Russell Foster: How does the body clock work?

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.