Titans of Science: Russell Foster
This episode of Titans of Science features body clock guru Russell Foster, who talks all about our body’s circadian rhythm, and how paying attention to it is crucial for a healthier and happier life…
In this episode
00:52 - Russell Foster: What is the body clock?
Russell Foster: What is the body clock?
Russell Foster, University of Oxford
Every organism on Earth lives by some kind of clock. Our bodies are calibrated to the day night cycle of the area that they live in, and processes like hormone release and brain function are attuned to this periodic cycle too. But up until recently, we didn’t really know what drove this process. That was until work by Russell Foster and his team discovered which specific cells set the rhythm for the rest of our body. But before that, I began by asking him exactly what a body clock is, and how our understanding of it has evolved over time…
Russell - In the early days, we really thought there was 'the body clock', and there's a structure within the base of the brain called the suprachiasmatic nuclei. And that structure was shown way back, actually in the late 20s, to be really important in generating 24 hour patterns of rest and activity. But it wasn't clear how it worked. And certainly in the old days we thought that it was a sort of a cell cell interaction, that cells would interact in a form of a network to generate an oscillation. And what we thought is that this master clock imposed rhythmicity, so changes in our blood pressure, in our hormonal rhythms and all the rest of it, over the 24 hour day. And then it became clear that every cell in the body can probably generate a circadian oscillation. And I remember being at the meeting at the time when this emerged, and it was sort of an audible gasp because it changed the way we thought about the clock. And in fact, it's now very much considered to be a circadian network with billions and billions of individual cellular oscillators, all coordinating with each other, and with respect to that master clock in the brain, to produce an essential biology. And if you think about it, what do we need to do? We need to deliver the right stuff at the right concentrations to the right tissues and organs at the right time of the day. And that's what the circadian system, the body clock if you like, actually does it. Fine tunes our entire biology to the varied and complex demands of sitting on a planet that revolves once every 24 hours producing light, dark cycles, temperature cycles, and different availability of stuff.
Chris - That suprachiasmatic nucleus, the structure in the brain in the hypothalamus that does this, there's a sort of genetic clock ticking in there with one gene turns on, turns on the next one, turns off the first one. And it ticks around. So when that genetic ticking is taking place, how does that translate actually into a clock signal? How do those nerve cells change in response to that? And how do they transmit that time, if you like, to all those other cells in the body and all those other oscillators as you put them, all the other cells in our body that are keeping time in sync.
Russell - So what you've got is this fundamental molecular feedback loop with regulatory elements in the clock genes, but you also have those regulatory elements in a whole host of other sorts of genes. And so in the same way that they can feed back on themselves, they can also feed onto other genes and regulate their output. And so they may be genes which are involved in the generation of electrical responses or genes involved in the release of hormones. So this fundamental molecular oscillation could be translated into lots of different delivery mechanisms. And that's all turning out to be, again, amazingly exciting and interesting.
Chris - How far back in life's evolution do I have to go to find where these clocks started? Because you mentioned a planet that rotates in roughly 24 hours. Well, the world has always spun, so therefore, as for as long as we've had life, presumably we've needed to know the time
Russell - Well, exactly. And in fact, it's thought that the evolution of some sort of clock is a very, very ancient part of biology. It's been called a signature of life. And in fact, when individuals were looking for life on Mars, they were looking for the rhythmic production of organic molecules, for example. You know, because it's such a ubiquitous aspect of biology. I'm also really fascinated with evolution. And I find it extraordinary that the fundamental building blocks, the genes and their proteins that you find in us, are conserved in all vertebrates and invertebrates. So the same building blocks are present more or less in the entire animal lineage. Now what's fascinating is that the way we, the animal lineage, build its clocks is different from the green plants or indeed fungi. They have different genes and different proteins, but they also fundamentally use a molecular feedback loop. So it's a signature of life and it's very, very ancient.
05:43 - Russell Foster: How does the body clock work?
Russell Foster: How does the body clock work?
Russell Foster, University of Oxford
In this episode of Titans of science, body clock guru Russell Foster chats about the discovery of the body clock's mechanisms, as well as what can happen if you upset your body's balance...
Chris - How does it get set in the first place?
Russell - That's the question that we've been addressing for quite some time. You know, we talked about this extraordinary clock allowing us to adapt to all these varied demands, but it's of absolutely no use at all unless it's set to the external world. A classic mismatch between the internal day and the external world is jet lag. We get over jet lag, not completely, but primarily because we're exposed to a new light dark cycle. And so the clock uses the dawn dusk signal in the new time zone to lock its molecular biology onto the external world. When I first sort of started in this area, the assumption was it's the visual cells. We knew it was the eye in mammals because if you cover the eye, this ability to regulate, to entrain the internal clock, is gone. So light is that overwhelming signal. But it occurred to me that, well, this is really intriguing because what the clock needs is an overall impression of the amount of light at dawn and dusk. And that can take minutes or indeed hours. But what the visual system does is grab light and then in a sense forgets it's seen that light in a fraction of a second. So that's why we have a crisp image of the world. It's a series of rapid snapshots. And I couldn't quite understand how the visual cells could also collect light information to regulate the clock.
Chris - So how is it doing that then? If it's not the rods and cones that I'm using to see your face on the screen that are doing that. Is something else sending a signal to the brain about how bright it is?
Russell - And that's what's so exciting. So we started by using mice with hereditary retinal disorders, mice that were actually being studied to understand human genetic defects in their visual system. And many of these mice had gene defects whereby the rods and the cones, the visual cells, had degenerated and they were visually blind. And what completely amazed us, and it's still one of those goose bumpy moments, is that these visually blind mice could regulate their clocks perfectly normally. Not that they had some residual capacity. And we knew it was in the eye because if you covered up the eyes, this ability had gone. So we showed that there had to be something else. And it took us about 10 years because when we first presented the data, you know, I remember standing up at a big meeting in the states and saying, so our data are consistent with the hypothesis that there is another class of photoreceptor within the mouse and the mammalian retina. And one chap who was fairly close to the front stood up and he looked at me and I thought he was going to ask a question. So I sort of paused. He looked at me and said 'bullshit' and just walked out. The opposition to the idea that the eye could contain another light sensor was really ferocious. We had all of our grants got panned, and so we had to do more and more experiments. And finally we convinced the world that there is something else. And this led to our discovery in mice, working with Mark Hankins, that the ganglion cells were directly light sensitive. Other groups showed this in rats and in monkeys. And so we had in mammals a definitive proof. There was another class of light sensor. I should say, before we did this in mammals, we showed that there was an inner retinal non rod, non cone photoreceptor in fish, which was really very useful because when we were under sort of massive attack, we could say, look, we've shown this in another vertebrate. So the jump to a novel receptor in mammals is not so crazy. We were lucky in that our original hypothesis was supported by an overwhelming amount of data in the end.
Chris - We should of course explain when you say ganglion cells in the retina, that normally at the back of the retina are these ganglion cells that make nerve fibres that carry the visual message back to the brain. So the fact that you are saying that cells that would normally be getting input from the retina and transmitting it on, actually some of them themselves can see. You can understand why people thought that was a bit bizarre at the time. So what are those ganglion cells that are doing that then? What are they sensitive to? How are they working and where are they sending that message about the light signal?
Russell - These retinal ganglion cells are sort of the last layer of the retina, and it's their axons that leave the eye and form the optic nerve and enter the brain. And of course, what most of them are doing is providing information from the rods and cones, and they're projecting to the various visual structures in the brain. But about 1-2% of those cells are directly light sensitive. Using a novel photopigment, different from the light sensitive molecules in the rods and cones. And it's been called melanopsin or OPN4. This OPN4 is a blue light sensitive photopigment, which is maximally sensitive at around 480 nanometres. What does that mean? Well, if you look at a blue, blue sky that is about 480 nanometres, and that's where these cells are maximally sensitive. Now why is that? Is there any reason for that? We can't know for sure, but what's fascinating is that at dawn and dusk, there's a relative enrichment of blue light within the sky. Now your listeners will say, 'well, what on earth are you talking about? When you look at the horizon, of course at twilight it's this wonderful orangey red.' But if you look at the dome of the sky, it becomes intensified with blue. So the dominant colour wavelength of light at dawn and dusk is blue, which is where these receptors show maximum sensitivity. And it's not just in us, but also in most vertebrates that have been looked at, are peaking at that particular wavelength, which is fascinating.
Chris - And where do they send the signal to? If it's not going to the visual bits of the brain, are they informing the suprachiasmatic nucleus, that hypothalamic body clock structure, that they're alive, they're seeing that light, therefore it must be dawn or dusk?
Russell - Yeah, absolutely. And, so there's a direct projection called the retinal hypothalamic tract, which goes to SCN neurons. Actually, it's the lower bit of the SCN called the ventral part of the SCN, which receives this light information and it sets the clock cells there and they pass on this entrainment signal to the rest of the SCN and then ultimately throughout the rest of the body
Chris - That explains how we set the clock, how we recover from jet lag. And you've already mentioned that you've therefore got a master clock that can transmit the signal via various methods, neurological, hormonal, and so on around the body. So when it hits the rest of the cells in the body via these different messages about what time it is, how do the rest of our tissues respond and why does it matter that they know what time it is?
Russell - What we've been doing most recently is actually finding out what happens to the molecular clock in the SCN first of all, and how light is modifying gene expression. And what's turned out to be extremely exciting is that we now have a pretty good idea how an electrical signal, which is passed down from the photosensitive retinal ganglion cells, changes levels of intracellular calcium. And another second messenger system called cyclic AMP, that triggers a whole cascade, which then alters the gene expression of some of the key clock genes. And it's a bit like moving the hands of the clock, aligning the clock to the right time. And the molecular clock is not exactly 24 hours, so it needs daily adjustment. And that daily adjustment is provided by this extraordinary light signalling pathway. But what's so fascinating is that in the recipient cells, so the liver, the gut, and all the rest of it, they seem to have a similar signalling pathway. It's not light that triggers that pathway because that light is only coming via the SCN. So downstream from the light signal, you have a standard signalling pathway that can correct all clocks throughout the body.
Chris - Our body, I mean, we think there's 37 trillion cells or so in you and me, <laugh>. We think we've got basically 37 trillion clocks running in us, and they're all ticking in time with that master clock in the brain, which has the capacity to reset them all. But why does it matter? Why do we need all these clocks? And what role does that serve? How does it make us function better as human beings?
Russell - What you have to do for our bodies to function is deliver the right stuff, the right concentration to the right tissues, to organs at the right time of day. And the varied and complex demands of the 24 hour day means we have to do different things at different times. So our metabolism at nighttime is completely different from the metabolism that we use during the day. Our levels of alertness, our hormonal profiles, our stress axis, all completely different. Good way to think about it is jet lag. I mean, you don't feel grim when you fly from London to New York, say, because you're simply five hours shifted. It's because the entire body is experiencing a sort of a temporal smear. The master clock is at one phase, the liver, the gut, the rest of the brain are all at different times.
15:27 - Russell Foster: The health effects of bad sleep
Russell Foster: The health effects of bad sleep
Russell Foster, University of Oxford
In this episode of Titans of science, body clock guru Russell Foster chats about the discovery of the body clock's mechanisms, as well as what can happen if you upset your body's balance...
Chris - So if we screw around with the body clock, for instance, I do go abroad and cross time zones, or more commonly for most people, you end up pulling a night shift, pulling an all-nighter. Or in radio, working the breakfast show <laugh>, horrible, A&E shifts for me, did it for me. I didn't want to ever do A&E again. What effect does that have? I know I felt pretty awful, but are there health consequences from that?
Russell - There really are and sort of a misfiring, a misaligned biology can produce short-term effects and also long-term effects. So the things that many of us have experienced as a result of sort of short-term disruption, whether that be jet lag or or night shift work even just a couple of days, you find that your emotional responses start to fall apart. So you see greater fluctuations in mood, greater irritability, increased anxiety. Loss of empathy. I think this is fascinating. You fail to pick up the social signals of your friends, colleagues, and the people you live with. Increased frustration, risk taking and impulsivity. This is also fascinating. The tired brain does stupid and impulsive things, 'ooh, I think I can go through that traffic light before it turns red.' This is daft. You'd never think of doing it if your brain wasn't tired. And also the tired brain remembers negative experiences, but forgets the positive ones. So your whole worldview is based upon, you know, negative information. So that's some of the emotional things that can happen. Our cognitive responses. While our entire cognitive performance is impaired to a greater or lesser extent, depending on how much disruption you get. One thing that goes pretty quickly is your ability to multitask. So we are bombarded with bits of information and we have to prioritise what we're going to respond to. And that prioritisation falls apart when we're tired. Memory consolidation, information processing, and coming up with novel solutions to complex problems is profoundly affected by lack of sleep. Concentration, communication, decision making. All of that can be really badly disrupted. Then we go into sort of the longer term impacts. As you see in night shift workers after 5, 10, 15, 20 years. One thing that can happen fairly early on is microsleep; falling asleep at the wheel. And a study incidentally from junior doctors, showed that 57% of junior doctors had either had a crash or a near miss on the drive home after the night shift. Then we have altered stress responses. Perhaps the only way you can deal with being chronically tired and to stay awake is to activate the stress axis. Now the stress axis gets a bad wrap. It's a really great short term. It's like the first gear of an engine for a car. It gives you that acceleration to get away. But if you keep the car in first gear, then you're going to destroy the engine. And so what you see is lowered immunity, some really very interesting stuff there. One night of no sleep before vaccination can actually reduce the efficacy of that vaccination, very significantly so. Tired people show a lowered antibody response to vaccination. You see higher rates of cardiovascular disease. And this lowered immunity has been associated with increased levels of cancer. And in fact, the data are so strong that the World Health Organization has designated night shift workers a probable carcinogen. And of course, poor sleep increases the vulnerability to depression and psychosis. There's even some data suggesting that really poor sleep during the middle years can be a risk factor for dementia later on in life. And the connection seems to be this recently discovered glymphatic system, which you can think of as a clearance system within the brain. And one of the things it does is to get rid of a misfolded protein called beta amyloid. And beta amyloid has been associated with a high risk of dementia and Alzheimer's. So there's some serious impacts driving our biology outside of its normal range.
Chris - The body also does other important things when we sleep, it releases various hormones, growth hormone, for example. So we grow, we repair at night. So what are the impacts then? If we think about medical treatments, if we've got a disturbed body clock or we give certain treatments at certain times of the day, does that mean they're going to be better and work better if we give certain drugs and certain things at certain times of the day?
Russell - This is such an important point Chris, because chronopharmacology, giving a drug when it's most effective, I think is going to be one of the really exciting areas of development in the coming decade or so. But we know that there's an increased risk of a stroke between 6AM and 12 noon. The increased risk is about 50% compared to any other time of the day. So you could say, well, what time should I take my antihypertensive? And, and of course, because people know that the strokes have a high frequency first thing in the morning, the sort of knee jerk reaction is, well, you take it in the morning. But if you think about it, by the time you've actually got up, you've taken the drug and it's actually getting into the body to have an effect, you are past that dangerous window. So a Spanish group looked at taking your antihypertensives either first thing in the morning or immediately before you go to sleep, bedtime. And it had a really big impact on long-term survival. Over a study period of over 10 years, there was a 50% drop in death rate for those individuals who took their antihypertensives before they went to bed compared to those individuals that took their drugs in the morning. Other areas such as cancer have turned out to be really fascinating. Fairly old studies now in childhood leukaemia showing morning versus evening treatment with chemotherapy. The kids that were on the evening chemotherapy had 75% survival versus 35% survival for the kids that had it in the morning. And so there's big differences. Our body doesn't do the same thing. And so it's going to process drugs at different times.
21:58 - Russell Foster: Could we cure jet lag?
Russell Foster: Could we cure jet lag?
Russell Foster, University of Oxford
In this episode of Titans of science, body clock guru Russell Foster chats about the discovery of the body clock's mechanisms, as well as what can happen if you upset your body's balance...
Chris - Let's turn to teenagers for a minute because I'm the proud parents of a couple of them. So I know all about this. I'm an authority. I think you've been there. Now they really do try and sleep all day. I wish I could still do that. Now what's the difference between them and me? And is this true, that teenagers do perform worse in the morning and therefore should we give them an extra few hours in bed, we probably get a better set of teenagers for it?
Russell - Well, yes and no. And really this brings us to the topic of chronotype, whether you're a morning person, evening person, or somewhere in between. About 10% of the population are extreme morning types. 65% of us are in the middle and 25% tend to be on the owl spectrum. But this changes as we age. There are three important factors that contribute to our chronotype. One is age. So from about the age of 10, there's a tendency to want to go to bed later and later. And this peaks in our late teens, early twenties. And then there's a slow move to a more morning chronotype. So the bottom line is, when you're in your late fifties, early sixties, you're getting up about two hours earlier than you did when you were in your late teens, early twenties. So there's a very significant effect there. So one is age. And that is almost certainly linked to the changing levels of the sex steroids, the steroids that underpin puberty. The second factor is genetics. So we talked about those clock genes and subtle changes in those clock genes can predispose you to be a morning type or an evening type. So there's a couple of factors you can't do much about, which is your genetics and your state of puberty and how old you are. But the third factor is what's so interesting. And of course I'm a light bore. And it's the impact of light on the clock. Morning light advances the clock. You get up earlier and go to bed earlier. Whereas dusk light delays the clock. You go to bed later and you get up later. And we did a wonderful study a few years ago on university students around the world showing that the later the chronotype, the less morning light they got, which would make them get up early, but they got lots of late afternoon, early evening light, which would delay the clock. So one thing that we do have some control over is our light exposure. So if you are a late type, if you're a teenager, it's brutal. But what you need to do is you set the alarm and then you get outside, you sit near a window or you sit in front of a light box to make sure you get that morning photon shower to advance the clock. So yes, teenagers are delayed biologically, but it's made worse if you don't get light at the right time.
Chris - I heard that you are trying to rope in our political system as guinea pigs now. Is this true? Because you're interested in studying how they work, how our legal and political representatives work.
Russell - Well, I've had the privilege of working with an organisation Liminal Space to deliver educational information to night shift workers. Now I think what's so fascinating about night shift work is that it's a genie that we can't put back in its bottle. It's here to stay. And so what we've got to do is be aware of the problems associated with night shift work, but think about ways in which we can mitigate some of the issues we've talked about. Poor physical and mental health. And so why don't we have higher frequency health checks in that vulnerable group to try and detect the problems before they become chronic? We know higher levels of obesity, diabetes 2, metabolic abnormalities in night shift workers. So why aren't we providing that sector with appropriate food? What we've got available to that group is fast food, high fat, high sugar. And it's amazing to me that with a food industry that is so vibrant in the UK, we haven't come up with high protein, low fat, nutritious, pleasing to eat snacks for night shift workers during the night shift. We've got to produce educational materials for our night shift workers to not only let them know of some of the problems, but also the people they share their lives with. The divorce rate in some sectors of night shift workers is six times higher than day shift workers. We've got to let their partners know that this person hasn't turned into a monster, but this is an inevitable consequence of driving one's biology outside of its normal range. And then finally, because these pathologies develop over time, maybe we should do the studies, and we don't have the studies yet, to limit night shift work to three to four years and then hopefully wind back some of the long-term health issues. So you cycle out of night shift work onto day shift work, and you stabilise biology and then you could potentially go back to night shift work. Now the economic formula for that is tricky because people don't invariably do night shift work because they want to, it's because they get paid a higher rate. So there are issues that we need to resolve. So this is a really important sector. And Lord Tom Watson has been really a fantastic advocate of trying to improve the health status of our night shift workers. And so we suggested to him that we institute a sleep health questionnaire for our members of the House of Lords and the House of Commons coupled with a mood and stress questionnaire. So hopefully that'll be instituted in the new Parliament in the coming months and we'll do it at the beginning of the parliament and then towards the end of the parliament. So, this has a serious aspect. I think it would be very interesting to find out how tired our decision makers are and how their ability to function is being affected by long hours and disrupted hours. But also I think it'll raise public awareness to this really important problem and start an informed public debate about what we should be doing in terms of our night shift workers, their health. And just because we can invade the night, should we always? Clearly our frontline staff, police, firemen, hospital workers, yep, they're going to be needed and we need to find interventions for them. But do we really always need to run our society on a 24/7 basis in view of the problems? I'm not sure that we do. And it's a debate that we need to have.
Chris - Short of changing how the world works. And that's a big ask, isn't it, because you've got eight and a half billion people on earth and many economies run very differently and are less sympathetic actually to the way we tend to run our country. Although it's hard to believe it sometimes. Are there any things we can do perhaps with drugs or pharmacologically? Because there are people, of course, who take drugs, caffeine being the obvious one to wake us all up. Is there anything we can do to help with this body clock resetting or to make us all healthier and combat some of these desynchronisation that are happening that make us less healthy?
Russell - The first line of attack has to be sort of behavioural change and behavioural modification. But what's so exciting for me is that the curiosity driven research that has led us to understand how light interacts with a molecular pathway has identified drugs which can fool the clock that it sees light. Why do we want those drugs? Well, if you have no eyes, if you're profoundly blind, then you're drifting through time constantly. And so where we are, we've done all the preclinical work, we know we've got a drug that can fool the clock that it's seen light. We know that it's safe in humans. And our big hope is that we can then introduce this into individuals, into clinical trials and then use those drugs to stabilise sleep weight patterns in the profoundly blind, but also in other groups where you have massive circadian rhythm disruption. So for example, in schizophrenia and neurodevelopmental conditions. So I'm very excited that this curiosity driven research could translate to really new and powerful ways in which we could regulate the circadian rhythms across multiple conditions and across the health spectrum.
Chris - And cure jet lag?
Russell - <laugh>. Well, that isn't our primary aim, but you know, that's what these drugs will do. They will shift the clock. And so yes, as a cure for jet lag, they could be incredibly effective, far better than anything else we've got because they activate the pathway that light activates.
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