Killer Proteins: The Science Of Prions : Short Wave Prions are biological anomalies – self-replicating, not-alive little particles that can misfold into an unstoppable juggernaut of fatal disease. Prions don't contain genes, and yet they make more of themselves. That has forced scientists to rethink the "central dogma" of molecular biology: that biological information is always passed on through genes. The journey to discovering, describing, and ultimately understanding how prions work began with a medical mystery in a remote part of New Guinea in the 1950s. The indigenous Fore people were experiencing a horrific epidemic of rapid brain-wasting disease. The illness was claiming otherwise healthy people, often taking their lives within months of diagnosis. Solving the puzzle would help unlock one of the more remarkable discoveries in late-20th-century medicine, and introduce the world to a rare but potent new kind of pathogen. For the first episode in a series of three about prion disease, Short Wave's Gabriel Spitzer shares the science behind these proteins with Emily Kwong, and explains why prions keep him awake at night.

Killer Proteins: The Science Of Prions

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EMILY KWONG, HOST:

Hey, everyone. So if you know SHORT WAVE, you know we love data, which is why we've crafted a SHORT WAVE-specific survey for you all. Tell us what you think of the podcast. It's short. It's anonymous. Now is truly the time to weigh in on our show. Fill out the survey at npr.org/shortwavesurvey Thanks so much.

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KWONG: You're listening to SHORT WAVE from NPR.

Hey, hey, SHORT WAVErs. Emily Kwong here. Joining me today is senior editor Gabriel Spitzer. Hi, Gabriel.

GABRIEL SPITZER, BYLINE: Emily.

KWONG: Hey.

SPITZER: Emily, I'm here to tell you about this, like, kind of mild obsession I have with a protein.

KWONG: OK. I'm guessing you're not talking about tofu.

SPITZER: Love tofu, but no, no, I'm going a little more basic...

KWONG: OK.

SPITZER: ...Than that today. This is, like, proteins as the building blocks of biology. So every cell has, like, 40 million of them. They're...

KWONG: Yeah.

SPITZER: ...The most ordinary things in the world in some ways. But there's one protein in particular that I personally find deeply unsettling.

KWONG: What's that?

SPITZER: Well, it's called the prion, and it could cause a bunch of different neurodegenerative diseases.

KWONG: OK. And what is it about prions that gives you the creeps?

SPITZER: Well, for one thing, they're not alive. Proteins are just this kind of basic building material that's not really supposed to have a mind of its own. And yet, once they go wrong, they're kind of unstoppable. Like, when a person's been diagnosed with prion disease, they usually have months, maybe a few years to live.

KWONG: OK. I'm getting the picture.

SPITZER: Yeah. And some of those diseases can incubate in the body for decades and then strike out of the blue. And then outside the body, prions are really, really hard to destroy.

KWONG: So you're saying the things that reliably destroy bacteria and viruses have a harder time knocking out prions?

SPITZER: Right. Exactly, Emily. Prions, they just - they play by completely different rules than viruses or bacteria. And trying to understand how they can replicate and cause disease - it's been a long trip for the prion scientists.

KWONG: All right. Well, today we are going to kick off a little series of episodes on prion science.

SPITZER: Today on the show, Part 1, killer proteins - how they work, where they come from and why they keep me up at night.

I'm Gabriel Spitzer.

KWONG: And I'm Emily Kwong. And you're listening to SHORT WAVE, the daily science podcast from NPR.

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KWONG: OK. Gabriel, so where does this story start?

SPITZER: Well, it starts with a medical mystery in a remote part of New Guinea. So, you know, this huge island in the Southwest Pacific, it's home to a whole range of Indigenous cultures. And in the 1950s, Australian colonial officials started to get word that this particular group called the Fore were experiencing a horrible epidemic.

KWONG: What was the cause?

SPITZER: Nobody really knew. The Fore called it kuru, which meant to shiver or tremble. It was basically a superfast brain-wasting disease. It affected people who were otherwise young and healthy, which was weird. And it seemed to hit women and children especially hard, which was also weird.

KWONG: Wow.

SPITZER: And in this population of, like, 11,000 people, kuru was killing about 1% of them every year.

KWONG: Wow. Oh, that's really terrible.

SPITZER: Yeah. It was really devastating. And then the symptoms of this disease were unlike almost anything that scientists had encountered. It was like losing the ability to walk and to eat and to speak. There were tremors. There was involuntary writhing. And then the other thing that emerged pretty quickly was that every person diagnosed with kuru died within usually months.

KWONG: And no one knew the cause?

SPITZER: Yeah. Scientists had a lot of theories, like maybe it was genetic, maybe an environmental toxin, but nothing held up for very long. Blood from the kuru victims didn't have antibodies or signs of inflammation or any of the things you'd expect to see after an infection. And then when scientists autopsied the brains of kuru victims, they found a really unusual pathology. They were full of holes.

KWONG: Holes.

SPITZER: Yeah.

KWONG: In the brain tissue?

SPITZER: Yeah. Like, there were all these clumpy little growths that sort of killed pockets of neurons and just left the brain with the consistency of, like, a sponge.

KWONG: Oh, that's so weird.

SPITZER: Yeah. And so they published those results, and it caught the eye of a veterinary pathologist named Bill Hadlow at Rocky Mountain Labs in Montana. I talked with Byron Caughey, who's a biochemist at that same lab.

BYRON CAUGHEY: Bill Hadlow said, you know, this pathology looks quite a lot like what we see in sheep that have scrapie.

KWONG: What's scrapie?

SPITZER: Scrapie is a brain disease that causes sheep to, like, scratch and rub themselves raw. It was known to be infectious, from one animal to another. And so in lab experiments, scientists tried introducing some kuru brain tissue into a healthy animal, and they found that the disease can be transmitted.

KWONG: All right. And did they ever figure out how the kuru itself was spreading?

SPITZER: So later, people zeroed in on the Fore practice of funereal cannibalism. Scientists knew about this practice, but they didn't connect it with kuru. The Fore people would sometimes eat the bodies of loved ones after death as a way to stay connected to them. And women and children would typically handle the bodies. And it emerged that that was probably how the disease was spreading.

KWONG: So that solved at least one part of the medical mystery.

SPITZER: Yeah. Well, one smallish part.

CAUGHEY: Then the big mystery, of course, then was, well, what's the infectious agent that is causing transmission of kuru between these human patients and scrapien (ph) sheep, for that matter?

SPITZER: So the scientists turned their attention to those little clumpy growths that made holes in all the kuru brains.

KWONG: OK.

SPITZER: So it became clear that these clumps were made of protein. I talked to this neuroscientist, Carlo Condello at the University of California, San Francisco. And he said, among other oddities, these little clumps were almost impossible to destroy.

CARLO CONDELLO: You know, you can blast it with heat. You can blast it with acids and bases, all things that would typically totally destroy any virus in a flash, but these proteins resist.

KWONG: So these clumps of proteins in the brains of kuru victims, in the brains of scrapie sheep, they're, like, indestructible proteins.

SPITZER: Yeah, almost, almost. And unlike viruses or bacteria, proteins don't have any genetic material, so they cannot replicate on their own.

KWONG: Yeah. Right, right, right. Remind me - where do proteins even come from?

SPITZER: Yeah. OK, so little bio lesson here. In our cells, we have DNA, which are like, you know, blueprints of the body. That information gets translated into RNA, which looks like a little single strand of the double-helix DNA. And that RNA brings the instructions to a tiny cellular machine called a ribosome, which sort of 3D prints the protein.

KWONG: Yes. Ninth-grade bio is coming back to me here - DNA to RNA to proteins.

SPITZER: Yeah. This is so important to understanding life that it is literally called the central dogma of molecular biology.

KWONG: OK. Wow.

SPITZER: So a protein basically starts out as a chain of amino acids. And you can think of it kind of like a little string of beads, where each amino acid bead has its own unique shape, its own electrical charge. And that leads to this crucial thing happening when the string of beads folds together in a precise way. And so you end up with this elegant molecule designed to do something really, really specific. This is neuroscientist Vinita Chittoor, who's also at UCSF.

VINITA CHITTOOR: So for a protein to reach its correct destination, where it can perform its native function, it needs to be recognized. And that all depends on how it folds.

SPITZER: Yeah, so the folding is really important. And guess what happens when a protein folds wrong?

KWONG: I don't want to know. I'm guessing that can be a bad thing.

SPITZER: It can be a superbad thing. And I think that's the technical term for it. And in the late '70s and early '80s, a scientist named Stanley Prusiner hypothesized that in diseases like kuru, maybe there's no infectious organism in the process at all. Like, maybe it's only the proteins and that the problem here is that the proteins are literally getting bent out of shape. So Prusiner coined this term, prion, for an infectious protein.

KWONG: Wow. So it was the proteins all along.

SPITZER: Exactly.

KWONG: Wild. I still don't understand the infectious part, though, because how can a protein reproduce without any genes? How can it spread on its own?

SPITZER: Yeah, it's a really good question. What seems to be happening is that a misfolded prion protein bumps into its neighbor, healthy prion protein, and makes it misfold, too. Here's how Carlo Condello describes it.

CONDELLO: In a way, it acts like a scaffold or a template for how these naive proteins, which otherwise would normally, potentially fold correctly. But if they run into one of these bad guys, it'll take on or adopt that conformation. And then so the process continues over and over.

KWONG: How rude. It sounds almost like a crystal or something, where you have a little seed, and everything that sticks to it takes the seed's shape.

SPITZER: Yes. That's pretty much right. It's, like, a really similar process. And it works essentially just by the laws of physics and chemistry. But in biology, Vinita Chittoor says this was completely radical.

CHITTOOR: The whole thing with prion was that it challenged the central dogma of biology. And it took a long time for people in the biology field to accept that the protein without a mind of its own, without any nucleic acid or code in itself, was able to reproduce.

KWONG: Totally. That must have been such a shocking discovery at the time.

SPITZER: It was Nobel worthy.

KWONG: Yeah.

SPITZER: Prusiner won the Nobel Prize for it. And that reproducing that she's talking about creates these long fibers made of one prion protein stacked on another. So it's like a chain reaction that burns like a long, slow fuse, killing neurons and making holes in your brain. And, Emily, this could take years. There were still Fore people dying from kuru decades after being exposed, like way after funereal cannibalism disappeared.

KWONG: Interesting. OK. What is the state of prion diseases now? What do we know?

SPITZER: Yeah. Well, kuru is basically a thing of the past. But prions cause a few other human and animal diseases. One that people might know is bovine spongiform encephalopathy, which is better known as mad cow disease.

KWONG: Oh, OK.

SPITZER: Yeah. BSE infected millions of cows in the 1990s and even jumped the species barrier. About 230 people died from prion disease from eating contaminated beef.

KWONG: Yeah, I remember this. That was a really scary time.

SPITZER: It was quite frightening. Kind of turned the world upside down for a while.

KWONG: Yeah.

SPITZER: So there's that. There's Creutzfeldt-Jakob disease, or CJD, which is like a super rapid, fatal dementia. There's fatal familial insomnia, which in some families leads to people losing the ability to sleep until they literally die from it. And then I mentioned earlier that, you know, kuru didn't seem to be genetic, but it turns out that other prion diseases can be inherited. So even though they're rare, they can be infectious or inherited or sporadic, meaning the disease just comes on spontaneously.

KWONG: What a bouquet of nightmares. I feel like this is one of those things you just can't unknow - that there are these little, not-alive, infectious particles that misfold into an unstoppable juggernaut of fatal disease. I can see why prions freak you out.

SPITZER: It carries such a mechanistic, kind of Terminator-type vibe that I just find, I don't know, existentially terrifying.

KWONG: Sure.

SPITZER: But yeah, actual scientists, like Vinita Chittoor, have a little bit of a different take.

CHITTOOR: The fact that it's all based on biochemistry - there's no internal notion of it wanting to propagate and make more copies of itself so it can flourish; it's just pure biochemistry - I just find it so fascinating.

KWONG: Pure biochemistry. Well, given your terror-slash-fascination with this topic, Gabriel, I hear you're coming back to tell us more about it.

SPITZER: Yes. In coming episodes, we're going to meet this couple whose lives were turned upside down by prion disease. And they decided to do something about it.

KWONG: I am looking forward to this story. Gabriel, thank you so much for coming on the show.

SPITZER: You are so welcome, Emily.

And quick reminder, too. If you've been listening to SHORT WAVE, even for a little, we would love your thoughts on our show. You can find it all at npr.org/shortwavesurvey.

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KWONG: This episode was produced by Berly McCoy, edited by Gisele Grayson and fact-checked by Abe Levine. The audio engineer for this episode was Natasha Branch. Special thanks to George Carlson at UCSF for help on this episode.

I'm Emily Kwong.

SPITZER: I'm Gabriel Spitzer.

KWONG: And tune in tomorrow for more SHORT WAVE, the daily science podcast from NPR.

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