Studying the molecular clockwork

AcademiaNet Interview with Professor Martha Merrow

14. 12. 2017 | This year's Nobel Prize for Medicine and Physiology went to three chronobiologists: Michael W. Young, Michael Rosbash and Jeffrey C. Hall. The award has put a spotlight on an exciting, yet rarely discussed, field of research. We spoke with Professor Martha Merrow from the Ludwig Maximilians University of Munich, who researches circadian clocks in different organisms. She told us about the inner clock of cells, how chronobiology could help us live healthier and the problem some individuals' chronotype.
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(© BarrySheene / Getty Images / iStock)

Clockwork | Scientists are getting closer to deciphering the workings of the "inner clock" of cells. In 2017, three chronobiologists received a Nobel Prize for their work in this area.

The Nobel Prize was awarded to scientists researching our inner clock. How much influence does this clock have on us?

Our inner clock – the circadian clock that cycles once a day – guides when we sleep and wake. That is a pretty big effect I would say! But there are also more subtle ones, such as physical performance, cognitive performance or mood.

How does the circadian clock impact physical performance?

All of us have a time frame during the day when we are best at physical activities. This summer, a research team from Northwestern University in Illinois in the USA repeated some statistical analysis of major league baseball players to see how circadian disruption impacts their performance. They analysed their travel in the east-west direction with respect to performance in games. The results were quite interesting, as the players that flew eastwards showed a stronger effect on their performance. This suggested that they played worse when they were jetlagged. The simplest explanation is that when you disrupt a clock, you disrupt optimal performance.

You just mentioned our inner clock is set to 24-hour-rhythm. Do we have a little clockwork in our body for that?

On a molecular level we do in some ways: In each of our cells there is a molecular machinery [that creates the circadian rhythym]. The break-through discoveries on this were made by the scientists who won the Nobel Prize in Physiology and Medicine this year. They were the first to clone a "clock gene".

Circadian clocks work through a series of interconnected feedback loops. These oscillations take approximately 24 hours when shielded from time-giving signals such as light and dark. In a natural 24h light-dark cycle, the circadian clock repeats itself exactly once a day. It is synchronised with the outside world. Evidence suggests that there are oscillators besides the transcription factor loops, but they have yet to be molecularly described.

Does each cells use their own clock or is there a, let's call it, “higher order” or “masterclock”?

There is a hierarchy of circadian clocks: cell, organ, organism. Cells sitting together with a similar function form organs and have organ-specific clock-regulated programs. This is probably directed by cell-specific differentiation programs. This is extremely complex and we don't fully understand which clocks communicate with one another.

We do, however, know that the clock that regulates our behaviour, our sleep-wake behaviour for instance, sits in a part of the brain that is called the suprachiasmatic nucleus. But – there is a ‘but’ again (laughs) – in a recent study colleagues showed that if you alter the clock in a muscle of a mouse in a laboratory, you can impact on the clock in the brain. Basically you change the sleep-wake behaviour. That makes us question if the brain is really dictating all of our behavioural aspects or if there is some kind of feedback from the periphery to the brain.

Does everybody have a 24h circadian rhythm?

It depends a bit on the protocol with which the circadian rhythm of an individual is measured. Most of the times [test subjects] are taken out of synchronized environment. For people, this might mean dark caves - as were used in the first experiments on humans - and dimly lit rooms nowadays. These people – in temporal isolation – then start to wake up and go to bed with a period that is not entrained by external zeitgebers such as daylight. The first ever conducted studies on that topic found that most people have a slightly longer than 24 hours period, more like 25ish hours. Some people showed rhythms substantially longer than 24 hours. Others were shorter.

There is an alternative protocol commonly used now, called forced desynchronization, which gives circadian rhythms with a period very close to 24h in most people. So, it depends on the protocol what period you get out in temporal isolation. The same can be said for other organisms. The period in constant dim light is different than that in constant darkness. That tells us something about how the system is put together: that the signals from the environment themselves change the properties of the circadian clock.

What effect does it have on life if people tend to have slightly longer rhythms than the average 24-hour day?

There is a correlation between period of the rhythm and how early or late is one’s chronotype. Some people are so-called larks [i.e. early risers] and some people are so-called [night] owls. There are only few real larks and few real owls. Most of us are right around the middle. The few people that are real owls will tend to have a longer free-running period of 25 or 25+ hours.

Do we inherit our chronotype or is that something we develop throughout our lives?

It's a complicated mixture of things. A part of it is definitely inherited. We know that, in most people, there are many genes involved. But the environment also has a lot of impact on the chronotype. If you live in a low-light environment or spend a lot of time inside and little time outside, most people will move to a later chronotype. I suspect this is the reason why more and more people need to use an alarm clock.

What other factors influence our chronotype?

Age has a big impact. You can see this when looking at population level. Teenagers for example become biological late chronotypes as they go through adolescence. When they enter young adulthood they start to reverse this effect and become earlier and earlier until they are between 40 and 50 years old. Then they stabilize again and are as early as they used to be as children. So, our chronotype is influenced by – at least - three different things: genes, light environment and age.

How can I find out what kind of chronotype I am?

The easiest way is to use questionnaires. I prefer the Munich Chronotype Questionnaire [editorial note: Prof. Merrow is one of the co-creators of this questionnaire] because it is not as psychology-based as other questionnaires. It asks things like “When do you sleep” and “When do you get up”, “When do you do that on work days” and “When do you do that on free days”. There are also feedback sheets that come up explaining where your chronotype lies in relation to others. It's quite educational and it comes with an explanation about the biological clock. Unfortunately, it is offline just now but in the coming months, it will be up again.

What use do people have when they know their chronotype?

If you are aware of your chronotype you can either try to change your working situation and start to work later or earlier. Or you can use light intelligently to advance or delay your chronotype.

Most people who are working have to use an alarm clock several days a week to get up on time. By definition, they are depriving themselves of sleep every day they use an alarm clock. It also leads to a mismatch between circadian and social clocks called social jetlag. We know that this social jetlag is associated with certain health risks such as overweight. Sleep deprivation even has a cumulative effect: The more sleep deprivation one accumulates through the week, the worse their performance is through the week.

How can I advance my chronotype?

Most people can advance their chronotype by getting more light in the morning. Outdoor light is optimal. But if you can't get outside, then blue light is most effective at adjusting the circadian clock. There are only few people who are so late that if they 'take' light in the morning they actually do the wrong thing and make themselves even later.

I’m looking forward to the time when we know enough to prescribe light, like we would prescribe a drug, in order to help people get to a certain daily timing pattern. That's why it is so fantastic that this year's Nobel Prize goes to chronobiologists. More people will know about chronobiology now and hopefully more people will also learn about social jetlag and what they can do to prevent it, to live with their clock and not against it.

Thank you for this timely interview, Professor Merrow.

Questions were asked by Sonja Klein for AcademiaNet.

Social Jetlag - what is it all about?

Social jetlag
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(© Alex Potemkin / Getty Images / iStock)

Social jetlag

If your biological clock is not in tune with the 24-hour-day cycle, you might be more likely to develop social jetlag. The condition is best explained with an example: Let's assume your biological clock is off by one hour, so that you are tuned to 25-hour-days. This makes you a true owl. Despite your chronotype, you need to get up at 7am on weekdays. The extra hour in your "biological" day makes you feel like you get up earlier and earlier. On the weekend, you may let your natural cycle roam free: you go out, meet friends, and then go to bed in the middle of the night. Sunday morning, you wake up hours later than during the week. But on Monday, your alarm goes off at 7am again.

The fatigue you feel is similar to a jetlag, like you spent the weekend in a different time zone, and came back just in time to go back to work on Monday. Maintaining this pattern – getting up early during the week, but staying up late and sleeping in on the weekends – can harm your health in the long term. Studies have suggested that social jetlag increases the risk of people to suffer from depression and makes them more prone to drink excessive amounts of caffeine or alcohol.

  (© AcademiaNet)
Sonja Klein

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