Alzheimer’s, Creutzfeldt-Jakobs, Parkinson’s Disease All Part Of Prion Spectrum
Editor’s Note: On September 9, 2015 additional research adds to the evidence that suggests that Alzheimer’s disease is a transmissible disease. Scientists have shown that tissues can transmit symptoms of the disease between animals. A new study published in the journal Nature raises additional concern about the transmissibility of Alzheimer’s disease between people and between species.
A scientific truth triumphs not by convincing its opponents but because its opponents eventually die, said influential physicist Max Planck. For Nobel prize-winning neurologist Stanley Prusiner, the quotation is “so mean” that he doesn’t like to use it. “But it is absolutely true,” he says.
Prusiner won the Nobel prize in 1997 for his discovery of prions – infectious proteins that cause fatal neurodegenerative diseases in people and animals, the most famous of which is BSE or mad cow disease and its human form, variant CJD. But his claim to have found an entirely new type of disease-causing agent, which he first termed a prion in 1982, was treated as heretical by many of his peers and the media for years. Bacteria, viruses, fungi and parasites are the only known infectious agents – a mere protein, with its lack of genetic material, is not alive so can’t transmit disease – so an army of naysayers maintained. Even his Nobel prize in physiology or medicine, for which he was the sole winner, didn’t silence all the critics.
“I understood the skepticism,” says Prusiner. “When there is a really new idea in science, most of the time it’s wrong, so for scientists to be skeptical is perfectly reasonable…[But] it didn’t make it any easier.”
Prusiner tells the story of his discovery in a new autobiographical book, Madness and Memory. He wrote the book, he says, both to ensure that the story was recorded in his own words and the science was properly described.
Prusiner was born in Des Moines, Iowa, in 1942. As a youngster, he had no interest in science and was happy to get Bs in school with little effort. When, later, he wanted to take advanced chemistry, a subject he liked because he didn’t have to memorize anything, the school said he wouldn’t be able to comprehend the science. He took a lower course, but went on to major in the subject at the University of Pennsylvania, following it up with a medical doctorate received in 1968.
It was during his chemistry degree that he got his first taste of research – a summer project to help boost his application to medical school. He found the project, studying hypothermia in rats, fascinating and by the end of medical school had become excited about the possibility of pursuing biomedical research as a career.
After completing a grueling internship in medicine that was required for the post, he took a research job at the US National Institutes of Health. He remained at the NIH for three years, studying enzymes in bacteria, before deciding it was time to move on and build his own laboratory.
Prusiner found his scientific destiny after an encounter with a patient with a rare brain disorder in San Francisco in 1972. He had recently begun a clinical residency in neurology at the University of California, San Francisco (UCSF), with the goal of identifying a big problem to investigate, when a patient dying of Creutzfeldt-Jakob disease (CJD) was placed under his care.
The disease was thought to be caused by a “slow virus” that took many months or years to produce symptoms and, intrigued, Prusiner began reading up. “The more I read, the more fascinated I became,” he says.
Other seemingly related slow virus diseases included scrapie (which occurs in sheep) and kuru (found in the Fore people of Papua New Guinea and spread by cannibalism), all three causing a spongy degeneration of the brain and being transmissible to similar species via injection of infected brain tissue. Yet no actual viruses had ever been isolated and previous work by British scientists on the scrapie agent had even found it had some strange properties, including being resistant to killing by radiation.
They had raised the controversial prospect that it may not even contain DNA or RNA. Prusiner had his problem: he would isolate and characterize the elusive infectious agent responsible for scrapie, which could be studied with rodents, and in so doing shed light on these so-called slow virus diseases.
He began work in 1974 having accepted an academic position at UCSF and despite colleges’ warnings that the problem would be too difficult to crack. It was tough going. He lacked funds to pay for the upkeep of the thousands of laboratory animals he needed and the work was slow because the disease took so long to manifest (he found crucial private funding and sped up the work by moving from mice to hamsters and redesigning his measurement method). “I could now do in one year what would have taken me 80,” he says.
As experimental data began to accumulate, Prusiner grew puzzled. He had anticipated that the scrapie agent he was enriching and purifying from brain material would turn out to be a different and interesting virus. Yet his preparations lacked any genetic material that would indicate one. All he found was a protein. He summarized the work in a journal article in Science in 1982, introducing the term “prion” to denote such a particle.
“I just thought it was really counterproductive to keep calling it a virus when it wasn’t,” says Prusiner. “If you call it that and you believe it at some level, then you miss the next set of experiments.”
The word came from Prusiner’s pondering how “protein” and “infectious” might fit together. When “proin” didn’t sound quite right, he flipped two letters. “What else was I going to do?” he laughs. “I couldn’t come up with some clever Greek words because I don’t know any Greek.” (He pronounces it “pree-on“.)
The word and the concept elicited what he describes as a “firestorm” of criticism and skeptics began staking careers on hunting down the scrapie virus (it has never been found). One particularly low moment he recalls was a 1986 article in the science magazine Discover, which accused him of being more interested in fame than science. He adopted a policy, which he maintained for years, of not speaking to the press.
Prusiner’s answer to his scientific doubters was to keep producing data. Among his contributions, he characterized the scrapie prion and added CJD and other diseases to the list caused by prions. He also showed how prions replicate. They come in two forms, he found, with different shapes: a normal uninfectious form that all animals and people have that is particularly abundant in the brain (it is encoded by a prion protein gene) and a more stable disease-causing form. The disease-causing form can act like a template to guide the normal form to refold into the disease-causing one.
In the late 1980s, as scientific data converged, the tide began to turn on the acceptance of the work. He was elected to various professional bodies and began winning awards. Soon afterwards, so-called knockout mouse studies (which abolished the prion gene in mice making them resistant to prion infection) added further evidence.
Then, in 1996, the first cases in Britain of the human form of mad cow disease were reported and prions were implicated. Variant CJD, it was suspected, had arisen from the consumption of beef infected with BSE, which had been identified as a prion disease using Prusiner’s methods after it was first reported in Britain a decade earlier. A year later, Prusiner won the Nobel prize.
Did the spotlight on prions influence the Nobel committee’s decision?
“It didn’t hurt,” he says.
At the press conference that followed, he faced incredulous journalists still insisting prions were an impossibility. “A Nobel prize doesn’t wipe the scepticism away for some people,” he says.
Prusiner attributes his tenacity in the face of years of doubt to the nature of the problem itself. He would have quit, he says, except there was no alternative that excited or captivated him more. But good scientist, he adds, also stay focused on the problem, going deeper and deeper trying to understand it. That is where the “real opportunity to discover something lies”, he says.