wellcome Images
