This Podcast Will Kill You - Ep 20 Prions: Apocalypse Cow

Episode Date: February 19, 2019

This week's episode is nothing like any of our past episodes, and there will never be another quite like it. How can we be so sure, you ask? Because this week, we're covering prions, the terrifying, genetic material-less infection that is 100% fatal and caused by nothing more than a humble protein. And not just any protein, a protein you already have in your body. Are you sweating yet? Good. Then settle in and listen to the amazing biology of this terrifying twisted proteinacious particle, the fascinating and fraught history that led to its discovery, and the current research on just how scared you need to be of prions in your brain. See omnystudio.com/listener for privacy information.

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cybersecurity and expert partnership, Comcast Business is powering the engine of modern business, powering possibilities. Restrictions apply. Typically, one day in middle age, the sufferer finds that he has begun to sweat. A look in the mirror will show that his pupils have shrunk to pinpricks, and he is holding his head in an odd, stiff way. Constipation is common. The women suddenly enter menopause, and the men become impotent. The sufferer begins to have trouble sleeping

and tries compensating with a nap in the afternoon, but to no avail. His blood pressure and pulse have become elevated, and his body is an overdrive. Over the ensuing months, he tries desperately to sleep, sometimes closing his eyes, but never succeeding in falling into more than a light stupor.

Their exhaustion is immense, beyond comprehension. Once the sufferer can no longer sleep, a downward progression ensues, as he loses his ability to walk or balance. Perhaps most tragic, the ability to think remains intact. Sufferers know what is happening. At first, they can talk about it and even write down their thoughts. After a few more months, some lose this level of functioning. Once their bodies shut down, only the desperate look in their eyes shows that

they know what is going on, but others can talk and reason until the end. In the terminal phase, usually about 15 months after the disease has begun, they fall into a state of exhaustion resembling a coma and die. Yeah. God, that's a bad one. Yeah. Do you want to hear what that is? Yeah.

So that is a case of fatal familial insomnia. which is a prion disease. Welcome to prions, everyone. And that is an excerpt from the book, The Family Who Couldn't Sleep by D.T. Max, which is all about preons. Wow. Yes. Hi. Hi. I'm Erin Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you. Yeah, today we're talking about preons.

This is a big one. I know we've said that before. We say that almost every time. Yeah. But it's always true. It is, yeah. We haven't really covered any, like, baby diseases yet. Before we get into the nitty-gritty of these many different diseases,

what time is it? It's quarantini time. What are we drinking today? Well, this week, we're drinking the chronically wasted. because one of the preon diseases is chronic wasting disease. It has milk naturally, bourbon naturally, coffee naturally, no, just because those things taste good together, and then a little bit of cinnamon and nutmeg. And you just shake it all up and then strain it into a glass.

And as always, this season will also be put. posting this recipe along with our placebo-rida, the non-alcoholic version of our quarantinies, on all of our social media accounts and our website. So check it out there. Excellent. Okay. Prions, I have read so much about the history, about the whatever, but I really avoided the biology and understanding exactly what's going on. So please enlighten me. Dinner shows up every night, whether you're prepared for it or not. And with Blue Apron, you won't need to panic order takeout again. Blue Apron meals are designed by chefs and arrive with pre-portioned ingredients so there's no meal planning and no extra grocery trip.

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So preons are a pathogen unlike any that we've ever looked at before and unlike anything that we'll ever look at again. which is kind of thrilling. It really is. So every other infectious disease that we've discussed so far, and that we'll ever discuss again, has been either a virus or a bacterium or a protozoan. In the future, we'll probably do a bunch of worms.

But even at their most basic, all of these infectious diseases are some kind of organism, which I'm putting in quotes, because some people don't call viruses, organisms. But at a bare minimum, even viruses, they've got either RNA or DNA and protein. And the genetic material is required because basically that's the only way

that an organism can reproduce. The DNA or the RNA serve as templates to actually make the protein. And so then they also serve as the template that's replicated to make a new version of that organism. So for anything to be considered even close to alive and for sure to be able to reproduce, it has to have either DNA or RNA, except for prions. Preons. I'm excited. So preons are just protein. No nucleic acids, no genetic acids, no genetic

material, no DNA, no RNA, just protein. The word preon literally comes from proteinaceous, infectious particle. What? So creative. I, it's so amazing to me because there's no biological incentive. Oh, my God, you're still right. I don't get it. I don't get it. I don't get it. How? Why? Okay. I'm going to try and answer this two questions. As you can imagine, you are not the only person to feel like this. Like, what, how, why? And I can't wait to hear the story, the story of how just mind-blown scientists must have been when they finally were accepting that this was just, just a protein. It's, there's nothing like it. Okay. So here's how it goes. we're going to talk about proteins for a minute. Imagine that a protein is basically a rope. Okay?

There are lots of different material that you can use to make rope, and there's lots of different lengths to which you can cut that rope, just like protein. In our body, we have lots and lots of different types of proteins. They're all made up of different amino acids, and they're all different lengths and sizes, and they all have different functions. And a large part of how that function is determined is how they're folded.

Or if you're imagining our protein rope, how they're knotted. Okay. So think of how many different ways you can tie a knot. There are thousands. Hundreds, probably. And if you think of all of the different types of materials of rope, some of them are going to be better at holding certain knots than others. So proteins, yeah, right? This is a good analogy.

I didn't come up with it. Brett did. So different materials of rope or different types of proteins are only going to be stable and therefore functional in certain confirmations, certain knots. With me so far? Oh, yeah. Great. So in the case of preon diseases, there's this single protein, this single protein, this single.

rope. It's called PRP, which just means get ready for the creativity here. Preon protein? Preon protein. No joke. So this protein is in your body. It's in your body. It's in my body. It's in everyone who's listening's body. It's a cell membrane protein, which means it's found in the walls of your cells, in a whole bunch of our different cells, especially in our neurons. and we're not entirely clear what this protein does exactly. We don't know its exact function. We think it has to do with neuronal communication and the transport of stuff inside and outside the cell. That doesn't really matter right now for my purposes. The thing that matters is that this protein is normal most of the time. And when it's in its normal state, it's normal not,

it's benign. It doesn't cause any disease. But for some reason, if it unknotts itself and then re-nots itself in an abnormal way, it can begin to cause disease. And here's the scary part. When it interacts with other normal proteins in your body, it can cause them to change shape. And then those newly misfolded proteins interact with other normal proteins and cause them to change shape. And then, do you see where I'm going with this? It's a domino effect of terrifying misfolded proteins. That's exactly what it is. And it's outrageous. It's similar in some ways to how a virus or a bacterium will get into your body and replicate and grow in number. But in this case, it's just a misfolded version of a protein that's already in your body.

And in its normal form, it's not a big deal. But if it comes into contact with a misfolded version, it becomes misfolded. And that's how it replicates. And exactly how this happens to begin with, we don't know. I'm just struggling. struggling for words right now. I'm struggling for words because it is, it sounds like it's from a sci-fi book. Yeah, it totally does. And it's, it's just very, it's outside of this, this paradigm of infection or disease or proteins that we have all, that we have been taught throughout school,

throughout life, whatever. Yeah, we kind of mentioned this at the beginning, but there are a lot of different names for preon diseases. But the thing that I did not realize until starting to research for this episode is that all of these different diseases that you've probably heard of are all caused by misfolding of the same protein. The same one, that PRP protein. It's not tons of different proteins in a cow versus a sheep versus a human. It's the same one. How? How? How? Great question. Honestly, I did not know that at all. Now, the thing is, each of these misfoldings, these different knots in the rope, they're slightly different versions.

So they kind of refer to them as different strains, the way that we would call different strains of Ebola virus. It's the same virus, but there are multiple strains. It's similar in this, except that, again, it's just a protein. but they're all misfolded in slightly different ways. So these different variants of the misfolding of the preon protein, they cause different diseases that were named by and classified by their incubation period, which varies really widely and the actual neuropathology. So the way that they affect your brain and the symptoms that they cause

are actually a little different in each version of pre-pathology. disease, even though it's the same misfolded protein. So what I'm going to do is go through the different human diseases, and I am going to focus on human diseases, but we can talk about some of the other mammal diseases too, because they're also really interesting. Don't worry. I'll get there. Oh, good. So we'll go through the different human ones. But first, I just want to talk to you about what they all have in common. So the other name for prion diseases is transmissive. transmissible spongiform encephalopathy. Which is a mouthful?

James. So what does that mean? It means this. Transmissible just tells us that this is an infectious disease, meaning it can be passed from one person to another or in some cases from one mammal to another. Encephalopathy just means it affects your brain. And spongiform tells us how it affects your brain. It actually causes spongiform changes. so your brain becomes wholly like a sponge.

And importantly, these holes that happen, it happens without any inflammation. So inflammation is a response of our body. It's a natural response to either tissue damage or the presence of some kind of non-self, like bacteria or viruses. But in this case, with preons, your body doesn't react to the preon proteins or to the damage they cause with normal inflammatory responses. So you have neurons and other brain cells actively dying, leaving gaping holes, empty space in their place with no white blood cell invasion,

no activation of the inflammatory cascade or anything like that. So that's what they have in common. Let's talk briefly about the different variants of this disease. Okay. So the first one, since we touched on it briefly in our first-hand account, is fatal familial insomnia. Now, this is a weird one. It's super, super, super, super rare, like very rare. But it causes insomnia. That's one of the major symptoms. It also causes speech and physical coordination problems and dementia. This one is not necessarily infectious, but it is for.

familial. So it's actually transmitted genetically. And it's autosomal dominant, which means that if one of your parents has it, you have a 50% chance of getting it as well. Like Huntington's. Exactly. Just like Huntington's. So it's a weird one. Okay. The next one, we're just going to blow through these. The next one is called GSS. Gershtman-Strauss-Shaechniker syndrome. Was that good? I don't know. I don't know either. I don't speak German. This is another weird one.

It's also familial. So just like fatal familial insomnia. It doesn't cause insomnia, though. Instead, what happens is you first start with dysarthria, which means difficulty speaking. So you might not be able to talk. And then you'll get what's called ataxia, which means you can't coordinate your body movements. So you might have tremors, you might have an unsteady wobbling gait. And then you'll progress to dementia, memory loss, visual disturbances, and eventually death.

That sounds like it's going to be the common thread. I know that it is, but... It is the other thing that I didn't mention that ties all of these together is that they are 100% fatal. Cool. Yeah. So that's our second this season. Yeah, well, I mean, rabies was like almost 100%. At least you can treat it if you catch it or like...

You're optimistic. Yeah. We've got to have one. Yeah. Now let's get into the diseases that you've probably heard more about. Kuru. Have you heard of it? Oh, yeah. Well, I know you have. Listeners, have you? Tell us. Kuru is a disease that is transmissible and it's believed to have been transmitted to people from the consumption of deceased family members during burial rituals, which I'm guessing you're going to talk a lot more about, Erin. Oh, yeah. I avoided the history of this. What I do know is that this was one of the early pre-on diseases that people sort of found out about, right?

Yeah. And one of the first ways that we figured out that this was actually a transmissible disease and how people actually got it from eating meat that had been contaminated with prion proteins. So for this one, the symptoms start often with body tremors. So all over body tremors. And then bursts of laughter, which I find so interesting and scary. Because what was described as people would become very depressed, which is understandable, but then they would have these bursts of uncontrollable laughter that they just couldn't stop. Yeah. Yeah.

Then you would also get that same ataxia. So tremors combined with a wobbly gait and just not being able to coordinate your body movements. And then in the later stages, you can actually get ulcerations. So open wounds, like on various places of your body, that lead to secondary infection. Oh. Yeah. And so actually one of the major causes of death in Kuru is pneumonia or another secondary infection. Not necessarily the preon proteins itself.

Interesting. I didn't know that. Yeah. Huh. And then we have the most famous, or should I say actually, the two most famous, probably forms of preon disease in humans, Krutzfeld-Yakup disease. Also,

variant Khrushfeld-Yakop disease. There's actually more than two forms, but these two forms are very distinct. So let's talk about the classic first. Classic CJD is sporadic. This is not what you get from eating cow meat that's been contaminated. This is not mad cow.

So Kruitsfeld-Yakub disease is a preon disease that we don't know why or how it happens. We think maybe it's just age-related random mutations. Who knows? You can get them. You can get them from things like corneal transplants. There have been several documented cases of people who received cornea transplants, from someone who had documentedly, who had died from Crucfield-Yacup disease, who then got Crucfelt-Yacob disease and died from the cornea transplant. And also Duramotter transplants. Duramotter is the outer layer of your brain meninges.

So like the tissue that covers your brain, essentially. Sometimes you might do a graft of that from one person to another in the case of some extreme trauma. And if that person died from Cruzefelt-Yacob, then you will also. So this type of CJD is characterized by a rapidly progressive dementia and memory loss. Those are the first two things that tend to happen. And then you'll get personality changes, hallucinations. So when you say rapidly progressive, what's the time frame we're looking at?

So most of the time, that was something I didn't mention about all of these diseases, but they all have very different durations of illness. So fatal familial insomnia, the average age at death is 50. And the average duration of illness, so from the time you start showing symptoms until you die, is 18 months for FFI. Okay. For Gershtman-Strauss-Snyker, GSS, the median age at death, it's really variable because it's such a small population. But the duration of illness is anywhere from three months to 13 years with an average. of five years.

Oh, my God. Yeah, it's a very long progressing disease. Kuru, the duration of illness is only about 12 months, but they think that the incubation period could be as long as 50 years. That's the time from when you first get exposed to Priyans until they build up in enough number in your brain to actually start causing disease. But with Khrzfeld-Yakab, classic CJD, the median age at death is six. but the duration of illness is only four to six months.

So once you start showing symptoms, you're probably dead within five months. Holy cow. The longest that's been documented that somebody has survived after starting to show symptoms is about two years with classic CJD. Wow. Yeah, so very rapidly progressive. You'll also end up with hallucinations, myoclonus, which means muscle spasms. And then late in the disease, you can have things like ataxia, again, that wobbly gait.

So we're seeing some overlap with symptoms, speech impairment. Again, here, the cause of death tends to be pneumonia, which I find very interesting, especially that it can happen that rapidly. Well, and also, I don't understand the mechanism behind. Like, this is a neurological disorder primarily. Yeah. So how? How?

Well, if it's affecting the parts of your brain that cause you to breathe normally, and if you're not breathing normally, or if you're not coughing up normally, or if it's even just affecting all of the functions of your organs, right? Everything is controlled by your brain. It's maybe impairing more of our unconscious functions that it is our conscious functions. Okay. And then the last human preon disease that we need to talk about is variant Krutzfeld-Yakup. This is the one associated with. with Mad Cow. So this is the one, which I'm sure you'll talk about, the outbreak that started it all.

Don't you know it? Where a bunch of people became infected, presumably after eating contaminated cow meat, beef, that had those cows had died from Mad Cow, also known as bovine-ingeiform encephalopathy, or B-S-E. So that is the form of preon disease that happens in cows. And if you eat a cow that's died from that, you will get V-CJD. Very different from classic CJD, the median age at death is 30 or under. So these were young people who are affected. And the median duration of illness is 13 to 14 months. So it's a longer duration of disease.

Hmm. possibly because it came from a cow? Yeah, yeah. So it presents in a way that's much more similar to Kuru. And that's part of the reason that they were able to make that link between V, CJ, D, and Kuru, both being transmitted by consuming preon infected meats because they do present very similarly. With VCJD, it's a hard acronym to say, you present. Not so much with dementia and memory loss, like with classic Chris Felt-Yacob, but with other psychiatric and behavioral symptoms.

And also very classically with very painful what's called diesthesias, which means nerve pain and like your nerves are firing in ways that is really painful and not under your control. So maybe you'll have hands cramping and things like that. Yeah. You don't get as much of the A-TACC. and things with V-CJD as you do with some of the other diseases. But you do die, just like with all the others. And one of the scary things about V-C-J-D is that it is believed that it can also be transmitted by blood products. So that means like blood products.

What's another way to say that? Serum? Serum. Yeah, if you give blood transfusions. Blood transfusions, that's what I'm trying to say. Whereas there isn't really evidence that other forms of this disease can be transmitted in that way. Oh, yeah. So while you can get CJD from corneal graphs or dural graphs or things where you're actually coming in contact with neuronal surfaces,

there isn't evidence that you can get it from blood products. But with V-C-J-D, you can potentially transmit that because you do find prion proteins in the peripheral blood, not just in the nervous system. That's very strange. Yes. Uh-huh. Yeah. And the other thing that's similar between Kuru and V-C-J-D is that you get more deposition of the actual prion proteins into plaques, which means that these misfold proteins, aggregate, clump together and deposit into your brain in a similar way that you get aggregates

in something like Alzheimer's. And it's also, we have no idea how long the incubation period is for these two diseases. These are the most sort of transmissible of the transmissible spongiform encephalopathies in humans. And we don't know how long ago some people were infected. It could be, in some cases, it seems to be a matter of months. In other cases, it could be 20, 30, 40 years. So a lot of people think that there are going to be more and more cases of VCJD down the line from people who were exposed back in the 90s. That's alarming. It's alarming. And probably the most alarming thing about prions is that we can't do anything about them. So there's no treatment. Is it because it's a protein that's in your body? And so by attacking that

protein, you're liable to attack other proteins that you actually need and function? It's part of it, yeah. But I mean, cancer cells are also your body cells, but we have ways that we can kill those. The reason it's so hard to deal with preons is because most of the drugs that we use to target diseases, infectious diseases and things like cancers, target DNA. So they target reproduction in the way that we know that reproduction happens. We don't know why this protein becomes misfolded and we don't know how it causes other proteins to become misfolded. So we don't know how to target it. And because we don't know exactly what the PRP protein does normally, it makes it even harder to actually find ways to try and stop it from misfolding or, you know,

make it go back to its normal confirmation. Ooh. Yeah. Is there at least promising work on stuff like how it's analogous to Alzheimer's? Or is that telling us anything more about these other neurodegenerative diseases? It's a good question. We'll talk a little bit more about it in this sort of current event section. There's definitely a lot of parallels, especially in terms of understanding how proteins fold

and why they misfold in certain ways. these don't tend to be misfolded, at least from what I read, they don't tend to be misfolded in the same ways that Alzheimer's proteins are misfolded. So it's not the like same confirmations that cause Alzheimer's plaques, if that makes sense. Okay, yeah. But yeah, we don't have, we don't have a lot currently. And they're also just really hard to get rid of. Like if your meat becomes contaminated, there's not much that you can really do about it because

proteins don't degrade as easily as DNA or RNA. So the ways that we normally use to sterilize things don't always work on prions. They're not impossible to kill, though. People who are like, you can't ever kill a preon. Like, that's not true. It just takes a lot higher heat. It takes things that denature proteins rather things, rather than things that, denature DNA and RNA.

So it's different techniques. It is possible, though. It's not impossible. Right. Yeah. How's that? That was preons. Very scary introduction, too.

Yeah. And we didn't even talk about scrappy or BSE or chronic wasting disease, which I think is actually the scariest one. So, Aaron, tell me what is up with these preempties? Ones, how did they get here? And why should I be so afraid of them? I think that last question you're going to have to answer. Actually, I think that last question you just answered. Oh, okay. Well, then just tell me how they got here and what's going on with them. Okay, happy to do that. Anyone who works long hours knows the routine. Wash, sanitize, repeat.

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It keeps them soft and smooth no matter how harsh it is outside. We're offering our listeners 15% off their first order of O'Keefs. Just visit O'Keefscom slash this podcast and code this podcast at checkout. have we asked our contractor we found on Angie.com to be our kids' legal guardian? Because he took such good care when redoing our basement that we knew we could trust him to care for our kids, all eight of them. Should something happen to us? Are you my dad now? No, sorry, I do basements.

Connecting homeowners with skilled pros for over 30 years. Angie, the one you trust to find the ones you trust. Find pros for all your home projects at Angie.com. This is Matt Rogers from Los Culture Eastust us with Matt Rogers and Bowen-Yang. This is Bowen-Yang from Los Culture Easters with Matt Rogers and Bowen-Yang. What if your Wi-Fi was more than just Wi-Fi? What if your Wi-Fi made everything in your whole house just work together better? Well, Xfinity Wi-Fi pretty much does exactly that.

It's powered by their best, most elite, high-performing tech. Allow us to paint a very realistic example. Everyone in your house. Everyone is on their devices at the exact same time. gaming, working, swiping right, because of course they are. And the finale of your favorite show of all time of the week is on at the exact same moment. Well, you can boost the Wi-Fi to your device with Xfinity. And have you ever asked yourself, what if my Wi-Fi could keep watch over my kids for me?

Well, probably not, because that's a weird thing to ask yourself. But Xfinity Wi-Fi has parenting skills, even if you sometimes forget yours. Xfinity's like, don't worry, I'll monitor the Wi-Fi. It's completely proactive, fixing issues. before they even happen. Bottom line, Xfinity is smart and reliable. You deserve the peace of mind of having Wi-Fi that's got your back. Xfinity. Imagine that. I'm warning you now. The history of Priyons is a huge one, in part because it's not really just one disease, like you just talked about. Each preon disease has its own detective story and each contributes to the story of Priyons as a whole. And that story is going to

take us all over the world from the pastures of Spain to the highlands of Papua New Guinea, from the grocery stores of Britain, to the forests of North America. And we're going to meet some rather interesting people along the way who will show us that changing people's minds can be exceptionally hard, especially when ego and glory seem to be driving you more than a quest for truth. Let's get started. Even though the word preon was only invented, a few decades ago, the history of prion diseases stretches back much farther, probably hundreds of thousands of years. But before I get to that, let's try to track when preon diseases first became known to modern humans. There are many early references to a prion-like condition that have been

put forth as evidence for the disease being present at a certain time or place. Hippocrates may have mentioned it. There's strong support that Shakespeare refers to it in Macbeth. What? Yeah, I didn't read it, but a lot of things were like, oh yeah, and Macbeth, blah, blah, blah. Okay. I should probably find that line. And it was probably around during those times. But let's get down to when it first started making big waves. Between the 18th and 19th centuries in Europe, human population was on the rise, and that meant figuring out ways to make more food, to make more clothing, housing, etc., to support the growing populace. And one way that people maximized efficiency and productivity was through selective breeding,

which wouldn't actually go by that name for almost 100 years when Darwin would discuss it in his books. But the concept of breeding plants or animals to select for certain desired traits was known, and one of the biggest developers of selective breeding was a dude named Robert Bakewell, who applied it to sheep, and in doing so, changed the course of history. Always the Bakewells with a sheep. What is the fastest way to get the traits that you want in a sheep? I don't have the slightest idea.

Okay. Well, you would breed the sheep, who already look the closest to your ideal image. Okay, that makes sense. Bakewell started doing what was known as in and in breeding. Uh-oh. Yeah. Which means mating parents with offspring, offspring with each other,

really Game of Thrones type stuff. I was going to say just like, you know, England, but. Back in the day. You know. This practice wasn't really. done because it was common knowledge among farmers that inbred animals tended to have more hereditary defects. But the results that Bakewell had gotten in a really short amount of time were too impressive to ignore. And soon enough, Bakewell was studying out his best Rams and farmers everywhere

started their own in-and-in-in breeding practices. In those years, the relatedness of those sheep sharply increased, as you might expect. And things were about to get a whole lot more related. English sheep weren't known for their fleece, unlike the Spanish marino breed. Your favorite sheep, I believe. Marino wool is one of my absolute favorite things. Yeah, I know. I know.

So anyway, yeah, so a guy named Banks decided to turn a profit by shipping a handful of Spanish marino sheep to farmers all over England, where they were bred in and in. even more so they could get that nice fleece. By the end of the 1700s, A, most of England's sheep were intensively inbred, and B, the inbreeding was not in pockets, but rather all over. It was the only way you could maintain sheep. Then a few sheep started acting strange. They seemed to have an itch. They could not scratch enough. They would rub their heads and their rumps on posts, on trees, on rocks, on fences, on anything to try to get some kind of relief. But this was a one-direction disease.

The sheep never recovered from their itch and in later stages staggered around until they suddenly dropped dead. Soon this phenomenon was all over England and Scotland, earning various names along the way, such as rubbers and yuki pine, the frenzies, the giddies, scratchy, Chrewcroft, Turn sick, the dizzies, the shaking.

No. The dizzies. Like getting dizzy. Oh, the dizzies. I was like, I'm sorry, Prion is now officially the least creative group of people. We're just going to call this one the disease. I kind of like it.

It's like the band. Yeah. Just classic. The shaking, the mad staggers, which might be my favorite, the goggles, and finally, the one that stuck with it. Scrappy. Scrappy. Everywhere sheep were dropping by the dozens hundreds, and no one knew what was causing it. Hypotheses, of course, abounded.

It was the air, it was a maggot, it was too much sex, it was not enough sex. It turned out that it had previously been described by Spanish Shepherds decades before, but this outbreak probably wasn't caused by the import of those sheep. Just a matter of high sheep density and a lack of scrappy resistance in the inbred sheep. No real progress would be made for years on what the actual cause of Scrapey was, but solving that mystery lost a little bit of its urgency as scrapy resistant sheep breeds began to take over. Wow. Let's say goodbye for now to our beautiful marino sheep in England and travel to Papua New Guinea in the 1950s, which was at the time partially under Australian rule.

The Australians in charge didn't really know a lot about the islands, cultures, ecology, etc. But they were looking to change that. In particular, they wanted to know who was living in the dense rainforest of the highlands to make contact. I'm saying that in air quotes, rather than concrete. Yeah. Anyway. One of the groups that was contacted was called the Foray. Right away, those making the contact noticed a couple of strange things. For one, there weren't many women around, but there were a lot of unmarried men. And after spending a bit more time with them, they noticed a mysterious illness that was circulating, resulting in a high number of deaths. Those afflicted, mostly women, would shiver and jerk uncontrolled. for weeks, occasionally hit, as you mentioned, by this involuntary hysterical laughter, and then this would continue until they died. The foray called it shaking, or kuru, and it was devastating villages. Seeing this, the Australians decided to send for a doctor to investigate

what exactly was going on. The doctor, a man named Victor Zegas, interviewed sufferers and took many samples to send off for analysis. But no one was. could find anything in the blood or serum or even brain samples he sent. No bacterium, no virus, no fungus, no worm, nothing. Enter Carlton Gajusek. I want to pause here and warn anyone who is listening that I'm going to talk a bit about Gagiske's criminal history, which includes his conviction as a child molester. So if you don't want to hear about that, fast forward about two and a half minutes. Let me give you a little bit of background on this piece of work. Gadjasek was a convicted child molester and self-proclaimed pedophile. He was also a Nobel Prize

winning pediatrician. I'm sorry. What? Oh yeah. Yep. Medically, Gadisic was fascinated by rare incurable diseases. Personally, he was interested in so-called non-Western sexuality, particularly as a related to children. Ew. I hate this already. Yeah, he's a despicable human being. He was not well liked by many of his colleagues, or liked it all, and some would refer to him

as inhuman and just short of a sociopath. Along the path of his research were scattered the remains of former collaborations and friendships. At the same time, Gadjasek was widely admired by his academic peers for his drive, ambition, and intelligence. And many of these peers would later beg leniency from the judge for Gadgisic sentencing for child molestation. Quote, Carlton was a complicated man, his peers would say, or something along the lines of,

no, he wasn't perfect, but he was a genius, which seemed to excuse his behavior as a child molester as the cost of conducting important medical research. Oh, my God. Or they would take a stance of cultural relativism. If pedophilia was practiced in a certain culture, then it was okay if Gajusac sought out those cultures as his hunting ground. Ew! Yeah, that was part of his defense. The reason that I'm spending so much time talking about who Gajusik was is because I am extremely frustrated with the fact that his molestations, his crimes, are so often relegated to a footnote when discussing him or his.

his research. Yeah. It's so frustrating to me when I read an entire book about Priyons, the family who couldn't sleep discusses it in depth, but Stanley Pruseners book very briefly mentions this. And it is so appalling. Because then it just like it, it, it almost excuses it like we can just ignore that piece of history. Exactly. So now that you know who Gadisic was, let's get back to Papua New Guinea in the 1950s. Gajasic was always on the hunt for new diseases and new, in his words, uncivilized, places to explore. When he was in Australia looking for his next adventure, he learned about this mysterious illness that was devastating the foray. This could be the medical find of the century, and he wanted to be a part of it.

Not just a part of it, the whole of it. He shouldered his way into the investigation and took it over, irritating many people along the way, who started to wonder if he had a medical degree at all. Wow. Yeah. Once in Papua New Guinea, he took samples and more samples and tracked cases as the numbers climbed every month. In June of 1947, he had recorded over 200 deaths, and these deaths followed a strange

pattern. It appeared that for every one male struck by Kuru, up to 14 females were sick with a disease. And still, the origin of this disease, or even, even its pathology, had yet to be figured out. But slowly the pieces were falling into place. First, a researcher working in one of the labs to which Gadjusik had sent victims' brains, noticed strange deformities in some nerve cells, and these deformities reminded him of a disease he had just seen in a textbook,

Krusfeld-Yacob disease. Oh. Yeah. Anxious to make similar headway on the source of the disease, Gadisik's supervisor told him he was, wanted to assemble a team of anthropologists, epidemiologists, physicians, etc. But Gadracek refused. Couldn't they understand?

He was the team. Oh, my God. Yeah. But he wouldn't end up actually solving that riddle, even though he would later claim to have known about the disease's origin all along. Oh, cool. Yeah, no, I knew about it. I just didn't tell you guys.

Yeah, he said it was too obvious to publish. Oh my God. I don't know that I've ever hated a person that we've talked about on this podcast more. Yeah. I despise him. No, the origin of the disease would actually be uncovered by anthropologist Shirley Lindenbaum and medical researcher Michael Alpers. Yeah, Shirley. And Michael, too. They did the careful methodical work that Gaggajusek never had the time for, like drawing family trees and tracing relationships, and more importantly, they listened to the foray.

Since the disease was relatively new to the foray, dating back only 40 or 50 years, whatever had caused it was probably new as well. And while numerous people had noted their observations of cannibalism practiced by the foray, what they didn't know was what these two researchers. researchers would learn by listening. Cannibalism had only been adopted by the Foray about 50 years prior. Uh-huh. Yeah. Timelines. Lining up. This wasn't revenge cannibalism, eating their enemies.

The Foray used cannibalism to honor and mourn their dead loved ones. And this practice seemed to be at the root of the Kuru epidemic. It explained the recent emergence of the disease and the skewed sex ratio. and when the 4A stopped practicing cannibalism at the insistence of some missionaries, the disease started its decline. This was a controversial explanation, for many reasons. But if this was an infectious disease, it was unlike any that had been described. The years-long, decades-long incubation period, the absence of any detectable virus or bacterium, it was bizarre. Around 1960, Gadgasek returned to the U.S. to work on Kuru in a lab setting when he was contacted

by a Scrapey researcher named William Hadlow, who had seen an exhibit on Kuru in a museum that included pictures of brain tissue showing the damage. Oh! Hadlow thought that Kuru looked strikingly similar to Scrapey, so he published this observation and also wrote to Gajusik directly. Earlier, I left off with that. Scrapey in the early 1800s, but the disease hadn't disappeared. Occasional outbreak still occurred in sheep all over Europe, and it showed up an American sheep in 1947, so it was still getting

a lot of research attention. The biggest development with Scrapey, though, came about when it was shown to be transmissible after thousands of sheep developed the disease after being given a vaccine for looping ill. For what? Looping ill. It's a tick-borne illness. What a ridiculous name. We'll cover it. We'll cover it someday. Good. The vaccine had been prepared from sheep brains that had been treated with formalin,

which should kill pretty much all living things. It sure should. But not Priyans. Okay. Also, people don't get scared of vaccines because of this because we don't make vaccines from brains for humans. Okay. No, we don't. So relax.

This also showed that there could be a very long period. from exposure to development of symptoms, just like Kuru. The note from Hadlow gave Gadjasek the idea to see whether Kuru could also be transmitted. He said about acquiring chimpanzees, other primates, mice, hamsters, basically whatever he could get his hands on to inject with tissue from Kuru victims. He left someone else in charge of doing the actual work and went to go explore new places. Within 21 months, which is an eternity in. in the lab, a chimpanzee named Georgette started showing signs of the disease.

Wow. I never thought about how difficult it would be to do research on prions in the lab because of how long the incubation period is. It's really difficult and I think very emotionally taxing. And also, it's a gamble. Right. Yeah. Man. One by one, the rest of the chimps developed what looked like Kuru and died.

Oh, poor babies. I know, Georgette. The damage to their brains looked incredibly similar to that of Kuru, Scrapey, and Khrushfeld-Yakab sufferers, and Gygiasik ordered more injections, not just with Kuru, but with tissue from other neurodegenerative diseases as well. These experiments show that Kuru, Skrapey, and Khrushfeld-Yakab could all be transmitted. He published his results and hypothesized that these three diseases were all caused by the same thing,

a slow virus, a vague explanation that he didn't really expand on. For this and for his description of Kuru, he would be awarded the Nobel Prize in 1976. Jeez. Yeah, a decision that baffled many, including me. Can they take it away? Like, does that ever get taken away?

That's a great question. I don't know. We should look into that. We should look into it. Meanwhile, Plenty of other researchers were hard at work on these diseases, such as Tikva Alper, who demonstrated that even radiation could not destroy the scrapy particle. Whoa. I also have to say, she sounds amazing.

So she refused to accept a royal 60th wedding anniversary greeting from the queen because it was addressed to her and her husband under his name, even though she didn't take his last name. Oh my God, she is, I feel so strongly about, whenever we get a letter that's addressed to Mr. and Mrs. Brett Updike, I throw it at him. And I'm like, this is for you, which like, it's not his fault. Oh, my God. I feel that so strongly. She's awesome. Another big discovery was that there seemed to be multiple strains of scrapy, judging by the different patterns of disease. But still, what was the agent? Where was the virus? How could it survive being irradiated, desiccated, cooked? Researchers could isolate the protein coat of this mysterious virus that supposedly existed, but they couldn't detect any nucleic acids. I'm getting so excited. I'm sorry. I'm getting so excited. Could it actually be just a protein causing these diseases?

Could it? Most researchers gave a firm no. But a handful were more open-minded and largely ignored. Tickva Alpert was in this open-minded and largely ignored category, by the way. A British mathematician actually named J.S. Griffith publishes a paper proposing several different mechanisms by which it could be a protein, but it doesn't really gain a lot of traction. And the scrappy, Kuru, Khrushfelt-Yacob, Slow Virus Field, was about to gain a new member, who would give Priyons their name and earn a little notoriety for himself.

Meet Stanley Prusiner, MD. With a background in neurology and biochemistry, Pruseners' career trajectory became a whole lot more focused when he saw his first Crisfelt-Yacob patient in 1972. This was a problem he knew he wanted to work on. He collaborated with the scrappy researcher William Hadlow and began attempting to purport the scrapy particle. Having that isolated agent was super important because you could do experiments directly on it to see how it would react. For instance, Prusiner and his group showed that the particle did not lose its infectivity when treated with chemicals that destroyed nucleic acids,

but it did lose its infectivity when it was treated with chemicals that destroyed proteins. With this purified particle, you could also design an antibody test for it, which really spread up diagnosis. Previously, you would have had to inject a lab animal with tissue from a person or sheep or whatever and then wait for signs of disease for confirmation, which can take at least a year. Yeah. The field of Prion research, as it would soon be known, seems to have been filled with egos, with prisoners, perhaps the largest.

Wow. I'm shocked. Yeah. To say that he was not well liked by most of the field is probably understating it. Prisoner was fiercely driven, often combative, selfish with his findings, and obsessed with getting credit. God. He painted himself as a martyr and fighting the good fight against conventional thought. And part of the reason that I say this is because it was how he was written about in the pre-on book that I read, which I understand is going to be, it's a story. right? It comes from a certain angle. It's biased.

But I also read the book that he wrote, his memoir. And this comes through very strongly in that as well. Oh, yeah. Anyway, Prusiner really did advance this field. And one way he did that was to give it its name. When he started working in this area, Kuru, Skrapey, and Khrushfeld-Yaka were all still generally referred to by the term given to it by Gajasek, Slow Virus. Prusiner didn't like this name.

It wasn't really accurate since no virus had been found, so he said about trying to think of a new one. He came up with preon for proteinaceous infectious particle. So creative. Props. This wasn't a popular move in the field. First of all, he was criticized for making it sound like his own name. Secondly, it dodged the question of what this particle actually was.

was a priona protein, a virus, or just a particle? Just a particle, man. Relax. Despite the disdain for this word, it worked. The press loved it, and it rolled right off the tongue. But Pruseners still needed to get more evidence for the protein-only hypothesis to show that a protein could be infectious. He had to synthesize a protein and then introduce it to an animal.

I'm so excited about this part because I read a little bit about it in the biology, and I can't wait to hear more about it. Oh, man, I hope that I give you enough of what you're looking for. I'm not sure. So a problem arose when they had purified this protein, only to find out that it was just an ordinary protein produced by the own host. Can you imagine how bizarre that must have been? You're like, no, we really think we've got it.

It's this thing. What? Yeah. It called into question the entire concept of an infectious protein. Oh, man. Especially when he, in collaboration with other labs, found the location of this gene that produced the preon. Yeah.

And he found that it was highly conserved across so many animal species, indicating that it was probably super important to keep. Right. It's this gene that, like, all these mammals have. That's why you get preon diseases. in so many different mammals. Yeah. It must have just been like, well, this was a wild goose chase. How were we so wrong? Right. Where do we go from here? Where did they go? Aaron. Okay. So if the only function of this gene was to produce a protein that killed the animal,

why would it still be around? How could it still be around? Couldn't. Proser had an answer for that, too. The same one that the mathematician Griffith had proposed years earlier. A protein could have two forms. one that was normal and the other that was disease causing. I'm sorry. This is the first time that people realized that proteins could misfold was because of preons? I don't know. But that is so cool. Yeah.

I think so? I think it is because at this point, this was still just a concept. It had not been observed or demonstrated that proteins could do this. Oh, my gosh. there needed to be an experiment. Yeah. And there actually kind of was one that nature had already set up. So, like you talked about, some prion diseases can be inherited, like Cruzefelt-Yacob disease and GSS.

And those diseases show that there were mutations in the prion gene leading to a state of disease. So, Prusiner created mice with mutations in this gene. He observed them getting sick. killed them, and then took the infectious prions from them and injected them into mice that didn't have the mutation. And? Those got sick. And, yeah, so you could see easily how a protein could be normal or infectious.

Oh, my gracious. But, but there still remained the mystery of the sporadic case. Yeah. So, Cruz-Fod-Yacob, like you. you said could be infectious, as had been demonstrated. It could be inherited, as it often was, but sometimes it would just appear randomly. This sporadic form of the disease was a bit harder to explain. If someone had a normal non-disease-causing form of the preon gene, how could the disease suddenly develop? Prusiner once again had an answer. Confirmational influence. This doesn't

fully explain it really. But this is basically the concept of the domino effect of one misfolded protein causing all the other ones it came into contact with to readjust themselves. But this completed the three components of infectious, familial, and sporadic to create this unified prion protein-only hypothesis. I mean, it still doesn't explain how the first one becomes misfolded sporadically in a person. Unless it's just probability. Right. Exactly. Yeah. Because then it's just, if just randomly it might get misfolded. Yeah. But, oh man. It's, yeah. I know that we keep saying this, but preons are super bizarre. And it's, it's, it's no surprise that they remained such a mystery for so long. It's really, it's, it's, it's more incredible.

that some of their secrets have been revealed at all, I feel. Yeah. I'm also presenting this research as though it was accepted as a fact as it happened, but in reality it was and continues to be debated. There are still researchers who firmly believe that there is a tiny virus hiding out that will one day be uncovered. Yeah. But Prisoner was awarded the Nobel Prize for a new biological principle of infection in 1997. When you hear the word preon, what's the first disease that comes to your mind?

Mad cow. Of course. Of course it is. Mad cow disease reared its ugly head in the late 1980s in Britain and flashed across headlines for years. It awakened the public to tragic failures in agricultural and public health oversight. It resulted in the deaths of hundreds of people and almost a million cattle. and it showed how much we still don't know about preons. It started at least in the 1970s.

Normally, docile cows started acting aggressively and had trouble walking. Death was always the outcome. Like Scrapey-infected sheep, when you stroked a cow's back, it would uncontrollably nibble and lip smack. But the connection between Scrape and this new disease wouldn't be made until 1986. Wow. A veterinary pathologist checks out some brains of a cow that had been acting like it had scrappy, according to another vet. Sure enough, this brain looks like scrappy in a cow.

And scrappy in a cow is huge news. Initially, the authorities weren't that worried about the human risk. Scrapey had never been shown to be transmitted from sheep to human, but this might not follow that same pattern. One worrying finding was that it had jumped species. A niala? I don't know if I'm saying that right. Which is an antelope-like animal in a local zoo had died of a scrapy-like disease. Bovine spongiform encephalopathy, which is the mouthful of a name given to the disease, started appearing all over England. And the hunt was on for the common exposure.

Though quietly, of course, mustn't worry the public. That was good. That was a good line. The Ministry of Agriculture, Fisheries, and Food was housed under one roof, bureaucratically speaking, and they were in charge of both the, as the name suggests, the agricultural sector and human food safety, which kind of seems like an inherent conflict of interest. They could either keep the mad cow meat out of the human food supply and economically devastate the farmers, or keep it in and potentially expose millions of humans to an incurable disease. The silence about the potential danger to humans didn't last long, nor did the original name.

It was soon dubbed Mad Cow Disease. Much more memorable. So much more memorable. At this time, Mad Cow Meat was still making its way into the markets. Mad cow meat. How could you call it anything but Mad cow after? at that. If your cow died in the pasture, you couldn't sell it for human consumption. But if you got a sick cow to a slaughterhouse before it died, that was fine. Oh, no. Screenings found

evidence of mad cow in farms all over England. Where was it coming from? The short answer? Cake in parlor. What? Cake? In parlor. Like, well, having cake in the parlor, dear. That was bad. Precisely. Okay.

Cake was a high protein concentrate that farmers would give to cows who were milking in parlor. So in parlor means milking. Oh, this is cows eating cake in the parlor, not humans. Yeah, where was it coming from in the cows? Got it. The protein in this. This cake didn't come from soy. Oh, no.

Oh, no. It generally came from farm animals that couldn't be sold to the human market. Yeah. Just all bits ground up and molded into a cake. I'm sorry. I'm thinking about my dog food right now. Yeah. Gross, man.

This explained how the disease was showing up all over the country and how the Niala had gotten sick. The zoo had recently switched from soy to meat pellets. Oh my gosh. Guys, cows are not carnivores. Nope. But once they start being fed it, they don't do well without it. They go mad for it.

They go mad for it. Nerd alert. Yeah, I push my glasses up. Despite this very clear evidence of how Priyons could be introduced to cows through their food, it would be eight, eight whole years until animal protein in cow feed would be banned. Oh. The author of this book, The Family Who Couldn't Sleep, compared it to keeping the Broad Street water pump operating for eight years after John Snow showed it was the source of cholera.

We all know how bad that would have been. Yeah. It was like, that's an analogy I can get. Everyone listen to episode four if you haven't already and then you'll get it too. Nice plug. Thanks. During those eight years, certain protective measures were enacted. For instance, any cows showing signs of bovine spongiform encephalopathy were to be reported and killed with full compensation.

Schools banned British beef. Many people stopped eating it, but other worrying things started to emerge. A cat nicknamed Mad Max was diagnosed with feline spongiform encephalopathy. I think he was Max and then he got named. Mad Max? That's the cutest and saddest thing. Yeah. Cows were still getting sick after Mad Cow meat was banned from the cow food supply. Two marmosets began showing signs of the disease after being experimentally inoculated,

demonstrating that the disease could be spread to primates, big news there. And finally, tragically, human teenagers started to be diagnosed with Khrushfeld-Yakub disease. This was not the sporadic form. This was a new variant. A cluster marked by a common exposure. Europe banned British beef. Millions of cattle were slaughtered. Estimates of the number of people who had developed this new Khrusfeld-Yacob variant,

range from the hundreds to the millions. As of this year, 2018, only 231 cases of the disease have been reported, but screenings of tissues from healthy people in the UK have revealed evidence of preon infection and at least 4,000 people. Wow. It's not really clear whether these people will eventually develop the disease because there's still so much not known about the tipping point from infection to. disease. Right. But because the story is still unfolding, didn't even mean to make that pun.

That was a protein joke, guys. And because the UK received such an enormous dose of preons, a lot of countries have regulations against blood donations by people who lived in the UK during the 1980s and 1990s. Yeah. Mad Cow has also popped up elsewhere in the world, including the U.S. Many mysteries remain about the mad cow disease outbreak. For instance, why England? How are cows still getting sick? Proteins are really tough things.

Even preon ash is apparently infectious. And why did only a handful of people get sick? The answer to that last question might be in our DNA. There is variation in susceptibility to preon diseases, not just among people, but also among animals, like sheep and scrappy-resistant breeds. Molecular research has shown that those who have two copies of the mutated gene are more likely to get the disease, while those who have one normal and one mutated copy of the gene never get the disease but can act as a carrier.

Nearly all of those who developed variant Cruzefeld-Yacob from infected beef had two copies of this mutated gene. More recent research shows that in the 4A people, a new variation in the prion protein emerged super recently, maybe 10 generations ago, and those with this variation have resistance to Kuru. That's genetic evolution that's happening on a scale we can observe. So cool. Yeah.

The final chapter, almost done, of preon history I want to cover, is a short one and one that will take us back to the present, to the forests of North America, where thousands of deer and elk and moose are dying of chronic wasting disease. Yet another prion disease. Where did this one come from? As usual, the answer isn't entirely clear, but we may have a guess. In the 1960s, young biologist Gene Schoenfeldt decided to study starvation in mule deer in Fort Collins, Colorado.

Laura and Rick and Laura. Schoenfeld kept some starvation. starving deer in one pen and control deer in another pen so he could compare the two. This control pen also happened to house sheep. Ooh. Now, there isn't universal agreement on this, but several people on the project say that Scrapey was present in those sheep. If that were the case, Scrapey could have passed from the sheep to the deer who began showing

signs of disease. Wow. After the experiment was over, Schoenveld released the control deer, so the ones who had been in the enclosures with the sheep, back into the wild. Ten years later, researchers started noticing scrappy-like behavior and brain damage in wild deer populations in Colorado and Wyoming. Since then, it has spread every year throughout the American West, plains, and more recently, the Midwest and Canada, Saskatchewan and Alberta. Chronic wasting may pose a threat to other ungulate species as well. It's been spotted in elk, moose, reindeer, etc., and to other parts of the world. It's been seen in South Korea, Norway, and Finland, for instance.

How is it spreading? Deer aren't forced to eat deer meat, and they aren't in as high of population densities as sheep. Prions are incredibly tough, so it's probable that chronic wasting is transmitted among these ungulate species. species by direct contact via bodily fluids, indirect contact through a contaminated environment, or by a crow acting as a vector for dispersal of the preon. Weird. A crow? Yeah.

I don't know. So a crow. I don't know. Basically, a crow eats a bit of deer. This is in terms of long distance dispersal. I don't know. A crow eats a bit of a deer that died of chronic wasting. The preon survives the digestive journey.

And then it poops it out to contaminate a different part of the forest. Seems a little suss, but... I mean, I'm not sure. Yeah. But this is still an area of very active and interesting research. There's people at Illinois doing cool research on chronic wasting disease. Yeah. The whole time I was researching Priyons.

I kept getting this feeling that I was just seeing the tip of the iceberg. We obviously know so much more about Priyons today than 50 years ago, but so much seems left to be uncovered. truly is a new frontier of health and medical research, and it's changed the way we think about infection. Like we talked about, preons don't have this biological imperative to pass down their genes. It's just a protein. And yet, it is an infectious disease and one that has told us a lot about ourselves. So what I want to know is, A, what do the numbers look like today? and B, what's the latest on cures or treatments or technologies or whatever?

Yeah, okay. It's interesting that you described this as like a new frontier of research, kind of, because even in just hearing what you were just talking about with chronic wasting and what I've read about what's going on in research today, it seems like there's a lot of open territory and possibilities for research. If I wanted to keep doing research, maybe I'd switch to preons right now. But in terms of the research that's going on, it seems like, and I'm probably missing a lot of it, but it seems like there's kind of two main branches because there's two big areas that we still lack a lot of information on.

One of those areas is focused on actually understanding the mechanism behind this pathophysiology of disease. And a lot of that has to do with figuring out what this protein does in our body when it's not misfolded. So because we still don't entirely know what this normal protein does, it's a protein that is very abundant in neuron cell plasma membranes. And there's a lot of thought that it has to do with possibly calcium. channels, possibly copper, maybe bringing things into cells or pushing ions out of cells. It's not entirely clear. It does seem to be a really important protein and it makes sense that it's in such high density on your neurons since those seem to be so highly affected. But we still don't know. Like there is no clear answer as to what this protein does. The other field of research is what do we

do about it. We know that this disease exists. So how do we treat it? And yeah. Yeah. So at this point, it doesn't seem like much of that research in that realm is out of the screening phase or maybe at best the animal models phase. So a tiny background on drug development, any drug that gets developed, especially if it's a brand new drug and not a drug that we use for a different disease that you want to use to treat some other disease. It goes through a lot of stages of screening. Usually it's tested in cell culture first to make sure it does the thing that you're trying to get it to do. And then you screen it, you often screen a whole bunch of different compounds and you say, okay, which one of these compounds has an effect on this protein or against this

pathogen. So there's a lot of papers, especially from the early 2000s, where they were screening hundreds or sometimes thousands of compounds to see if any of them had an effect on diminishing the accumulation of misfolded preon proteins. So there was at least some work that has been done so far and is, I'm sure, continuing to be done to try and just find compounds. Once they find those promising compounds, then you test those on animals, usually in mice, but also in other animals as well, to see if they're safe and if they actually work once you take them out of a cell culture and put them into a real animal. Then once you can show that a compound actually works on a disease in an animal, you have to

test it on small groups of humans to make sure that it doesn't kill people or cause any other serious reactions. And that's a phase one trial. And then you do a phase two trial, which is a larger group of humans. and now you want to look at, does it actually work? Like we know it doesn't kill you. Now we can ask, does it actually work? Then you have to do even bigger trials.

So it's a very, very long process before you actually get any sort of drug to market. And as far as I can tell, any potential drugs seem to be in the very early stages still. There are some drugs or some treatments that have been used to treat other diseases. is there's an anihistamine, which it's super random. Anihistamine is like Benadryl. It's like what you take if you have allergies or something like that. Yeah. That in those early trials of trying to identify compounds seemed to have effect on binding to Alzheimer's proteins, misfolded Alzheimer's proteins.

So it was suggested that perhaps it also could bind to misfolded preon, proteins. Oh. It has been shown in cell culture also to inhibit the prion protein, but I haven't, I haven't found any papers that it has been tested on beyond the cell culture level. But that's a drug that already exists and has been used in humans. It's not generally used because it has a lot of side effects, but, you know, whenever we look at drugs, we have to look at the side effects versus the disease. And if you're treating something as benign as allergies, you want to make sure you have very little side effects. But if you're treating something where the only alternative is death, you might tolerate a lot more side effects. So who knows? There's another treatment called PPS,

which is pentosin polysulfate, that it's been getting some press in trying to treat prion diseases. But it has not been shown to work. So people have actually tried this in at least a couple of humans. and they died. It didn't work at all. But it's still getting press? It's still getting press. Or at least it got press. I don't know if it's still getting press. There's at least one study that suggests that it delays the progression of disease and decreases the amount of abnormal protein deposition in mice brains. But you had to inject it directly into the mouse brain. So that's not likely something that's going to be inhuman.

trial soon. Yeah. Yeah. So I don't know. It seems like there's a lot of open territory. And I do think that a lot of this kind of hinges on being able to figure out this protein. Because with a lot of other diseases, even if we don't fully understand everything about a bacterium or a virus, we know generally how they replicate.

We know generally, you know, how they operate. And so we can use drugs that we have to try and stop them. There are targets that we know that we can aim for. But with this, it's really hard. And it is, like you said early on, it's a protein that's in our bodies. And presumably it's an important one, you know. Right. It has to be.

Yeah. In terms of numbers, the only one where you can get sort of good numbers on is classic cruzfeld-Yacob disease. And so the majority of those cases, 85% are sporadic. About 5 to 15% are inherited. And overall, those are at a rate of about one to three cases per million people per year. Oh, it's quite rare. Okay. Yeah, it's pretty rare. So in the U.S., for example, there have been 11,000 cases reported from 1979 to 2016. So between 180 and 400 cases per year. And when you look, so on the CDC's website, you can find a chart essentially of the number of cases that have been reported in the U.S. each year of classic CJD.

And the numbers get bigger every year, but it's important to keep in mind that it could be in part due to better screening and recognition. recognition. It also could be because our population size has grown a lot since 1979. So when you see 400 versus 120, it's sometimes easy to go, oh my God, it's growing and it's, but it actually has been at a pretty constant rate. I've also read that a lot of, or at least like a proportion of CJD patients have been misdiagnosed as Alzheimer's. Absolutely. Yeah, because with CJD, you present with similar symptoms. You present with, you know, rapid onset dementia. I think, The difference is the onset of time and then the time to death. Alzheimer's is a very, very slow progressing disease generally.

It's faster if it's earlier onset. This is what I want to end on. Okay. I think that chronic wasting disease is so important. And I hope that I know that there are so many people studying it, but I just want them to get so much money for research. Because so there have been no, there has been so far no evidence that chronic wasting disease in deer can cause disease in humans.

There have been at least a few studies that have looked for those links. Because here's the thing about chronic wasting. Even though we haven't yet found any evidence that chronic wasting disease in deer can cause disease in humans. It has been found at very high prevalence in deer populations. In wild deer populations, rates up to 10 or 25%. But in captive herds, up to 80% of deer have been found to be infected. And if you combine that with data from the CDC that suggests that up to 20% of

people surveyed had hunted deer at sea. some point and up to two-thirds of Americans have eaten venison. If it... I've eaten venison. I've eaten venison. Our neighbor hunts, dear. And brings them over and there's chronic wasting disease in Illinois. I find the prospect terrifying.

Yeah. Tip of the iceberg. Tip of the iceberg. It's so interesting. because it's not outside the realm of possibility, right? We know that it can happen from eating contaminated cow meat. Right. Because I don't think there have been any cases of humans getting any kind of preon disease

from eating sheep meat infected with screpey. Is that correct? That's what it seems to be, yes. And so I'm curious if maybe it's because the outbreaks of variant CJD that were from mad cow disease, I wonder if it's just that the preons were in higher concentration in the cow because of the ways that the cows got infected. So then now they're in higher concentrations in humans. I don't know. I don't think anybody knows.

Right. Something about the folding of that particular fold. Who knows? Yeah. Who knows? I want to know, though. I know. I know.

Yeah. You know, and kind of in retrospect, despite that being one of the longest histories that we've ever discussed. it feels premature because it seems like there's so much more to be done and that there's so much more that's going to be discovered. Yeah. And I feel like in talking about what's currently happening, it's kind of just like so many things. But I don't know how to talk about any of them because they're all kind of in their infancy. Like there's no, you know, there's no, here's the new drug or here's we have an answer. It's all just currently being figured out, which I find so exciting. Yeah, it's super, super, super, like, cutting edge news is happening. Right. Yeah. On that note, should we share our sources?

Yeah, great idea. So I read a couple of books. One is called Madness and Memory, and that was by Stanley Prusner. So that is his memoir of Preon Research. I also read the family that Couldn't Sleep by D.T. Max's great overview of Prion history. And then I have a few articles, which I will put on our sources list. And then finally, if you're interested, there is a documentary about Carlton Gajasek called The Genius and the Boys. I have so many articles.

They're all going to be posted on our website. This Podcast Will Kill You.com under the episodes tab. So we post all of our sources from every single episode. This one in particular, I have a lot of cool articles. about the current research that's being done. So if you're interested in reading more about what's going on with pre-on research now, definitely check that out. Cool.

Yeah. Well, thank you everyone for listening. We couldn't make a podcast without you. Well, we could, but then it would be just us. Be weird. It would be weird. Thanks to Bloodmobile for providing the music for this and all of our episodes. Thanks. Thanks so much.

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