The Clock Inside

IRA FLATOW: This is Science Friday. I’m Ira Flatow. Chances are, you have many ways you keep track of time, right? You may be looking forward to tomorrow’s solstice, the official start of winter, the slow return of daylight. Or you may be thinking back on everything that’s happened in the last decade, as we prepare to enter the year 2020.

And you may, this very moment, be looking at the clock and thinking about everything you still have to get done before the sun sets and the day is done. But you know there’s another timekeeper that you can’t see inside your cells, telling you when to sleep, when to wake up.

These are the clock genes and they don’t just say when you snooze. They determine your heart rate or hormones. We’re ruled by circadian rhythms. There are cycles under scrutiny in the field of chronobiology. Yes. And my next guests say a better understanding of the clock genes might help us with more than our holiday jet lag.

There are whole frontiers in health opening up as research and time march on. So let me introduce my guest. Dr. Erik Herzog, professor of biology at Washington University in St. Louis, president of the Society for Research on Biological Rhythms. Welcome to Science Friday.

ERIK HERZOG: Hi, Ira. Thanks for having me.

IRA FLATOW: You’re welcome. You know, I think it’s probably new to everybody that there’s a gene that keeps track of time of day.

ERIK HERZOG: That’s right. There’s a handful of genes that we call clock genes that we say are essential for scheduling our day.

IRA FLATOW: And how does that work? What’s going on there?

ERIK HERZOG: Well, inside individual cells in our body, there are 19,000 genes, a subset of which are expressed in any given cell type. And of those expressed genes, there’s a handful that are really responsible for keeping near 24-hour time for those cells.

So these are genes we call clock genes because when they’re mutated or messed up, the cells lose their ability to keep near 24-hour time. And the way the clock works is something we call the TTFL or the transcription translation feedback loop. Where a clock gene is turned on and it makes its message, that message then gets turned into its protein. Those proteins accumulate to a critical level, and then they go back into the nucleus of the cell to turn off the transcription of that clock gene.

With that repression, the gene then turns off, the messages go away, the proteins go away. And about 24 hours later, the repression goes away and the gene can start expressing itself again. So this internal intracellular clock can keep near 24-hour time in just about every cell in our body.

IRA FLATOW: So if each cell in our body has one of these timekeepers, are they all synced together? Because if they’re not, wouldn’t you have chaos?

ERIK HERZOG: Yeah, exactly. So to be a good rhythmic person, sleeping at night, awake during the day, having hormones like cortisol rise just before we wake up, melatonin rise as we go to bed, we need to have a coherent rhythm amongst all of these cells. All the cells need to agree on what is local time. They need to be synchronized to each other.

IRA FLATOW: And how does that happen?

ERIK HERZOG: So synchrony seems to be mediated, the action is all in our brain. There’s a teeny tiny spot in the base of our hypothalamus, right on top of where our optic nerves cross. So if you follow your eyes back into your brain, sitting right on top of where your optic nerves would cross is a spot that’s about a millimeter by a millimeter by a millimeter called the suprachiasmatic nucleus, the SCN meaning sitting on top of the optic nerve crossing.

And that spot is comprised of about 10,000 neurons on the left side of the brain, 10,000 neurons on the right side of the brain in the base of the hypothalamus.

And that acts sort of like the atomic clock which synchronizes the clock in all of our alarm clocks and computers. It’s the atomic clock for our body. It is responsible for sending out timing signals to the brain and body to keep us as a coherent orchestra of clocks.

IRA FLATOW: Now, we always hear about that you depend on sunlight to sort of reset that clock. Is that why the optic nerve or your eyes are connected to that, to know that there’s light out there?

ERIK HERZOG: Exactly. So light enters through our eyes and it stimulates our rods and cones, the photoreceptors in our eye. But it also stimulates another population of photoreceptor cells, that were really only recently discovered.

It’s pretty amazing that we’ve known all the cell types in the retina basically since 1865, but within the last 20 years, there was a new photoreceptor that was identified called a melanopsin cell. It expresses a special pigment called melanopsin.

And those cells are the ones that actually project down your optic nerve and make synapses or connections in the body clock, the SCN, to communicate when it’s day and when it’s night, to synchronize your body clock to the local light dark cycle.

IRA FLATOW: And the biggest 24-hour cycle most of us think about of course is sleeping. What about this process determines our sleep schedule?

ERIK HERZOG: So the master clock in the SCN is intriguing in that it’s the same in diurnal and nocturnal organisms. It’s metabolically active during the day and relatively quiescent at night.

But it’s sending out signals to different parts of the brain, we think, that are interpreted as now it’s time for you to sleep. And those signals include regulating things like the hormone melatonin, which is secreted by your pineal gland, and is a signal that helps to promote the onset of sleep.

IRA FLATOW: So what happens when you have a night owl or somebody who sleeps, doesn’t go to bed before midnight, something like that? Does that upset the sleep center in the brain or the release of melatonin? What’s out of sync with that?

ERIK HERZOG: Great. So first I think it’s important for us to say that it can be perfectly normal and healthy to be a night owl, to be a late bird, or an extreme early bird. There is natural variation amongst all of us. And at least some of that variation can be explained by variation in our clock genes.

So there’s really beautiful work, for example, on one of our clock genes called the period 2 gene, showing that different mutations in that gene can turn you into either an extreme early bird or an extreme late bird. Just changes in the sequence of that one gene change how fast your clock runs. And if your clock runs with a short period, less than 24 hours, you tend to be an early bird. If your clock runs with a long period, longer than 24 hours, you tend to be a late bird, a night owl.

So at least part of the difference between all of us who prefer to wake up either early or late can be explained by our genetics. That’s not the whole story.

IRA FLATOW: And that’s interesting because we tend to think of, well, I’m abnormal because I’m an early bird or a late bird. But you’re absolutely normally just have variable genes that are doing it for you. The winter solstice is upon us, and for many of us in the northern hemisphere that means going to start seeing more daylight soon, though at least one listener is not excited by this. He’s Mark from Wisconsin on our Science Friday VoxPop app.

MARK: I think I might be an outlier, but I actually prefer the shorter days and longer nights. I like the cold weather. And I sleep a lot better when the night is really long. During the summer I have trouble sleeping. It’s hard to go to bed when it’s light out and get up when it’s light out.

IRA FLATOW: Erik Herzog, does that mean he has maybe a genetic variation to the norm?

ERIK HERZOG: No, in fact we, like many of the animals on this planet, are seasonal creatures. So many of us will describe feeling differently in the summer than we do in the winter. Personal preference aside, I think it’s important for us to appreciate that lots of creatures on this planet are seasonal breeders, for example. They adjust to the long days by actually changes in their circadian system.

So the circadian cells in our body are adjusting their relationship to each other to say it’s summer, compared to now is winter is coming. These cells are changing their relationship to each other to help us adapt to these seasonal challenges. And in the extreme, this clock can be related to things like hibernation and migration.

IRA FLATOW: Let’s go to the phones, because we have a couple of interesting calls I want to get to. Elizabeth in Woodland, California. Hi, Elizabeth.

ELIZABETH: Hi. I love your show. Happy new year and all.

IRA FLATOW: Thank you, you too.

ELIZABETH: Anyway, I’m calling about, he said light affects the brain. I have three questions. One, how does jet lag work when you’re going across the world? Or daylight savings. I have friends who say one hour makes a major difference. Or what about light for people in northern regions, where you have six months sun and six months not?

IRA FLATOW: OK. Happy new year to you too. What do you say Erik?

ERIK HERZOG: Those are three fantastic questions. The first question about how does light affect the brain. We think that it’s sending signals to indicate when dawn and dusk are occurring locally.

So when we travel across time zones and we are suddenly challenged with the sun is coming up let’s say six hours early, because we just flew from St. Louis to Paris, we have not yet adapted to be able to adjust to that big change.

We’re a species, just like every other species on the planet, that’s had to experience small changes in day length, like a minute or two each day. But now, with the ability to fly across time zones over the last 100 years or so, we are challenged to be able to shift our clock much bigger shifts, many more hours.

And so we’re going to try and make our clock wake up six hours earlier when we fly east. And that’s why we feel jet lag. The clock, the internal clock system, is not able to make that shift completely in one day. And what we feel is sort of an internal desynchronization.

The clocks in our body are not synchronized to each other and to local time, and until they get on local time, we can actually feel a form of depression, getting back to the caller from Wisconsin, how this clock system can really affect how you feel.

IRA FLATOW: Let me go beyond our discussion about sleep, though. There’s been research on how we eat and circadian rhythms, and I’m thinking of a recent clinical study finding that eating within a 10-hour window could stave off diabetes, heart disease other problems. Are you familiar with that, and why would that work that way?

ERIK HERZOG: Yeah. This is a really beautiful study from Dr. Satchin Panda’s lab and his colleagues at the Salk Institute. In that study, they asked whether just restricting your eating hours to 10 hours of your waking period would have any effect on your body weight.

And this particular study was on people who have metabolic syndrome. So they have trouble processing food. And what he showed was that they could actually better manage the digestion of that food. They actually lost weight. They were able to stave off some of the symptoms of diabetes by just eating at the right time of day.

So we like to say, it’s not just what you eat, but it’s also when you eat. And how that works is something that’s really still being actively studied, but I’d like you to think about it like this. You have evolved to eat during your waking periods and starve of all night long while you’re sleeping. And so your body has adapted to move the sugars around from when you’re eating, to processing those sugars to keep you going while you’re sleeping. Maybe an easy example is thinking about a plant which has to photosynthesize in the light and then starve all night long in the dark.

IRA FLATOW: That’s quite interesting. Our number, (844) 724-8255. I’m Ira Flatow. This is Science Friday from WNYC Studios.

Are there other medical applications to our understanding of circadian cycles, besides just talking about when we eat?

ERIK HERZOG: Yeah. It’s really an exciting time for the field of circadian biology or chronobiology. Two years ago, three scientists in the field won the Nobel Prize for their discoveries of the molecular basis for how these rhythms get started.

And I think in part they won the Nobel Prize in medicine or physiology because this really beautiful intracellular clock seems to be regulating so many aspects of our biology and our health. So there’s a very active area of biology that’s being applied to medicine called chronomedicine, where for example, drugs can be delivered at particular times of day to get better results.

And nice examples of this are asthma medications that are designed to be slow release during the night and act while we’re sleeping when asthma attacks are more frequent. Or drugs that are used to treat heart disease and protect us against the increased risk of heart attacks just before we wake up in the morning.

My lab is actually in collaboration with two oncologists here at Washington University. And we’re studying the potential of a drug that’s being used in treating brain cancers, glioblastoma. And we’ve shown that that drug is actually much more effective at killing the cancer at one time of day compared to at other times of the day.

IRA FLATOW: That’s interesting–

ERIK HERZOG: Another fun–

IRA FLATOW: Yeah, go ahead.

ERIK HERZOG: Yeah. One other fun example that I’ve really become very excited about is we have an ongoing collaboration here at Washington University with folks in the [? obstetrics ?] and gynecology, where we’re asking whether the risk for preterm birth might be associated with disruption of circadian rhythms.

So we’ve been following 1,200 women here in St. Louis with funding from the March of Dimes, to ask whether their daily schedules are associated with their risk for delivering preterm.

IRA FLATOW: That’s interesting. So if you look to make use of this knowledge, do you– what can you learn that could help us or make us healthier from your research?

ERIK HERZOG: So I think the first thing that folks in the field would like everybody to think about is throwing away your alarm clock. If this biological clock is there to tell you when to wake up and go to sleep, and every time we use an alarm clock we’re waking up unnaturally, if we could just listen to our body clock, that probably would be a good step in moving towards a healthy lifestyle.

The applications of this in terms of things like when schools should start are obvious and many people in our field are really working to start high schools a little bit later than they currently are so that kids can wake up naturally instead of by alarm clocks.

We’re thinking a lot about lighting scenarios in medical settings like improving the lighting in hospitals. Dr. John Hogenesch in Cincinnati has worked really hard to help the hospitals there think about best lighting conditions for the patients and for the clinicians.

IRA FLATOW: Fascinating. I want to thank you. Wow, thank you for taking time to be with us today, Dr. Herzog.

ERIK HERZOG: It’s my pleasure.

IRA FLATOW: And time, as they say, flies. So I’ll have to say goodbye. I’m sure you’re tired of hearing time jokes by now. Dr. Erik Herzog, professor of–

ERIK HERZOG: I have jokes.

IRA FLATOW: Professor of biology at Washington University in St. Louis and resident of the Society for Research on Biological Rhythms.

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