Animals such as grizzly bears and Arctic ground squirrels have evolved the ability to hibernate as a way to survive winter months of extreme cold. During hibernation, their core body temperatures drop and their heart rates and metabolic activities slow to conserve energy. They also consume less oxygen during this inactivity.
But what if you could make non-hibernating species — including humans — hibernate? How could you control hibernation as a therapy to help people recover from strokes or heart attacks, or administer it to astronauts to help them endure a yearslong trip to Mars? Scientists at Oregon Health & Science University have embarked on a first step to exploring these questions by inducing a state of hibernation in rats, which don’t normally hibernate. Joining us to discuss this research is Domenico Tupone, a research assistant professor of neurology at OHSU.
Note: The following transcript was transcribed digitally and validated for accuracy, readability and formatting by an OPB volunteer.
Dave Miller: This is Think Out Loud on OPB. I’m Dave Miller. Animals like grizzly bears and arctic ground squirrels have evolved to hibernate as a way to survive months of extreme winter cold. Their core body temperatures drop, and their heart rates and metabolic activities slow down to conserve energy. What if you could induce a version of this in non-hibernating species, including humans – a kind of controlled short-term hibernation as a form of therapy to prevent damage from strokes or heart attacks?
Domenico Tupone is a research assistant professor of neurology at OHSU. He recently pioneered a version of this in rats, and he joins us now to talk about the implications. It’s great to have you on the show.
Domenico Tupone: Well, thank you for having me.
Miller: I want to start with the real world, or non-interventionalized hibernation. So what happens inside, say, a bear’s body when it hibernates?
Tupone: What they do is actually reducing their metabolism. Let’s suppose outside is cold and normally we will start shivering to defend our body temperature. What they’re trying to do is trying to save energy so they reduce the metabolism. And this comes with a cost. They also reduce their temperature, the whole system slow down, brainwaves slow down, so that they consume less energy and they can survive the winter time. In bear, their temperature doesn’t drop as much.
But if you look at arctic ground squirrel, that are present in Alaska in the tundra, they have another feature that is called torpor. They enter hibernation during the winter season, but they have this ability to shut down the metabolism so strongly that their body temperature can reach the freezing point. They of course will not freeze, but their body temperature is dramatically reduced. So they can save a lot of energy and they can survive a very harsh winter.
Miller: How is it that their tissues don’t die when they get close to freezing?
Tupone: Well, the tissue doesn’t die because if you turn off the machinery of the cell by reducing the metabolism, so the tissue itself doesn’t really need oxygen, then they don’t go into an ischemic kind of situation.
Miller: Ischemic means damage from lack of oxygen?
Tupone: Yes, correct. So in this kind of stage, they don’t use too much oxygen, they don’t use too much energy, the cell is turned off. You can imagine a car, if you have a car with a turbo, the car is using a lot of gas to run with a turbo. And if you remove the turbo to the car, the car becomes just working slowly, then it’s consuming less energy. And if you stop pushing on the accelerator, then you save even more energy. That means that the machinery in the cell works to a less powerful state, less efficient state, then they’re gonna save more energy. But they don’t get damaged because the system is still up and running, but to a very, very slow idle kind of situation.
Miller: What did you do with the rats in your study to induce a version of this, to mimic this?
Tupone: So the idea is this: this is how we work as a human, and rats and mammals in general, and this is true also during the summer in Arctic ground squirrel and hibernating animals in general. If we are getting exposed to the cold, the skin is feeling this cold, and there are sensors that communicate to the brain, a thermostat into the brain, that outside is cold.
In order to maintain our body temperature constant, we need to activate thermogenic organ. To give you an example, you can imagine in your house if you like. becomes cold, you have a sensors to feel the cold, communicate with the thermostat that is cold, and the thermostat is going to start the heater, the heating system in your house. The opposite will happen if the house is warm, the thermostat will turn off the heater. Then the same system is pretty much present in mammals, and we can defend body temperature in that way.
So there is a large interest in trying to induce this hypothermic state. And one way to do this is to just remove the heating system. You cut the cable to the heating system. And then what is happening is you still feel cold, the thermostat is trying to turn on the heating system. But now the heating system is not working because you have disconnected it.
Miller: Is the heating system more than shivering? What else do we have literally that makes us warm – blood circulating to bring warmth to the extremities? How do we heat ourselves?
Tupone: We have two thermogenic organs that are producing heat. One is muscle for shivering, and this is very largely present in humans. This is what we use the most. The other one is a little tissue that in animals is present in the back of the animal, called brown adipose tissue. For a long time, it’s been thought that this tissue was also present in human just in neonates. But we recently discovered that even adults have this organ, and we can warm up our body through this kind of system. We of course will rearrange also the blood to extremities. If it’s cold outside, we’re trying to reduce the amount of blood to the extremity so that we can conserve, we can save more heat inside our body.
So we control these three different organs – one that redistributes the blood and another two that are instead producing heat actively.
Miller: And with these rats, what did you do with them?
Tupone: Many other researchers are trying to just block the heating system. You can give a human an anesthetic and that will shut down the shivering, so the person will probably become more cold for that reason. What we were looking for was something different, not just removing the heating system, but trying to figure whether we have a different kind of thermostat working in a different way. You can imagine that an hibernating animal must have a way of regulating this function. It must have a different thermostat that works in a different way.
So what we have done in these rats is we have blocked the activity of the original thermostat, the one that will respond normally to cold and warm ambient, and allow us to maintain our body temperature. And when we have done so, we discovered that the system is now responding in a completely different way. So if you are exposed to the cold outside, now this alternative thermostat is blocking the activity of this heating system – brown adipose tissue and shivering. And if you are instead warming up the skin outside, now you turn on the shivering and you turn on the heating system.
So we have figured out a way to invert the response to cold and warm, so that the thermostat is working in an inverted way compared to the original function. And this mimics much more what is happening to an hibernating animal. As I was saying before, an hibernating animal during the summertime is responding to warm and cold in a normal way, like we do if we are exposed to the cold, we shiver to maintain our body temperature. So an hibernating animal does during the summertime. But during the winter time, we will respond in same way during the summer. But these animals during the winter time, they are able to feel the cold outside, but they decide not to use the heater. They stop the function of the heater, so they become cold. And eventually, if you warm them up, they can emerge by activating the system.
So we figured out that the rats may have an alternative thermostat that works in an inverted way. And maybe this is the same system that hibernating animals use naturally to enter the state of torpor or hibernation.
Miller: If this research were to progress, and you could go beyond animal models and eventually get to human therapeutic applications, how do you imagine it might be used?
Tupone: Well, the first thing that comes to mind is the use for stroke, cardiac ischemia, particular types of surgery. Let me give you the example of stroke. If you are in a stroke, you have an ischemic situation, lack of blood in the tissue. And the tissue that is lacking the blood can be damaged. So if you can induce the state, you can reduce actively the metabolism of this person. By reducing all the metabolism, these cells are not in need of oxygen anymore, because you have reduced their activity. So you can save this cell from damages. Trying to imagine a person that is very far away from a hospital and you can get a stroke, it’s gonna take quite a bit of time to get into the hospital, so the brain damage can be devastating. But if you have a drug that can induce the state, this person will go in a kind of suspended animation that is going into a hibernation state. So the temperature is low, you save the cell, and you buy time for the doctor to save the life of this person or to reduce the damage from ischemia.
Miller: What you just described, so that would be different than the way controlled hypothermia or therapeutic hypothermia is already used today for some patients who’ve had heart attacks or brain injuries? There is cooling that already happens, but what you’re doing is fundamentally changing the thermostat in a different way – is that a fair way to put it?
Tupone: Yes, it’s a fair way to put it. The big difference here is that what they do now is trying to block the heating system from working. This new thermostat is regulating the system in a completely different way, we can manage the hypothermia much better, we can bring this person in and out from the state much faster. This will be more physiological, more closely related to what is happening on hibernating animal, and then we can decide when they can go in and go out.
The other thing is that this will facilitate the speed of cooling these people, because this is an active system and the brain is not fighting back to try to warm up the body. If you use an aesthetic, it’s true, you can block the activity of this thermogenic organ, shivering and brown fat. But not as much. As soon as you reach certain value of core temperature, if the temperature goes below 33°C, 32 °C, eventually they will start shivering again. With this other system, the whole system works in an inverted way, so we are fully in control of the situation, so we can manage this hypothermia much better.
Miller: What about things that maybe many of us have seen in movies and TV shows, of somebody on a spaceship in a kind of frozen or very cold suspended animation for months at a time. Is that pure science fiction or is that in the realm of far possibility?
Tupone: I mean, there is a big difference. First of all, this is not freezing. We are not freezing bodies. If you freeze, you’re dead. The body must be alive. I think it’s very far away and it’s probably not really feasible to reach that kind of science fiction that we see in movies. But we can get close to it. That would be much more complex.
Miller: Domenico Tupone, thanks very much.
Tupone: Thank you.
Miller: Domenico Tupone is a research assistant professor of neurological surgery at OHSU.
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