Scientists peer at the inner clock

Circadian clocks are found across all higher species, controlling daily rhythms of behaviour and physiology. The clocks are thought to tick by the continuous creation and degradation of clock proteins in a 24 hour cycle. The principle clock in humans is the suprachiasmatic nucleus (SCN) which is governed by Period genes (Per1, Per2).

Recent research by The University of Manchester and The University of Cambridge has dispelled the previous theory that in mammals Per 2 is let in to the cell nucleus by a ‘gate’ from the outer cytoplasm. Previous studies in fruit flies had shown that Per2 builds up in the cytoplasm until it reaches a critical level at which point the gate would open, allowing it to enter the nucleus.

It is this movement from cytoplasm to nucleus that dictates the tempo of the fly’s body clock.

According to Professor Andrew Loudon from The University of Manchester, this gated mechanism found in flies does not happen in mammals. Instead, the protein moves from the cytoplasm to the nucleus straight away.

Professor Loudon said:

“We have discovered that the level of the per2 builds up in the nucleus and it is this build-up of protein that gives the clock its rhythm.

 

This is an important advancement in  our understanding of the body clock at the cellular level.

 

As new insights into how our body clocks function are discovered, drugs are being developed which will  effectively target the mechanism responsible for circadian imbalances.

 

We think that this non-gated system is likely to be susceptible to drug intervention – but clearly more work is needed on that front.”

Disorders of the circadian clock, ranging from jet-lag, through shift-work to sleep disorders associated with ageing, dementia and psychiatric illness have a major impact on our health.  This work went on to show how particular drugs affect the behaviour of the clock proteins and could provide a first approach to developing suitable therapeutics to treat sleep disorders.


The work was funded by the MRC and BBSRC.

Further references:

Andrew Loudon’s group page

Michael’s Group page

 

Rotation speed may be bad news for Red Planet pioneers

New research has revealed the importance of a circadian body clock that matches the rotational speed of the Earth.

A team of scientists from Holland, Germany and the UK’s University of Manchester  studied animals in which variation in a single gene dramatically speeds up the natural circadian cycle from 24 to 20 hours.

It is the first study to demonstrate of the value of having an internal body clock which beats in tune with the speed of the earth’s rotation.

The researchers released animals with 24 hour or 20 hour clocks into outdoor pens, with free access to food, and studied how the proportion of animals with fast clocks changed in the population over a period of 14 months.

the-planets-4-1155754This allowed the team to study the impact of clock-speed in context of the “real-world” rather than in captivity.

Mice with the 20-hour clock gradually become less common with successive generations, so that by the end of the study, the population was dominated by animals with “normal” 24h clocks.

This supports previous research which shows a connection between people who have abnormal body clocks because of things like night-shift work, and their chances of developing diseases like Type 2 diabetes.

But these studies now extend to the potential implications of space travel in the future. For instance, the Martian day is 37 minutes longer than that on earth.

Professor  Andrew Loudon, from The University of Manchester said:

“The rotation speed of Mars may be within the limits of some people’s internal clock, but people with short running clocks, such as extreme morning types, are likely to face serious intractable long-term problems, and would perhaps be excluded from any plans NASA has to send humans to Mars.

If we ever do get to the Red Planet, I suspect we will be faced with body clock problems; those people with abnormally slow body clocks would be best suited to living there.”

He added:

“A correctly ticking body clock is essential for normal survival in the wild, and this has to be in phase with the rotation speed of the earth.

“Animals with clocks that do not run in synchrony with earth are selected against.

“Thus, the body clock has evolved as an essential survival component for life on earth.”


Professor Loudon is available for comment

A copy of the paper Natural selection against a circadian clock gene mutation in mice is available. It is published in Proceedings of the National Academy of Sciences

Seasonal body clock discovered in animals

Scientists have discovered the cells driving the annual body clock in animals which adapts their body to the changing seasons.

The BBSRC team from The Universities of Manchester and Edinburgh reveal that cells in a structure called the ‘pars tuberalis’- which is situated in the pituitary gland – there are specialised cells that respond according how much daylight there is, providing an internal genetic calendar for the animal.

The activity of these “calendar cells” changes dramatically over the year, with different proteins produced in winter or summer months. The switching between proteins in calendar cells is what drives the seasonal cycle in sheep and other mammals.

The findings, published in the journal Current Biology, advance our understanding of how the environment affects animals – but could also be relevant to humans.

Lead Author Professor Andrew Loudon from The University of Manchester said: “Scientists have long puzzled over how many animals seem to change their physiology according to the seasons.

Animals need to change their physiology to predict the changing environment and increase their chances for survival.

For example, some animals hibernate through the winter and others, including sheep, will time mating to the winter so they can give birth in the spring – when more food is available.

Now we have a much stronger understanding about how the body’s so-called circannual clock regulates this process.

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The study took three years to complete and involved analysis of how sheep respond to seasonal changes in daylength.

Dr Shona Wood, Research Associate from The University of Manchester said:

A similar structure can be found in most animals – including humans.

Scientists once believed that humans did not show seasonal adaptations, but more recent research has found that this may not be the case and in fact there is seasonal variation in protection against infectious disease.

Our study gives more increases our understanding of how this may work.

Professor Dave Burt from Edinburgh said:

The seasonal clock found in sheep is likely to be the same in all vertebrates, or at least, contains the same parts list. The next step is to understand how our cells record the passage of time .


Wood, Et al. Binary Switching of Calendar Cells in the Pituitary Defines the Phase of the Circannual Cycle in Mammals, Current Biology.

Tuesday Feature Episode 17: Qing-Jun Meng

Qing-Jun Meng has been no stranger to the media over the last few weeks. Having recently been part of a duo that were awarded a grant worth over £1 million from Arthritis UK, Qing-Jun has since appeared on BBC Radio Manchester and on the brand new channel That’s Manchester to talk about his research. (You can watch the TV segment here: https://www.youtube.com/watch?v=mu-x2I6VcL4) All of this interview practice should mean he can give a great Tuesday Feature interview! Read on to find out if all the practice was worth it. (Spoiler: It was!)

Please explain your research for the layman in ten sentences or less.

I work on body clocks – 24 hour rhythms and how they change with age. I look at how these changes could contribute to age-related diseases. One tissue of particular interest to me is cartilage in the joint right at the surface of your long bones. We’ve discovered recently that even these cartilage tissues and cells contain functional clocks and these clocks seem to be important in the homeostasis of this tissue, and presumably in aging, the disruption of circadian rhythms could be an underlying risk factor for developing osteoarthritis.

DSC_0400How could your research benefit the person reading this blog?

Osteoarthritis affects about 8 million people in the UK and 27 million in the US – it’s a big big problem and there’s very little we can do to help at the moment. We can offer pain killers and at later stages joint replacement. There are approaches, like regenerative medicine, which are undergoing intense investigation which could help with treatment. But overall, we know very little about how the disease initiates and develops so we are hoping that our research into body clocks could help understand the disease and hopefully lead to some treatments which could help slow down the (progression of) symptoms and eventually cure the disease.

How did you first become interested in your area of research?

In terms of body clocks, when I was teaching in China, one of the lectures I gave was on body clocks. It was on jetlag and how we tune our own internal rhythm to the environment. When I came to England I took the first opportunity I could to embark on a field in chronobiology. Then in 2007 I went to a conference in Cold Spring Harbour on Chronobiology and that really inspired me to start a career in this particular field, because I realised that there were so many things you could do in this area. I thought, maybe I could make a contribution to the understanding of body clocks.

Do you have any science heroes? Who inspired you?

Yes. If you ever go to some of my lectures or talks, I always start with a story. It’s a true story that happened in Professor Ueli Schibler’s lab, he is one of the pioneers of the modern clock field. He made many important discoveries about body clocks. For example, one of the discoveries was that almost all of the cells, including the most common cell type (fibroblasts), contain autonomous clocks. He also found that temperature cycles can entrain your body clocks as well. There are many examples of that. In many ways his discoveries have inspired me to research this topic.

How has working here in Manchester helped you? 
I think that this is a great environment to do science. I came to Manchester about 12 years ago and never left. I did my post-doc here and got my MRC fellowship (based) here, and now I got my Arthritis Research UK senior research fellowship (based) here. I think the excellent support I received from the Faculty, the Wellcome Trust Centre for Cell Matrix Research and colleagues has been incredible. I have a lot of excellent collaborators who are all very enthusiastic about their own science and are also very keen to help me in my career progression. They are happy to collaborate with me in terms of tackling big, challenging questions in the field.

What do you do outside of working here?

I like playing guitar and I play table tennis as well. I ice-skate and I like to go to the field to do field trips like hiking.

Tuesday Feature Episode 16: Andrew Loudon

For episode 16 of our Tuesday Feature, we are joined by Faculty Scientist Professor Andrew Loudon. Professor Loudon is one of the world’s leading experts in body clocks and circadian rhythms. He is the Beyer Professor of Animal Biology here in Manchester. It is for his work on clocks that he was recently awarded a fellowship to the prestigious Academy of Medical Sciences. Who better then to star in this week’s Tuesday Feature!


Explain your research for the layman in ten sentences or less.

I’ve been interested all my life in biological clocks – timing systems in biology. I got into this by studying seasonal breeding animals in their natural environments. Their behaviour is very strongly driven by clock based processes. My initial interest came from studying hormone cycles and the mechanisms that control the activation and suppression of reproduction in wild animals. Then, around about 20 years ago, I came particularly interested in some of the genetic mechanisms that were being unravelled for the circadian clock. So I’ve maintained an interest in annual cycles and seasonal breeding but more recently in circadian mechanisms with a very strong interest in genetics.

Andrew loudonHow could your research benefit the people reading this blog?

Well in the context of circadian biology, there’s an awakening interest in the way in which this field can contribute to medicine at multiple levels. One of the most obvious applications is so called chrono-therapy. This is where you try to deliver drugs or therapeutic treatments to patients at the optimum time of day. That’s a non-trivial business. There are a number of drugs for instance that have to be delivered at a particular time of day. Probably most people know about statins and some people take low-dose aspirin – those sorts of drugs are really not effective at the wrong time of day.

This is the tip of the iceberg and there are a large number of other pharmacologies that would be much better if they were adapted so that they were highly potent, one time of day drug. We would then not have to expose the body to a continuous high dose of this drug throughout 24 hours when we really have to only expose the target tissues for a matter of 2-3 hours.

I think there’s likely to be a very large amount of interest in this area. There’s evidence now that pharmaceutical companies are finally waking up to this and it has been led very much by university based scientists around the world.

How did you first get interest in body clocks?

As I said earlier, it relates to my original studies of the reproductive biology of wild animals. My PhD actually was in territorial and sexual behaviour. That’s what introduced me first to hormones. I was studying wild animals. Rather like Springwatch, I was out there at 4 o’clock in the morning with my binoculars for several years. My animal was a small species of deer (the Roe deer) and I spent several happy years tracking deer in the wild doing endocrinology and taking tissues samples from them. My background is really in behavioural sciences and then I moved very quickly in my 20’s to endocrinology, the study of hormones, and then as I’ve indicated, I moved into areas such as genetics.

Have you got any science heroes? Who inspired you?

Of course I’ve been around a while so I’ve got quite a few. I’ve been fortunate to work with and interact with terrific people. I guess one of the early mentors was a wonderful man called Roger Short who was a reproductive biologist. He had a huge impact in the UK on developing the field of reproductive sciences and endocrinology. He then moved to Australia. He’s still alive and I keep in touch with him, he’s well in to his 90’s now. Then another colleague in the United States who I worked with when I was over there, Michael Menaker, who is kind of the grandfather of all biological clock researchers around the world. All of the key people seem to have interacted with him; he was an absolutely wonderful man – a terrific insight into biology generally. I guess other colleagues like Joe Takahashi, who is really quite a friend, has been extremely helpful to everyone in the field and has taken a major lead in pioneering new genetic approach to how biological clocks and timing processes operate generally.  It’s quite a long list, but there’s three there for a start! Without these people in science, life would be so much duller.

How has working in Manchester helped you?

Manchester has got the major asset that it is very large and yet it is possible to interact at multiple levels in different disciplines without the enclaves and territorial/departmental structures that you find in some of the older Universities.  The thing that attracted me to Manchester and the reason I came here, to be quite blunt, was the animal facilities which are unique. They are very well run and the head of the animal facility has been extremely accommodating to myself and all of the other circadian workers in allowing us to kind of take over the facilities and put lots of equipment in there to allow us to monitor the behaviour of the animals. That really was very important to me because I’m very focused on studying the behaviour of animals and seeing how they operate in real time. I don’t just study cells and tissues so obviously that’s important.

More recently, the growing alliance between the Life Sciences and medicine has been extremely important and is very much the future of all of us. I’ve been working very closely for the last 10 years or more with a good friend and colleague called Professor David Ray in the medical faculty and we have a lot of very exciting science going on together.  Manchester is a great place to be – it offers a great opportunity to undertake science across multiple levels with lots of different colleagues and disciplines.

What do you do outside of work?

I’m a keen woodworker and furniture maker. I turn wood. I also fly fish and I’m a life-long, passionate motor cyclist. I have several motorbikes including one very large one and I haven’t fallen off it recently! All of those hobbies have one common feature which is that they require an enormous amount of concentration. If you let your concentration drop in any of those activities the result is chaos. Especially, if you’re motorcycling particular! It’s kind of relaxing to have to concentrate on something different. Those are the kind of things that I do when I’m not working.


Thank you again Andrew for a thoroughly enjoyable Tuesday Feature. Good luck for your induction to the Academy on July 1st and we hope it all goes well! 

How the blues could help reduce jet lag

Faculty researchers have revealed that the colour of light has a major impact on how our body clock measures the time of day.

It’s the first time the impact of colour has been tested. The research, published in PLOS Biology, demonstrates that the colour of light provides a more reliable way of telling the time than its brightness.

University Sunset1Faculty members, led by Dr Timothy Brown, looked at the change in light around dawn and dusk to analyse whether colour could be used to determine time of day. Their key discovery was that light was reliably bluer during twilight hours, compared to daytime.

The team recorded the electrical activity of the body clock of mice while they were shown different visual stimuli. They found that mice were much more sensitive to changes between blue and yellow in the colour of light, than to its brightness.

The scientists then created an artificial sky which imitated the daily changes in colour and brightness. Mice were placed underneath the synthetic sky for several days whilst their body temperatures were recorded.

Researchers found that the highest temperatures occurred just after night fell – when the sky had turned a darker blue, optimal for a nocturnal animal. When only the brightness was altered, the mice became active before dusk, demonstrating that their body clock wasn’t properly in sync with a normal day/night cycle.

The team concluded that colour must therefore play a role in the determination of the time of day.

On the importance of the research, Dr Brown says:

 “This is the first time that we’ve been able to test the theory that colour affects the body clock in mammals. It has always been very hard to separate the change in colour to the change in brightness but using new experimental tools and a psychophysics approach we were successful.”

He continues:

“The same findings can be applied to humans. So in theory colour could be used to manipulate our clock, which could be useful for shift workers or travellers wanting to minimise jet lag”

Body Clock Day on the BBC

On Tuesday 13 May, the BBC is having a day focusing on our body clocks. They will be looking at what body clocks do and how they a clockwork. The Faculty’s leading clock researcher, Professor Andrew Loudon, will be on BBC Breakfast TV and several radio stations, while Professor David Ray will be on the Sheila Fogarty Show on Radio 5 Live. A film of one of his patients will also be shown.

Other clock researchers from around the country will also be involved. Professor Russell Foster will be on the Today Programme on Radio 4 and there will be various items on radio and TV news programmes.

 

New research links body clocks to chronic lung diseases

pulmonary-fibrosisFaculty research has shown that the body clock’s natural rhythm could be utilised to improve therapies that delay the onset of chronic lung disease. Dr Qing-Jun Meng and his team have discovered a rhythmic defence pathway in the lung, controlled by our body clocks, which is essential to combatting exposure to toxins and pollutants.

The team have found that the circadian clock in the mouse lung rhythmically switches genes on and off, controlling the antioxidant defence pathway. This 24-hourly rhythm enables the lungs to anticipate and withstand exposure to pollutants on a daily basis. Dr Meng said:

“We used a mouse model that mimics human pulmonary fibrosis, and found that an oxidative and fibrotic challenge delivered to the lungs during the night phase, when mice are active, causes more severe lung damages than the same challenge administered during the day, a mouse’s resting phase. Our findings show that timed administration of the antioxidant compound sulforaphane effectively attenuates the severity of the lung fibrosis in this mouse model.”

The research suggests that paying attention to the lung clock could increase the effectiveness of drug treatments for oxidative and fibrotic diseases, allowing for lower doses and reduced side effects.

Research team member Dr Vanja Pekovic-Vaughan said:

“This research is the first to show that a functioning clock in the lung is essential to maintain the protective tissue function against oxidative stress and fibrotic challenges. We envisage a scenario whereby chronic rhythm disruption (during ageing or shift work, for example) may compromise the temporal coordination of the antioxidant pathway, contributing to human disease.”

This study is a part of ongoing research exploring how chronic disruption to body clocks contributes to conditions such as osteoarthritis, cardiovascular disease, breast cancer, and mood disorder. Dr Meng said:

“Our next step is to test our theory that similar rhythmic activity of the antioxidant defence pathway also operates in human lungs.  This will enable us to translate our findings and identify the proper clock time to treat chronic lung diseases that are known to involve oxidative stress.”