Mad cow and the history, cause and spread of prion diseases

Tiny Matters

Mad cow disease, also known as bovine spongiform encephalopathy (BSE) was first discovered in cattle in the UK in 1986. In 1996, BSE made its way into humans for the first time, setting off panic and fascination with the fatal disease that causes rapid onset dementia. In this episode, Sam and Deboki cover the cause, spread and concern surrounding mad cow and other prion diseases.

Transcript of this Episode

Sam: As a young kid I became pretty fascinated by the things that could kill me, particularly infectious diseases. Don’t ask me why, I just was. And the first one I remember becoming obsessed with was mad cow. The formal name for mad cow disease is bovine spongiform encephalopathy or BSE. The name makes sense — the brain of a cow with BSE looks spongy under a microscope, because of holes left by the disease. Although it can take years from the time a cow is infected to the time it first shows symptoms, like issues with coordination, once it does show symptoms things escalate quickly and the cow is usually dead within a couple weeks to six months.

Deboki: Mad cow disease was first discovered in 1986 in the UK, where it wreaked havoc for over a decade, killing nearly 200,000 cows and devastating many farming communities. In 1996, BSE made its way into humans for the first time, causing a decline in coordination, issues with vision, and the rapid onset of dementia. Over 200 cases of BSE have been reported — mostly in the UK — and everyone who was infected has died.

And in December 2003, mad cow made its first appearance in the US when an infected cow was discovered on a farm in Washington State. Today cases of BSE and of BSE making its way into people are pretty much nonexistent, thanks in large part to practices designed to keep us safe.

For example, mad cow kicked off because the feed being given to cows was infected. But since August 1997, the US FDA has banned the use of most cow parts and other animals to be used to make cow feed, limiting the risk of infected meat making it into their food.

Sam: I think we’re all used to hearing about infectious diseases caused by bacteria, viruses and a bunch of different parasites. But BSE is quite unusual: it’s not caused by any of those things. It’s caused by a protein, a fundamental building block of all living things.

Welcome to Tiny Matters. I’m Sam Jones and I’m joined by my co-host Deboki Chakravarti.

Deboki: Today on the show, we’re going to be focusing on prion diseases — rare, fatal brain diseases like mad cow that are caused by a protein malfunctioning and folding in a way it shouldn’t. I know the concept might sound a little weird and confusing, but Sam and I, and the scientists we chatted with, are going to break it down for you and talk about what’s being done to detect these diseases before something like mad cow happens again.

So what is a prion? It’s a protein that can take on two forms. The first one is what we consider the normal form, which doesn’t cause disease. Normal prions are found in the brain, although researchers don’t know much about what they do. But when people say “prion,” they’re usually not talking about the normal form. They’re usually talking about the other form…the bad, misfolded form that causes disease.

Mark Zabel: You can think of the normal form as sort of a really nice three-dimensional structure. Sort of balloon looking. When it misfolds into the prion, that balloon, three-dimensional structure becomes basically almost a two-dimensional structure. Think of it as like a bathroom tile. Very small, thin, flat.

Sam: That’s Mark Zabel, who’s the associate director of the Prion Research Center in the College of Veterinary Medicine and Biomedical Sciences at Colorado State University. He told us that when the misfolded prion — the bathroom tile as he described it — comes into contact with a normal prion, it causes it to also misfold. I think of it like a domino effect.

Deboki: And once you get a bunch of misfolded prions, those tiles stack up together and form fibers that tangle around each other, which then kills your neurons. As your neurons die off, it leaves holes in your brain—like the spongy brains seen in mad cow. And when you have holes in your brain it causes dementia, difficulty walking and speaking, sometimes even hallucinations, and ultimately death.

So how many misfolded prions is enough to cause disease?

Brian Appleby: I would say we don’t know that for sure except that prions aren’t desired to have. But is one misfolded prion protein enough to cause disease? Probably not. But the problem with prion disease is they aggregate, you know, they're kind of like the bad kids in the schoolyard. The bad kids recruit the good kids, and you have more bad kids, and that keeps amplifying and amplifying until you get disease. So that's kind of what happens — you get enough bad prions in the brain that it causes a variety of diseases in animals and humans.

Deboki: That’s Brian Appleby, a professor of neurology, psychiatry, and pathology at Case Western Reserve University.

Sam with Brian Appleby: What are some of the ways that someone could develop this disease? What would allow for these proteins to misfold?

Brian Appleby: So in humans, there's three main causes of prion disease. The most common cause by far is what we call sporadic. And there's a lot of similarity to that with Alzheimer's disease and Parkinson's disease, which are also sporadic illnesses for the most part. And what that means is that for reasons that we don't really understand, that normal protein becomes misfolded and misshapen spontaneously within the body after it's already been made. I equate it a lot to cancer. We all make cancer cells as we get older, but our body's generally able to detect them and get rid of them. The same is true with our proteins — we make bad proteins every day, but the likelihood of making bad proteins increases as we age, as well as our ability to detect them and clear them. And then you get these protein misfolding diseases like prion disease and Alzheimer's.

Deboki: Brian told us around 85% of prion diseases are sporadic. But there are also prion diseases caused by a mutation in the gene that codes for the prion protein PRNP. This genetic mutation makes it more likely for the prion protein to misfold over a person’s lifetime.

And in addition to sporadic and genetic causes of prion disease, there are also acquired prion diseases. This is by far the most rare version and typically happens because of a medical procedure — say brain surgery, if there’s prion contamination on surgical equipment. It can also be caused by eating meat that contains infected nervous tissue. I think this is the version most people know about, because that’s what happened with mad cow.

People came down with the human version of BSE by eating beef that had been contaminated with nervous tissue of infected cows. But the cows developed BSE in the first place because they were fed sheep products infected with a prion disease called scrapie that’s been documented in sheep for over 300 years.

Sam: Another somewhat well-known acquired prion disease is kuru, which is caused by eating contaminated human brain tissue. In the 1950s and 60s, the Fore people in the highlands of Papua New Guinea experienced high levels of the disease, which turned out to be the result of ritualistic cannibalism where relatives prepared and consumed the bodies of deceased family members, including their brains.

So overall, there are 3 main categories of prion diseases — sporadic, genetic, and acquired — and within those categories you have more specific diseases like kuru which is of course acquired, fatal familial insomnia which is passed on genetically, and Creutzfeldt-Jakob disease, or CJD, the most common prion disease that affects humans. CJD falls under all 3 categories — it can develop sporadically, genetically or be acquired. This is a form of prion disease that people exposed to BSE — mad cow — developed. 

Deboki: And because the symptoms are pretty much identical throughout all of these diseases, the only way to really tell them apart is by looking at brain tissue under a microscope to see the size and distribution of the holes or prion protein deposits.

Brian Appleby’s work focuses on all three categories of human prion disease.

Sam with Brian Appleby: So what is it about prion diseases that you find so interesting?

Brian Appleby: A lot actually. So I am a trained neuropsychiatrist, geriatric psychiatrist by training. And I really got interested in the field primarily from the caregiver side because this is a very rapidly progressive neurodegenerative illness. It's horrible for families to go through and there's not a whole lot of clinical expertise to help them out. So that's how I originally got interested in it. And then of course at that time I was also kind of a dementia doctor, so there's a good overlap between the two. And then I got really interested in the science, which of course is extremely interesting. I think from the clinical side, seeing the patients, they're very difficult to diagnose sometimes. And then of course the biology and trying to understand that and how it affects public health.

Deboki: Brian is the director of the National Prion Disease Pathology Surveillance Center.

Brian Appleby: the National Prion Disease Pathology Surveillance Center was founded in 1997, mainly in response to the mad cow epidemic. Most countries wanted to develop surveillance programs to know whether or not people were being affected by mad cow disease. It's funded by the CDC and we're funded to do neuropathologic surveillance. So we collect brain tissue on patients who had CJD or another form of prion disease and examine it underneath the microscope to see whether or not it is in fact prion disease, because that's the only way to definitively diagnose it.

Deboki: They’re also working on developing tests to be able to more specifically diagnose people who appear to have a prion disease.

Brian Appleby: We also do a lot of outreach and education to clinicians, but also to funeral home providers because there's a lot of fear of potentially contracting this disease and people that deal with that.

Sam with Brian Appleby: I actually have a follow up based on what you just said, which was this sort of fear for people who are handling bodies of people who have passed away from prion diseases. There is some anxiety that you could actually get prion disease. How likely is that?

Brian Appleby: My predecessor used to say that the fear of prion disease was way more infectious than prion disease itself. And that's certainly true, right? It’s difficult to transmit prion disease and you really can only do it in certain scenarios. So you need to have infectious tissue which is almost always gonna be brain tissue. And then that either needs to be injected into a person, consumed orally by a person, or placed in another person's brain for transmission to occur. Now most of those scenarios don't happen in everyday life, right? So there are specific scenarios where it could happen though — neurosurgery, brain surgery, autopsies where we were removing the brain, and then in the past we used to reuse brain tissue and pieces that surrounded the brain in healthy individuals.

And in fact, that's how some prion disease got transmitted. One example is we used to get human growth hormone from cadavers through their pituitary gland, which is part of the brain. They would grind it up and inject it into children of short stature to treat their short stature and it would transmit prion disease. But we don't do that anymore. Now we make what we call recombinant human growth hormone or made in a laboratory human growth hormone. So we don't have to do those things. So it is hard to transmit. There are certain scenarios where you have to take precautions, but they are few.

Deboki: One place where precautions are of course necessary is if someone is doing laboratory research involving prions. In 2019, a researcher in France named Émilie Jaumain died of acquired CJD — at age 33, 10 years after pricking her thumb during an experiment with prion-infected mice. In 2021, a second lab worker in France was diagnosed with CJD, leading to a months-long moratorium on prion research at a number of public research institutions in the country.

Sam: Again, prion diseases in humans are incredibly rare and the scenarios where you’d be at risk for acquiring one are quite specific. But in other species, a prion disease called chronic wasting disease spreads easily and is on the rise.

Mark Zabel: Chronic wasting disease is a prion disease that affects cervids. Cervids include elk, deer, moose, caribou, reindeer, red deer. It’s a highly infectious disease. It's one of the most infectious prion diseases we've ever studied. It’s very similar to the sheep prion disease known as scrapie.

Sam: That’s Mark Zabel again, from Colorado State University. You heard him briefly at the top of the episode. Mark’s research focus is chronic wasting disease or CWD.

Mark Zabel: Until recently, within the past five to 10 years, it was thought that it jumped species and was caused from sheep scrapie and thought that maybe some deer came in contact with some contaminated environments, or came into contact with infected sheep. And that has been turned on its head just a little bit, based on some studies that my lab has done and others, but also the fact that CWD has most recently been found in Northern Europe, in Nordic countries, first in Norway, but since then, Sweden and Finland, and it's interesting because there's no known connection of CWD in those Nordic countries to North America.

There is sheep scrapie in Scandinavian countries, so there's a chance that it could have been a trans species event from sheep scrapie. We can't rule that out. But there's a really interesting story emerging in the Nordic countries, and that is they're finding a lot of moose with CWD. And the reason that's interesting is moose, unlike other cervid species, they're solitary animals. And we think that CWD is passed from deer to deer, elk to elk, by direct and indirect contact. But moose don’t behave that way, so how do they get it? That indicates that it's potentially a spontaneous disease.

Deboki: Remember a spontaneous disease is just that — it’s spontaneous. It’s like a form of cancer where, for no rhyme or reason, you just have cells that go rogue and start dividing like crazy. In the case of prion disease, it’s the prion proteins going rogue and misfolding like crazy.

Unlike human prion diseases, prions that cause CWD can be excreted in saliva. Deer are super social, they have nose to nose contact. Which is very cute, unless one of them has CWD. They can also excrete prions in urine and feces. And those prions can stick around in the environment for a long time, even decades.

Mark Zabel: We think they can accumulate to a point where now a deer sniffing around in the ground eating plants that have been contaminated with urine or feces can now be ingested in that way as well. So that's another indirect transmission. Also decaying carcasses in the environment from deer that passed away from CWD and other deer, elk or moose will come and kind of sniff around that carcass as well.

Deboki: The good and very important news to share is that at this point, there is no documented transmission of CWD to humans. But that doesn’t mean we should assume it will stay that way. Remember, BSE did cross the species barrier, from sheep to cows and then cows to humans.

Mark told us that one of his biggest concerns is that hunters are being exposed to CWD in large quantities. When people were exposed to mad cow, they were usually eating a burger that had been made from different cows combined into one patty, and maybe just one of those cows had the disease, so it was watered down. But for hunters, things are different.

Mark Zabel: Consider a hunter who’s killed a CWD infected animal. They're gonna feed that animal to a very small number of people, family and friends, maybe a handful, maybe a half dozen. The prion titer, the load that they get from eating that one sick animal, it's not diluted into a bunch of other animals. The infectious dose they're receiving is orders of magnitude higher than the people who ate an infected hamburger. So that could really stress the species barrier to breaking. That's one of my big fears.

Deboki: By the species barrier breaking, Mark means that with enough of that infectious protein present there’s a greater chance of infection and CWD could go from a deer problem to a human problem.

Sam: And I feel like we should say this again, because Mark reiterated it many times throughout our conversation: no cases of CWD jumping to humans have been reported. And there are ongoing studies looking at hunters to see if they’re dying of prion disease at a higher rate than the general public. Mark says that so far there's no evidence suggesting that.

I also asked Mark if there was concern about dogs contracting CWD. I’m a dog owner, and if you’ve ever owned a dog, chances are you know they're prone to sniff around and seek out gross and dead stuff. So I wondered if they were at risk.

Mark Zabel: I do have some good news for you about your dog though, and my dog. It seems that there's some species, some mammals, that are particularly resistant to prion disease — dogs are one of them. If you're a cat owner, unfortunately there is feline spongiform encephalopathy, and that was produced during the BSE outbreak. So not only did humans get it, but they also made cat and dog food out of some of those infected cattle and some cats in Europe ended up getting this new FSE, this new prion disease of cats, but no dogs. There is no canine spongiform encephalopathy.

Deboki: Mark and his colleagues are working on a bunch of things. One is developing tests that can easily detect CWD in feces found in the environment to monitor its spread. Just like human prion diseases, there are no current treatments for CWD, so they’re also working on therapeutics that could interfere with production of the diseased prion protein.

And Mark told us something else that’s really important about prion research. It’s applicable to a huge range of diseases where proteins don’t fold correctly.

Mark Zabel: Prion diseases belong to a larger family of diseases that we refer to as protein misfolding diseases. These are diseases that also are caused by normal proteins that we all express that misfold and start causing these amyloid or these plaques in the brain. Many of these diseases are much more common than prion diseases. So Alzheimer's disease, for example, Parkinson's disease, Lou Gehrig's disease, ALS — amyotrophic lateral sclerosis — traumatic brain injuries, chronic encephalopathies, are associated with proteins that misfold. So prion diseases are just a member of these much larger family of protein misfolding diseases.

Sam with Mark Zabel: That's interesting. And it also is interesting because I would imagine that, to some degree, the work that's done to try and understand those other contexts in which you have protein misfolding like a traumatic brain injury or Alzheimer's, that what you gather from those studies could often be more broadly applied.

Mark Zabel: Absolutely. And, since obviously I'm a prion researcher, I would turn that converse, because one thing that's really interesting about prion diseases that helps researchers, is that these lab animals I'm talking about rodents, especially, that we can genetically manipulate, they actually get a prion disease, and it is a bonafide prion disease, unlike Alzheimer's, right? Where we do study that in the lab and we use these genetically altered animals from mice, but it's just a model because they don't really get Alzheimer’s. We can manipulate them so that they get a form of something that looks like Alzheimer's, but it's not exactly Alzheimer's. But prion diseases can be completely recapitulated in a mouse, and that disease is exactly the same disease that humans will get from a prion disorder as well.

It’s really changing the way we think about proteins and how they function and what they really do.

Sam: Prion diseases are no doubt scary but hopefully this episode made you feel a little better about them. Unless you didn’t know they existed before this episode and in that case oops sorry. I can say with certainty that this episode would have made kid me — the one obsessed with mad cow — feel better, knowing that prion diseases are incredibly rare and being monitored, and that there are researchers making big strides to catch these diseases early, develop treatments, and prevent them altogether.

I think we can hop into this Tiny Show and Tell.

Deboki: Yeah, I can go first.

Sam: Perfect.

Deboki: My Tiny Show and Tell, it's not relevant to this episode, but it's also very related, because it's about a condition that kind of comes on very quickly and is very, very hard to test for, but that people have been making really exciting progress on recently. And this is preeclampsia, which is a condition that comes up around the middle of pregnancy that basically causes a lot of issues with blood pressure and can be really, really dangerous for people. It usually happens in around one in 25 pregnancies and in the US it affects black women more than white women.

I remember from previous experiences of being pregnant that it's like a thing that they ask you about very early on and that you're kind of like, "Ah, I don't know. I don't know how to tell you what my risk factors are for this." Doctors and nurses, they're always just trying to make sure to mitigate the risk of preeclampsia.

And one of the things that's really exciting is that the FDA has approved a blood test for helping pregnant people figure out if they're at risk for preeclampsia. So it's not necessarily something that I think you can take from my understanding super early on. But the way that it works right now, at least in Europe where this test is used, is that if you're around those middle weeks of pregnancy and you're starting to show symptoms of preeclampsia or things that could maybe be preeclampsia-like, you could take this test to figure out just how likely you are to actually have preeclampsia develop. Like I said, this is something that comes on very quickly. So you might have the symptoms of it, but you might not actually know for sure that's going to happen. But then once it does happen, it just happens so quickly that you need to be able to address it really quickly.

So having a test to help people figure out are these symptoms potentially preeclampsia earlier on, is super helpful. And it looks specifically at two proteins in the placenta and their ratios of one versus the other because if these two proteins are really unbalanced, you're more likely to develop severe preeclampsia. There's about a 96% accuracy for predicting who won't develop preeclampsia. And meanwhile, two-thirds of the people who do get a positive test result will end up developing severe preeclampsia. There's still a lot that needs to be done in terms of monitoring how well this test works, but I think it's just super important because I didn't mention this earlier, but some of the things that can happen with preeclampsia is that you can have kidney and liver failure, you can have seizures. So having some kind of test that can help people who are pregnant figure out what's going on so they can get the right treatment is super important.

Sam: Yeah. That is really important. And I think preeclampsia is something that a lot of people don't really know about maybe until they're trying to get pregnant or are pregnant. And in graduate school, actually, the research group right next to the lab I was in worked on preeclampsia.

Deboki: Oh, interesting.

Sam: And that's how I learned about it. I had no idea what it was and I like the idea of a test that could help tune a lot of people in to the fact that they could have preeclampsia, that it's likely that and not something else, so that if things do escalate, they can say to the doctor right away, "Look, I'm high risk for preeclampsia. That could be what this is," and just save that time that would be spent trying to figure out what might be going on. That's I mean lifesaving, right? So-

Deboki: Totally. Yeah.

Sam: Yeah. Thanks for sharing Deboki.

Deboki: Mm-hmm.

Sam: That's good news. I like that.

Deboki: Yeah.

Sam: In my Tiny Show and Tell this week, I'm going to take us back 5,000 years. So this is not current day testing developments. This is very different. So in 2008, archeologists discovered a 5,000 year old grave in the town of Valentina in southwest Spain. And so in this super old grave, they found ivory tusks, amber, ostrich eggshells, and a crystal dagger. And so they thought, "Okay, this probably belonged to an elite leader." And so then they dubbed the individual, The Ivory Man. But now there's a team of researchers, and they use this new technique I had not heard about before. It actually looks at this enamel forming protein, amelogenin, which I guess sticks around much better than DNA does. And the other thing is, apparently male and female chromosomes have different versions of the gene that produces this amelogenin protein.

And so you can actually use it to determine sex. And so by analyzing these proteins on two of the teeth of this person found in the 5,000 year old grave, they confirmed that's not The Ivory Man. It's The Ivory Lady. So yeah, it was a woman.

They also found a bunch of chemical traces of cannabis, wine, even some mercury, because people loved mercury back in the day. They were using it as a pigment. They were ingesting it, thinking it was curing a bunch of things. Oops. But yes, they found a lot of other stuff near her body, which would suggest that maybe she was involved in some sort of religious rituals. And this was during the Copper Age. And it seems like in the Copper Age in the Mediterranean, that this was actually pretty much in line with a lot of what was happening.

A lot of prehistoric women actually had some prestige. They held authority. And so our modern assumption, which is very paternalistic and male dominated, we're kind of viewing the past through that lens. And actually, in some ways, a lot of these societies were more progressive than the ones we have today. And it also reminded me that last October, we did an episode about some of our travels last year, the travel that I shared was going to Greece. And so one of the islands that I went to when I was in Greece was Crete, where you had the Minoan Society. So the Minoans were around during the Bronze Age. There's some overlap with the Copper Age, but it's generally slightly after. So the Copper Age ends around 2000 BCE, whereas the Bronze Age ends around 1000 BCE. Again, with the Minoans, initially people thought, "Oh, it was all men that were in charge," the usual, and then more and more evidence kept coming forward really making a compelling argument that like, "No, the people in charge, the rulers, they were women."

Deboki: That's so cool. And it's so interesting how we've developed these techniques to be able to understand these questions in different ways and to look at these remains. And I got very excited just when I heard crystal dagger too. I was just like, "That sounds so amazing."

Sam: I know. I know. Right?

Deboki: Thanks for tuning in to this week’s episode of Tiny Matters, a production of the American Chemical Society. This week’s script was written by Sam, who is also our executive producer, and was edited by me and by Michael David. It was fact-checked by Michelle Boucher. The Tiny Matters theme and episode sound design are by Michael Simonelli and the Charts & Leisure team. Our artwork was created by Derek Bressler.

Sam: Thanks so much to Brian Appleby and Mark Zabel for joining us. If you’d like to support us, pick up a Tiny Matters coffee mug! Or through August 11th send us your questions and we’ll enter you into a raffle to win a Tiny Matters mug. These can be science questions, questions about a previous podcast episode, questions about how Deboki and I made our way to science communication. Truly the sky's the limit. Send your questions to You can find me on social at samjscience.

Deboki: And you can find me at okidokiboki. See you next time.