 Hello, and welcome to the OIST podcast, bringing you the latest in science and tech from the Okinawa Institute of Science and Technology Graduate University. Today we speak with Professor Fred Turrick. Professor Turrick is the director of the Center for Sleep and Circadian Biology and Charles and Emma Professor of Biology in the Department of Neurobiology at Northwestern University. He's also the founder and first president of the Society for Research on Biological Rhythms and has served as a consultant to numerous government agencies, most notably NASA, the Defense Department and the National Institutes of Health. And he came to OIST to deliver a lecture entitled The Molecular Circadian Clock and Its Impact on Health and Disease. In his talk, Professor Turrick brought to life the body of work on circadian rhythms, including the surgeon interest in recent decades, the impact of these rhythms on our health and the unsolved questions currently being asked by the field. In this talk, we cover the basics of the so-called master clock in the brain and its control on downstream processes in the body via two well-known circadian rhythms, the sleep-wake cycle and the feed-fast cycle. We also make the leap to discuss the health implications of this basic science work and an even bigger leap to discuss shifting policy and culture. Finally, we wrap up with some of Professor Turrick's recent studies, including the famed NASA twin study, exploring the impact of space exploration on the gut to microbiome. It's a fascinating discussion on a universal topic that affects each and every one of us, and we hope that you enjoy. Professor Turrick, thank you very much for joining us today. I'm pleased to be here. To begin, what got you interested in this research space? Well, the research space is really all around what we call circadian rhythms or 24-hour rhythms, and I got interested in it from an unusual perspective in that when I was a PhD student at Stanford, I met somebody who was studying seasonal rhythms. So these are rhythms that occur on an annual basis, so animals will migrate at one time of year or they'll reproduce at one time of year. And that's all regulated by the length of the day. And it turns out, if you know that it's regulated by the length of the day, meaning that, let's say, a small rodent will reproduce during the long days of spring and summer and won't reproduce during the winter, and you can regulate that by altering how long the day is, even in a laboratory condition, well, then you've got to ask, how do they measure the length of the day, and it turns out they use their circadian clock, the 24-hour clock. So I got into the circadian clock by looking at seasonal rhythms and how animals measure the length of the day. Then I started studying 24-hour rhythms in behavior, in physiology, and ultimately into molecular and cellular circadian rhythms. What is the basic mechanism of the circadian clock? The main master clock is in our brain, and it regulates all of our 24-hour rhythms, and it's in an area of the brain called the hypothalamus. And the hypothalamus is involved in many, many, many autonomic behaviors such as your body temperature regulation, reproductive behavior, feeding behavior, and it turns out there's a small area there that has the neural basis of generating circadian. Circadian means about a day, circadian. And so the clock is actually located within our brain. It's entrained or synchronized by the 24-hour light-dark cycle, which is due to the rotation of the earth on its axis, and then it then regulates all the rhythms of the body through neural and hormonal pathways. Now, then we start asking, you can ask the question, well, this neural clock, how does it generate 24-hour rhythms? And that's been the new discoveries over the last two decades and still ongoing, finding how at the molecular level what genes and proteins are involved in generating a 24-hour signal. I'd like to say that when I look at the, let's say, a 24-hour rhythm of an animal that's in a constant darkness or a constant light, the rhythm is not exactly 24 hours. It's maybe 24 and a half or 23 and a half. So it's got to be synchronized by the light-dark cycle. But that rhythm is so precise, I used to say that an animal from day to day is so precise if it's 24.2 hours, it's 24.2 hours every day plus or minus one minute. I used to say that your internal clock is better than a cheap Swiss wristwatch. I don't say that anymore because even the cheap Swiss wristwatches are very accurate now. But still, we have in our brain this timing mechanism and we now know that all the cells of the body actually have the timing mechanism at what we call the molecular or cellular level but that it's synchronized all the cells of your body by the central clock in the hypothalamus. And sitting underneath that central clock in the hypothalamus, two of the big circadian rhythms that are some of the most important? Well I call them sometimes the master circadian rhythm. So you have the master clock but once I regulate the sleep-wake cycle, for example, timing of the sleep-wake cycle, then when you're asleep certain processes get turned on or get turned off. So for example, you have a rhythm of growth hormone. That growth hormone is high at night. But if I don't let you sleep, the growth hormone doesn't increase. But if I let you sleep, then it increases. So by regulating the sleep-wake cycle, I'm regulating a lot of downstream rhythm from the sleep-wake cycle. The other master circadian rhythm is the feeding cycle. Animals eat at one time of the day more than they eat at another time of the day. We humans are diurnal creatures. This means we're active during the day, we're eating during the day and before the invention of light devices, before really electrical lighting, we were synchronized to eat during the daylight hours and to sleep and not eat during the dark. But once I regulate that feeding cycle, then the intake of food affects the rhythms in your liver, the kidney, the muscle, other areas of your body. So in a sense, the master clock is regulating, some rhythms are regulated directly by the master clock in what we call the suprachiasmatic nucleus, which is a part of the hypothalamus. But it also regulates behavioral rhythms and those behavioral rhythms regulate many other rhythmic processes of the body. And one of the distinctions between humans and other living things is often talked about in the context of language, but in the context of your work, we're also the only species to voluntarily disrupt these circadian rhythms. What are the consequences of that? Well, first off, you put that very, very nicely. And I like to say that when I'm studying circadian rhythms in my rodent models, particularly mice now, the mice never stay up late to go to a movie. They never read a book late. They don't play on the social media. And so we are the only species really that when our clock says time to go to bed, we just say, hey, I don't want to go to bed. I want to go to a party. I like eating late at two o'clock in the morning when that would be a time one would not normally be eating if you were living in the environment where the only light you had was from the sun. And so what we're finding is that this circadian, we call it misalignment, where you're doing something at one time of day when your body clock is telling you don't eat, don't eat, and you're eating, then your gastrointestinal system, for example, is saying, OK, time to rest, and you're putting food into me now, and I'm shutting down for the night. And so what we're finding is that this sort of mismatch, where our lifestyle is not in synchrony with our internal biological clock, and we're finding that this is leading to, particularly in animal models, but also in human epidemiological studies, that this sort of mismatch can lead to obesity, can lead to diabetes. There's suggestive data that even can impact neurological functioning, that can maybe even associate it with the onset of neurological diseases, because you're just, when you think of yourself, you look in the mirror and you see your body in space. What you don't realize is that you are temporally organized as well as being spatially organized. And so if I disrupt that internal temporal organization, that's going to potentially have, and now that's being demonstrated, have negative effects on various physiological systems, the liver, kidney, cardiovascular function. So these can be disrupted. And OK, if you disrupt them for a day or two, probably not a problem, but if you have 20 years of disrupting, the analogy I always use is if you smoke one cigarette once in your lifetime, hey, don't worry about it. It's probably worse just living in a city, right? Yeah, a lot worse, right. But if you smoke a pack of cigarettes a day for 20, 30 years, we know that you're going to have a very negative impact on your health outcome, your wellness, your longevity, obviously lung disease. And so it's the same thing that if you have sort of prolonged periods of circadian disruption, we know that a short period of circadian disruption can be discomforting. So when you travel rapidly across time zones, you not only have a problem sleeping, you may have some digestive problems, but within a week or so, you resynchronize to the local time, which I'm in the middle of doing right now, having flown from Chicago to Tokyo and Tokyo to Okinawa. Not suffering too much, but some people really have a hard time with that jet lag as it's referred to. But it's something that I only do three, four times a year. But if somebody is a shift worker, they're doing it every week. By shift worker, I mean someone was working at a time when their body clock is telling them to be asleep. So that would be, say, somebody working from midnight to eight o'clock in the morning. That would be okay if they did that all the time. But what happens on the weekend, they don't stay awake from midnight to eight o'clock in the morning, they will immediately try to adapt so they can be with their family and friends and have social activities. So they're essentially altering their relationship of their external life with their biological clock on a weekly basis twice a week, because then come the Monday, let's say, when they go back to work, they're going to switch back. So they're almost in a constant state of jet lag. And that has consequences for the rest of society. So if you're a shift worker who's in charge of a train, for instance, or a doctor working with patients through the night, that has real consequences. Yeah. And I can say, I can solve all those problems. Just don't have any shift work. Well, that's a silly statement. In our society, it's like if you go to the emergency room at three o'clock in the morning and they say, oh, I'm sorry, the doctor doesn't come in until eight in the morning and you're going to die. So we live in a society where we have our whole lifestyle and it's not just shift workers. It's individuals who want to stay up late and who are not in synchrony. So we need to figure out ways to decrease the adverse health effects of that. And I wouldn't say we're really there yet other than if somebody's in a dangerous job like a truck driver and it's three o'clock in the morning, we want to make sure the truck driver is educated to make sure that he's slept well before coming on the job, recognize that his body clock is telling him to go to sleep when he's got to drive the truck. OK, so what can we do about that? We can have perhaps devices in the truck which can recognize when he may be falling asleep because his body clock is telling him to go to sleep and then those devices in the truck would wake him up. But we do know that the incidents of accidents involving rail or truck, they have to work all night long. There has to be somebody working all night long. And so we are looking for ways of trying to regulate their sleep bike cycle, educate them about some of the difficulties of something as simple as when they go home and then they have to sleep, say, from 8 o'clock in the morning till 4 in the afternoon, like making sure that they're in a dark room, making sure that the husband or wife knows to keep it quiet. Don't wake me up. Let me sleep during this time period, even though it's not the time I normally would sleep. And that's why we have laws on hours of service, for example. You can't drive a truck for 24 hours, at least in the United States. And so therefore we try to make regulations which will mitigate as much as possible the adverse effects of not getting enough sleep or the adverse effects of doing something at the wrong time of day. Yeah, and moving out from the basic science then, answering some of those questions in the lab is tough enough. And then when you begin to sort of see the bigger picture in the wide reaching health implications of that basic science, that's another big leap. But then move even further out to the kinds of situations you're describing with culture and policy. I know that some of your research has had an influence on policy around schools and the timing of education. How do you grapple with those cultural challenges when it comes to policy? Well, I think you've picked a very good example, I think, of school start time. So without going into too much detail that around the time of puberty for teenagers, they have a hard time falling asleep. Their body clock, we say, has been delayed. They have a hard time falling asleep until, let's say, one in the morning, which is not a problem if they don't have to get up until nine. The problem comes in when they got to get up at six or seven to catch a bus to go to school. And so they have had a truncated sleep time. So there are studies which have shown that when they delayed the onset of the school, there's been an improvement in the grades, let's say, of the individual or their test scores. That's nice, but so does that mean we should all be starting school at a later time? And well, there are other factors involved. If I start the school at a later time for high school students, do the young children, say, seven, eight, nine years of age, who don't have this problem, they might have them go to school early. Well, if they go to school early, they may be waiting for the bus in the dark. So it becomes a complex society issue. And I think education is one of the things we can do. But we've got to put into, like I said, you can't say we're not going to have any medical or safety people working during the night, we've got to have them. And so we've got to think about solving these sleep circadian problems in the context of our whole lifestyle. There are so many factors involved that it really has to educate the public about what some of the issues are and then try to mitigate them as much as possible the negative consequences. Can you tell us about the NASA twin study? Oh, wow. Okay, the NASA twin study, there was a mission. It was a one-year mission where Scott Kelly was on the space station for one year. And that was the longest time any American had been in space. And so there was an interest prior to that, the longest time that anybody had been in space was six months, an American. And I say an American because while the Russians have had cosmonauts in space for longer periods of time, they didn't do a lot of studies on what impact did that have on the Russian cosmonauts. So we have a lot more data on American astronauts. So the fact that he was going into space for a year was interesting itself, but what made it really interesting was he had a twin, Mark Kelly, who was retired astronaut. So he had been an astronaut and had flown on the space shuttle. And so we had an opportunity to study Mark and Scott Kelly before the mission. In other words, we could look at, in my case, I was interested in the microbiome so we could collect fecal material before his flight and then was able to determine if there were any changes in his microbiome during flight compared to pre-flight. And then did those changes reverse themselves if there were any changes and there were changes when he was on the ground? Why the microbiome? Well, first off, I should say that there were 10 teams that were studying the twin. And we happened to be the microbiota team because I was very interested. I've talked about 24-hour rhythms and the sleep-wake cycle. And the gut microbiota is very interesting in itself in that it turns out that we have 10 times more bacteria in our gut than cells of our body. And these microbiota, in our gut, we are finding literally on a daily basis, certainly even a weekly basis, that changes in the microbiota can impact many organ systems of the body, including the brain. And so we're interested in what changes in the microbiota are associated with various disease states or stress or post-traumatic stress disorder, depression. And so our understanding that we have the microbiota and that they're changing in various disease states is something that's only about 10 years old. And we're learning something new every day. And so because I was interested in disrupting rhythms and sleep and the microbiota, and I had published some papers on that prior to the twin mission, when NASA announced that they were going to have a twin in space and a twin on the ground, various people applied to study different aspects of the twin. So somebody studied gene expression in space versus mark on the ground. And so the twin study ended up being a multi-investigator, multi-team. And in fact, the paper that we published first reporting the results, many other papers will come out afterwards, but the paper that gave the general overview involved 85 investigators. There were 85 authors on the paper. So the microbiota was just one component of and that happened to be my interest. And of course, Mark was on the ground and he was eating different food than Scott was eating in space. Scott in space was N of one. And of course, in science, we like to have a greater number than one. And so then I subsequently proposed to NASA, we'd like to study the effect of the space environment on twin mice and min. So by that, we studied man, what subject of one. But it turns out that there are many strains of mice, which I call twins, because they are genetically identical. They've been bred to be genetically identical. And so we then had the opportunity to fly 20 mice to the space station and had control mice on the ground, eating the same food. Before they eat, I'll call it space food, it has to be a compact bar that you just can't have pellets of food floating around, remember they're in zero gravity. And so we launched in June of 2018 20 mice to the International Space Station and then the samples were returned in February of 2019. And so we're in the process of analyzing that. Now we're looking at the microbiota, but other people will be looking at other tissues of the body. They were in space for 75 days. How did that 75 day exposure affect, let's say, gene expression in the eye or gene expression in the heart or gene expression in the female reproductive tract? The 20 mice we send up were all female, in part because the females, when they're group housed, they don't fight as much as the males do. And so we flew females who are much friendlier to each other. So we're going to have a bigger sample size. We'll be able to determine whether or not the changes that we saw in Scott Kelly are going to be reproduced in mice. And because we'll have a larger number of animals, we're I think we'll be able to make much stronger conclusions. And what do you anticipate some of those conclusions might be? Let me put it this way. We can't send humans on a long mission to Mars, for example, which will take somewhere around two, two and a half years, depending on how long we're going to stay there, without knowing what is the effect of the microgravity environment on all the physiological systems of the body. And now we have this new, I'll call it an organ, a new organ, the microbiota, who we have evolved. And there are good microbiota that help us digest our food and our cardiovascular activity. And there are bad microbiota. And exactly which ones are good and which ones are bad is still being studied. It's an emerging field in itself. But we need to begin to understand what is the effect of the space environment on the microbiota. Based upon our data so far, we don't see that there's major problems. But again, we had an N of one, even that was a one-year mission, not a three-year mission or two and a half or three-year mission. So we have probably until 2035 to determine what effects there may be on long-term exposure to microgravity, on cardiovascular function, muscle function, bone function, brain function, microbiota composition in the gastrointestinal tract. Well, it sounds like you've got your work cut out for you and I look forward to seeing how all of that unfolds. Well, we're really excited about, like I said, the data on the mice that we will be analyzing over, probably over the next year. There's an immense amount of data that we need to analyze. And so, yeah, it's exciting times for us because no one's ever done an experiment looking at rodents for 75 days in space. And so what is exciting for many of us is, first you have to say, should we be setting humans into outer space? Should we be going to Mars? And I'd say yes, it's human destiny to explore. That's part of what makes us human in a sense. And we've explored lots of regions on Earth, although I could argue that, boy, oh boy, we ought to be also spending a lot of money and time on studying deep oceans. We still don't, there's a lot of things we don't understand about deep oceans. We've been exploring for literally- Forever. Forever, let's just put it that way, right? So I just happen to be one of those people who thinks that in addition to what we may discover in outer space, it is our part of our destiny to explore and establishing a lunar colony, going to Mars. Those are things that we can at least see we can do on the horizon, the horizon over the next 50 years. And there may well be 50 years from now, we'll have technologies and the ability to explore further into space. But let me also then make a point that's very important is that we have to create new technologies, we have to create new ways of doing things to get to Mars and many of those get translated into improving life on Earth. There are a lot of discoveries that are made through the space program that translates into improvement in our lives on Earth. There are many, many advances to be made by studying living organisms in the space environment and also studying the technology that will get us there. So before I let you go, I thought we could wrap up with some rapid fire questions on sleep, how does that sound? Okay, rapid fire. If we know that sleep is so important, why are we still arrogant or are we still arrogant? Yes, we are very much so. And we are interested in sleep disorders such as insomnia. Insomnia is where you wanna sleep but you can't sleep. I won't go into the details of that or sleep apnea. But what we're finding more is that people who have short sleep have more health problems. And so we say, hey, get more sleep. And people will say, oh no, I, my- Sleep is for the weak. Sleep is, oh, sleep, not only sleep is for the weak. I've heard one person say, I can sleep when I'm dead. Well, yeah, that's good, you'll probably die sooner if you're not getting sleep now. So yeah, I like your word, arrogant. We think we can overcome mother nature, let me say. If I could call the biological clock, mother nature. But we do that at our own peril. And that's one of the messages we want to get out to the public is that sleep is important for your health, just like exercise, diet, sleep, keeping up sort of a regular circadian schedule. And a good example I can give for that is that there's still this sort of stigma for people who take a nap. They can't nap at work. If you nap at work in many places, you'll get fired. If the boss comes by and you're just, wow. What am I paying you to sleep? Yeah, exactly. And a new study just came out, and I'm not surprised at all, showing that people who take naps have a decreased risk for heart attack. So that kind of information has to get out to the public. And if I could use the analogy with smoking again, smoking used to be thought to be good for you. Seriously, I mean, it was only when they started following people for 30, 40, 50 years, they noticed that, gee, just large number of people are dying of lung cancer, and what do they have in common? They've been smoking. One of the hardest things to do is to change human behavior. And we've come a long way with smoking and getting a decrease, at least in the United States and in some of the other industrial areas of the world. So we change that behavior. Can we change the behavior so people take sleep more important? I think yes, but again, it becomes education. It becomes changing the way you even view the importance of sleep. If you had one piece of advice for us on how we can sleep better, what would that be? Keep a regular sleep awake schedule and make sure you leave enough time. I think that's it, leave enough time to sleep. And if you have a hard time sleeping, make sure you have a darkened room to sleep in. Don't even have a television. Well, I forget television anymore. People don't watch television anymore. It shows how old I am. Particularly with looking at your iPhone or looking at your tablet for an hour or two before you go to sleep, it's bad for you to then sleep. And it's also bad for another reason that people don't think very much about. You want your brain to slow down before you go to sleep. You don't want it to be highly active. And when you're on, let's say social media, tweeting President Trump, your brain is very active. To answer your question, very simple. Save enough time to sleep the amount you need to feel rested and not fatigued during the day. So there you have it folks. Stop tweeting President Trump and get some sleep. Professor Tarek, thank you so much for your time. Okay. Thank you for listening to the OIST podcast. 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