NOMIS Awardee Adriano Aguzzi and colleague Elena De Cecco published an article in Science on Oct. 2, 2020, exploring the evolution of prions.
Paradigm shifts are drivers of scientific progress, yet the shifters of the paradigms often experience scorn rather than immediate applause. That was the fate of Stanley Prusiner’s 1982 paper claiming—to the initial amusement of his colleagues—that scrapie, a degenerative disease that affects the central nervous system of sheep, is caused by “proteinaceous infectious particles,” which he called prions (1). Prusiner’s intuition, which earned him the 1997 Nobel Prize, is influencing our approach to an ever-expanding variety of seemingly unrelated diseases and physiological processes, and its implications reverberate to the present day.
The two decades preceding Prusiner’s paper had witnessed the immense success of molecular biology, including the cracking of the genetic code; the elucidation of DNA replication, transcription, and translation; and the cloning of genes. These discoveries prompted Francis Crick to conceptualize the “central dogma”: Information flows unidirectionally from DNA to proteins. But although religious dogmas may be eternal, the shelf life of scientific dogmas is inevitably limited. Prusiner postulated that prions carry on their replicative cycle without the participation of nucleic acids. This hypothesis, reminiscent of John Griffith’s 1967 suggestion of the existence of self-replicating proteins (2), had the potential to explain the prodigious resistance of the scrapie agent to DNA-damaging radiation.
Daniel Carleton Gajdusek, who won a Nobel Prize for showing that Kuru was a human disease transmitted by cannibalism in Papua New Guinea, proposed in 1959 that the neurodegenerative disorders Kuru, scrapie, and Creutzfeldt-Jakob disease (CJD) are caused by “slow viruses.” Indeed, prions behave similarly to neurotropic viruses in many surprising ways, including the colonization of extraneural organs followed by neuroinvasion of the brain through peripheral nerves (3). Yet, Prusiner purified the agent and found it to be smaller than a virus: No informational nucleic acid would fit into it. Over time, the group of prion diseases grew to include other human (fatal familial insomnia) and animal (bovine spongiform encephalopathy, also called mad cow disease, and chronic wasting disease) disorders, but no causative virus has been identified and their prion etiology is now well accepted.
Professor of neuropathology and director of the Institute of Neuropathology
University of Zurich
Exploring the Locales of Cognitive Decline
NOMIS RESEARCH PROJECT