9UNP0180SD_Hannah_Carey_WordPress

Exploraing Hibernation at the UW Biotron	Hannah Carey	9/24/14

- Welcome, everyone, to Wednesday Nite at the Lab. I'm Tom Zinnen. I work here at the UW-Madison Biotechnology Center. I also work for UW-Extension Cooperative Extension, and on behalf of those folks and our other co-organizers, Wisconsin Public Television, the Wisconsin Alumni Association, and the UW-Madison Science Alliance, thanks again for coming to Wednesday Nite at the Lab. We do this every Wednesday night, 50 times a year. Tonight it's my pleasure to introduce to you Hannah Carey. She is a professor in Comparative Biosciences in the School of Veterinary Medicine, and she is also the director of the Biotron here at UW-Madison, one of the more remarkable research facilities we have on this campus. So there's going to be kind of two thrusts of her stories tonight. 

One is as director of the Biotron, which recently had some pretty intriguing upgrades in its mechanicals. And the other is the work that she does on hibernation. And since it's early days in the fall and all our thoughts are turning to winter and how we get ready, it's going to be great to hear how things like bears and rodents get ready by hibernating. We can't, but we get to live through Wisconsin winters. Please join me in welcoming Hannah Carey back to Wednesday Nite at the Lab. 
[APPLAUSE]

- Thank you, Tom. It's great to be back. This is my second appearance at Wednesday Nite at the Lab but the first time that I'm being recorded, so that's kind of exciting and special and fun. Also, as Tom mentioned, I have dual role tonight. 

I'm going to tell you about some of the research I've done. Actually, I have a slide to point out what we're going to talk about. We're going to start off, though, talking about this interesting facility here on the Madison campus, the Biotron, and then I'll talk a little bit about some of the interesting research. Some snippets, some highlights of the research that goes on in this really cool, literally cool, building. And then we'll talk a little bit about some of my research involving hibernation. And this really is the only place on this campus, and really for many places around the country and around the world, there's only a number of facilities that can support this kind of research. So let's get started. What is a biotron anyway? It sounds kind of science fictiony. Well, let's have a little history where this comes from. 

The word actually came from the original word phytotron. And what is phytotron? What could that mean? Any ideas? Phyto? 

- 
[INAUDIBLE]

- Plants. That's exactly right. 

Phyto comes from the Greek for plants. So a controllable artificial environment used for the study of plants under well defined conditions. And back in the late 1940s, the first one was built by a scientist by the name of Frits Went who was a plant physiologist at Caltech. So that's where it all started. And probably one of the more famous of these phytotrons, given the name Climatron, is found in St. Louis at the Missouri Botanical Gardens. If you've ever been down there, you might have seen the geodesic dome that is a great example of a controlled environment for plants that can grow in many different climates. What about UW Madison? Well, it was part of the, going into the 1950s, where at a national level it was recognized, this idea about having facilities to do environmentally oriented research would be very important. So the National Science Foundation, the leading funding agency in our country for the non-medical type research, decided to have a call for proposals, a competition, for regional phytotrons. 

They would put money into this. So they said, well, let's hear from all you universities. Give us your best shot at what you would propose. And 43 institutions were interested. Eventually they narrowed it down to the proposals from Purdue, Duke University, and UW-Madison. The grant came to Wisconsin. It was awarded in 1959. And then the planning started with a committee of people on campus, and they also had experts from elsewhere, including Canada, to weigh in on what was the idea. So, Biotron, that's because there was such an interest in this controlled environment facility idea that researchers that studied animals, organisms besides plants, wanted in on being able to do research projects, so it was christened the Biotron. So the main mission of the Biotron here at UW is to provide a controlled environment for biological research for plants and animals. 

Hence the word biotron. And in our administrative structure here in Wisconsin, the Biotron is part of the graduate school. And this is then really a facility that serves researchers from all over the campus. It's not wedded to any particular specific administrative unit but open to researchers across the campus and actually across the UW system. So major construction finally was completed in 1967. It took some time for the planning and construction of this unique building, and then with some more tweaks to the final specialty rooms, the official dedication was made in September of 1970. So over 40 years old. Of course, getting towards our 50th year anniversary at the Biotron. Where is the Biotron? Well, here's a bit of a campus map I got off the internet for you. 

Off to the right, down at the bottom, Camp Randall, to orient you. It's cut off farther down on the right where you'd have Bascom Hall and a lot of the letters and sciences part of the campus. Then there's the agricultural part of the campus over here. Okay, I'm not going to show that. And then there's the Biotron. Now, the Biotron used to be on the outskirts, the western edge of this campus, until the last couple of decades when the University Hospital and Clinics and now the Wisconsin Institutes for Medical Research and all the basic sciences associated with the School of Medicine and Public Health have moved down. So now we're situated right smack dab in kind of the middle of where things are happening in terms of scientific research on the campus. So that's where we're located. So, the Biotron. This idea of controlled environments is really the heart of the mission of the Biotron. 

And there are a number of rooms of different sizes that allow researchers to control very precisely things like temperature, light, humidity, pressure, CO2 levels. Because of the nature of the way the building was built, we're also able to offer the ability to quarantine organisms in a very isolated area such that there is bio isolation for what's going on. Transgenic plants, for example, and other kinds of organisms. So you want to just keep close tabs on what's happening. And then in the mid-1990s a research grade greenhouse was added on to the back of the building, and that also provides automatic watering systems, precise control of turn-on/turn-off watering, supplemental CO2 systems. People have said to me, I go by that building and it looks kind of imposing. There's no windows to speak of. Maybe in one little corner. And that one corner of the building on the left in the front that you see there is really where our big machinery, the big chillers and the HVAC type units are housed, but the rest of the building, not a lot of windows. And this is why: because we want to be able to cordon off certain parts of the building for specialty environments. 

So if you come inside, actually, there is a world of environments and light and temperature and sunshine, if you will, artificial, provided to plants and animals and other things. So this is just some of the details of the kinds of things that the Biotron offers. Standard controlled environment rooms going from 15 degrees Celsius, that's somewhere in the 50-degree Fahrenheit, above 50, up to 35 degrees Celsius. We have some super cold rooms that go well below zero and can also go up quite high. We can monitor and control relative humidity, CO2, especially for certain types of plant experiments, and different forms of lighting. And some research going on in terms of how different lighting systems might benefit plants, for example. This is the door for one of the typical smaller controlled environment rooms that a researcher might use. So you open up that door and you see an empty room. Nothing inside this one. You'll see something inside it in a little bit. 

But this is the type of room that a researcher can move in, depending on the room, animals, plants. Some of them are slightly differently set up so that you can really get as close as possible to what you want to achieve in terms of research in these rooms. Now, Tom alluded to the fact that we've just been undergoing, we're just coming to the end for almost a two-year energy renovation project. Now, you know the history now of the Biotron and that it opened, it really opened for business in the late 1960s. And when you compare the machinery then, state of the art at the time, built to do amazing stand-alone, separate from campus, amazing stand-alone things for research, but in today's world, almost 50 years later, a lot of that machinery, well, it's old and it's not as energy efficient as we would like now in the day when we think a lot about the energy usage on the campus and in our societies. So a few years ago, the Biotron was moved up into the circuit for state funding to do a major energy upgrade. And this really is infrastructure. There's not that much different when you walk inside the building, but behind the walls and inside the major equipment rooms there's brand spanking new, highly energy efficient equipment. And that's infrastructure mechanics, much more efficient lighting in a lot of our rooms. It will hopefully save us a lot of money. 

That is the plan, and I think we're well on our way. This is just some of the details of these mechanical units that were put in over the last now coming up to two years. But after the machinery goes in, of course, then there's the fine tuning to get us back to that highly precise controlled environment in each room. So a lot of testing, a lot of testing over and over and over to make sure we can still deliver that precise control to our clients, to our researchers as we've done before. Let me give you an example of before and after. This is one of the units that was providing the cold chiller for one of the super cold rooms. It could be one of the rooms I use for my ground squirrels. In fact, this might be it. So this was the state of affairs for this machinery before the renovation, and now we've got beautiful new, energy efficient, all ready to go for the next hopefully 50 years for the Biotron's usage. So this has been happening throughout the building. 

It's taken some time and some effort for all involved, the contractors coming in and the Biotron staff, but we're excited about opening up. Actually, we're just about, now in the fall, ready to open our doors again and bring a lot of our clients back in that we had to put on hold until all this testing was done. As we did before, as I mentioned, precise control over environmental conditions through electronics, through computers, but now we are connected, which we were not before, to the main campus control system from METASYS. This is the software program, and it's through Johnson Controls, a major Wisconsin company out of Milwaukee. And so we have control room operators that are always keeping an eye on this, and, of course, these are electronically set up for alarm systems. So lots of data points per minute are collected on all of these rooms when they're in use. Alarm points to detect critical set point deviations. And then we have people every day who if they're not there at their normal work hours, we have people walking through the building every day, and someone always carries the alarm pager so if something goes wrong, we're there to take care of it or troubleshoot as best we can. Okay, let's talk a little bit about the use of the Biotron. As I mentioned, it is a University of Wisconsin-Madison building. 

It's open to everyone on campus, as well as throughout the UW System. And through collaborations, of course, other researchers from other places have contributed to some of the research that come out of the UW Biotron through the collaborations with faculty here. It was set up to be a biological research unit, and it still is primarily plants and animals. That's the most common very basic research as well as research that's applied towards, for example, plant diseases and animal diseases. But we also have the non-biological side. The facility is used by UW Madison faculty in, for example, the School of Engineering. We've had one very recently about freeze thawing of concrete. Bringing concrete down to subzero temperatures and bringing them back up again for testing, and developing new ways to make concrete that can withstand those long, cold, polar vortex type winters. So we've had a number of types of materials research as well. And so all of this is university based research. 

And when space allows, when we have the room and we're not compromising research from the scientists, we can open up the building to industrial users, and there are quite a few who, over the years, and we have some right now, that are very interested in the unique capabilities of this building. Draperies, we've had, over the years, several times where people are coming in and using some of our controlled rooms to just see how materials respond to different temperatures and humidity. Motorcycles, medical devices, testing injectables that deliver medicine at low and high altitude. And the industry does help provide us the bottom line so that we can give our researchers the best rates possible, and the industry people are very happy to pay the rates they do because they can't get these facilities elsewhere. So some particulars. Plant research at the Biotron. This, of course, is part of the history, the early origins of the Biotron, and it's still a vibrant part of what we do. Here's just a few examples pulled out from over the years. Plant disease research has certainly been a theme in the Biotron. Here is an example of one of our misting greenhouse rooms that was used to study the organism that's responsible for potato blight. 

So this is what was the origin of the Irish potato famine, for example. And so this kind of research project requires very high humidity without outright water sitting on the leaves, and that's something that the Biotron could provide with its humidity controlled rooms. From Dr. Bill Tracy's group in agronomy, heat stress effects on pollination of field corn. In fact, it often seems like we have some corn growing somewhere in the Biotron, sometimes to great heights as well. We've had giant corn in the Biotron, and I think we still do today. Now, this is a really exciting program. We've been the long time home of a major portion of the Wisconsin Fast Plants program. Maybe you've heard of this. This is a program that was started originally by Dr. 

Paul Williams, shown here in the upper left, and others over 25 years ago, I believe. And Dr. Williams was keen on working on ways to increase the generation time for a particular group of plants, the brassica plant. These are the cruciferous vegetables, broccoli, cauliflower, etc. And the idea here was develop a plant that was fast, that was able to grown and turn to seed and cycle at a pace that would speed up the research on understanding the biology of the plants and their economic potential but also education. This is a great way to bring education into the classroom by making it such that students can, in a relatively short period of time, study the biology of these plants. So, again, both education and research is part of this, and, in particular, the Biotron provides that home for the rapid cycling brassica collection, the RCBC, which provides the seeds of various varieties of these cruciferous plants to researchers worldwide, actually. So this is quite a well known program. And the Biotron, the University of Wisconsin Biotron, is also a long-term home of the tissue culture laboratory associated with the Wisconsin Seed Potato Certification Program. And this is an extremely important program that benefits, in a big way, potato growers here in the state of Wisconsin, but also researchers and other users throughout the United States, and possibly, I believe, worldwide some of these might be sent to. 

So the idea here is to use very carefully controlled pathogen-free tissue culture techniques from seedlings to develop these plantlets of different varieties of potatoes that we know are pure and disease-free. And then these go on to be provided to researchers and growers and on to other parts of the seed certification program for other uses. So these are one of our long-term wonderful clients that we have in the Biotron. Over the years, the Biotron has been the home to a wide variety of creatures, and I've just put some of them up on this slide, pictures of some of them. The range of science that's been carried out on different types of animals in the Biotron under different conditions has been really impressive, really astounding. As I mentioned, there are features that we can provide in terms of temperature and lighting, etc, that are just not available elsewhere. And although not in recent days, in the past there's also been another animal, the human has been studied, especially aspects of exercise physiology and temperature, for example. And we've had chambers that one could simulate high altitude. So a wide variety of animal and human type research over the years. I want to highlight one that's been a long time recent use for animal research, and that's for snails. 

And these are snails that are part of the research program of Dr. Tim Yoshino, also a faculty member at the School of Veterinary Medicine here on campus. And Dr. Yoshino studies the biology of the host/parasite relationship for the disease schistosomiasis. So this disease, which is really a devastating disease that's primarily in Sub-Sahara Africa in the tropics, and it's due to a parasitic worm that infects the blood vessels of people. But how it gets in there is through a fairly complex parasitic life cycle and involves an intermediate host, the snail. So Dr. Yoshino studies that interaction between the snail and the parasite worm, but he needs to have a place where he can grow up these snails and do the research in somewhat of a tropical setting. So this Biotron has been a great place for Dr. Yoshino and his work that's been continuously funded by the National Institutes of Health, actually. 

We've been able to provide that level of research support so that this important research goes on. The Biotron, besides some of the more unique animals, also supports research in their regular ambient housing conditions, not extreme controlled conditions, for laboratory rodents that are used in a wide variety of research, much of it biomedical. So we now have a pathogen-free mouse housing facility so that researchers can bring their laboratory mice in and have a pretty good feeling that there's not going to be an outbreak of some of the mouse diseases that can occur that can really bring colonies down. So we now have an animal research service that provides some very clean, very beneficial housing for these mice. We also support laboratory rats as well. There is currently a really interesting project that looks at the disease progression related to Lou Gehrig's disease with the rats and the Biotron. And sometimes there are other critters as well that are not your typical laboratory rodents. I can't not mention this important user of the Biotron for the last number of years. The animal research on our campus comes under the regulatory guidance of the Research Animal Resources Center on our campus, and this RARC unit has a really top notch breeding service facility that they can provide to people who use particularly lab mice throughout the campus and take care of a lot of the husbandry and the breeding and weening of the babies and that sort of thing so they can deliver the animals to the researchers' laboratories in good condition and take that out of the equation for them. And so this is an important part of what we do as a unit to help research not only just in the building but research in other laboratories throughout the campus. 

So I think we should now turn to that little critter who scampered on to the slide just now and talk a little bit about who that is and what's going on here. So this animal, close to my heart, is the thirteen-lined ground squirrel, Ictidomys tridecemlineatus. You'll notice the species name, that Latin word, nicely corresponds with his common name, thirteen-lined. And this is a great Midwestern hibernator. It's a wonderful animal because it carries out its yearly cycle that involves hibernation, it wants to hibernate under most conditions that you could try to put him in, it's a good hibernator. So it's a wonderful animal to study. They're also very easy to get around here. In fact, we often are dropping in on golf courses to catch our ground squirrels. They are very happy when we come by and want to trap some. What we now usually do is get pregnant females so we can raise up the babies in-house. 

So it's kind of a Caddy Shack sort of situation as we're running around. 
[LAUGHTER]

 They'll give us a golf cart, and it's an active process. We don't use traps. But it really is a nice way to provide some research fun for the people in the lab in the summertime when we go out to catch our squirrels. So the annual cycle is very fascinating, and, as I said, is really engrained in the biology of these animals. So they emerge from hibernation in the springtime. They're a little lean. They're ready to start getting back to normal life again, and breeding happens right off in the springtime when they come out of hibernation. And after the males come out first, they're getting everything all set up, fighting with each other, getting ready for the females. 

The females come up, this is all right after hibernation, mating occurs. Then the males' work is done. Their job then is to get fat. That's literally what they do. The males breed and then gain weight and start to tune out. The females, of course, raise the young. They're pregnant and then lactation, and then they're ready to get fat. And then the babies come out in mid to late June, and their job, of course, is to grow and then get fat because that is the goal of a hibernating animal after you've got your DNA passed. So you feed voraciously. The food is out there. 

They eat grasses and flowers and some seeds and little insects. Ornithologists have told me, hey, they're eating my favorite bird's eggs. So they're kind of omnivores, but they're fattening and fattening. Why? Because they use their fat to get through that long winter in Wisconsin, and they're using that fat because they give up eating. So these are great examples of animals that know when to eat, when it's good and perfectly fine to overeat, but when to say nope, I'm done. And they stop eating voluntarily on their own even before they start hibernating. So they've really got this down. This when to eat and when not to eat, and nobody yells at them about it. So there's something else very interesting about these animals besides this feeding/fasting cycle of course, and that is during this active season from spring through the late summer, early fall, they're what you'd call homeotherms. 

And a homeotherm is? 

- 
[INAUDIBLE]

- They maintain roughly a constant body temperature. That is correct. The same therm. The same therm. Maintains a constant body temperature. And then in the winter they are heterotherms. 

So they're different in their temperature. They don't just get cold; they become variable in their body temperature in the wintertime. So we'll talk a little bit about that. Here are some of the details, the stats, on what it's like to be a hibernator. And this is the thirteen-lined ground squirrel, but other rodents that are in this group, we call it the ground squirrel group of rodents, woodchucks and marmots, which are relatives, are in that group. Prairie dogs, chipmunks, and various species of ground squirrels. These are all related, and a lot of them go through these cycles. So during the active season, their body temperature is similar to a typical mammal, like yours or mine. 98.6 Fahrenheit, about 37 degrees Celsius. The homeotherm. 

Their heart rate and respiratory rates are shown there. They're typical for a small rodent their body size. It's very common. And their metabolism is what you'd expect for an animal at that body temperature. Then in the winter, they spend most of their time in a state we call torpor. It really is technically metabolic depression or metabolic suppression. So they have the ability, actively, voluntarily, to suppress their metabolism and let their body temperatures, that drives their body temperatures down. They don't just give up being warm. They actively turn the dial down on their metabolism. And they go to less than 4%, I mean some of them that's been recorded, 1%. 

They're barely, you'd say, alive, but they are very much alive. They are just exquisite. It's like the controlled environment rooms in the Biotron. They're able to just change their body temperature and metabolism to get it just the way they want it to conserve energy. So they don't have to eat. They don't have to run around in the cold Wisconsin winter. They don't have to make themselves exposed to predators. They've got it covered. So body temperature drops. In our squirrels, it doesn't go below zero Celsius, that is 32 Fahrenheit. 

But there are examples of hibernators that do drop down below zero, and the best one is the arctic ground squirrel. Regularly clocks in at minus two, minus three degrees Celsius. That is below freezing. They're not frozen. They're supercooled. So that's another whole really interesting aspect of hibernation. But most of them here down in the lower 48 don't go below zero. Now here's the thing about heterothermy. They're not in this torpid state for the entire winter. In fact, the winter is quite a dynamic period. 

All underground. Hibernation, really, the word I use for hibernation is repeated cycles of torpor arousal. Torpor arousal. They arouse periodically underground. I'll show you that in two slides. One is this fun cartoon that actually was the cover of a journal article just earlier this summer, a colleague of mine in the Scientific Illustrator decided to make the life cycle of the thirteen-lined ground squirrel. You might notice his suit has some lines on it. I don't know if you can see that up there. So in the summertime they're eating veraciously. The winter, they underground. 

And then in the spring, they come back up, they're ready to breed and ready to start all over. But what's happening underground? Well, here's what's happening. Things are happening. They're undergoing cycles. Sometimes they're in deep torpor They're not sleeping. This is not sleep. This is an active depressed metabolism. They're in torpor, and then something tells them to wake up. And it is an abrupt kind of a violent response, all natural, to rouse themselves up from torpor, get back up to normal body temperature. 

They sit there for a while. They're maybe grooming a little. They're sleeping. They're sleeping at high body temperature. And then something says time to go back in again, and they go back into torpor. And that's the cartoon. Oh, let me show you, I'll show you the actual data in a minute. This is the room that you saw earlier. Remember, I said I put something in that room? Here's one of those rooms with thirteen-lined ground squirrels. 

Very happy in a room set at about three degrees Celsius Almost freezing. And this is a little lit right now because I was taking the picture. But we turn off the lights and eventually take the food and water away when we know they're well into their hibernation cycles. They're on autopilot. We don't have to change the cages. They're just happy as can be. A lot of the the squirrels are trying to hibernate even before we put them in the cold room. In the normal animal room, they're getting sluggish, not eating. Their body temperature is going down. We put them in this cold room, and they're just within 24 hours 90% of them are in torpor and like great, let's go, ready for hibernation. 

So that's what the Biotron does for us. It gives us a great facility that we can then study hibernation. So I just wanted to show you some of our squirrels have body temperature telemeters. They look like little Mento candies. It's a little battery, cold-resistant battery that keeps on chugging along even at zero Celsius. And we cover it with paraffin wax so it looks like a Mento candy. And then it gives us this recording of body temperature through the year. And that's what you see here. And this is exactly right. You can see the room temperature, three or four degrees Celsius. 

And when they're in torpor, they're body temperature is almost equilibrated with the room. Maybe a degree or two above. So they are still, their physiology is still aware that they're cold. They haven't given up. They're regulating themselves just above the room temperature. But it's very good conservative state to be in at low temperature because you're not burning up a lot of your fat. You want to conserve your fat for as long as you can because you don't want to come out until the weather's gotten better, the plants are growing, you can eat, the mothers can afford to be pregnant and all of that. So you want to conserve energy. But you see those periodic, we call them interbout arousals. Every few days in the dead of winter, it's almost two weeks before they undergo one of these arousals. 

Most of the hard earned body fat that they just stored up all summer long is used to fuel those arousals. That's the most energy draining part of the winter hibernation season. So you may be saying to yourselves, why the heck are they doing that? They don't eat during those arousals. They don't drink. They're sleeping a fair bit of the time. But the main thing is those arousals, which last about a half of day, they're about a half a day at high body temperature until something tells them in their bodies, we still don't know what the signal is, to go down, plunge down again, and then they're in torpor for a couple of weeks. So if any of you have any ideas, let me know because this is the $64,000, maybe million dollar, question of why do they do this. All mammals that we know that go to low body temperature like this in hibernation have these arousals. Clearly, there is something, a limit for a mammal at low body temperature that we're missing, they're missing, and they have to come up to high body temperature, to spend a certain amount of hours doing whatever this is. 

Maybe it has to do, it's a likely hypothesis, with the brain. Resetting neurons. We know that the dendrites, the nerves in the brain, the neurons, come apart when they're in torpor, and they come back again during arousals. So that might be a limiting factor right there. Or it could be other things. So, that's what's going on with hibernation. A very dynamic part of the year, contrary to what you might think. So physiology changes dramatically as these animals are going into and out of torpor. Do you remember we talked about the heart rate? The heart rate is a few hundred beats per minute in the active season. 

In torpor, it's just like six beats a minute. Breathing slowed down. That means blood flow throughout the body is slowed down. Everything slows. And then it comes up. And then it goes down. And then it comes up. That's a big, it takes a toll on the body. All these big changes in blood flow. So for that and other reasons, many of us in the field not only want to know how the heck do they do this, but how do they protect their bodies from damage, from injury? 

We know things like a stroke, ischemia, when you cut off blood vessels, slow down blood flow, that can really do damage to your cells and your tissues. But these animals, they're very good at it. We'd like to know how they protect themselves. So there is a variety, this is just some of the topics that people have and currently around the world are studying to use hibernation as a natural model for protection for extreme physiology that we should be able to, if we're clever, figure out how they're doing this, and maybe there are ways to translate that therapeutically through pharmacology or preconditioning the body in some way to mimic hibernation and reduce the severity of diseases of traumatic events. Just imagine if you're in an accident and you get hit by a car and you're bleeding out and the whole body is starting to plummet down because all the organs are starting to shut down. Well, what if you could just dial down your metabolism and slow all that down until the ambulance comes. You can get off to a hospital, and then they know what to do, revive you, you're ready for care, you're ready to go. The Defense Department, for example, DARPA, the army research office, the medical research office, they're very interested in hibernation because they'd like to know what can we give our war fighters behind scenes on the battlefield that if they're in trouble before we can get them to the triage unit, is there something we can learn from nature to just kind of get them into a stasis kind of a state? Maybe not all the way down to the temperature of our ground squirrels, but just enough to slow things down in a safe, reversible way. What a great thing that would be. 

These other ones that you see here, I won't go through them all, but you can see now from me telling you about the basic biology of hibernation. Body weight regulation, they know when to eat, when to not eat. What are those signals? What can we learn from that? Heart function, on and off, stroke, ischemia, organ preservation. My lab collaborated a number of years ago with people at the UW who discovered the University of Wisconsin's solution that's used worldwide to cold preserve organs prior to transplant. Well, we got together and they said I wonder if organs of hibernating ground squirrels are more resistant to cold storage because even though cold is protective to store organs, there's a certain point where those organs are no good anymore. Well, maybe we can learn from the hibernators. And sure enough, hibernator organs are better if you take them out and cold preserve them than a typical lab rat. And so we worked on how that could be. 

This is my baby right here. As a physiologist, I'm an ecologist by training, now a physiologist thinking about real animals out there in the real world, I have this love of the gut. It's my favorite organ system, and I've always wondered what happens to the GI tract. They use it all summer long and then bam, no food. That's not a good thing for the rest of us mammals that are used to eating on a regular basis. In fact, when you're in the hospital, if you can't be fed by mouth for a period of time, the doctors are always trying to get you back on oral feeding again, enteral feeding they call it, because it's healthier for your gut. So my lab, over the years here at Wisconsin, because of the wonderful Biotron, have been able to study that. And we've worked on a number of different features of what happens to the intestine, the GI tract, during hibernation. Well, I can tell you, the intestine shrinks, not surprisingly, when food is not taken in. The GI tract kind of atrophies. 

It shrinks because there's no food anyway to conserve what protein there is. And sometimes in an animal that doesn't hibernate, it gets leakier, and the cells are not happy. In fact, we found that the gut is leakier in hibernation. These pictures of the inside of the intestine, the mucosal lining of your intestines. Food would be facing up there. That tissue that's so important, that finger-like villi they call them, that's what absorbs the food that comes into you bloodstream. The gut gets leakier. But you know, no problem. The squirrels are very happy. Function is well maintained. 

In fact, the smaller gut seems to be better in an aroused state than in the summertime. So Mother Nature, evolution, has come up with a way to maintain this. A few years ago, we started to direct our attention to the immune system. People don't always realize this but one of the most highly dense parts of our bodies, in terms of immune cells, is lining our guts. But then you think about it, maybe that's not surprising because the inside of your intestinal tube is kind of exposed to the outside world, right? So you want to have a really good immune system right in the gut wall to make sure that nothing comes into the rest of your body. And this is just a cartoon of different parts of the immune system. The wavy thing up there is the lining of the intestine. Food would be up there. And on the bottom part would be the inside of the intestinal wall where all these immune cells are. 

We started to take a look at that with what changes with hibernation, and you know what we found? We found all these things in circles are things that changed. I'm not going to go into the details, but things that changed from summer to winter. And we thought, what the heck, there's no food being taken in, they're sequestered underground, why is the immune system changing? And it's changing in a way, based on the literature from other studies of people that study lab rats or even humans, that these changes are beneficial. They promote a more tolerant, anti-inflammatory tone to the intestine. Then we realized, wait a minute, we're forgetting the other big players in the gut. The other players are at the very top there floating up. That's the bacteria. All mammals, all vertebrates, most animals, we're teaming with bacteria that live inside our bodies very happily with us. 

So a few years ago we turned our attention to we've got to get a handle on what's happening to those bacteria. Maybe that's explaining why the intestine is doing so well and the immune system is changing in a way that's keeping everything kind of in check. We have to have a good, we, all mammals, have to have a good relationship. We have to be on good terms with our symbiotic bacteria. And when that relationship breaks down, we're learning more and more that's when we can lead to GI disease or even other things in the rest of the body because you might have seen these in the news lately, we're starting to learn so much about these resident bacteria do for us. And so we thought here we have a model of extreme change in hibernation, let's go figure it out. So I'll just show you a couple of slides here before I finish up of what we've been finding. And as I said, you may have read about this or heard about it. Our bodies, we evolved, all animals evolved in a microbial world. From the very beginnings of single, from bacteria on to multicellular animals, we're awash in bacteria. 

So maybe it's not surprising that our bodies reflect relationships with bacteria. In fact, a lot of our genes have a bacterial imprint on them. So we have to be thinking these ways now about we're not just us. We're living with a lot of other guys in here that we should learn about, and they call that the microbiome. And people are starting to realize animals, humans, we get a lot of great things from let's say our gut. That's where most of our microbes are in our bodies is in our gut. It produces more energy from our diets, especially the fibers you take in, the fibrous food. We can't digest that very well. We don't have the right enzymes, but bacteria do. And when that indigestible fiber that you eat with you vegetables goes into your large intestine, those bacteria are there to start working on that fiber and they produce molecules that we absorb and we benefit from that. 

So you get more out of it. Vitamins are another possibility. Ruminants really rely on their gut microbes for vitamins. We might be getting some too. Regulate the immune system. Good bacteria help keep the bad guys at bay, keep the pathogenic bacteria out if the good guys are happy. So that's another reason why scientists really want to know what's the dynamic of the good microbial communities because we like reducing the pathogens. And in other ways, bacteria now are realizing effect our energy metabolism in our body. And the microbes rely on the host. Their biology is affected by what we do. 

Well, early on, we get our microbes, all animals get their microbes during birth. That's your initial colonization. And aspects of your environment, genetics, and your immune system, all of these play a role in your resident bacteria. But diet is a big part of what shapes the microbial community. And that's why there's a lot of research in understanding how what we eat affects our microbes and what the microbes give back us and vice versa. But back to the hibernators, this is why I think we started to think, well, let's look at this because we have an extreme dietary model. We have diet and no diet. Very clear cut. What do microbes eat? Well, they eat diet, which are the little green blobs. 

Let's just say that's glycans. That's a word for polysaccharides. Fiber. Let's just say fiber that gets in. But us and animals, we have things that we shed. Normal things that come from our gut that are part of the environment there. Especially the nice mucous coating that we have that protects us from microbes. Some microbes can eat that mucous lining, and they do just fine. So you'd call it host derived. So you have diet and you have host and in the summertime those squirrels are just like us, like a typical mammal. 

They can eat dietary substrates that are floating around in the insides of your intestines and any host derived things. This mucous, that's that yellow area. The mucous lining and sometimes cells are normally shed off. So everything's good in the summer. The winter? No diet. The hibernator microbes, they have to live off whatever they can scrounge around and find from the host, but that's important. They've evolved together, these hibernators and their microbes. And I wanted to show you this plot and to simplify this. I want you to look at each of the dots on this plot, and each of these dots is plotted with a certain number that represents the community of microbes. 

Each dot is a squirrel's microbial community that we studied with collaborators that we have in bacteriology. And these dots represent how related the microbes are in that gut community. So if we look at this from all these different activity states that you see up there, we had mother squirrels and babies throughout the year. We wondered, does it make a difference in the ground squirrel microbiome what season the animals are in? And the closer these dots are to each other, the more they're related. Well it turns out that any animals in the active season, their microbe communities are pretty related to each other. But in winter, they're different. Their family history, their phylogeny is different. And it makes a difference where you are in the winter. The winter, the late winter, four or five months of hibernation. 

They're farthest from the active season. And the early winter, one month of hibernation only, they're just getting into their hibernation season, the microbes are in between. So these are the kinds of things we're looking at, and we're trying to understand how does the microbial community change. We know it does. How can we learn from that? And we can get pretty plots like this which are bars that tell us the abundance of certain bacterial types. And you can look at the changes of these colors, the two bars over here are the winter bars. One month of hibernation and four or five months of hibernation. And the colors are shifting. Some groups are falling out during hibernation. 

Others are expanding in hibernation. Like, for example, this one. These green bars are much bigger in the two hibernation groups. It turns out, interestingly, this is a relatively newly described bacteria in the gut. It likes to live off of these mucins which are part of the mucous lining, the molecules that are in the mucous. So it's happy to live in the wintertime when there's no diet, and it's getting a lot of press, this organism, in the biomedical community because there's more and more associations of this particular one, Akkermansia muciniphila, with health. So it seems to have a very close relationship with the host and provides healthy benefits. So these are just the sorts of things that were coming out of this. And as we do more and publish more and we got to conferences and talk to people, we're starting to get collaborators that are interested in this from the biomedical world. One is someone named Marty Blaser. 

He's at NYU School of Medicine. Just published this really interesting popular book. If you're interested in this, I love it. It's a great book. Missing Microbes. And his idea is that in our western more modern society, we're doing things that are reducing the abundance of the good microbes, especially early in life. Antibiotics is one example. We love antibiotics because there are diseases, boy, you need them to kill off those pathogens, but overuse of antibiotics can make a difference in the good microbes. And, in fact, in the work they've done with mice, they've found that it leads to later problems with obesity and pre-diabetes symptoms. So we've been doing some studies with their lab with our ground squirrels that if we give low dose of penicillin just to the moms while they're pregnant, does that affect the babies? 

This is just during pregnancy and four weeks of lactation and that's it. Low dose penicillin. And you know what? It does. And I'm going to show you the next picture has the inside of a ground squirrel after we euthanize it humanely and were studying the fat levels and different aspects, and this is just sort of an example of the inside of the pups from the mothers that were in control. No penicillin. But the ones from low dose penicillin, they have a lot more fat. Just three months of life. So it fits with what they're finding at NYU and other researchers, and it goes to things like food allergies and other disorders. So playing around early in life with that relationship with the normal microbes, we have to really pay attention to that. 

And we're starting to notice that in our animals too. So we're going to finish up here with a question. Who knows what this animal is? 

- 
[INAUDIBLE]

- Very good. There's many different types, as you know. This one's called the fat-tailed lemur. Got a lot of press about 10 years ago, a short report in the big international journal Nature. 

Hibernation in a tropical primate. Yes, we have hibernation in the primate lineage now, particularly with these lemurs it's turning up. But people are looking even farther. So these things that I'm talking about of translating hibernation to humans, you might say, well, come on. And there's different forms. Not all hibernators go as low as my ground squirrels. These lemurs do hibernate in the true word that we would call it, they just don't go as low. But they give up eating. They go into a depressed metabolic state. Think about, we're getting closer to thinking about how we might translate that. 

What are other ways? I don't know. Maybe long-term space travel. You'd say, well, I don't know. I have to say someone advised me, my very first NIH grant when I was a young junior investigator, he said at the end why don't you put in something like, and I was going to study hibernation and the gut, he said put in implications for long-term space travel. And I said no, no, I'm not going to. He said, no, you should. So I did. I got the grant, and I put it aside. This actually comes from, I got it off the internet. 

It's a company that put in a proposal to NASA to develop putting people into a stasis like state, like hibernation, for long-term space travel. And I thought, yeah, really. But you know what? European Space Agency, they're interested. And I'm now part of a small working group. I go for my second visit to Frankfurt in two weeks, advising them on whether they should really put the effort in to crack this puzzle of how hibernators do what they do because they're thinking about long-term space travel. So we're getting closer. I want to finish up by telling you that this amazing, cool building could not be the way it is if there hasn't been the decades of dedicated workers who have kept this really a stand-alone field station on our own campus. I like to call it a field station right on the campus. This is our current line up led by our associate director Isabelle Girard. 

She's in the back of the room. We have Bjorn Karlsson, the head of our plant program here as well. Great people. And this was the first field station, I did my PhD work in, a high altitude research station out west and I used to say, wow, it would be so cool to be the director of a research station like this, a field station, and now I get to be the director of our campus field station. Thank you for listening. 
[APPLAUSE]