Prions are mostly protein. Although protein is a fundamental component of living cell material, prions are not alive. The behave something like viruses, without DNA or RNA yet able to reproduce by forcing living cells to do the reproduction for them. Prions were hypothesized in the 1960’s (Alper and Griffith) but not discovered until 1982 by Stanley Prusiner (for which he received the Nobel Prize in 1997). Like the role of proteins in epigenetics (adaptation or change in gene expression not caused by DNA), the more molecular biologists dig into proteins the more versatile and important they become. New research shows that includes the ability of prions to evolve.
Prions are chains of proteins (polymers) that exist in many cells in a native harmless form. There are also infectious prions, from which the name is derived (proteinaceous infection). The infectious prions force normal prions to assume a misfolded shape, thereby reproducing the infection. In the misfolded shape, called an amyloid beta sheet, prions are very stable. The stability lets them accumulate in infected tissue, eventually causing tissue damage and cell death. This is the basis of some very nasty illnesses such as bovine spongiform encephalopathy (mad-cow disease) and Creutzfeldt-Jakob disease in humans. All known prion diseases are incurable and fatal.
A new study, carried out by the Scripps Research Institute, started with the notion that perhaps prions could become resistant to drugs through selective adaptation (i.e. evolution). To test the idea, they started with removing diseased brain cells to a culture medium (petri dish). In this environment, a non-infected strain of prion soon became dominant, indicating that mutation produces strains that prefer different environments. A second test used a drug known to inhibit prions (swainsonine). Where the drug was present, a different strain of prion reproduced more rapidly. When the drug was withdrawn, the previous strain regained dominance. Both tests showed that prions adapt to the environment and that adaptation is carried on through successive reproduction.
The study from Scripps Florida in Jupiter shows that prions can develop large numbers of mutations at the protein level and, through natural selection, these mutations can eventually bring about such evolutionary adaptations as drug resistance, a phenomenon previously known to occur only in bacteria and viruses. These breakthrough findings also suggest that the normal prion protein – which occurs naturally in human cells – may prove to be a more effective therapeutic target than its abnormal toxic relation.
“On the face of it, you have exactly the same process of mutation and adaptive change in prions as you see in viruses,” said Charles Weissmann, M.D., Ph.D., the head of Scripps Florida’s Department of Infectology, who led the study. “This means that this pattern of Darwinian evolution appears to be universally active. In viruses, mutation is linked to changes in nucleic acid sequence that leads to resistance. Now, this adaptability has moved one level down – to prions and protein folding – and it’s clear that you do not need nucleic acid for the process of evolution.”
The appearance of different strains of prions was something of a surprise, but indicative of the evolutionary sophistication available even to proteins. Scientists are still trying to unravel the complex functionality of prions – both normal and toxic – as they relate to various kinds of brain activity. The ability of prions to evolve adds an interesting wrinkle, or shall we say ‘folding’ to the story.