The Nobel Prize in Physiology or Medicine was awarded today to Jeffrey Hall, Michael Rosbash and Michael Young for discoveries of molecular mechanisms controlling circadian rhythms.
Nobel Prize Explainer: Circadian Rhythm's Oscillatory Control Mechanism
The Nobel Prize in Physiology or Medicine was awarded today to Jeffrey C. Hall, Michael Rosbash and Michael W. Young for discoveries of molecular mechanisms controlling circadian rhythms. Following the announcement and press conference, Anna Wedell, chair of the Nobel Committee for Physiology or Medicine, spoke about the research.
Steve Mirsky: Welcome to Scientific American Science Talk, posted on October 2nd, 2017. I am Steve Mirsky.
Thomas Perlmann: The Nobel Assembly at Karolinska Institutet, it has, today, decided to award the 2017 Nobel Prize in Physiology or Medicine, jointly, to Jeffrey C. Hall, Michael Rosbash, and Michael W. Young, for their discoveries on molecular mechanisms controlling the circadian rhythm.
Mirsky: Thomas Perlmann, secretary of the Nobel Assembly, shortly after 5:30 this morning, Eastern time.
Perlmann: Jeffrey Hall was born in New York and performed his seminal work at Brandeis University. He's now retired and lives in Cambridge in Boston. Michael Rosbash was born in Oklahoma City, and performed his prize-winning studies also at Brandeis University, where he's still on the faculty. And finally, Michael Young was born in Miami, and did his work at Rockefeller University in New York, where he also remains on the faculty. So, this year's prize concerns the circadian rhythm. The word "circadian" originates from the Latin word "circa," meaning "around," and "dias," meaning "day." But in a way, it is actually about astronomy. Ever since the emergence of life on earth, about four billion years ago, evolving life forms had to adapt to the rotation of our planet. This ability to prepare for the regular daily fluctuations is crucial for all life forms.
But how is this possible? This year's Nobel Laureates have been studying this fundamental problem, and solved the mystery of how an inner clock, in most of our cells in our bodies, can anticipate daily fluctuations between night and day, to optimize our behavior and physiology. This existence of an inner clock was first described already in the 18th Century. The French astronomer de Mairan studied a mimosa plant that opens its leaves towards the sun during day, but closes at dusk. De Mairan asked what would happen if the plant was exposed to constant darkness. And he found that even then, for several days, the leaves continued to follow the regular 24-hour daily rhythm. In the 20th Century, it was established that, also, other plants and animals, including rodents and humans, have their own biological clocks following the daily circadian rhythm.
Studies of the clock in fruit flies show that many different behaviors are controlled by the clock. Fruit flies are really excellent model organisms for studies of genetics, and in the 1970s, a mutation that affected the flies' daily rhythm was identified. That mutated locus was called "period," but how did the mutation affect the internal clock? This year's laureates, they wished to peak inside the clock and figure out how it actually works. The first breakthrough came in 1984, when Jeff Hall, in collaboration with Michael Rosbash, and Michael Young working independently, were able to isolate the period gene. Now the scientists could begin to disentangle the cellular wheels and cogs of the clock machinery. Jeff Hall and Michael Rosbash showed that the period protein itself was cycling, and peaked during night, and was low during day.
In 1990, they showed that the period mRNA also oscillated, and accumulated several hours before the period protein. These and other important observations led to a brilliant idea for how the clock works by feedback control mechanism. When the period gene is active, period mRNA is made. The period mRNA is transported to the cell's cytoplasm, where period protein is made. When period protein accumulates, the protein moves into the cell's nucleus, where it blocks the activity of its own gene. When the gene is blocked, no more RNA can be made, period protein levels will decrease, and the gene will no longer be blocked, and the production of mRNA can start all over again, and the cycle can continue.
But it remained unclear how the period protein could accumulate in the nucleus, to inhibit the gene. This problem was solved when Michael Young discovered a second gene, called "timeless," that is also critical for the clock. But how did the timeless protein affect the period gene? Additional experiments show that timeless protein bound to the period protein, and together, they entered the cell nucleus, where they could inhibit the period gene. It was also critical to understand how the speed of the oscillations can be controlled. Michael Young identified yet another protein, called "double-time," or DBT. This inner clock adapts our physiology to the dramatically different phases of the day, and regulates many critical functions such as behavior, hormone levels, sleep, body temperature, and metabolism.
We do not feel well when there is a temporary mismatch between our external environment and internal biological clock, for example, when we experience jetlag. Studies have also indicated that chronic misalignment between our lifestyles and the clock is associated with increased risk for various diseases. Since the paradigm of shifting discoverings by Hall, Rosbash, and Young, circadian biology has developed into a highly dynamic research field, with vast implications for our health and wellbeing. I would now wish to present our expert panel, who would be happy to respond if there are questions.
So, at the far end, we have Professor Juleen Zierath, who is a member of the Nobel Committee. In center, we have Anna Wedell, who is the chair of the Nobel Committee. And on her side, we have Professor Carlos Ibanez, who is also a member of the Nobel Committee. So, please, if there are any questions, please go ahead.
Questioner: Yeah, I'm curious about the dynamics of this system. So, if one were to change the cycle to, like, 6 hours instead of 24 hours, for humans _____ _____ they're being kept in very short cycles, what happens with this system? Does it adapt to very short [crosstalk]?
Perlmann: I think I'll ask Anna to respond to that question.
Anna Wedell: Well, we know that, in rare cases, there are humans who have a little bit altered length of the period – not as you described, six hours, but a little bit shorter – and they get sleep problems. We don't know of any drastic disruptions, in humans, of the clock. There are, of course, animal experiments, and if you disrupt the clock in animals, you get effects on metabolism and on various physiological parameters. But in humans, it's not really possible to do those kinds of experiments.
Male: But are there any treatments, or possible treatments, for sleep disorders that could be based on this finding?
Wedell: Well, an obvious answer would be a melatonin, which is a hormone that is secreted before we go to sleep, and that can also be used for those kinds of problems, and some people even use it for jetlag. And also, if you're blind, for instance, your rhythm will still be going, but it will be out of sync with the – or misaligned – it will be free running and it will not be _____ by light. And then you can use similar compounds to melatonin, to try to adjust that.
Fred: I've got one question. I'm Fred, from China's National _____ News Agency. Regarding to this year's discovery, do you think this discovery by the scientists can solve the problems especially that we encounter in the Nordic countries where you've got long dark winter days [laughter] _____ people tend to have depression? And is this discovery actually shedding light to solving the problem to boost, you know, people's energy?
Perlmann: Could Juleen answer?
Juleen Zierath: So, I guess the question was how this discovery might solve the problem of how people cope with extreme changes in darkness or sunlight. And I think what it can do is raise awareness to the importance of proper sleep hygiene, and the importance of really making certain that we allow ourselves to go to bed at an hour that's suitable – I guess for many of us it's around 10:00 or so – even if the sun is shining on midsummer day. And it probably helps us to be aware of the fact that we need to be in a dark environment to get the best sleep. And that we shouldn't be afraid of using our alarm clock even when it's the darkest times of the year. So I think what it can do is help raise awareness.
Mirsky: Following the announcement and press conference, an unidentified viewer spoke with Anna Wedell, the chair of the Nobel Committee for Physiology or Medicine.
Questioner: Could you describe to us what is circadian rhythm?
Wedell: So, "circadian," it derives from the Latin, so, "circa" is "around" and "day" is "day." And this is the daily rhythm we have to anticipate and adapt to the dramatically different conditions during day and night, that arise from the rotation of the earth.
Questioner: So, the three laureates, what problem have they solved?
Wedell: So, it had been known, for a long time, that there are diurnal or circadian rhythms, but how it worked wasn't known at all. And it was debated, for a long time, whether it was a response to external signals or something endogenous. And before they started their work, it was understood that it was endogenous, and it was even understood that single genes could influence the circadian rhythm, but nothing was known about the mechanism. And there were different hypotheses, but they found out the mechanism that controls the machinery of the clock.
Questioner: So, if we turn to the discovery, what were the key findings, and who did what?
Wedell: So, first of all, they used the fruit fly as the model system, and before their work, there had been a classic experiment by _____ and _____. They had used the fruit fly to ask can you identify mutants that arise due to mutations in single genes, so that was sort of a basis before our laureates started their work. And they took advantage of that, because the gene wasn't known – there were mutant strains known, who had long or short or no rhythm at all, that were known to map to the same locus. So the laureates used these flies, and went on to isolate the gene and determine what gene it was, but that didn't prove the mechanism, either. So what they then did was experiments to understand the function of the system, by this gene and then several others that they did in sequential experiments.
Questioner: Why is circadian rhythm important?
Wedell: So, we need the circadian clock to anticipate the daily changes. There are dramatically different conditions during day and night, and we need to be very active in the day and other processes need to take place during night. And evolutionarily, it's been a very great advantage to use the early critical light hours, minutes, of the day. For instance, if you're hunting, you need to be active, or if you're hunted, you need to run and hide. So you need to be prepared and take advantage of and be one step before the environment. That's why we need it.
Questioner: And is this _____ kind of clock, is it in all our cells, or – ?
Wedell: Well, we know that most of our cells have this clock, and we also – we knew, before these discoveries, that there is a central clock in the brain that controls the rhythm. And then, later it was found that we also have them in other parts of our body. But it's actually the mechanism that the laureates have _____ _____ it's an autoregulatory self-sustained inhibitory feedback loop. It's a little bit difficult, but it's an oscillator, so you build up a substance, and then when the substance is there, it turns off its own production. And then it can start over again, so it becomes an oscillation, so, a negative feedback of its own synthesis. That's the best I can do. [Laughs]
Questioner: Also, this _____ is for physiology or medicine, so, what are the medical implications?
Wedell: Well, there's a huge field of chronobiology, chrono medicine – it's really exploding. It's a fascinating area. But in humans, most data on specific diseases are, so far, correlations, so we don't really have the firm evidence to postulate _____ the circadian clock does this or that when it comes to disease. There are some examples: there are sleep phase disorders where you actually have mutations in some of the core clock genes, and then you have a shorter or a longer phase, and that causes problems with sleep. That's the solid thing. But in humans, apart from that, there are lots of correlations. There's more known, of course, in animal models, where you can disrupt the clock and then see effects. Another example is jetlag, of course, but that's not really a disease. But that indicates that when we're misaligned – so, our inner clock does not match or is misaligned to the environmental clock – then we really feel bad. Then, of course, there's a lot of interest in trying to understand if our lifestyle today, with sort of a social jetlag, has implications for disease. And that's very actively studied, but so far, mainly correlations.
Questioner: Sometimes you feel kind of bad when, in wintertime, when you're in Sweden and the darkness – how should one cope?
Wedell: How one shall cope? Well, that's a big question. [Laughs] What I can say regarding that is that there's so many things that we need to understand. And also, the core machinery, it's a lot more complex, but the concept is the same. But we now know that there are more factors regulating and stabilizing, there are interconnected loops, and there are mechanisms for entrainment, so you adjust the clock, mechanisms for synchronizing clocks throughout the body, and output mechanisms. So, other genes are sort of hitchhiking on the system and controlled by the same mechanism, and all of this is really, really dynamic, and we are learning so much. So, all of these implication questions, what it means for our health, that really remains to be nailed down, now. And they have provided tools for that – by understanding these mechanisms, we now have a way forward to address these issues.
Questioner: What do you think is the best about this prize?
Wedell: The best _____, well, it's such a fundamental prize. It's a detailed molecular mechanism, but it explains how we are adapted to the planets. I think it's a very fundamental thing, and it's important for so many things. And it's opened so many questions and enabled so many questions.