Setting the circadian clock
Chris - The ancient Greeks are credited with first pointing out that some plants appear to be able to tell the time by altering their leaf shapes during the day and some of the first evidence of the existence of a similar internal clock in animals, including in us, was produced about a hundred years ago when scientists showed 24-hour patterns of activity even in the absence of any time cues. Now we know a lot more about how this whole system works and that's partly thanks to one of the pioneers in this area of study which is Oxford University's Professor Russell Foster who's with us this week. Hello, Russell...
Russell - Hello, Chris.
Chris - Thank you for joining us. First of all, how does this body clock actually keep time?
Russell - Yes. First of all, each of those individual SCN cells are talking to themselves and that coupling is really important in part of the 24-oscillation and then there are two ways in which the body clock will communicate with the rest of the organism. One is via direct neural connections and there are other humoral routes; some sort of neurohormone release from the SCN. Really, that's where our understanding is not so good because we don't really understand in fine detail how the master clock communicates with the rest of the body.
Chris - It's one thing for a bunch of nerve cells to have an activity like this. It's another for other cells around the body to pick up on and respond to that if they don't have a direct nerve connection.
Russell - Yes and what we used to think is that this master pacemaker simply imposed and drove a 24-hour oscillation on the rest of the body. Then, from Schibler's group in Switzerland, he showed that individual cells could still regulate - not SCN cells - in fact, these were fibroblasts. They've been in culture for 30 years.
Chris - Skin cells.
Russell - Yeah. He shocked them by putting 50% serum in the medium and then showed that there was gene expression with a pattern of 24 hours, showing for the first time that essentially, every cell has this capacity to generate this 24-hour rhythm. What's so exciting is that the SCN has to act as this master pacemaker, rather like the conductor of an orchestra producing a rhythmic signal from which the rest of the body takes its cue.
Chris - What is the nature of the actual clock work? What are the cogs in those nerve cells that are ticking around, keeping time?
Russell - The molecular clock. It's fundamentally a feedback loop whereby a gene produces a protein, interacts with other proteins to form a complex and then enters the nucleus, and then regulates its own expression. So you have essentially a molecular oscillation.
Chris - A sort of genetic domino effect, one thing turns on, the next trips on the next, turns off the first, and it goes around in a circle that happens to take 24 hours.
Russell - Very much so. And of course, the rate at which you turn those genes off, the rate at which the proteins are produced, the rate at which they form a complex, the rate at which they enter the nucleus, all of those things interact to form the 24-hour dynamics. Therefore, you need a whole range of other proteins, sort of kinases, regulating the activity of the protein complexes.
Chris - What about the fact that we don't live in a world where time is static in the sense that I can jump on an aeroplane, I can go forward and backwards in time zones, because of the latitude we live at, we have days which are longer and shorter at certain times of the year? How does the clock accommodate that?
Russell - Well, the clock, to be of any use in actually fine-tuning physiology and behaviour to the varying demands of the rest-activity, light-dark cycle, has to be set to local time. The critical mismatch when one travels, let's say, from Cambridge to New York, is that you need to realign to New York time. The primary, but not exclusive way, that the body does that is exposure to the light-dark cycle. The new light-dark cycle sets the internal master clock in the SCN to local time, and we know that it's the eye that's detecting that light in us and there's a special cell within the eye that's detecting this light. So for example, it's not the classical visual system, the rods and cones of the eye, that are required for this light detecting mechanism, but another cell class.
Chris - Go on. I'm intrigued. What is the cell?
Russell - Well, it's a small group of photosensitive ganglion cells. Now the ganglion cells are those cells in the retina that are almost the last bit of the pathway. They're the cells that form the optic nerve and then go off into the brain. What's become very clear over the past 15 years, I suppose, is that about 1 in 100 of those ganglion cells is directly light sensitive and will project to the clock structures in the brain, the SCN.
Chris - So, you are exposed to bright light, these ganglion cells interpret the bright light, and they tell the brain about it, so the brain has that time of bright light exposure. It knows when morning is and it uses that to refine the clock.
Russell - Absolutely. What's turned out to be completely remarkable is that you can be visually blind, have no conscious perception of light, and yet these photosensitive ganglion cells are still there, working away, regulating your internal time. We've studied several individuals now who have lost their classical visual cells, they've lost their rods and cones, and yet, they can regulate their body clocks perfectly well.
Chris - What happens if you have individuals who have no eyes for one reason or another, or they've lost their eyes through injury? Would their body clock fail to reset in this way then?
Russell - Absolutely and this is why we're working with our colleagues in ophthalmology, because ophthalmologists not only need to explain what it's like to lose your vision, but in those circumstances where you've lost your eye, they also need to know what it's like to be plunged into unremitting jet lag for the rest of your life.
Chris - Sounds awful.
Russell - It's terrible. And of course, jet lag is so ghastly, not because you're simply 5 hours let's say, shifted from Cambridge to New York. It's because we were talking about the mismatch between the internal clock, the master clock in the SCN, and all those peripheral clocks. It's as if you've got a temporal smear. Everything is slightly misaligned. It's rather like the conductor is at a different beat from the violin section to the brass, the whole cacophony of sound rather than a symphony.
Chris - It really does sound awful. So all of your tissues are effectively running on different time zones and so, there's a communication problem between them, which is why you feel so awful when your jet lagged but that could be at the root of diseases where the body clock doesn't work properly there.
Russell - Absolutely and that's the thinking. That in fact, it's internal desynchronisation which is such a problem for overall health and it may be one of the problems that for example, night shift workers get.
Chris - What about people who have other disorders, mood disorders, psychiatric disorders, bipolar disorder where people can't go to sleep, depression where people struggle to get to sleep, and then they wake up very early? Is the sleep disturbance a cause of their symptoms or actually, is it just one manifestation of the underlying process?
Russell - In severe mental health, in psychosis for example, it's been reported that abnormal sleep has been recorded way back from the 1880s, but it's always been assumed more recently to be, well, you know, individuals with mental health problems don't hold down a job, or the antipsychotics they're on, and the bad sleep is a consequence of that. What we're discovering is that that's not right. There seems to be a fundamental overlap between the mechanisms that predispose you to poor mental health, and those that are generating a normal sleep-wake cycle. What's become very clear is that of course, sleep is a lot more complicated than just the body clock. It's involving multiple brain structures and multiple neurotransmitters. A defect in one of those, that gives rise to a mental health problem, will also have a ripple effect across sleep and sleep problems.
Chris - Brilliant! We'll leave it there for now. That's Professor Russell Foster, he is from the University of Oxford.
And if you'd like to see how the body clock works, we've put together a special Naked Scientists scrapbook episode for you this week, which takes you through graphically how the circadian clock works.