In Our Time - Circadian Rhythms

Episode Date: December 17, 2015

Melvyn Bragg and his guests discuss the evolution and role of Circadian Rhythms, the so-called body clock that influences an organism's daily cycle of physical, behavioural and mental changes. The rhythms are generated within organisms and also in response to external stimuli, mainly light and darkness. They are found throughout the living world, from bacteria to plants, fungi to animals and, in humans, are noticed most clearly in sleep patterns. WithRussell Foster Professor of Circadian Neuroscience at the University of OxfordDebra Skene Professor of Neuroendocrinology at the University of SurreyAndSteve Jones Emeritus Professor of Genetics at University College London.

Thank you for downloading this episode of In Our Time, for more details about in our time, and for our terms of use, please go to BBC.co.com.uk slash radio 4. I hope you enjoy the program. Hello, circadian rhythms are a biological version of a clock inside humans and all other animals, and they're in plants and quite possibly in almost every living cell. And their origin can phrase back to the beginning of life itself three and a half billion years ago. These rhythms are a response to the most predictable condition of life on Earth, that is, dark at night and bright during the day. For billions of years, life has depended on circadian rhythms

to ensure the best use of daylight hours and to promote rest in the darkness, when cell repairs and memory adjustments can be carried out for the next day. Daylight regulates the clock. In modern times, it has been increased interest in the effect of artificial light on humans, and whether that can disrupt our circadian rhythms and disrupt our sleep with grim consequences for health.

With me to discuss circadian rhythms are, Russell Foster, the Professor of Circadian Neuroscience at the University of Oxford, Deborah Skeen, Professor of Neuroendocrinology at the University of Surrey, and Steve Jones, Emeritus Professor of Genetics at University of College of London. Steve, circadian rhythms first. Well, it's all in the name, circadian, almost a day. And a circadian rhythm is any biological process on any level, from biochemistry to human behaviour,

which has an approximately 24-hour... timing mechanism, and that's driven by what biologists call an internal oscillator, a clock for short, which can persist even in pure light or pure darkness for some time, but can also be altered as the periodicity of light and dark change, as we see, as we get close to the shortest day now on the 21st of December, the clock can cope with that, the internal clock can cope with that. So that's what a circadian rhythm is. It's an internal timer, but it's really much more than that.

Well, can we start with the impact that sunlight, that connection between sunlight and cell evolution and circadian rhythms? Well, it's a very deep one. You know, we do live on a rotating planet. And if you look at the earliest days of life, the blue-green algae, as they call cyanobacteria, they have circadian rhythms.

Although when they, if you look at their fossils, they were living in a 22 rather than a 24-hour day. And we know a lot about the mechanics of that particular rhythm, which is quite different from ours. but what it consists of is just, I think, three proteins. And in the day, daylight, ultraviolet light, damaging, much more in those days, these gather around the DNA and protect it. And at night, they move away from DNA,

and the DNA starts doing all those essential repair mechanisms to the cell. And that's probably how it began, as a protection against the damaging effects of ultraviolet. And it's more than a coincidence, I think, that some of our genes for circadian ruse, look very much like some of the genes which repair DNA damage. So they're really fundamental to the evolution of life.

So we've carried those genes through for three and a half billion years. Well, I think the mechanism has changed. I mean, the mechanism in humans is different from blue-green algae. The mechanism is plants. It's different from the ones in mushrooms. But the actual, the output, the 24-hour clock, has persisted all that time. One of the things these do, as I understand from reading for this program,

is to anticipate what's going to happen. What advantages are these rhythms give us a sense, or build up, a sense of anticipation? What advantages are there in that, and how do they do that? Well, I mean, you know it's going to get dark at, if you happen to live on the equator, it's going to get dark at six o'clock. So that gives you a framework in which you can live your life.

And people can then alter their behavior, often in a shared manner across the society. And it sometimes argued, actually, that the circadian rhythms are what led to the ability of humans to live in societies, groups, because they're doing the same things at the same time.

And it's noticeable that humans sleep much less than any other primate. And chimps on the average sleep about 12 hours a day. Some primates, Gibbons, sleep about 15 or 16 hours a day. But we sleep much less, where brains are much more active, than when we're asleep, and we sleep much more economically,

and we probably slept in groups as early humans when we came down from the trees. So I think they pervade every aspect of our lives from social biology all the way down to the DNA. And this ability to anticipate, although it seems very simplistic, it's getting darker, so anticipate, but it's a built-in, intricate mechanism in the cells

and it allows us to get a flying start in the morning, for instance. Yes, all those things. I mean, it was always one's thought that sleep was simply resting. Okay, it meant you didn't walk about and fall under a bus and you weren't eaten by a tiger and that kind of stuff. But actually sleep is some of the busiest times of day for any one of us. And parts of your sleep process, your brain is enormously, enormously active. It's not just cooling down and going to sleep.

Animals like polar bears that hibernate, they warm up now and again because they're asleep. We're doing sleep later, but that's a good introduction. do it. And they turn the program this is there. Thank you. Russell Foster, what are the essential components of a body clock? In humans. So, in humans and in fact, most systems, you have, as Steve was saying,

a central pacemaker or an oscillator purchasing this about a 24-hour signal. But it's of absolutely no adaptive value to anticipate predictable events within the environment unless it's capable of being set to the external world. And most of the

time, it's light that provides this this essential signal or zeitgeber, as it's called, to set the internal world to the external world. And of course, the classic mismatch between internal time and external time is jet lag. We ultimately get over jet lag as a result of exposure to the new light dark cycle. And then the third component is essentially an output pathway.

This clock has got to communicate with the external world. And in fact, I suppose that's the area we know least about. We know about the photoreceptors, the light sensing systems that set the internal clock. But it's those signals from the clock to the external world. the rest of the body, coordinating the sort of circadian network of biology that we know least about. So to go to recap, the body through the eye sets the clock in motion. So we know that much.

We know how it sets it in motion, what motions it sets it into, what complications there are. And then the next step is even less research. Yes, yes. We're kind of at the beginning of this, aren't we? I mean, I think we've got enough components. So in mammals, we actually know where the master pacemaker, resides within the brain. So in the hypothalamus, in the sort of base of the brain, there's a small paired structure called the supra-chizmatic nuclei, or the SCN for short. It's about 50,000 cells,

and that is absolutely essential for generating these 24-hour oscillations. If that area of the brain is damaged and that can occasionally happen in tumors of the brain, for example, you see these beautiful 24-hour rhythms, they simply dissolve and collapse. Ossolations are a bit like ticking, are they? Yeah, you can think of a... And we all have oscillations in all the cells in our... That's right. And so you have this master clock with these 50,000 cells. And what's turned out to be

truly extraordinary is that we thought originally the clock was a network property, cell cell interactions generated a 24-hour rhythm or near 24-hour rhythm. Now we know that you can take a single neuron, stick it in a dish, and you can see 24-hour oscillations of electrical

activity or gene expression. And that told us that the mechanism, the fundamental fundamental mechanism of the circadian rhythm is a subcellular molecular feedback loop. Can you tell us more about the hypothalamus? It's fascinating, isn't it? When did you discover? Who discovered it? Not who, it doesn't matter who. When was he discovered it and what effected that how? Well, the idea that there was a central pacemaker started from the work of Richter in what the 20s and 30s, and he was fascinated about how you can get a seemingly endogenous independent 24 hours. which generated from within.

And then later on in the 1970s, people tracked down this part of the brain to the supra-cahismatic nuclei. If this brain was destroyed, then those 24-hour rhythms were lost. And then we go, we stepped forward really to the 1990s and 2000s, where our real understanding of this bit of the brain became clear. And Uli Shibler, for example, showed for the first time that a single cell can generate a 24-hour oscillation. And we seems to me from reading that what we, what you, you actually, literally you and Deborah are working on now is how pervasive, how important, how much more important than ever thought of before this is. Yeah, I think when Deborah and I sort of started in this field, we were sort of, it was a sort

of a peripheral interest and it was sort of kind of quaint. And what's been extraordinary is to be in a field which has now come of age. So not only if you want, in fact, if one of the great goals. is try and understand how genes ultimately give rise to behaviour. This is one of the best examples we've got. We actually understand how those genes and their protein products interact to generate 24-hour behaviour. And then using that information all the way through

to the timing of anti-cancer drugs and indeed getting an exquisite understanding of actually what happens to the body in night shift and jet lag and things like that. Deborah Skiene, can we take that forward? We discovered that dodgous means, and Dongeness Me's inside. Can you develop that? Yes, it means generated from within. So one of the questions when we try and measure rhythms is how much is our environment influencing the rhythm that we

see, whether they're factors like posture changes are sitting up or standing or whether it's because we've had a meal. So we need to sort of get inside to see if we can understand what is generated from within. So we... But can I just interrupt? I'm sorry, because I'm really ignorant about this. But this thing goes on, what you're now looking at, what affects it, what adds to it, what takes away from it,

what moderates it, but it's ticking away all the time. Millions of it will ticks in millions of cells going tick, tick, tick, all the time. It's ticking away all the time. But it's a question of how do we know how fast it's ticking or how slow it's ticking.

We then need to try peel away all the other things, all the external things that could be influencing it. So, for example, if we wanted to reveal the endogenous ticking nature of a plant or a person, we need to take the people or the plants out of the rhythmic environment. And so one of the fundamental properties of these circadian rhythms is that they persist and they're rhythmic in constant conditions. So when we have... What do you prove by doing that?

We can see the clock. We can actually then reveal the true nature of this internal timing, this endogenous nature, because we've taken away all the external factors, like the light-dark cycle. So, for example, in people, we study them in dim light, total dim light for two days.

and we don't allow them to have these big meals. We don't allow them to move around. We don't allow them any knowledge of clock time. So we've taken away all the possible confounders or external environment. And then we can measure hormones, we can measure temperature, performance, and we can then see the rhythmic true circadian. Rhythm. And this was like the early plant experiments

where they indeed just took a plant and it naturally opens and closed its leaves. And if you take that plant out of the light dark cycle and put it into a dark cupboard, what they saw was that the plant

continued to open and close its leaves in the absence of the light dark cycle. So what conclusions are you drawing from that? That we have an endogenous internal timing mechanism. This is a reinforcement of the fact of the rhythm.

The fact of it and how pervasive and how constant, but not always regular, but how constant and essential it is. Correct. We know that it's close to 24 hours. That's what we know from this. Steve Jones, there are other, there's

cannual rhythms as well. But do you want to take on from what Deborah was saying there? I saw your hand was about to go up. Well, I mean, that's right. I mean, there are a number of heroic experiments on these circadian rhythms, if you can call them that, where people will lock themselves away in caves

for months at a time. And the traditional view was always that they've begun. Scientists these are, well, the scientists, and of course there are inadvertent experiments where people are, for example, in American prisons in solitary confinement, kept in bright light 24 hours a day

and that really is a form of torture. There's no question of it. But the cave stuff is really fascinating because, until quite recently, what seemed to be happening was that if you were down in this cave for six months, you had to turn the light on now and again in order to feed yourself. And people's rhythms

began to drift away. They'd stay awake for 36 hours or 40 hours, then they'd sleep for 20. And the idea sort of became that humans were kind of different from everything else, because our rhythms were very flexible. But it turns out that that's because people were doing, without realizing

what we all do, which was they were setting their own rhythms by turning the lights on. They turn the light on and they think, oh, it's dawn. So if they were a bit off, then they'd get more off and more off and more off. Now, if you repeat these heroic experiments today, it has been done quite recently, and you put them down in the cave, and you control the light, it only goes on very briefly and it's very dim. It turns out that the human rhythm is almost exactly, not exactly, 24 hours. So we're just another primate, really. Russell. One of the other properties of...

Russell Foster. Yeah, one of the other properties of circadian rhythms. We've talked about their And Dodgers nature, they arise from within, that they can be locked onto the external world, usually by light. But one of the third property, the third property is truly extraordinary, and that is that they are temperature compensated, which means that there can be huge changes in external temperature, but it won't change fundamentally the period of the clock. So what you might expect in a biological reaction is you increase the temperature, you speed up the rate of the reaction, and it goes faster. And that doesn't happen with a circadian clock. So, in fact, in the 1960s, the chap called Brown was saying, I cannot conceive of a mechanism that were, a biological mechanism that will be independent of temperature. Therefore, circadian clocks cannot exist.

Pittenrigg said there must be temperature compensation. And we still don't know much about temperature compensation, but they clearly have this capacity to keep the period around about 24 hours, despite fluctuations, big fluctuations in external temperature. I mean, really important in plants and insects, for example. Have you any idea why? Well, in the same way that Harrison developed a temperature compensated clock for navigation, this clock is of absolutely no use if it changes its period as environmental temperature changes.

It could no longer be a really beautifully adaptive clock for predicting changes in the environment if the period changed. So this is one of the most extraordinary things about the clock that we have. Yes, and we still don't understand much about it, but it is a really truly remarkable. bit of biology. You know, you can keep ticking away despite huge changes in external temperature. And you tick, as Steve, you make, you tick at much the same rate, whatever? Yeah, yeah. Can you, it brings us back to your favourite word, the hypothalamus. How does it receive its information? Well, we've talked about light being the most important timegiver. And for mammals,

the eye is the only source of light information. So the eye has a projection directly to the master pacemaker within the hypothalamus. Now, what puzzled us some almost 20 years ago is how the eye, which of course is this exquisite organ for detecting vision, an object against its background, can also provide brightness information, because the clock needs an overall impression of the amount of light at dawn and dusk to set the clock. And in fact, vision isn't very good at doing that. You grab light and then you forget you've seen it to make an image of the world.

And to get a long story short, we... You didn't cut it all that short, just, isn't. and we wondered how this second function of the eye, brightness detection, could also be achieved by the classical visual cells, the rods and the cones. So we started studying mice who had lost. Just a second.

The rods and the cones, what do you mean classical? So the rods give us our sense of dim... Rods inside our eyes. Yeah, yeah. And then the cones give us our sense of colour. So you can think of the retina in the eye. It's a bit like a carpet, the tough, the fluffy bit, or the photoreceptors.

and then the weave at the bottom is where some information processing goes on, and then the ganglion cells, which is the bottom layer of the retina, fire their projections into the brain. And that forms the optic nerve, and that sends the information into the brain for vision, but also for regulation of the clock. Now these mice lacking the classical visual cells, the rods and cones. We're under mice now.

We're onto mice, but we'll talk about humans. Debra, I'm sure, we'll talk about humans. We'll come to Debron humans. You just finished mice or not humans. And what was truly extraordinary is that these... these mice that lacked visual responses, they had their eyes, but their rods and cones are gone, could still regulate their body clock to the external world. And that led to the discovery that there's a third light sensor within the eye.

And those ganglion cells we talked about, which form the optic nerve, about one in every hundred of those ganglion cells is directly light sensitive. It uses a photopigment, a light sensitive molecule called melanopsin, which is maximally sensitive in the blue part of the spectrum. And so what became very clear is that the eye is this organ, of course, gives us our sense of space, but also is this organ that gives us our sense of time. And if you have no eyes, then the clock will keep on ticking. And for most of us, you'll get up later and later and later each day.

Without that daily synchronising queue, it's essentially unremitting jet lag for the rest of your life. Do you want to take that on, Deborah? Yes, because we ask this question in blind people rather than... I mean, you two talking about research you are doing currently, aren't you, basically? Yes. Right, away we go. So Russell had done these experiments in mice, and so the obvious-looking model for humans was to study blind people.

Now, you get different types of blindness, so some blind people can see light, have light perception. They can count their fingers, or you can see how their hands move. And others are totally blind. They have no conscious light perception. so completely unaware of whether it's light or dark. And we wondered what the different circadian rhythms were in these blind people. And again, to cut a long story short and after studying a lot of people,

what we found is blind people who have some degree of light perception, who are aware of the light, have enough light to synchronize their circadian timing system to the light dark cycle. So they have circadian rhythm just like you or I. Whereas totally blind people, they've lost that connection between the light, dark cycle, and the clock. So there isn't anything wrong with the clock, but the clock ticks and oscillates at its own endogenous period. Just the same as if I were to put you in a dark cave. Your biological internal clock would oscillate at your indogynist.

circadian period. And there's a range of endogenous circadian periods in humans. We said it's around about 24 hours but it can range from about 23.8 hours to about 24.8.

So we've got about an hour's range around that 24 hour. And it's no more than that even if you're blind in a cave. No. Those are the sort of limits at least on all the experiments that we've done and not only our It's remarkably consistent, isn't it, durable really.

I've interrupted, interrupt. Can you just midway through? Yes, so we have that range and you might say, well, how would we know whether we have a fast clock or a slow clock? Because that, of course, dictates the period length. Well, the way we see that in all of us living on a normal light, dark cycle is whether we have a preference to be a morning type or a preference to be a late, up because that is related to your endogenous period length. Steve, you're already going to take something up there? Well, yes, I mean, the blindness thing is remarkable because, of course, if you're living entirely according to your own time cycle in society, life is very, very difficult.

You know, everybody else is going to bed and at the same time, you're running on. So blind people, many blind people actually begin to medicate themselves using some of the the hormones involved. Melatonin is a famous one which you can take allegedly to reduce jet lag and that's available over the counter in the States. It's rather in the grey market here but you can certainly get hold of it so that these people are sufficiently informed that they begin to control their clock with artificial means often reasonably successfully.

There's a new new drugs have been developed to do it in other ways but these are far far more expensive. Debra, you want to come back in? Yes, I just wanted to add to that that we've actually systematically studied the effect of melatonin compared to placebo in totally blind people.

And I think what really we found was that we were able to improve the sleep at night and people are less tired during the day because, of course, a consequence of this desynchronized free running, we call it free running, when you are desynchronized from the light-dark cycle.

This free-running clock means that your timing, your internal timing system is separated from your regular social life, meaning that in the middle of the day, your body is saying it's the middle of the night, and we get increased napping during the day, and then when you try to sleep at night, you get very short sleep. Can I come to switch it to plants, Steve? Is the same thing going on there?

Yes, I have to put in the compulsory nod at Darwin here because Charles Darwin, in his later years, was quite frequently ill. And like every good scientist, all he really wanted to do was to do science. And as he was lying in his bed, he noted that plants moved. He noted that some of them had a circadian rhythm, the mosa, the sensitive plant closes at night. one of the reasons it's called

the shyness grass in China because it's shy if it touch it it closes but it also touches it closes at night there are good biological reasons behind that because it reduced many plants to it of course and they have a circadian rhythm it stops predators reduces predators eating your leaves

it keeps the water in the leaves and these rhythms are really very very persistent plants actually kind of introduce you into the wider field of rhythms, which isn't just on the daily basis, but on the annual basis. And of course this year, as we well know, the autumn has been very strange

because it's been so warm. And certain flowers are blooming when they shouldn't really in December. But the trees have still lost their leaves. And that's because their internal timers, which tell them the length of the... They assess the length of the day. They can adjust

that their behaviour in terms of flowering or dropping their leaves in relation to day length. And so these circadian rhythms can also control annual rhythms, and you see that very, very much in plants. Some plants need a short day, or put it in other way, a long night in order to flower. These are short day plants, and these are things like cotton and rice. Other plants, like lots of garden plants, carnations,

need a long day to flower. And this is all back to the same kind of rhythm. Russell, Russell, We're going to talk about sleep extensively, I hope, in a two, three minutes But what other bodily processes that might interest our listeners Have we missed up to now?

Well, they're controlled by these rhythms. A huge amount, but if I can just sort of jump in Because one of the thoughts, we haven't really talked about what this clock actually constitutes. So we've said that a single cell can generate a rhythm and that every cell in the body is capable of generating these 24-hour rhythms,

which means it's a subcellular process. And what we've got so far is around about 12 to 14 key genes and their protein products. You mean in each cell? In each cell. And they are driven. They produce a message. The message is converted into a protein. That protein complex then enters the cell and turns off that transcription, that gene drive.

So what you've got is sort of a rhythm of protein production and degradation. in terms of a molecular feedback loop. And Deborah was talking about morning people and evening people. And in fact, polymorphisms, subtle changes in some of those genes and their proteins, have been associated with either morningness or eveningness. So our understanding of the molecular clock itself is now reasonably good. And as Steve was saying, the animal lineage, so all animals have very similar. clock genes, whether you're a fly

or a human. The plants have different sets of genes. The cyanobacteria have different sets of genes, as do the fungi. But in essence, it's all a molecular feedback loop with a period and oscillation of around about 24 hours.

There's a fascinating spin on that in the human case, because of course, historically in most for most of evolution of Homo sapiens, species to whom most of your listeners belong, I imagine, We lived in the tropics in Africa with 12-hour days, roughly speaking, and then we made this giant mistake of moving to the climate of Britain

with enormous differences through the seasons. And if you look at the rhythmicity of African clocks versus northern European clocks, it turns out that African clocks are much more firmly fixed, 12 hours on, 12 hours off. European clocks are more labile, and so they're set to move with the seasons. And that's happened really in the last 20,000 years or so, or 30,000 years, which is nothing in evolutionary terms. So the whole thing is very finely tuned. Deborah, Deborah Skinner, we've talked about light. Could there be other ways that these clocks are influenced?

Yes, I mean, there's any other time queue that we have in our society. For example, food, exercise, caffeine. Can I just get to proportion? These are not as powerful or as important as light. No, they're not. They're way down the scale of importance, but they're still of some importance. They're possible contenders. And really we get this from our blind work because we were surprised when we studied these totally blind people

because they have very strong non-photic, as we say, non-photic cues. Like they're working, they have families, they have guide dogs, and they eat meals and do exercise. And we wondered why the clock was still desynchronized despite all of these strong social cues. And so it emphasized the importance of the light-dark cycle because that was the one thing they were missing. However, we do think that exercise and food, caffeine may be able to modulate in some way. So has some influence on circadian timing, but not as strong. strongly as the light-dark cycle. Russell.

And so really fascinating studies in rodents have been able to uncouple the various bits of the circadian system. So light, detected by the eye, hits the clock, sets the SCN. However, if you feed rats in the middle of the day when they'd normally be asleep

just for two hours, then what's turned out to be really fascinating is that the liver clock and the gut clocks actually move in time. They uncoupled themselves from the master clock in the brain, and then move to that particular feeding rhythm. So what feeding can do at the wrong time

is actually cause internal desynchrony, whereby the master clock, the SCN, can be different from the peripheral clocks and the liver and the guts. Steve, we've talked about light, but we live in artificial light an awful lot of the time, which is far less powerful than sunlight and effect, and so on, right.

What other rhythms are the way that? Well, I think there's an enormous amount of interest in this recently, We now live literally in the twilight zone, most of us. And I came in this morning. It was rather a bright morning in London, even though it's in middle of December. The studio seems to us, equivalently bright, but our eyes are brilliant at setting the mental level, so it seems the same.

But the circadian clog doesn't listen to that. It says, you know, this is a dim play. This is dim. This is dim. There's not much light in here. I'm not going to reset myself to do with it. this dim light. So it's not as good, but it does, people can reset their clocks inappropriately by going to bed late with bright lights and that kind of stuff, and they begin to drift. And there's a lot of interest in the way that more and more people are just not living

in daylight anymore and are living their own circadian rhythms. People in Britain now go outside an hour a day less than they did just 20 years ago. So they're getting less. So they're getting less entrainment, as it's called, by daylight. And they're sitting more and more in front of computer screens and televisions and so on, which are entraining them, particularly as the colour of the light that comes from these screens, it's rather blue, which is good at doing that. And I think optimists, or maybe pessimists, blame some of the illnesses of modern society, obesity above all, depression.

They blame these, to some extent, on shifts in these rhythms. Russell? Well, moving on from what Steve was saying, it was assumed for years that shift workers working on the night shift would adapt, and they don't. They're largely working on three shifts. We're talking, aren't when we're talking about six or two,

two to ten to ten to six, yeah. The assumption was that essentially if you're working on the night shift, you know, that the body clock would move. And bits of it may do, but the majority of it won't. And the problem is, as Steve was saying, we're inside under relatively dim light,

then you go outside, and then you experience bright natural light, and the clock always defers to the external, brighter signal as being the most important one. So you clock on when you clock off. But what you can do, and Deborah is part of some of this research, is that you can increase the amount of light in the workplace

and then hide people from natural light during the day, and then the clock will eventually lock on to the night shift. So let's get to sleep. How do Cocaine and Reef? which is a big part of your research, a big part of our lives. And it's one of the things that's been heavily examined by people like yourself. How do they influence, these rhythms influence the impulse to sleep? So sleep, I suppose, has two essential timers.

There's the circadian clock, which we've talked about, and that provides a time stamp for essentially everything. Now is the appropriate time to be awake. Now is the appropriate time to be asleep. But there's a second process, which is, I suppose, the intuitive part about sleep, which is the longer you've been awake, the greater the need for sleep, the greater the sleep pressure. So from the moment we wake up in the morning, the sleep pressure builds and builds and builds.

But we don't fall asleep because the clock is saying, no, now is not the appropriate time to be asleep. So come 11, 12 o'clock or whatever, the sleep pressure is very high. And then the clock essentially opens a sleep window saying now is the appropriate time to be asleep. And so we go into then consolidated sleep. And it's very likely that the clock not only tells us it's the appropriate. time to be awake, but it's also driving sleep as well. You refer to Deborah in your remark in that answer. Let's talk about people who work through the night, as has been mentioned, people who start

very early in the morning, and so on. What are we learning from studies which you're doing, intensive studies, on people in those occupations? Well, there's always a lot more to learn. I think the answer really is that it very much depends on the shift schedule. and across England lots of people work different shifts. And if you're having a shift where you might work for three weeks of nights, then you might want to try and adapt the circadian timing system to that night shift schedule.

Whereas other people, nurses, for example, they might work one night or two nights a week. And in that case, of course, you don't want to adapt because it's just one or two nights, and you want to be able to be back on your day job and your day mode. So the biggest question about whether we should adapt to shift work and how we could try and help that or not is do we need to adapt or not? And it really depends on how long your night shifts are. It also depends on whether you have a rotation, you know, in a rotational shift, you can go forwards or backwards.

and it also depends on what time your early starts are. Are the results that you're getting from these studies, always negative, always this is harming people? No, not at least in the lab. A lot of epidemiological studies, so general survey studies, when they ask people, have you done shift work and how they've related that to disease, that's a sort of association. and that's where shift work is looking like it is a risk factor for some of the major diseases, cancer, metabolic syndrome, etc. But it's merely at the moment in association. Steve, we started, and what about the Eurysleep?

And one of the things that it does, as the man said, was knits up the ravelled sleeve of car. Yes. So what's happening there? Well, I think that's the most astonishing thing that's happened in the study of school. sleep. Sleep was always, you know, the dark period. Nothing was happening. You were just resting your body, and your body temperature drops a little. You might dream now and again. But we know now that sleep is really as full of excitement and events, as is the waking world. And if you interfere with those events, you're going to damage the waking world. And much of that, not all of it takes place

in episodes of what's known as REM sleep, rapid eye movement sleep. For much of sleep, we're just there snoozing, really, and the brain waves are going up and down. Your eyes aren't moving. And then suddenly, several times a night, often later in the night, there's a certain spasm. When your eyes begin to dart around, for some time, you're completely, you're completely paralyzed. How long? Seconds, minutes? Minutes, I would say, yeah, minutes. You're completely paralyzed. You can't move. You can't move. Your muscles are just like that. You maybe suddenly have violent dreams. And this all seems rather odd, but this is the brain

reorganising itself to deal with both the damage and the experiences it's had on the previous day and readying itself for the next day. And one of the things that happens in those periods is it has to do with memory. One of the really startling things,

I mean, I remember as a student being, as I'm sure many of us were in the studio, being a complete nerd and working hard late at night for an exam in the morning. And the odd thing is that if you have a good night's sleep, you remember things better then you would have done when you went to bed because the brain is consolidating memory.

And that's an essential part of the sleep process. And if you interfere with all that brain function during sleep, then you begin to feel terrible. We all know how terrible it feels to have jet lay 12 hours difference. There's a partial cure, business class, as it's called, which I've recently begun to experience. But it's pretty awful, come on, eh? and it's very...

Not a not for the BBC No, no, no, thank you very much, right? But what's striking is that I think my two colleagues will put me right I think for every mental disorder is associated with sleep disorder. Now what's cause and what's effect is another issue,

but depression is often preceded, severe depression, is often preceded by periods of interrupted or fragmented sleep. Russell, Russell, Yeah, a big chunk of what we're doing at the moment is trying to understand that relationship between sleep disruption and mental illness. And it's always been thought of as cause and effect. But actually, what we're learning is that the networks in the brain that generate normal sleep and the networks in the brain that generate normal mental health overlap.

So if I have a defect in a particular gene that predisposes you to mental illness, chances are it's going to have a parallel effect upon the sleep systems. Now, disrupted sleep may exacerbate the mental illness and the mental illness may exacerbate the sleep. disruption, but the origins lie in those overlapping pathways in the brain. That's really exciting because we're genuinely understanding the neural basis of both sleep and mental illness. I believe

there's quite a lot of research now on treating various forms of mental disorder, depression more than anything else, with bright light. Now that may or may not work, but there's some very recent stuff which combines bright light and drug therapy and that seems to work quite well. Deborah, you're working on that. Absolutely. And

the light, you know, we now know the neurotransmitter systems in the body that this is affecting, and one of them is the serotonergic system, and it's well known, of course, that antidepressant drugs are also acting there. So there's a mechanism for light, and that's brought me to another point I was thinking about, to remember to say, which is that light has a lot of other effects

than just affecting the circadian timing system. We've said how important it is for that, but it does have neural connections, with a lot of other brain areas so we can get this direct effect of light on alertness, improving alertness, improving performance. What are the unanswered?

What are you working on now? What's the big next problem in this? Well, the big question, we've talked about discovery of these new photoreceptor systems and we've talked about the molecular clock. Well, how does light genuinely change the pattern of gene expression which allows this molecular clock to lock onto the external world? And we've discovered a number of really,

exciting elements. So for example, why isn't light more effective at shifting the clock? Why does it take a day for every time zone when we cross time zones? And we discover that there's a break, there's a protein which acts as a break. And when you remove that protein in a mouse and you shift the light dark cycle mimicking jet lag, the clock will adapt very rapidly to the new time zone. So there's a number of ways I think that we can use this information to hopefully develop pharmacological agents that will mimic the effects of light on the clock. So that's one big Gero that we're working on. And you said, very briefly, Steve, why'd you say it's now becoming the center of modern biology?

Because it seems to overlap with everything. It's in the phase, the science is in the developmental phase that genetics was, maybe 20 years ago, when suddenly everything became genetic. Well, now we've become a bit cynical about that. If you ask us back in 20 years, we may say the same about circadian reasons. Can't wait. Right. Thanks to Russell Foster, Steve Jones and Deborah Ski.

Next week we were talking about the extraordinary 19th century experimental scientist Michael Faraday who worked in a very small laboratory just down the road from here. Thank you for listening. And the In Our Time podcast gets some extra time now with a few minutes of bonus material from Melvin and his guests. Thank you very much. That was terrific. Time flew. Now's the time. Now's the traditional time for you to tell me what I didn't ask and what we didn't do. And I didn't answer, which is what other physiological processes are being regulated by the clock. And so, I guess I would say that if you think of the different states between wake and sleep, they couldn't be more different.

Pnegalic states. Slipes, yeah. And so in advance, in anticipation of waking up, core body temperature rises. Cortisol goes up. Yeah, cortisol, the glucose mobilization. That's what I was trying to get up. That's the anticipation. Yeah, but I didn't get the question right.

And so, essentially, because of the time, it takes to go from the sleep state to the wake state, it can take two to three hours to have it perfectly aligned. So if you know, as it were, that in three hours' time, you need to function, the clock is really powerful because when the change conditions occur, you're biologically adapted to the new environment. When do we have to know? In time, say, I get up at, say, five, well, not say, I get up at five o'clock in Thursday mornings. Now, when do I have to know I'm going to get up at five o'clock? Hour before, you know.

Yeah. Well, you're still. You mean that your body will start. But when do I tell my boy? Do I tell it at 10 o'clock the previous night? When do you normally get up without the alarm clock? About 637. Okay, so you're still waking up

when you wake up with the alarm clock. And actually this is really interesting because it's the mismatch between biological time and essential social time. And a colleague of ours has called this social jet lag. And the greater the social jet lag, the greater the difference between when your body would want to wake you versus when the alarm clock drives you out of bed,

the greater the chance of depression, smoking, alcoholism, and obesity. On the other hand... I'm usually an alarm clock on Thursdays. Well, that's freezing me away, you're looking so good. On the other hand, look on the bright side, you're only really a man when you're asleep. Because that's when testosterone does its job. Why didn't you say that on the programme?

This is for the privilege for you who are listening to the adorn that we put for podcasts all around the world. They know that. Nobody else knows. The social jet-like thing is amazing. On average, there's about a two-hour difference between somebody in their late teens and somebody in their 50s or 60s.

So asking a teenager to get up at 7 o'clock in the morning is asking a 50-year-old to get up at 5 o'clock in the morning. That's the difference in the biological timing. So one thing we didn't talk about, of course, is... Oh, there's so much you didn't talk about it. You'd have to come back before 20 years, Steve. We talked about the genetics influencing

whether you're a morning person or an evening person, but actually development will do that too. So all the surging hormones during puberty probably serve to delay the clock and as puberty peaks and we then slide into senility we become more morning type. So we get later and later up to the 20s

and then we start to get earlier. By the time you get to 5560 you're getting up and going to bed at the time you did about pre-pubital, about 10. And in the states, in the states, I mean, in the state, I mean, when I lived there.

I was always amazed. I used to get out very early sometimes to collect fruit flies out in the deserts in California. And you've got to be up at five and moving. And everybody, all the kids are around you, up at five, are moving because schools, in some states, it's not at 6.30 in the morning. Now, that's just madness because they're, you know, and they're beginning to move because of the age of these children.

Slowly they're beginning to move into starting at 7, 8 or 9, as we do. Yeah, but studying Amazon people, for example, which we've just had an Amazon study where they haven't got electricity because I think one of the issues that you're talking about here is this artificial light and having it in the evening.

And we've been able to study people in a set area all from very homogenous group doing the same work, rubber tappers, and those that don't have electricity are much more entrained and synchronised to the dawn dust signals than those that have electricity.

You're completely right. I mean, because not only a kid's biology predisposed to go to bed late and get up late, but the massive exaggeration with social media and light exposure in the evenings adds to push that further. Absolutely. And is this pushing illnesses further? Well, you've got differences. We biologists, not like physicists, we know there's a difference between correlation and causation. Now, there is an obesity epidemic.

That's clearly the case. But that's a very complicated thing. you know, it's cheap, fizzy drinks and all that stuff. But it's hard to disentangle the fact that people who are on shift work, for example, tend to be more obese. Now, if you're on shift work, you're probably in a lower social class with the poorer diet. So it's difficult to disentangle it. Yeah, and you're eating at the wrong time, which is, again, you know,

your body isn't set to eat a big meal at the middle of the night. When does the body tell us to eat? Are we eating at the right time? Do we eat breakfast for once you'll be eating breakfast? The sort of perceived wisdom at the moment is going back to the... Going back to the old idiom, which is you should have a big breakfast and a big lunch and you should have less in the evening. That's what I do. Going back to the obesity thing. Oring is the way to start the day.

Evancata in the States has shown really very nicely that even in healthy young males who are sleep restricted, the hunger hormone grelling goes up and the leptin will go down. So even after seven days, I mean, you know, carbohydrate consumption in those young males went up by 35 to 40. So we're beginning to understand the metabolic basis for why sleeped up deprivation may give rise to obesity. I think that the producer of this programme is about to make his customary entrance. Simon. Simon. I'm really actually going to talk about you to your coffee. Oh no, we know how we're abusing our bodies.

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