In October 1976, 53-year-old Daniel Carleton Gajdusek shared the Nobel Prize for Physiology or Medicine.51 Although he was still attributing kuru to an unidentified “slow virus,” other scientists had their doubts. By now, with cases of kuru dwindling to a few per year and confined to a “stone-aged society” few outsiders had ever seen, research on the disease was winding down. Interest in kuru appeared to have run its course, and with it funding for kuru-related research. Fortunately for the researchers (but unfortunately for a lot of sheep herders), scrapie, a disease that mimicked kuru’s destruction of the central nervous system, was beginning to attract significant attention.
Considering the importance of the European sheep industry, it was no surprise that by the early 1970s many researchers, including Gajdusek, were pressing to understand the mechanism behind scrapie. At the forefront of the mystery was the observation that whatever the scrapie-causing agent was, it could not be killed or inactivated by disinfectants like formalin or carbolic acid. Additionally, extracts from scrapie-infected brains lost none of their lethality after being heated, frozen, or dried. In another set of experiments, South African radiation biologist Tikvah Alper and her colleagues bombarded the mystery agent with an electron beam from a linear accelerator. Although the beam was strong enough to disrupt the molecular structure of any known pathogenic cell or virus, there was no change in the infectivity of the scrapie extract. The researchers also tried mega-doses of ultraviolet light, a proven disruptor of viral DNA and RNA—all to no avail. The extracts retained their lethality.
Alper’s research team soon reached a pair of conclusions regarding the scrapie-causing agent: 1) it was far smaller than any known virus, and 2) it could replicate without nucleic acids—the chemical rungs of the helical ladder that became Watson and Crick’s model for DNA. Shockingly, this last finding appeared to contradict one of the central tenets of biology, the fact that all organisms require nucleic acids to reproduce.
After reading over Alper’s work, English mathematician J. S. Griffith came up with an unusual hypothesis. Perhaps, he suggested, the agent that caused scrapie wasn’t a virus at all but a self-replicating protein. Griffith proposed that this mutant protein could function as a template for the production of additional mutants, each in turn taking on its own role as a template.
Researchers from competing labs scoffed at Griffith’s idea and Tikvah Alper was ridiculed as a female version of virologist/biochemist Wendell Stanley, who had won a Nobel Prize in 1946 for determining that the infectious agent in Tobacco Mosaic Virus was actually a self-propagating protein—a fact that was disproven only after he won the award.
But Stanley Prusiner, a young biochemist out of UC San Francisco, read the papers by Alper, Griffith, and others, saw an opportunity, and jumped into the fray. In the early 1970s, Prusiner moved to Montana where his work with scrapie expert William Hadlow confirmed Alper’s findings about the absence of nucleic acids in the scrapie agent. Prusiner and Hadlow’s results also indicated that, when exposed to substances like enzymes that could destroy or denature proteins, the disease-transmitting ability of the scrapie extract was eliminated.
Prusiner tried to tell Gajdusek and the other NIH researchers about what he had found, but he was rebuffed. Among the kuru mavens, who were now mostly working on other projects, only Michael Alpers was supportive, inviting the American to the Goroka Institute in New Guinea, where Prusiner studied a group of nine kuru sufferers.
In 1982, Prusiner published his lab findings on scrapie in the journal Science. He coined the name “prion” (pronounced “PREE-on”) to describe an aberrant form of protein, which he claimed was responsible for the suite of neurodegenerative disorders known as Transmissible Spongiform Encephalopathies (TSEs). Prusiner claimed that, unlike viruses, prions were not biological entities, but they could be infectious—transmitted orally or through contact with infected material. They could also be inherited or spontaneous in origin.
When asked about why the body’s immune system didn’t appear to mount a defense against them, Prusiner explained that unlike viruses or bacteria, prions weren’t foreign invaders; they were an altered form of one of the body’s own proteins. Because of this, the body never recognized them as a threat. As a result, prions would spread through the body of a TSE victim unchecked.
Prusiner did hedge his bets by stating that current knowledge did not exclude the potential existence of a small core of nucleic acid within the prion—which might explain how they replicated. Nevertheless, he co-opted Griffith’s protein-as-template model, with his misfolded prion proteins (which were too small to see with even the most powerful microscopes) building up into the amyloid plaques that characterized fatal TSEs like kuru, Creutzfeldt-Jakob disease, TME, and scrapie.