̽��ֱ�� of Cambridge - circadian

Opinion: How your body clock helps determine whether you’ll get ill or not

Anonymous — Wed, 17 Aug 2016 10:55:31 +0000

From vitamin C and echinacea to warm clothes and antibacterial soap, there’s no shortage of ideas about how to prevent and manage colds and flu. Unfortunately, many of these are not based on solid scientific evidence. In fact, medical researchers are only starting to unravel the range of factors that affect our susceptibility to getting an infection. Now we have discovered that our body clock plays an important role – making us more prone to get infected at certain times of the day.

It is perhaps easy to forget that we have co-evolved on this planet with micro-organisms, including bacteria, which may be either beneficial or harmful to us. Similarly, viruses cannot copy themselves without help from our cells. Without us, they simply wouldn’t exist.

So what happens when a virus encounters a cell? First, it has to get in through a protective barrier called the cell membrane. Then it has to hijack the interior of the “host” cell to subvert it and divert all resources to copy itself millions of times. Once an army of identical clones is formed, it breaks out of the cell, usually destroying it in the process. Imagine millions of these new viruses then being able to do exactly the same to other cells nearby. ̽��ֱ��cycle goes on, with often rapid amplification of the virus through a tissue, and then through the body.

That’s if the virus had it all its own way … But there is always a battle in play between invading organisms and our bodies. Our immune system counteracts the invading organisms and will invoke mechanisms to stop the virus entering, replicating and spreading. This defence system works at the level of individual cells in the body, but also in specialised tissues of the body that are designed to mount a response to such invasions.

It now turns out that our body clock is also an important gatekeeper of virus infections. ̽��ֱ��body clock is an amazing piece of evolutionary biology. It’s thought that most organisms on our planet have a biological clock that keeps track of the 24-hour day. It can do this by orchestrating chemical reactions and genetic switches that rhythmically control thousands of genes in cells in the cell – turning about 15% of all genes on and off across the day and night.

Timely experiment

So why might viruses care about our body clock? Since our cells are miniature factories, making things that the virus must have to copy itself, the virus is less likely to succeed when the production line is shut down. This is what we tested in the laboratory, by infecting cells and mice at different times of the day. We found that viruses are less able to infect in the late afternoon. In contrast, in the early morning, our cells are hives of biosynthetic activity, at least from the virus’s viewpoint. So, if a virus tries to take over a cell in the early day, it is far more likely to succeed, and spread faster, than if it encounters a rather less favourable climate in the evening.

Perhaps even more interestingly, when the clockwork is disrupted, viruses are more prolific at taking over cells and tissues. Such “clock misalignment” can happen when we do shift work, get jet lagged, or experience the phenomenon of “social jet lag”, which is caused by changes in our sleep schedule on our days off. Therefore, it’s important to know about these interactions because it will undoubtedly help us to find ways to ensure better health for ourselves. For example, since we know shift workers are more likely to get infections, it might be a good idea to give them flu vaccinations.

Perhaps nightclub germs aren’t so threatening after all. *sax/Flickr, CC BY-SA

Knowing about the clock and viruses could also help us to design better public health measures to combat virus spread. You could imagine that during a pandemic limiting exposure during the early daytime could be a small but important intervention to try to prevent viral infection from taking hold. Indeed, a recent study by a team at the ̽��ֱ�� of Birmingham showed that vaccinating people against flu in the morning is more effective than in the evening. This principle could be the same for many unrelated viruses.

̽��ֱ��research could also help us crack a longstanding enigma – why do virus infections like flu happen more commonly in the winter months? It turns out that the very same molecular switch – called Bmal1 – that goes up and down in the day and night also changes according to the seasons, going up in the summer and down in the winter. When we artificially lower Bmal1 levels in mice and cells, the virus is able to infect more. As occurs on a daily basis, the waxing and waning of Bmal1 in our bodies could be a reason why we’re less likely to cope with viruses like flu in the winter.

So, if you’re desperate to avoid catching a flu virus that’s been going around the office, rather than trying to boost your immune system with various vitamins, you may want to try to simply work from home in the mornings.

Akhilesh Reddy, Wellcome Trust Senior Fellow in Clinical Sciences at the Department of Clinical Neurosciences, ̽��ֱ�� of Cambridge

This article was originally published on ̽��ֱ��Conversation. Read the original article.

̽��ֱ��opinions expressed in this article are those of the individual author(s) and do not represent the views of the ̽��ֱ�� of Cambridge.

Akhilesh Reddy (Department of Clinical Neurosciences) discusses how circadian rhythms can affect whether you get the flu.

Claus Rebler

Sick

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Time of day influences our susceptibility to infection, study finds

cjb250 — Mon, 15 Aug 2016 19:00:21 +0000

When a virus enters our body, it hijacks the machinery and resources in our cells to help it replicate and spread throughout the body. However, the resources on offer fluctuate throughout the day, partly in response to our circadian rhythms – in effect, our body clock. Circadian rhythms control many aspects of our physiology and bodily functions – from our sleep patterns to body temperature, and from our immune systems to the release of hormones. These cycles are controlled by a number of genes, including Bmal1 and Clock.

To test whether our circadian rhythms affect susceptibility to, or progression of, infection, researchers at the Wellcome Trust-Medical Research Council Institute of Metabolic Science, ̽��ֱ�� of Cambridge, compared normal ‘wild type’ mice infected with herpes virus at different times of the day, measuring levels of virus infection and spread. ̽��ֱ��mice lived in a controlled environment where 12 hours were in daylight and 12 hours were dark.

̽��ֱ��researchers found that virus replication in those mice infected at the very start of the day – equivalent to sunrise, when these nocturnal animals start their resting phase – was ten times greater than in mice infected ten hours into the day, when they are transitioning to their active phase. When the researchers repeated the experiment in mice lacking Bmal1, they found high levels of virus replication regardless of the time of infection.

“ ̽��ֱ��time of day of infection can have a major influence on how susceptible we are to the disease, or at least on the viral replication, meaning that infection at the wrong time of day could cause a much more severe acute infection,” explains Professor Akhilesh Reddy, the study’s senior author. “This is consistent with recent studies which have shown that the time of day that the influenza vaccine is administered can influence how effectively it works.”

In addition, the researchers found similar time-of-day variation in virus replication in individual cell cultures, without influence from our immune system. Abolishing cellular circadian rhythms increased both herpes and influenza A virus infection, a dissimilar type of virus – known as an RNA virus – that infects and replicates in a very different way to herpes.

Dr Rachel Edgar, the first author, adds: “Each cell in the body has a biological clock that allows them to keep track of time and anticipate daily changes in our environment. Our results suggest that the clock in every cell determines how successfully a virus replicates. When we disrupted the body clock in either cells or mice, we found that the timing of infection no longer mattered – viral replication was always high. This indicates that shift workers, who work some nights and rest some nights and so have a disrupted body clock, will be more susceptible to viral diseases. If so, then they could be prime candidates for receiving the annual flu vaccines.”

As well as its daily cycle of activity, Bmal1 also undergoes seasonal variation, being less active in the winter months and increasing in summer. ̽��ֱ��researchers speculate that this may help explain why diseases such as influenza are more likely to spread through populations during winter.

Using cell cultures, the researchers also found that herpes viruses manipulate the molecular ‘clockwork’ that controls our circadian rhythms, helping the viruses to progress. This is not the first time that pathogens have been seen to ‘game’ our body clocks: the malaria parasite, for example, is known to synchronise its replication cycle with the host’s circadian rhythm, producing a more successful infection.

“Given that our body clocks appear to play a role in defending us from invading pathogens, their molecular machinery may offer a new, universal drug target to help fight infection,” adds Professor Reddy.

̽��ֱ��research was mostly funded by the Wellcome Trust and the European Research Council.

Reference
Edgar, RS et al. Cell autonomous regulation of herpes and influenza virus infection by the circadian clock. PNAS; e-pub 15 Aug 2016; DOI: 10.1073/pnas.1601895113

We are more susceptible to infection at certain times of the day as our body clock affects the ability of viruses to replicate and spread between cells, suggests new research from the ̽��ֱ�� of Cambridge. ̽��ֱ��findings, published today in the Proceedings of the National Academy of Sciences, may help explain why shift workers, whose body clocks are routinely disrupted, are more prone to health problems, including infections and chronic disease.

̽��ֱ��time of day of infection can have a major influence on how susceptible we are to the disease, or at least on the viral replication, meaning that infection at the wrong time of day could cause a much more severe acute infection

Akhilesh Reddy

Alexandra Bilham

Clock

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Scientists wake up to causes of sleep disruption in Alzheimer’s disease

fpjl2 — Thu, 27 Feb 2014 10:10:58 +0000

Being awake at night and dozing during the day can be a distressing early symptom of Alzheimer's disease, but how the disease disrupts our biological clocks to cause these symptoms has remained elusive.

Now, scientists from Cambridge have discovered that in fruit flies with Alzheimer's the biological clock is still ticking but has become uncoupled from the sleep-wake cycle it usually regulates. ̽��ֱ��findings – published in Disease Models & Mechanisms – could help develop more effective ways to improve sleep patterns in people with the disease.

People with Alzheimer's often have poor biological rhythms, something that is a burden for both patients and their carers. Periods of sleep become shorter and more fragmented, resulting in periods of wakefulness at night and snoozing during the day. They can also become restless and agitated in the late afternoon and early evening, something known as 'sundowning'.

Biological clocks go hand in hand with life, and are found in everything from single celled organisms to fruit flies and humans. They are vital because they allow organisms to synchronise their biology to the day-night changes in their environments.

Until now, however, it has been unclear how Alzheimer's disrupts the biological clock. According to Dr Damian Crowther of Cambridge's Department of Genetics, one of the study's authors: "We wanted to know whether people with Alzheimer's disease have a poor behavioural rhythm because they have a clock that's stopped ticking or they have stopped responding to the clock."

̽��ֱ��team worked with fruit flies – a key species for studying Alzheimer's. Evidence suggests that the A-beta peptide, a protein, is behind at least the initial stages of the disease in humans. This has been replicated in fruit flies by introducing the human gene that produces this peptide.

Taking a group of healthy flies and a group with this feature of Alzheimer's, the researchers studied sleep-wake patterns in the flies, and how well their biological clocks were working.

They measured sleep-wake patterns by fitting a small infrared beam, similar to movement sensors in burglar alarms, to the glass tubes housing the flies. When the flies were awake and moving, they broke the beam and these breaks in the beam were counted and recorded.

To study the flies' biological clocks, the researchers attached the protein luciferase – an enzyme that emits light – to one of the proteins that forms part of the biological clock. Levels of the protein rise and fall during the night and day, and the glowing protein provided a way of tracing the flies' internal clock.

"This lets us see the brain glowing brighter at night and less during the day, and that's the biological clock shown as a glowing brain. It's beautiful to be able to study first hand in the same organism the molecular working of the clock and the corresponding behaviours," Dr Crowther said.

They found that healthy flies were active during the day and slept at night, whereas those with Alzheimer's sleep and wake randomly. Crucially, however, the diurnal patterns of the luciferase-tagged protein were the same in both healthy and diseased flies, showing that the biological clock still ticks in flies with Alzheimer's.

"Until now, the prevailing view was that Alzheimer's destroyed the biological clock," said Crowther.

"What we have shown in flies with Alzheimer's is that the clock is still ticking but is being ignored by other parts of the brain and body that govern behaviour. If we can understand this, it could help us develop new therapies to tackle sleep disturbances in people with Alzheimer's."

Dr Simon Ridley, Head of Research at Alzheimer's Research UK, who helped to fund the study, said: "Understanding the biology behind distressing symptoms like sleep problems is important to guide the development of new approaches to manage or treat them. This study sheds more light on the how features of Alzheimer's can affect the molecular mechanisms controlling sleep-wake cycles in flies.

"We hope these results can guide further studies in people to ensure that progress is made for the half a million people in the UK with the disease."

New research using fruit flies with Alzheimer’s protein finds that the disease doesn’t stop the biological clock ticking, but detaches it from the sleep-wake cycle that it usually regulates. Findings could lead to more effective ways to improve sleep patterns in those with Alzheimer’s.

We have shown in flies with Alzheimer's that the clock is still ticking but being ignored by other parts of the brain

Damian Crowther

Dr. Stanislav Ott

̽��ֱ��fly brain is half a millimeter across and contains approximately 100,000 nerve cells (green). ̽��ֱ��A-beta peptide forms plaques (red) that are linked to nerve cell death and behavioral abnormalities in the flies.

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Researchers show how plants tell the time

sj387 — Wed, 23 Oct 2013 19:00:00 +0000

Plants, like animals, have a 24 hour 'body-clock' known as the circadian rhythm. This biological timer gives plants an innate ability to measure time, even when there is no light - they don’t simply respond to sunrise, for example, they know it is coming and adjust their biology accordingly. This ability to keep time provides an important competitive advantage and is vital in biological processes such as flowering, fragrance emission and leaf movement.

BBSRC-funded scientists from the ̽��ֱ�� of Cambridge Department of Plant Sciences, are studying how plants are able to set and maintain this internal clock. They have found that the sugars produced by plants are key to timekeeping.

Plants produce sugar via photosynthesis; it is their way of converting the sun’s energy into a usable chemical form needed for growth and function.

This new research has shown that these sugars also play a role in circadian rhythms. Researchers studied the effects of these sugars by monitoring seedlings in CO2-free air, to inhibit photosynthesis, and by growing genetically altered plants and monitoring their biology. ̽��ֱ��production of sugars was found to regulate key genes responsible for the 24 hour rhythm.

Dr Alex Webb, lead researcher at the ̽��ֱ�� of Cambridge, explains: “Our research shows that sugar levels within a plant play a vital role in synchronizing circadian rhythms with its surrounding environment. Inhibiting photosynthesis, for example, slowed the plants internal clock by between 2 and 3 hours.”

̽��ֱ��research shows that photosynthesis has a profound effect on setting and maintaining robust circadian rhythms in Arabidopsis plants, demonstrating a critical role for metabolism in regulation of the circadian clock.

Dr Mike Haydon, who performed much of the research and is now at the ̽��ֱ�� of York added: “ ̽��ֱ��accumulation of sugar within the plant provides a kind of feedback for the circadian cycle in plants – a bit like resetting a stopwatch. We think this might be a way of telling the plant that energy in the form of sugars is available to perform important metabolic tasks. This mirrors research that has previously shown that feeding times can influence the phase of peripheral clocks in animals.”

Article credited to Biotechnology and Biological Sciences Research Council (BBSRC)

Plants use sugars to tell the time of day, according to research published in Nature today.

Our research shows that sugar levels within a plant play a vital role in synchronizing circadian rhythms with its surrounding environment

Alex Webb

Jucember

Arabidopsis Thaliana planted in Laboratory

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Royal Society announces new Fellows

bjb42 — Fri, 21 May 2010 00:00:00 +0000

̽��ֱ��new Fellows join the ranks of the UK and Commonwealth's leading scientists as the Society celebrates its 350th Anniversary.

Lord Rees, President of the Royal Society said: "These scientists follow in the footsteps of early Fellows such as Isaac Newton, Robert Boyle and Robert Hooke. ̽��ֱ��new Fellows announced today embody the spirit of enquiry, dedicated to 'the relief of man's estate' on which the Royal Society was founded. That spirit is as alive today as it was 350 years ago."

̽��ֱ��new Fellows are:

Professor Andrea Brand, Herchel Smith Professor of Molecular Biology at the Gurdon Institute and the Department of Physiology, Development and Neuroscience and a Fellow of Jesus College, is distinguished for her pioneering work on the development of the nervous system. Using Drosophila as a model organism, and using sophisticated live imaging techniques, she has explained how cell fate determinants become localised to one side of a cell, allowing neural precursors to divide asymmetrically in a stem cell-like fashion.

Professor Nicola Clayton, Professor of Comparative Cognition in the Department of Experimental Psychology and Clare College Graduate Tutor, has pioneered new procedures for the experimental study of memory, planning and social cognition in animals, all attributes that have been claimed to be uniquely human, and her work has changed our view of animal intelligence and its relationship to human memory and cognition.

Professor Ben Green, Herchel Smith Professor of Pure Mathematics and a Fellow of Trinity College, has proved a number of remarkable results in arithmetic combinatorics, the highlight of which is his proof, with Terence Tao, that the prime numbers contain arithmetic progressions of all lengths.

Professor Roger Hardie, Professor of Cellular Neuroscience in the Department of Physiology, Development and Neuroscience, is distinguished for his extensive studies on invertebrate visual transduction which have transformed our wider understanding of cell signalling. His demonstration that the Drosophila trp and trpl genes code for selective calcium channels was the seminal observation that launched the TRP channel field, now a major part of calcium signalling and a focus of medical research.

Dr Michael Hastings, MRC Staff Scientist at the MRC Laboratory of Molecular Biology, is distinguished for his highly influential contributions to our understanding of biological clocks through the study of the suprachiasmatic nucleus (SCN) of the hypothalamus. He was instrumental in taking circadian neurobiology to the molecular and cell biological level.

Professor Max Pettini, Professor of Observational Astronomy at the Institute of Astronomy, is distinguished for his extensive observational achievements and insightful interpretations of the chemical and physical conditions of interstellar matter seen in a wide range of cosmic environments. His early research led to the discovery that our Galaxy is surrounded by a halo of hot ionised gas, verifying a prediction made decades earlier.

Professor Wolf Reik, Honorary Professor of Epigenetics in the Department of Physiology, Development and Neuroscience, is distinguished for his fundamental discoveries of epigenetic mechanisms in mammalian development, physiology, genome reprogramming, and human diseases. His work led to the discovery of the molecular mechanism of genomic imprinting, and uncovered non-coding RNA and chromatin looping regulating imprinted genes, which he showed to be involved in foetal nutrition, growth, and disease.

Seven Cambridge researchers are among the 44 new Fellows announced by the Royal Society this week.

These scientists follow in the footsteps of early Fellows such as Isaac Newton, Robert Boyle and Robert Hooke.

Lord Rees, President of the Royal Society

Matt from London from Flickr

RSC busts

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