Richard Jacobs: Hello, this is Richard Jacobs with the Finding Genius Podcast series. I have Ying-Hui Fu. She’s a professor of neurology at UCSF, at the Weill Institute for Neurosciences. We’re going to be talking about circadian rhythms, sleep behaviors, and what’s happening genetically when people’s sleep looks like. So, Ying-Hui thanks for coming.

Ying-Hui Fu: Sure. You’re welcome. Thanks for letting me be on part of your podcast.

Richard Jacobs: Speaking as someone who has a very strange circadian rhythm, I’m interested to talk about this. I usually go to bed at like three in the morning and get up at 1 and I have been doing it for 20 years and most people are horrified.

Ying-Hui Fu: Yeah. But you feel like best that’s your best schedule, right?

Richard Jacobs: Close to it. Yeah, that’d be like 2 to 10. So that’s, yeah.

Ying-Hui Fu: Yeah. So I think that’s exactly what we have been doing. Part of what we have been doing. So my research or my lab’s general focus on humans sleep behavior and tried to understand our sleep behavior. And then two areas that we focus on. One is the circadian rhythm and the other one is sleep duration. So circadian rhythm is about our sleep schedule. And so what we learned from our work is that our gene actually plays a very important role in determining our sleep behaviors. So whether you are night owls like you or morning larks, how many hours of sleep do you need that actually depend a lot on our genetic composition.

Richard Jacobs: Well I have heard that people when they’re teenagers, their circadian rhythm ships forward, and then when people are adults it may shift back, and then when they get very old it seems to shift much earlier. Is that because of changing gene expression?

Ying-Hui Fu: No, I think the way it is that teenagers usually tend to shift backward and that’s caused by the hormonal changes in our body. And most teenagers, they like to stay up late and get up late. And that’s because of the hormonal change and when they get the to late twenties and they start to become stabilized and that’s when you can really understand what your true body schedule and when we get to be young, you know, a lot of papers say 60, but I would say maybe 65 or 70 after 65 or 70, then your body starts to shift forward. It became early risers, go to bed earlier and get up earlier. That’s true. And we still don’t know why when people get older and then usually they go to bed earlier. So,

Richard Jacobs: But even though hormones signaling changes, are you saying that people have an underlying preferred circadian rhythm based on their genes as well?

Ying-Hui Fu: Yeah, exactly. And that’s what we found in the last 20 some years. I mean working on this about 22, 23 years. And we have so far found more than a dozen genetic mutations in humans that make them morning larks with one single base DNA change will make them want to go to bed somewhere between five to 8:00 PM and get up 2 AM or 4 AM. Yeah. So genetics plays a very important role in, in this and of course, I think that for most people it’s not so obvious. So the people we are studying, they have a stronger genetic mutation that makes them have very obvious, significant change. I think most people are not like that. Most people probably have several milder DNA polymorphisms that make them have a certain tendency, for example.

Richard Jacobs: What happens if your hormone signaling is at odds with your underlying genetics? Genetically want to be a Lark, but for some reason, you know, diets or who knows what, you know, disease, whatever your hormone signaling counteracts that, what does that look like if that happens?

Ying-Hui Fu: I’m not sure, but I would guess that it will probably mess up your body a little bit. I’m not sure about that because I’m not a physician. I’m a scientist. So I started as a genetic effect. If your genetic composition makes you a morning lark or night owls and then there are some other factors that make your body want to go the other way, it probably will be mess up your schedule a little bit. And the people I study, they have a very strong genetic effect.

Richard Jacobs: How do you know genes do this? So a gene is mutated. What does it do to the body that causes the person to, I mean it must control hormone release and the timing?

Ying-Hui Fu: So our body clock, actually our sleep schedule is controlled by the circadian clock. And so circadian clock actually it’s formed by a set of molecules that forms almost like a molecular clock. It runs a rhythm, a cycle every 24 hours and it can really set our body rhythm according to this 24-hour cycle. And so a lot of mutations and we found so far are mutations happened on this set of genes and make them change their function a little bit and therefore make these people’s sleep schedule altered from what we call normal. But this is really not people who go to bed early or late is not abnormal. It’s just they are off from the majority of the population. So most of the mutations we found so far fall into this group of genes, but we are starting to find mutation is outside this group of genes. So it’s a very complex problem and we still have a lot to learn. We still don’t have a complete picture. I will say.

Richard Jacobs: Well, what is the normal method of action of our genes that govern our clock? Like again, when a gene activates, what does it do in our body, what changes it causes?

Ying-Hui Fu: Sure there are the proteins that we call transcription factors and so what happened is in the morning, the strongest signal to regulate our body rhythm is the light. So in the morning when our eyes receive light, it was sent the signal for our body, the molecular clock to set it so that a set of molecular reactions will happen. The transcription factor will turn on the genes or turn off the genes. And therefore our body is very complex. It’s very hard to, within a few sentences to describe it. But essentially that’s what happened. The light signal comes into our eye and sends a signal to our brain. And then this whole set of the molecule has a set of reactions that happen once every 24 hours. It was said it happened and then it goes through this whole set of molecular reactions. And then this whole set of the molecular reactions was regulated more than half of the genes in our body to regulate our body functions. And therefore it forms this body rhythm of 24 hours. So it’s very complex because more than half of our genes of any specific organs or tissues that you look at is under this circadian clock regulation. So it’s a very complex mechanism.

Richard Jacobs: So when we sleep, our liver is sleeping it’s on way and pancreas it’s on way.

Ying-Hui Fu: No, every organ has its own rhythm. I’m not a Chinese medicine doctor, but I know just enough to say that in Chinese medicine this clock and every hour, every two hours or every few hours, there is a special function. Like liver function in certain hours and it’s at the rest of certain hours or so. But where I come from is different. So about 20, 22, 23 years ago, I had an opportunity to work on fighting mutations or genetic alterations for a specific family about their extreme morning lark behavior. And that’s how we started it because we had no idea that genes can control our sleep behavior until this woman came to us and she asked us to help her because she’s realized that her granddaughters and many of her family members all have this very strange sleep pattern that they need to go to bed like six 7:00 PM and they get up like two 3:00 AM. And she felt that this was a very negative thing for her in her life because in the evenings she couldn’t do anything with her spouse and she didn’t want her granddaughter to suffer the same way. So she came to us and asked us to help her. And so we realized that by looking at her family, we realize that this looks like some genetic factor that regulating in her family. So we went looking for a mutation in her family and found the mutation and report it in 2001 so this was way back in 2001. And that’s really the very first time we realize that our gene can regulate our sleep behavior in such an obvious strong way. And of course, after 2001, we have many, many mutations. But what’s even more interesting was that over the years, and we were looking for mutations for people who are morning larks or night owls and the 2001 publication from this family was a big hit. All kinds of newspapers and TV shows. And a lot of people came to us and wanting to participate in our study. So we started to look at the mutations in a lot of these people. And somewhere around 2005, we find a mutation among this whole bunch of people participating in our study. And when we found the mutation, we went back to look at this family and we realized that these people are not morning larks. They’re not the typical morning larks because they go to bed at the same time as most people, but they get up much earlier than most people. In other words, they are naturally short sleepers. They just don’t need as many hours as most people are. So we published a paper in 2009, and again, it became a very big hit on all the newspapers and TV shows. And again, we had this huge number of people came to us to participate in our study. So since the 2009 paper, we have published two more genes recently and we have a few more genes that we are working on in it and hopefully, we can publish pretty soon.

Richard Jacobs: Okay. Question here. So what would be the role of someone either being a night owl or a Lark? What physiological function would it serve? I’ve heard of, for instance, the Sentinel hypothesis, you know, night owls were sentinels when the rest of the tribe would sleep. But I don’t know. Are there any other theories out there?

Ying-Hui Fu: I don’t know those theories, but I feel, I mean the data is there. The morning larks actually, they usually perform better in the morning and the night owls usually perform better or later in the day. And those are we know that in science. But other than that, I don’t know anything about how they come from, it’s possible, you know, a long time ago for some reason, some people need to adjust their body to a later schedule in order for their tribe to survive. That’s very possible. But I don’t know personally about that to confirm or not confirm it.

Richard Jacobs: So once you identify these genes, then what? What are you going to do with them?

Ying-Hui Fu: We study their function and understand why there are mutations and that would affect their sleep schedule in such a significant way. And so it will help us understand how to modulate our body clock. And this I think has a significant impact on our future because now our society is really running in a 24/7 manner, right? There are a lot of people who need to go and do shift work for nurses or whatever reason and so it’s really not good for their health. If someone who is not a night owl and constantly do the night shift and that has very significant consequences on their health, right? Or another example would be therapy or chemotherapy or whatever medicine therapy. We know that our body runs in a clock. Therefore there is certain time it would be better for certain medicines to give to patients. Because there will be the best time to give the patient or this time for them to get most out of the medication. So for me, it says there are a lot of advantages for us to know how to regulate our body clock. Or for instance, you are night owl but you need to get up early the next day. Maybe there is something you can take to help you adjust your body for one or two days or when we travel when we have jet lag and something can help us adjust our body clock. So if we can understand the molecular level, how our body clock is regulated, it will help us maybe to come up with something to help us adjust our body clock easily. So these are the idea and similar to the short sleep, people, that were studied, these are naturally short sleepers, they sleep fewer hours, four to six hours their whole life without any negative consequences. Unlike most people, if they don’t sleep enough on a long-term basis, they will have some significant negative consequences. So if we can understand why they don’t need as much sleep at the molecular level, it will also help give us an opportunity to really see if there is a way we can help people sleep more efficient because we think that these short sleepers, they can behave this way or they can survive in a short fewer hour their whole life without negative consequences is because their sleep is more efficient. And so maybe we can figure out some way to help us all sleep more efficient, therefore we can all become healthier.

Richard Jacobs: How do you determine the sleep efficiency just, I mean from the person’s diary of how they feel or their other sleepiness index?

Ying-Hui Fu: Yeah, so when I first asked them a lot of questionnaires and we interview them and see how they feel if they have any health consequences. But the group of people we study they sleep on average four to six hours and they are very, very active. They’re very optimistic and they are multitaskers. They are excellent multitaskers. They usually have two jobs or more jobs or they go to school full time and have jobs on the side. And they usually live a full life until a very advanced age and still very healthy. So these are people who seem to have better sleep efficiency than most people. And we want to understand why we are this way. So now while I was studying this and I’d be study sleep for 20 some years. Over the years I realized that a lot of people don’t really realize how important sleep is for us and therefore people don’t follow their sleep schedule in order for them to maintain their health. And so I recently wrote a book called Sleep to Thrive and in order to help people understand how important this is. So this is really I think the most important thing, for now, is to help everybody understand how important this is. And I’m very happy I saw your podcast at least sleep is one of the areas that you are focusing on.

Richard Jacobs: Yeah, well I’ve had a lot of sleep issues and my family does. So we might make good Guinea pigs for the labs.

Ying-Hui Fu: Yeah.

Richard Jacobs: What do you hope to figure out in the next few years here?

Ying-Hui Fu: Yeah, so like I say right now what I’m most interested in is really understand the sleep efficiency, how to regulate sleep efficiency. Because if we can increase sleep efficiency for everyone, then all the incidents for all kinds of diseases will drop significantly. And to me, that’s much better than trying to find a cure for one disease at a time by, because poor sleep actually can significantly increase your chance of getting all kinds of diseases a lot higher. Including Alzheimer’s, cardiovascular problems, all kinds of problems. So if we can understand how to increase sleep efficiency, it will help us decrease the incidents of all of these diseases. And I think that’s my number one priority now. And I hope within a few years and we can learn enough to help us come up with some idea of how to help everybody sleep better more efficiently.

Richard Jacobs: What do you think is going to be the way to do that? I mean, if you understand someone’s genetics, okay, great. What then?

Ying-Hui Fu: Yeah. So the thing about our approach is that we’re just taking advantage of this very rare human with the genetic mutation. We’re just taking advantage of their genetic inflammation to help us understand how sleep is regulated really because it’s very hard to sleep as to us to study sleep because we have no idea how sleep is regulated. So we simply want to use these people’s genetic information to help us understand the mechanism. But if we understand the mechanism, then we can probably come up with some therapies that can help us increase sleep efficiency and that can help a lot of people without knowing their genetic information. We don’t need to know everybody’s genetic information. If we know how sleep regularly mechanism works, right? So we’re simply using the rare human to help us understand the mechanism. If we can understand the mechanism, then we can, without knowing people’s genetics, come up with some idea to help with to tweak the regulatory mechanism to make it more efficient.

Richard Jacobs: The sleep architecture of short sleepers is it different? Or the sleep architecture of owls versus larks or super larks.

Ying-Hui Fu: I think the basic mechanism is the same. Short sleepers versus normal sleepers. It’s the same but somehow somewhere along the pathway, something makes them more efficient. Now, night owls and morning larks, I think part of them is because their body clock is a little bit off for some of them. And the other group of people which we are starting find is that they’re in tremor mechanism is a little bit off from most people because to determine our sleep schedule is not just our circadian clock. It also our body clock is in trend by light every day and the signal in the clock itself, the master clock itself needs to send out through different signal pathway in order to regulate our entire body physiology. So if you can think of a pathway in the middle of the pathway is the molecular clock, master clock and there is a signal coming from outside going into the middle of the master clock and also signal coming out on the master clock to all of our peripheral tissues to regulate out our body rhythms or our physiology. And you can see that anything that goes off in this input pathway or output pathway can also affect our body rhythm, our sleep schedule. So it’s quite complex actually.

Richard Jacobs: What’s the best way for people to find out more about your work?

Ying-Hui Fu: Oh so I have this book, it’s coming out to call Sleep to Thrive, and copy is in Amazon and I’m having trouble getting the guy that helped me do this to finish electronic copy. But they can associate my name, they can find me very easily. Search my name. And I am at UCSF, University of California, San Francisco, and they can find me that way, or if they search my name I’ve done a Ted talk so they can find me quite easily. And I think the main goal is really to help everybody understand how important sleep is for their health and not just physical health, also their emotional health, their mood. Because we know that if we don’t sleep well, we get up a little crabby. If we sleep well, we get up, we’re happy and another very important part is our cognitive function. So it’s really about how our health, happiness, and how smart we are, that these are all connected to sleep.

Richard Jacobs: Well. Very good. Well, thank you for coming on the podcast. Thank you for allowing me

Ying-Hui Fu: Thank you for allowing me to come to your podcast. Thank you.