What hibernating bears and extreme cave fish are teaching us about preventing blood clots and fatty liver disease

Tiny Matters

Although we look very different from many of the other creatures on this planet, we’re more connected than you might think. Our evolutionary history means we share many of the same genes and physiology, and that’s not just cool to think about — it’s useful. Because it means that, to learn about the things we lack or wish we could do better, we can study the exceptional abilities of other animals.

In today's episode, Sam and Deboki cover two species with extreme lifestyles— brown bears and Mexican cave fish — and what they are teaching us about avoiding blood clots and fatty liver disease, and how that could unlock the potential for new treatments. In this week’s Tiny Show and Tell, Sam asks "What is a species?" and Deboki ponders how a mushroom could grow out of a living frog.

Transcript of this Episode

Sam Jones: Around 4 billion years ago, Earth looked very different from how it looks today, in part because it was mostly covered in water — a primordial soup rich with organic molecules, on the precipice of spawning life. Soon, cells emerged, and over the next few billions years came multicellular plants and animals in the ocean, then on land, and then — just moments ago in the grand scheme of things — humans arrived.

Deboki Chakravarti: Although we look very, very different from many of the other creatures on this planet, we’re more connected than you might think. Our evolutionary history means we share many of the same genes and physiology. And that’s not just cool to think about, it’s useful. Because it means that, to learn about the things we lack or wish we could do better, we can study the exceptional abilities of other animals.

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

Sam: In 2022, we published an episode titled, “Regenerating a new limb or, you know, entire body” about what scientists are learning from these cute little flat worms called planaria that can fully regenerate from just a clump of cells. Cut their heads off, they’ll grow back, split an animal in half — you’ll soon get two fully formed animals.

At the end of last year, I was reflecting back on episodes we put out into the world in our first two years of Tiny Matters and those fascinating flatworms got my wheels turning. So today we’re going to talk about a couple extreme species that are allowing researchers to pursue answers to questions that could have big implications for human health. And we’ll start in the forests of Sweden, with bears.

Manuela Thienel: Of course I was very nervous and very curious to see them. And it's also kind of a big adventure. Normally I'm working in a clinic in Munich. It’s not too boring, but I never see a bear.

Deboki: That’s Manuela Thienel, a clinician scientist at the Ludwig Maximilians University hospital in Munich, spending half of her time as a cardiologist in the clinic and the other half as a researcher studying platelet function.

Platelets are sometimes called thrombocytes, and they’re small cell fragments made in our bone marrow that travel in our blood to form clots and prevent bleeding. If we get injured, we need our blood to clot, that’s super important. But if our blood begins clotting in other circumstances it can be very dangerous.

Sam: We often hear about blood clots in relation to strokes, which are typically caused by arterial thrombosis — when a blood clot blocks an artery, stopping the supply of blood to your brain.

You may have also heard of deep vein thrombosis, or DVT, which is part of a larger group of blood clots known as venous thromboembolism. These are blood clots that form in veins.

When a clot breaks loose from whatever veins it’s in, it can travel to the lungs causing what’s called a pulmonary embolism, blocking blood flow, damaging lung tissue. This can cause a drop in blood oxygen levels because you’re not able to breathe in as much oxygen, which can lead to damage of other organs. You can imagine this can quickly become life-threatening.

Deboki: There are an estimated 600,000 cases of venous thromboembolism each year in the United States. A number of factors can contribute to forming these clots, but a big one is short-term immobility. That can include a plane flight where you’re sitting for hours on end at high altitude, or possibly a traumatic injury or illness where a person is laid up for a few weeks or months.

But every year, brown bears — the species Ursus Arctos —  hibernate for around 6 months, and they don’t seem to have any issues with blood clotting. How could that be possible? Manuela and her colleagues wanted to find out.

Manuela Thienel: It was the idea of Professor Ole Frobert who was working as a cardiologist in Sweden.

Sam: Ole Frobert met Manuela and her colleagues at a conference in Munich where he told them about something called the Scandinavian Brown Bear Project, a research project that began in 1984 and has followed the lives of over 900 bears to understand their biology, physiology, behavior, and ecology.

Manuela Thienel: And then he said, ‘and I was just wondering why they do not get any kind of venous thrombosis when they're sleeping and they're lying in their dens for up to six months?’ And then we said, ‘yes, of course, it’s a very, very interesting and a very relevant question. What are bears doing different? Why do they not get any kind of thrombosis?’ And so we had the option to join this team in Sweden, and get some blood from active and from hibernating brown bears.

Sam: You might be thinking, “Hold up, collecting blood from a bear? How does that work?” Manuela told us that the research group was made up of veterinarians, biologists, cardiologists like Manuela and, very importantly, rangers, who were in charge of leading the group to find and anesthetize the bears. These bears have a collar that has a GPS tracker. In the winter, the group used that GPS info to find the dens where the bears were hibernating.

Manuela Thienel: You have to be very, very silent. And the rangers are digging a hole into the den, and then they're using a dart with anesthesia to make the bear sleep.

Deboki: They were able to tranquilize 13 bears, collect blood from their veins, and then put them back in their dens to finish up their winter snooze. Then in the summer they tracked the same bears, tranquilized them from a safe distance away — from a helicopter in fact — and collected their blood for comparison.

Manuela Thienel: The bears are not too big, to be honest. They're two to three years old, meaning they have a size of a larger dog, but they're not huge as the bears in the United States.

Deboki: Personally, I would be scared of a bear no matter the size. But luckily, these researchers are braver than me.

OK so by looking at a brown bear’s blood during active versus hibernating months, the researchers found that the platelets in hibernation months were less reactive than platelets in the summer. They weren’t clotting as much. So next, the scientists looked into what proteins could be involved.

Manuela Thienel: We found that there are over 150 proteins that are significantly regulated in winter compared to summer. And one protein was really striking. It was heat shock protein 47 — HSP 47.

Sam: The protein HSP47 hangs out on the surface of platelets, helping them bind to collagen and form clots. As it turned out, hibernating bears produce minuscule amounts of HSP47 compared to when they’re not hibernating. But bears aren’t the only species that can lower the amount of HSP47 when they’re temporarily immobilized — species like pigs do it too.

And humans can lower their levels of HSP47 too, but in cases of long-term immobility, for instance in paralysis. And that could be why those patients don’t seem to be at greater risk of venous thrombosis than the general population.

Manuela Thienel: For us, the question is now whether we could use this mechanism as a new approach for the prevention or the treatment of venous thrombosis. Because up to now,  if you are immobile after any kind of injury, after trauma, after you broke your leg, then you have to be treated with anticoagulation, making the blood kind of thinner.

Deboki: Right — so the current approach to avoid venous thrombosis is to take anticoagulants to prevent blood clotting, but that in turn puts a person at risk for severe bleeding if they’re injured.

What I find super interesting though is that lower HSP47 levels reduce the risk of blood clots but don’t increase risk of serious bleeding.

Manuela Thienel: We know that this blocking of HSP47 doesn't increase the bleeding risk because the female bears, they give birth to their cubs within the hibernation period.

Deboki: So these bears have super low levels of HSP47 but they’re able to give birth without bleeding excessively and have normal wound healing. Now the researchers are trying to understand exactly how HSP47 works and what kind of effects a person could experience if there was no HSP47 circulating in their body — both of which are important to understand if scientists want to develop some kind of HSP47-blocking medication.

Sam: We have one more extreme animal for you today, but first we’ll take a quick break to tell you about another podcast you might want to check out. It’s called LuxeSci, and it’s about the science behind luxury items that takes listeners on a journey into the microscopic worlds of the fabulous and unravels the fascinating intersection of science and opulence.

Deboki: LuxeSci is hosted by two overly curious nerds, Dr. Lex, a former parasitologist and Dr. Dimos, an electrical engineer. From how bubbles form in champagne to the molecular forces that harden clay in a kiln to the amount of thrust needed to send a rocket to space, no luxurious topic is safe from their insatiable curiosity. They’re on a mission to demystify science and show how it drives the world around us, no PhD or lab coat required!
So, if you’ve ever wondered how science and luxury seamlessly intertwined, join LuxeSci as they uncover untold stories, hidden marvels, and the inner workings of scientific discovery and sophistication.  
Sam: A new episode of LuxeSci premiers every other Thursday. You can find it on Spotify, Apple Podcasts, or wherever you listen to podcasts. Subscribe now and let the exploration begin! Alrighty, back to the episode.

We left off in the Swedish wilderness. Now we’re heading south, to the odd and quite extreme Mexican cave fish, Astyanax mexicanus. These are freshwater fish native to rivers in Mexico and Texas. And they’re small — typically just a few inches long.

Caves aren’t the easiest places to live. There’s no light, little biodiversity, very little food. It’s a weird environment to evolve in.

Deboki: There are more than 300 cave fish species in the world, which is around 1% of all fish species, so why would a scientist choose to specifically focus on the Mexican cave fish? Well, Astyanax mexicanus isn’t just a cave fish —there’s also a surface river version. It’s the exact same species, and it’s actually been around longer than the cave fish.

Nicolas Rohner: They look very different. I mean, a surface river fish looks like a normal, typical fish and has big, big eyes and this silverish color. And then the cave fish, they don't have eyes. They are very pale. They have only some pigment left. So they look very, very different. But they are the same species.

Deboki: That’s Nicolas Rohner, an associate professor at the Stowers Institute for Medical Research in Kansas City, Missouri. Among other things, he and his lab study this weird little fish.

Sam: Researchers think that the cave fish began separating from the surface river fish between 50,000 and 200,000 years ago

As Nicolas put it, they’ve been separated long enough so that they’re interesting and we can ask tons of questions by comparing the two forms of the fish, but they have not been separated so long to have become different species. They’re in a sweet spot that makes them great for comparison.

For years, scientists have studied blindness and loss of pigmentation in these fish, and what they’ve learned has helped us understand the genetic underpinnings of how those conditions manifest in people. But Nicolas and his lab are trying to answer a few different questions.

Deboki: Recently his lab along with the lab of Sumeet Pal Singh and Hua Bai made an interesting discovery about fatty liver disease. Fatty liver disease is caused by your liver not breaking down fats as it normally should, and so the fat accumulates. It’s often the result of conditions including diabetes and increased alcohol use, but what many people don’t know is that it can also be caused by starvation. Fatty liver disease can lead to fatigue, weight loss, and abdominal pain. And depending on how far it progresses can be fatal.

Remember, cave fish have adapted to an environment with very little food. They’re essentially always starving, and yet they don’t develop fatty liver disease.

Nicolas Rohner: We have fish in our facility that are starved now for more than a year and they're completely fine. So if you have fish, I don't know if you have fish or you had fish as a kid, I had some, if you forget to feed them a day or a week, it's fine. Usually they will survive. But after a month or two it's becoming a problem. And we see this with the surface fish — if you don't feed them, they start to get sick, but the cave fish do not.

Deboki: In the study, the researchers looked at fish larvae just a few days old. They chose larvae because at that stage they wouldn’t have had the opportunity to store any fat to live off of.

Sam: By comparing surface fish larvae and cave fish larvae they hoped to find genetic differences that would have an effect on developing fatty liver during starvation. What they found was that the cavefish evolved protection from fatty liver by reducing the production of a protein called ‘fatty acid transport protein,’ also known as FATP2. And by just blocking FATP2 production in the surface fish, they were protected from developing fatty liver. And that was the case for other species too, including fish and fruit flies.

Just like with the HSP47 finding in bears, there are many, many steps before any sort of drug regulating FATP2 makes it to people. These are early days — this work is still undergoing peer review — but you can imagine how it could contribute to fatty liver disease treatments down the road.

Deboki: OK so I want to share one more cool thing Nicolas and his lab are studying using these very sedentary fish. I’ve actually seen them referred to as “couch potato fish.” Honestly, you might be a couch potato too if you had so little food. You’d need to conserve your energy.  

Nicolas Rohner: Because of this unique combination of not having predators but wanting to save energy, they basically became sedentary. And so they lost a lot of their muscle mass. They have much less muscle than surface fish. They swim kind of slowly around… And so the idea is they scan the ground for some food, but they won't do it very quickly.

Deboki: We know that prolonged physical inactivity can increase risk of stroke, heart disease and other conditions in people. But the researchers found that the sedentary cave fish are quite healthy and can keep up with their surface fish counterparts.

Nicolas Rohner: We put them in a swim tunnel and we let them swim against the water current, and then we increased speed, so it was kind of an exercise training over 30 minutes. And they did actually quite well. They did as good as surface fish.

Deboki: They could swim just as fast as the surface fish and maintain their speed for a long period of time, which was pretty surprising given that they are lacking much muscle and their bodies are brimming with fat — even the area that used to be their eye sockets is filled with fat.

So how could they do it? The researchers found that the cave fish actually store energy differently within their muscles, in the form of glycogen.

Glycogen is a molecule made up of a bunch of glucose molecules. Typically we use glucose as our primary source of energy, but it turns out these fish can easily store and break down glycogen, quickly converting it to a ton of energy when needed.

Sam: Of course this work could be applied to the human experience, where physical inactivity is a huge concern, as time outdoors is swapped for screen time. Maybe changing how we store and quickly produce energy could make us healthier? And if we want to go kind of sci-fi for a second and think much further into the future, making those changes could be key to protecting the health of people making a long voyage, maybe to Mars or outside our solar system entirely.

I love this kind of work because it taps into the connection we have with other species. Like all other species. Bears and Mexican cave fish are two out of… how many species are there in the world? We don’t even know! I read that it’s somewhere between millions and trillions. So yeah, we have a whole lot to learn. There are always science questions to ask.

Nicolas Rohner: Generally, we're interested in these broader concepts of how evolution has come up with so many solutions of basically pretty much every problem they can think of… And so if we just learn from them, I think it will help us better understand ourselves… Basically, we're using this fish, but there may be at some point we may use another system that may be easier to work with also or different to work with.

Sam: All right. Tiny show and tell. I feel like I'm first this time, I don't know what I'm basing that on.

Deboki: I don't remember. You could go for it.

Sam: Okay. So Deboki, I'm doing something that you sometimes do, which I love. I am going to provide a story suggestion for people. The story is titled, “What is a Species, Anyway?” and it was written by Carl Zimmer for the New York Times. Also, I think it's so relevant for our conversation today about the Mexican cave fish because that's one form of the same species that also lives in surface waters, right? The premise of this article is that naturalists have been trying to catalog all of the species on earth for centuries, and of course they're still trying, like I just mentioned. There are predicted to be millions, possibly trillions of species on our planet. So we really just don't know at this point, about 2.3 million species have been identified just to provide context.

So other than just how much work it would take to catalog all the different species on our planet, big issue is that biologists cannot agree on what a species is.

Carl Zimmer, in the story, he cites a survey from 2021 where biologists used any of 16 different approaches to categorizing species. Yeah. So if you ask a couple different scientists, how do you categorize a species, there's a very good chance they're going to tell you something different. So why does this matter? Well, animals are going extinct fast. Some people say we're in the midst of the next great extinction, the last one being around 66 million years ago that led to the die off of the dinosaurs. So ideally we would catalog every species out there as quickly as possible. But again, it's challenging because what does it mean for something to be a distinct species? And I really love this story because it covers some of the history of scientists coming up with taxonomies and then how Charles Darwin really complicated things with evolution because as species evolve, when do you say, oh, hey, this is actually another species now.

So it makes me wonder when scientists are actually going to say, okay, this Mexican cave fish is now a different species than the surface river fish. When will that happen? Will it ever happen? When? And then genetics, I think a lot of people felt like, okay, once we can just sequence the genomes of all these different animals, it'll be so much easier to categorize them into different species. And no, it's made things less complicated in being able to see the conservation of genes between animals, which is so essential for almost every bit of biological research out there. But it also really complicates things in a lot of ways. And so yeah, this was just really fascinating. It's a really fun read. It's got that great combo, that great history-current biology combo that I just love.

Deboki: Well, I'm so glad you mentioned it. I was actually thinking about doing that for my tiny show and tell, except I didn't get a chance to read it yet, and it was on my list of things that I want to read.

Sam: Gosh. Well, now you got to.

Deboki: So this is perfect. I'm so excited. It is so interesting. I remember, I think we might've done an episode for Journey to the Microcosmos about this obviously focused on the microbial world where this stuff gets even messier I think. Oh, I mean, it's probably just as messy. I think it's always messy, but because I feel like one of the standard definitions you learn in school is that a species is defined by whether or not the organisms or the animals can mate with each other. And that already gets at the animal macroscopic level, there's some boundaries there that get confusing, but at the microbial level, it is just really hard to do because a lot of these organisms don't mate.

You can't really delineate species that way. And then there are so many stories of microbes that when scientists were first identifying them under the microscope, they looked really similar. Amoebas are a big one where they all look very similar and they all look very related. And then when we finally had the ability to look into their genes, it got so complicated so quickly because it's like actually a lot of these organisms are not that closely related. They're just all happening upon a very similar lifestyle and body type. And it's just really, really hard to tell. It's so fascinating.

I also have something about weird animal things, but I think it's more related to the end of our episode where you are talking about how many questions there are just left out there for us to explore. And so this was also an article in the New York Times, and it's really more of a mystery. And it starts with a mushroom that turned up in a strange place, and that is on the body of a living frog. Yes. So a group of friends, including a specialist at the World Wildlife Fund India, they were exploring the western gas, which is this mountainous area, and they were looking for amphibians and reptiles, and that's when they found this mushroom that was growing out of a frog. And they took some pictures, they posted them online for both scientists and citizen scientists look at, but they didn't actually collect the frog.

So it's hard to draw any firm conclusions about what's going on with this. But definitely I recommend checking out the article because you can see some of the pictures and it's like, yeah, it's a mushroom just grown out of a frog, or at least that's what it looks like. That is wild. So some of the people who looked at the images, they identified the mushroom as a bonnet mushroom, which is usually found on decaying plants, which is not what a frog is. But again, we can't say for sure that it was a bonnet mushroom just based on these pictures and without any more kind of genetic evidence. And actually one of the ecologists who was interviewed for this article, they weren't even certain that we can say it's a mushroom. So there is definitely a lot of mystery going on. If it is a mushroom, it's in an unusual place.

Fungi can grow in and on animals. There are pathogenic fungi. That's not inherently unusual, but apparently we haven't just seen mushrooms growing on live animal tissue a whole lot. This might actually be one of the only observations we know of it happening, and if it is happening, there's just so many more questions. Where are the mycelia? Are they in the body, on the skin? Just how did this all happen? So this is one of those tiny show and tells that's really more of a mystery, and we might never get a good answer to what's going on. But I liked it because I just feel like sometimes that's what science is. Something can be both exciting and vague at the same time.

Sam: So when you first opened that up, saying a mushroom growing in a place that it shouldn't, I immediately thought of college because I lived right when I graduated, I lived in this disgusting, dilapidated home right outside the university with a bunch of friends. It was like a place that was just like college students have lived there for just decades, honestly, at this point. And no one's ever been like, "We're pretty sure this whole thing is a biohazard." And one morning I walked into the bathroom and there was a mushroom growing out of the ground, like out of the tile. So not a frog, but mushrooms-

Deboki: Mushrooms will just grow anywhere.

Sam: They will. That was a first for me though, and thankfully the only time that I've lived somewhere where that has happened. So that's really interesting. Wait, so what happened to the frog? Where's the frog?

Deboki: I think they just let it go. They weren't planning to collect anything, so I think they just took a bunch of pictures of it. I think it was a pretty small frog too. So that's why we don't really have much more information than just the images themselves. But it seemed like it wasn't sick or anything. So yeah.

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.

Sam: Thanks so much to Manuela Thienel and Nicolas Rohner for joining us. Have ideas for episodes? Science-y things you just need to share? Email us: tinymatters@acs.org. If you want another way to support the show, buy one of our coffee mugs! We’ve left a link in the episode description. You can find me on social at samjscience.

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