Thirty years ago a scientist named Stan Prusiner coined a new word: prion. It turned out it was not quite a new word: "prion" was already the name of a small bird of the Southern oceans. But the research circles in which Stan Prusiner moved couldn't have cared less about the bird. They recognized the boldness of Prusiner's approach: a new word for a new way of thinking. Some liked it, some didn't, but most would agree today -- however reluctantly -- that prion science has turned out to be a diamond: captivating from any angle.
For one thing, It has provoked a complete re-think of infection. Prior to the recognition of prions, bacteria and viruses dominated thinking. Viruses in particular starred in the rise of molecular biology in the 1950s. Yes, they were ridiculously simple: just a few genes wrapped in a protein coat. But those genes were absolutely essential. It was difficult, if not impossible, to envision how any infectious agent could reproduce if it didn't have genes, any DNA (or RNA).
Decades before Stan Prusiner dubbed them prions, these agents were already known to be responsible for a disease in sheep called scrapie, and even a couple of (rare) human diseases. They were assumed to be viruses, because they were incredibly small, but since there were months or even years between the time of infection and the appearance of symptoms, they were called "slow viruses."
But even that qualified title wasn't good enough. If prions were viruses, they were weird in their virtual indestructibility. They shrugged off deadly doses of formalin and chloroform, and survived half an hour at 100 C. Especially worrying was the fact that doses of ultraviolet light that destroy DNA and its cousin RNA, did nothing to inactivate prions. How could that be? These were disease agents, causing fatal infections during which they multiplied like crazy. They just had to have genes.
But they didn't. A prion turns out to be a protein molecule and nothing more. Not a set of protein molecules locked together, like the coats of some viruses: a single protein molecule. But different than most, because it is twisted out of shape. It's misfolded.
Every protein has a shape; that shape enables that protein to do its thing, whether that's being a key element of a cellular structure, or accelerating a chemical reaction. Presumably the prion protein starts life as a protein folded into that correct shape, but at some point a catastrophic change is triggered. The protein flips, twists, unwinds and reforms into the "misfolded" version.
In prion diseases, misfolded proteins have a still mysterious ability to recruit normal ones. As that recruitment proceeds, brain cells are decimated of their arrays of normal prion proteins and hordes of new infectious versions are produced.
This is what Stan Prusiner was banking on back in 1982, when he said, in effect, I'm naming them, and I'm betting they are protein-only infectious agents. Prusiner was and still is a controversial figure, but he has his Nobel, won in 1997. And the numbers of legitimate prion skeptics has steadily shrunk.
The growth of the science, on the other hand, has been spectacular. The prion is a new way of thinking about human disease. Here's the perfect example: one of the hallmarks of a human prion disease, like the one-in-a-million Creutzfeldt-Jakob Disease, or the New Guinean Kuru, is the accumulation of clumps of misfolded proteins inside cells. Aggregates of the stuff. These are also seen in the brains of animals which have died of mad cow, or scrapie.
But for decades now it's been clear that there are similar plaques in the brains of people who have died with Alzheimer's disease as well. Not a prion protein, a different kind, but so diagnostic that a brain with unusual numbers of such plaques is, more often than not, an Alzheimer's brain. There are aggregations of misfolded proteins in Parkinson's Disease too, and in amyotrophic lateral sclerosis, and even in chronic traumatic encephalopathy (CTE) the brain disease of boxers, football and hockey players. Different proteins, but all misfolded and all with the apparent ability to increase their numbers, spreading through the brain as they do.
Misfolded proteins everywhere, but there's a red flag. These diseases cannot all be lumped together. One, the prion diseases, have infection at the heart. The misfolded proteins in those cases are agents of disease. But the group of well-known human diseases, like Alzheimer's and Parkinson's, are not infectious, as far as anyone knows. So can it be justified to see the prion diseases as models for the others?
That justification is suggested by the blurred lines between the two kinds of disease. Take CJD, the prion disease that strikes humans at a rate of one-in-a-million, apparently spontaneously. There are families whose genetics predispose them to get CJD, but there is no evidence whatsoever of infection, nothing to suggest some stealth transmission of a prion. The disease just seems to happen. So it is a non-infectious prion disease.
Yet if you inject CJD brain matter into lab animals, they will get a similar disease. So it is infectious. It is actually both.
What's much more startling is that you can do virtually the same thing using material from a 90-year-old Alzheimer's victim -- inject it into susceptible mice -- and you get animal Alzheimer's, accelerated plaque formation in the animals' brains.
In all these neurodegenerative conditions, something triggers misfolding. If you can interrupt that, then you stop the formation of plaques. If you stop plaque formation in a human brain, you could prevent Alzheimer's, or at least delay it. Or will it and its related diseases prove to be more complicated, forcing us to realize, sadly, that we are still just seeing a small piece of the puzzle?
Funnily enough, though the reaction to Stan Prusiner's 1982 article focused on the word prion and the idea of protein-only infection, Prusiner also made the bold claim that Alzheimer's, Parkinson's disease, amyotrophic lateral sclerosis and several others might ultimately involve prions. That may not be quite right -- we'll see -- but it sure was prescient.