Translator: Rhonda Jacobs Reviewer: Peter van de Ven And then . . .
there was light. So, two-and-a-half billion years ago life evolved on our planet, and because we live on a 24-hour world, all living organisms actually developed ways to anticipate the daily life - change in light, change in temperature. And we now know from bacteria to plants to animals to humans, we all have so-called biological clocks that can anticipate the 24-hour day.
Now, for us, perhaps the most familiar biological rhythm is sleep-wake. And the picture on the left shows Dr Nathaniel Kleitman, so-called father of the science of sleep, from the University of Chicago, who, in 1938, went into a cave for 42 days in Kentucky to ask the question: Does my sleep-wake cycle still go on? And the answer was yes.
So on the graph on the right-hand side in the purple is actually a sleep-wake record of a more modern experiment. It was done in Andechs, Germany, by Jürgen Aschoff. And it shows the record of a young medical student who volunteered to go into what I call an artificial cave.
It was an underground apartment that could be totally separated from the world. And he went into this apartment for 40 days as you can see here. Oops.
If I could go back please. One more. There.
Thanks. Sorry about that. Forty days.
And what this record shows you in blue, that's when he's awake; and the yellow's when he's sleeping. And this is time of day. And for the first week, the door to the apartment is open.
He's waking up at 8:00 in the morning and going to sleep at midnight. Then here the door is shut; he's completely isolated. And the first interesting feature happens, and that is his sleep-wake pattern continues, but the time that he wakes up is later and later each day.
So, for example, on this day, he's waking up close to midnight. Okay? And during this time that he was in isolation, he actually went through one fewer biological days than the number of real solar days.
He actually lost an entire day because his day was about 25. 5 hours instead of 24 - so he lost about an hour and a half each day. Now, the second feature of this record which is kind of interesting is here he lives in the apartment, but the door is open, and he goes back to a regular schedule of waking up at 8:00 in the morning and going to sleep at midnight.
And this shows, really, the second feature of our clocks, and this is, even though they're internally generated, we still synchronize to the daily cycle, and light turns out to be the primary synchronizer of our rhythms. So this is back in the 60s. What is it that generates and controls these rhythms?
Do we have an internal biological clock? If so, where is it? And so two strategies have really been taken over the last 50 years or so to try to understand how this clock might work.
The first is to try to find where in the brain is the clock located. And the strategy there was to follow the light. We know that light regulates the clock, and the strategy was to find light pathways into the brain and see if the clock was located there.
The second was to try to ask: Is this clock internal and genetically determined? And if so, can we find genes that control that clock? And so that's sort of where I come in.
Now, in people, light is the major synchronizer of our rhythms. It's mediated by our eyes, which project down these optic nerves into the brain stem, and at the very first weigh station, these two yellow structures, turned out to be the location of the biological clock. Within each of these weigh stations, or nuclei, are about 10,000 cells, each of which contains a biological clock.
So we actually know where the master clock is located in us and in most animals - it's in the brain, in the base of the brain, in the structure. How can we, then, try to understand how this structure might work? And this is where we really came in, and that was to try to find the genes, follow the genes that control circadian rhythms.
And to do this, we turned to the laboratory mouse as a discovery engine to find the gene. Now, how do we do that? So, it turns out the mouse has a beautiful circadian rhythm.
I have a couple examples on the right here. This is a normal mouse. In black is showing when the mouse is active.
It's analogous to that sleep record I showed you in the second slide. The mouse has this pattern, which is the 24-hour pattern. It's waking up a little earlier each day, and that's a normal mouse.
What we did is to make random changes in the genes of the mouse, and then ask: Can this change the behavior or sleep-wake pattern of that mouse? Okay? And this is where Rachael Chong mentioned "luck.
" In retrospect, you would probably say I was very lucky because we found this mouse here, which, as you can see, doesn't have this nice consolidated pattern. It has a very kind of random pattern. It lost its biological clock.
Okay? So this is a mutation - kind of like a disease in a human - that caused loss of the rhythm in this mouse. But then, what really causes that?
How can we understand the nature of this loss? Because this is a behavior in the mouse. Well, it turns out we could then show that this is caused by a single gene because it was inherited, transmitted to the offspring of these mice.
And then we could try to see where in the genome this gene might be located. So this is a representation of the mouse genome. It's very similar to our genome - the sizes are almost equivalent.
We have three billion base pairs of information in our genome. And so really, the goal is to to find out where this gene is. [On] which of the 20 chromosomes in the mouse is this protein or gene located?
Okay? So this turned out to be a very difficult project. This is a picture of my laboratory in 1997.
And it took about 30 person-years of effort in my lab to find the gene once we found this mouse. Ten people working together as a team for three years, each one of them doing a slightly different part of that project. So how is it that the clock works?
This is an animation, it's a cell. This is the nucleus, and this is the cytoplasm. And the gene that we found was named "Clock," which turned out to be a protein that regulates other genes.
So Clock works with another protein shown in blue. These two turn on two other sets of genes that are called Per and Cry shown in red and yellow. And these genes are turned on and off each day in us.
They're on in the daytime, the proteins are made, and then the proteins actually interact, come back into the nucleus at night, and then they inhibit their own genes. So you can see that the Clock is interacting with the Per-Cry. And then that turns off the Per-Cry genes.
So this leads to an autoregulatory cycle - a feedback cycle - in which one set of genes turn on another set of genes, and those genes feed back and turn off the original set of genes. Okay. So this is actually how the clock works in the cell.
So what is the clock doing? I decided not to go into the nitty gritty details of this, but instead to give you more of an artistic rendition of some of our recent work. This, you can imagine, is a day in the life of a cell, going from zero to 24 hours.
And all along in different colors are all the different components of genes and regulators of genes in cells. And what we found is that literally thousands of these are actually cycling on and off in every cell in your body, every day. And so the clock is actually doing something very fundamental in our cells.
The major thing it's doing is regulating the metabolism of the cell - the processing of fuel and energy - and creating a different state of the cell each day. So not only are we awake and asleep each day, essentially all the cells in our body are going through an activity-rest cycle. And this is really controlled not by the brain so much, but by a local clock working at a very fundamental level in each cell.
Okay. So how do we study these clocks? So this is the base of the brain where the clock is located - the master one in the brain.
And we can actually see the clock ticking. This movie, which is a little dark here, is showing you the Per protein, which is fluctuating over time. And using this method, which is shown here in a brain slice, we can take this to the level of single cells.
So this next movie over here shows you a field of skin cells under the microscope - you can see they're twinkling on and off. Each of those is a cell that is oscillating. And I've just shown you two graphs here - examples of one cell and another cell.
And so, literally, you can see the biological clock in a single cell. This particular experiment really changed our view of the entire system. We've extended it to many different cells in the body, and what we find is essentially almost every cell in your body contains a biological clock.
And so when we look at the mouse, there's one in the brain, but almost all your major tissues actually have clocks. This is a diagram of a mouse, but it's actually true for us also. Okay.
So given we have all these clocks, how are they integrated? How does the brain talk to the body, and how do the different pieces integrate? Well, the Oxford philosopher Derek Parfit proposed a very interesting thought experiment.
He said that a scientist gradually replaced the cells in your body with the cells from Greta Garbo. And what he asked is, at what point do you cease to be yourself and become Greta Garbo? Now, for those of you who don't remember Greta Garbo, maybe think Angelina Jolie.
(Laughter) Okay. So we can do this experiment in a mouse. It's incredible.
We can make a mouse that's a mixture of two other mice. So the white and the dark fur is the manifestation of an albino mouse and a pigmented mouse. Okay?
So how do you make a chimera? You mix two eight-cell-staged embryos - they come together and they form one embryo - and then you can create a chimeric mouse. And then you can ask, what does that do to the behavior of that mouse if we mixed normal cells and mutant cells, say, clock-mutant cells in this case?
Okay? And we can change the proportion. Okay.
So the answer is, if you have normal cells, which are blue in this case, your rhythm is normal as we saw in the normal mouse before. And if your cells are mutant, white in this case, then your behavior is disrupted as we saw in the original mutant. But what was interesting is when there is about a 50/50 mixture, we found a third, new phenotype.
There's an intermediate behavior when we mix these cells in the mouse. This says a number of things; one thing it says is that the cells are communicating, integrating that cell-cell information to generate a new kind of behavior. Okay.
So what about [Derek] Parfit? When did [Derek] Parfit - oh, sorry, wrong person. When does [Derek] Parfit become Angelina Jolie?
And what's going on in the middle here? We can only imagine. (Laughter) So for the last two minutes of my talk, I want to just return to sleep and give you just a couple interesting facts about sleep, which turns out to be a significant problem in the modern world.
So my good friend Till Roenneberg published this work recently, in which he asked how much sleep normal people get on work days and on free days. So work days are shown in red, free days in blue, as a function of age. So all of us know that as we age, we sleep less.
And of course, infants need lots of sleep; teenagers need nine to ten hours of sleep; and then adults, maybe seven to nine hours. But it turns out that in the modern world, we really are only getting about seven hours of sleep from the time we are 20 or so. And what happens is on the weekends, we make up for that sleep.
And we get a lot more, especially if you're younger. So this doesn't equalize until we're 65 or so. So, Till has called this phenomenon "social jet lag.
" Social factors are making our biological clock system, which is regulating sleep, not work properly. So, we have this great sleep deficit here. Okay?
So what are the consequences of social jet lag? Well, incredibly, one of them is actually metabolic. If you take his patient population, or actually, normal volunteers, who have a BMI index of over 25, and then you look at their social jet lag, as their social jet lag gets worse, over here, this actually is correlated with a BMI index that goes into the obese category.
So just as social jet lag can actually tip the balance and push you over the threshold if you already have a tendency to be obese. If you're normal - that's a BMI under 25 - it turned out it didn't have any effect; in fact, it had the opposite. Okay?
The second feature is, what happens with cumulative sleep loss? So these are three groups: They're allowed to sleep either eight hours, six hours, or only four hours each night over a 14 day period - two weeks. And this is just one cognitive test.
But as you can see, this sleep loss leads to a very significant reduction in cognitive performance in many different measures, not just this one. Okay. So, I'm going to stop there and give you the advice: Keep in sync, get enough sleep, and you'll be thinner, smarter, and happier.
Thank you.
