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Sleep quality linked to circadian genes

Variation in genes that regulate our internal body clock has been linked to how and when we sleep. Credit: Daniele Zanni.

We all have an internal body clock, controlled by our circadian rhythms. Most of the time this circadian clock simply ticks away in the background and is rarely noticeable – it’s only when it gets out of sync with your surroundings that you start to notice problems like jet lag. However, problems with circadian rhythms could contribute to more serious conditions, from obesity to mental health.

Sleep has long been known to be intrinsically linked to circadian rhythms, but our understanding of the exact dynamics of this relationship remains hazy. By investigating both the sleep habits and genetic variation of a group of young British adults, Michael Parsons and Patrick Nolan from MRC Harwell worked with researchers from King’s College, Northumbria University, the University of Surrey and Goldsmiths to pinpoint specific circadian genes associated with our sleep habits.

The study asked 952 participants, aged 18-27 years old, to fill in two questionnaires about their sleep habits over the last month. One of these tested whether they were an early bird or a night owl, referred to as their ‘diurnal preference’, by asking about their preferred time to sleep. The other asked various questions about how well they slept each night to give scores for sleep quality, duration and ‘latency’ (how long it took them to drop off). They then took cheek swabs to collect a sample of their DNA for analysis.

Analysis of circadian gene variants revealed a significant association between diurnal preference and the clock gene PER3, as well as another circadian regulator, ARNTL2, suggesting variations in these genes might help decide whether you’re a morning person or an evening person. Overall sleep quality, encompassing all three scores, was significantly associated with variation in the gene GNβ3. While this is not part of the core circadian clock, its expression in specific tissues follows circadian timing and modifies the effects of serotonin, which plays a role in sleep.

This research backs up past findings on PER3, and the GNβ3 variant has previously been associated with depression and sleep problems. The discovery that ARNTL2 might be involved in sleep regulation, however, provides a new gene to investigate. Altogether, it strengthens the case that these genes are not only involved in regulating our circadian rhythms, but also how we sleep.

Just like a sign at a cross-road, this research points the way forward for more detailed research into the relationship between sleep and circadian rhythms. With time, this could help to reveal the genetic differences that influence how we sleep, and the exact role played by our circadian clock.

Parsons et al. (2014) Polymorphisms in the circadian expressed genes PER3 and ARNTL2 are associated with diurnal preference and GNβ3 with sleep measures. J Sleep Res.(5):595-604.

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Atmin critical for normal kidney development

Collaborative research between colleagues at Imperial College London and MRC Harwell into mice with a mutation in Atmin has shown how this gene plays an essential role in the early stages of kidney development.

Stunted growth: an Atmin mutant mouse kidney (right) is smaller and less developed, with fewer tubule branches than a healthy kidney (left)

The development of the kidneys is a complex process. The kidneys consist of a finely-tuned network of tubules that serve to filter out excess water and waste products from the blood and channel it down towards the bladder. When this process goes wrong, it can lead to problems with the workings of the kidneys and conditions such as polycystic kidney disease.

Working alongside researchers at University of West London and the UCL Institute of Child Health, Evi Goggolidou, Dominic Norris and Charlotte Dean set out to investigate the role of the gene Atmin in kidney development and the mechanism by which it acts.

They showed that mice with a mutation that prevents this gene from functioning have small, oddly shaped kidneys which fail to develop properly. Using the Gpg6 mouse, which has a point mutation in Atmin, they followed the early stages of kidney development. They discovered that branching of the tubular network within the kidneys had gone awry. In a normal kidney, cells lining the tubules neatly align, whereas in Gpg6 kidney tubules these cells all point in different directions.

They determined that this was due to issues with a key pathway in development known at the non-canonical Wnt/planar cell polarity pathway. Defects in some genes involved in this pathway have been known to lead to the formation of kidney cysts, bulbous growths of the tubules that hinder the kidney’s functioning. With further analysis, they revealed that the Atmin mutation in Gpg6 mice disrupts the organisation of the cytoskeleton, the web of strings and pulleys that criss-crosses cells.

The study concluded that the ATMIN protein is involved in manipulating the cytoskeleton of kidney epithelial cells to move them into position and correctly mould the branched network of tubules. Therefore, if a mutation prevents it from functioning, as seen in the Gpg6 mice, the tubule network fails to develop properly.

This research therefore shows how Atmin can impact on Wnt signalling to shape and guide the early development of a mouse’s kidneys. It sheds new light on the genetics of mammalian kidney development, and may one day help in the search for new treatments for kidney disease. 

Goggolidou et al. (2014) Atmin mediates kidney morphogenesis by modulating Wnt signaling. Hum Mol Genet. 23:5303-16

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Harwell bioinformatics training workshop

On 17 July 2014, MRC Harwell hosted the training course 'Bioinformatics of Mouse Mutant Resources', which proved to be a great success.


 

Participants came from all across the UK for the training; Bristol, Oxford, Edinburgh and London. As an ice-breaker, everyone was asked to stand up, say who they were and place themselves somewhere between the four terms 'scientist', 'clinician', 'ontologist' and 'bioinformatician', and it soon became apparent that we had a diverse group of people present. This eclectic mix meant that we had questions from all spheres of expertise, and it was great to see the different elements of the resources shown that peaked their interest.

We had speakers from the Wellcome Trust Sanger Institute, EBI and MRC Harwell, and the morning consisted of a series of talks explaining how mouse mutant resources such as the IMPC web portal can be used to their full potential. After lunch, the participants then had the chance to try their hand at using this information in a set of tutorials, complete with worked examples and a team on hand to answer their questions.

There was a lot of information to take in, so the participants were provided with a booklet describing the different processes that you can use the IMPC portal for, such as searching for a gene, phenotype or mouse disease model. It also contained links to other resources, such as MouseBook, where data and archived material is stored from other mutant mice at MRC Harwell. They took this booklet away with them, and were provided with copies of the slides for future reference.

At the end of the day, just before they left, the participants were asked to fill in a short online form to let us know what they thought of the course. We had great feedback, with very positive responses and comments, as well as some really useful advice on how we could improve the course in the future. We also had some great feedback on the IMPC portal, with some excellent ideas for additional features. As the speakers there were the very people who have the power to implement these changes, this allowed them to take on board a whole host of ideas that they can use to make the IMPC portal an even better tool, finely tailored to its users needs.

Overall, the day was extremely successful, and we hope to run it again next year. If you would like more information on this training course or the many others that we run throughout the year, please visit our training section.

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Mary Lyon Centre celebrates a decade

The Mary Lyon Centre’s tenth year was celebrated by staff on the 3rd July with tea, cakes and cricket.

Dr Sara Wells, director of the Mary Lyon Centre (MLC), opened the event with a speech about all that the MLC has achieved over the last ten years. An assortment of cakes and drinks were laid out, and MLC and MGU staff sat, chatted and enjoyed the sun before getting kitted up for cricket. It was a wonderfully sunny day, and the perfect way to celebrate a decade of the MLC.

The MLC is a specific pathogen free (SPF) facility which was specially built to provide the ideal conditions to house mice for genetic research. The centre was originally established in 2004, named after Dr Mary Lyon in recognition of her discovery of X chromosome inactivation. Over the last decade, the MLC has been instrumental in both supporting research at MRC Harwell and offering a wide range of services, including specialised techniques, mouse lines and access to genetic archives, for the wider scientific community.

MRC Harwell is part of many large-scale projects, including the Harwell Ageing Screen, which aims to investigate the underlying genetic basis of ageing and age-related conditions, and the International Mouse Phenotyping Consortium (IMPC), which seeks to determine the function of 20,000 genes through the generation and systematic phenotyping of knockout mice. This is an enormous task, and the Mary Lyon Centre has played a central role in breeding and characterising Harwell’s mouse lines.

The MLC has built a dedicated community of staff over the last ten years, who have worked hard to make the centre thrive. We look forward to the next ten years of the MLC, and hope that it will bring just as much success as the first decade.

Harwell Campus Family Fun Day

We joined in with the Harwell Campus Family Fun Day on 28 June 2014, held in aid of the children's hospice charity Helen Douglas House. 

The day was particularly intended for families, with tickets sold per family group, and was a great opportunity for the organisations at Harwell Campus to pull together and showcase the amazing work we do. And with entry just £5 per family and most stalls free, it provided a great day out for the kids without breaking the bank.

At our stall, people had the chance to perform their own experiment – extracting DNA from strawberries. Overall we had about 200 children come to the stand to try our DNA extraction experiment, with some coming back a second time. The younger ones also really enjoyed building cells out of Air Dough, complete with multi-coloured internal organelles and their own artistic flair. Feedback was overwhelmingly positive, with most parents saying that their children had learnt something valuable.

Overall, the event attracted around 1200 people, despite the rain. Organisations from all across the campus and the local area came together to make it a wonderful day - there were science workshops, plant potting, finger printing, rocket building, windmill making, the Big Green School bus demonstrating the power of recycling, a wildlife bus and several experiments going on with Diamond and STFC. 

It was great to see so many people turning out to the event in aid of charity, and hopefully some of the children who came were inspired to learn more about science!

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Mitochondrial donation 'not unsafe'

MRC Harwell’s Dr Andy Greenfield chaired a panel which reviewed evidence on two methods of assisted conception that could potentially prevent inheritance of serious mitochondrial disease.

The Panel’s report, commissioned by the Government and published in June, and contains a wide-ranging survey of the scientific and clinical evidence concerning the efficacy and safety of two mitochondrial replacement techniques. These are not legal in the UK or many other countries, but the Panel concluded that there are no compelling reasons to think they would be unsafe in humans.

Chaired by Dr Andy Greenfield at MRC Harwell, the panel submitted the report to the Human Fertilisation and Embryo Authority (HEFA) for delivery to the Department of Health. A Parliamentary vote could now lead to the alteration of fertility regulations to permit mitochondrial replacement, which could be used to prevent mitochondrial disease being passed on from mother to newborns.

The mitochondria are the ‘power houses’ of cells, providing them with the energy they need to function, and have their own separate genome, in the form of a small circle of DNA, that contributes to this process. In mitochondrial disease, a mutation in the mitochondrial DNA can prevent them from effectively generating the energy required by the cell. While relatively rare, mitochondrial disease can be very serious and even lethal. It affects one in every 6,500 babies born, leading to an energy deficit that can cause muscle weakness, blindness and heart failure.

Preventing mitochondrial disease

Mitochondrial DNA is inherited through the mother, so if the mitochondria in her fertilised egg or newly fertilised embryo can be replaced with healthy ones, mitochondrial disease could be eliminated, not only from her children, but also in future generations.

Two techniques were reviewed; maternal spindle transfer (MST) and pronuclear transfer (PNT). Both follow the same principle: the transfer of nuclear DNA from the mother into an egg or embryo from a female donor with healthy mitochondria. The difference lies in the stage at which this is done – in MST it is done in the mother’s egg, whereas in PNT it is done in the early single-celled embryo, after fertilisation. In both cases, the mother’s egg is fertilised by the father’s sperm and implanted in her womb to develop, as with current IVF procedures.

This means that the child is still genetically related to both parents, as with normal sexual reproduction, but has healthy mitochondria from the female donor. Some have referred to this as the creation of ‘three-parent embryos’, but this is actually incorrect - the embryo is still the product of the union of genetic material from the mother and the father, as usual, but with donated mitochondria from a third person. ‘Three-person IVF’ might be a more suitable term. If the child is a girl, the hope is that her own children should also have healthy mitochondria, so preventing the inheritance of mitochondrial disease.

Overall, the panel decided that the current evidence did not suggest these techniques would be unsafe in humans, but accepted that any research moving into clinical trials carries an element of risk. The research reviewed included research that showed macaque monkeys born after this treatment are still healthy five years later, as well as laboratory studies with early human embryos.

However, the report does not comment on the ethical and legal issues this could pose, and advises that some experiments still need to be done before these techniques enter clinical trials as a new fertility treatment for mothers with mitochondrial disease.

“The Panel has examined, discussed and re-examined data from disparate fields of science, including biochemistry, evolutionary biology, the genetics and developmental biology of model organisms and, of course, clinical genetics and embryology," said Dr Greenfield. "We believe that our recommendations are firmly based on the data that we examined.”

Cheltenham Science Festival Fun

On the weekend of the 7th June 2014, MRC Harwell volunteers joined other MRC units to man our stand at the Cheltenham Science Festival, one of the biggest science festivals in the country.

The Times Cheltenham Science Festival ​attracts all the stars of science, be they eminent professors or TV presenters, and the 2014 programme was dotted with famous names. Through talks, workshops and stands, the festival provides a wonderful chance for scientists to explain their research to the public, and attracts visitors from miles around.

This year, the MRC stand was located in the Explore Zone, an area designed to cater for adults as well as kids. Away from the chaos of the Discover Zone, it provided a more relaxed scene for visitors to find out more about our work. Our volunteers from Harwell joined others from Oxford and Cambridge to man our stand on 7-8 June 2014, the final weekend of the festival.

Our stand focussed on MRC research into dementia. Dementia comes in many forms, the most common of which is Alzheimer’s disease. The hallmarks of this disease are the formation of amyloid plaques and tau tangles in the brain, which can be seen under the microscope post-mortem. These are thought to cause the cell death that occurs in certain brain areas, particularly those responsible for memory, resulting in large empty spaces within the brain. The problem with this method of diagnosing Alzheimer’s disease, of course, is that it is all much too late. While other tests, which measure memory function and other traits of dementia, do exist, they rely on subjective measures and it can take a long time to reach a diagnosis.

The MRC is therefore funding research to look into the possibility that brain scans could be used to help diagnose the early signs of Alzheimer’s disease. One of the researchers studying this designed an activity for people at the festival to try based on her own work. In her study, the participant sits under the scanner, just as someone having a perm would, and their brain activity is measured while they complete a task. One task is to watch a slideshow of images, each with a smaller image inserted in it, and identify when a particular slide is repeated. The repeated slides had a subtle difference – the smaller image was in a different position the second time – which, if the first slide was remembered, produced a change in the person’s brain waves. It was designed to test the hypothesis that people with Alzheimer’s disease would not remember the first slide and therefore their brain would not register the change. People at the festival were asked to try the same task (minus the scanner) and asked if they noticed anything odd. The volunteer then explained how it was used in the study, showing pictures of the brain scanner and an example of the results from it.

Our other activity was more hands-on. We had four pairs of googles that had been modified so that the person’s vision was skewed about 30 degrees to the left. They then had to try to complete a task; throw a ball into a bucket, try to shake hands with another person wearing the goggles, repeatedly touch the tip of a pen. It was surprisingly difficult, but after a few tries they gradually became better at it, learning to adapt to their distorted sight. But if you then suddenly remove their googles, they missed the bucket or the tip of the pen, before their brain had a chance to adjust back. While this was all good fun, it had a serious message; your brain just adapted to a new situation, but in Alzheimer’s disease people lose that ability, that flexibility of the mind.

Overall the festival was a great success, with a constant flow of visitors, who walked away knowing a little more about the MRC’s dementia research than they did when they arrived.

 
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IMPC virtues noted by Nature

MRC Harwell is part of the IMPC, a project to create a comprehensive catalogue of mammalian gene function – now a new Nature editorial explains why it’s so important.

While we now have the entire mouse genome at our fingertips, the exact function of most genes remains a mystery. Before you can read a book in another language, you must first know what each word means; before you can understand the genome, you must first know what each gene does. And so the International Mouse Phenotyping Consortium (IMPC) was formed, which aims to use knockout mice for every gene to create, in effect, the dictionary that researchers need to truly understand the first mammalian genome.

The IMPC has set the highest standards in mouse genetics as it works towards a comprehensive catalogue of the function of all mouse genes

A new editorial in Nature, Still much to learn about mice, now defends the role that the IMPC can play in ensuring high quality mouse lines continue to be produced and made available for the scientific community to use in research. The emergence of new techniques means that creating knockout mice will soon no longer require the same skill as it does now, threatening the quality and reproducibility of new mouse models. And a lack of such quality could mean that more of the therapies tested in mice prove unsuccessful in people.

This issue was raised when members of the IMPC, including MRC Harwell, met in Munich, Germany earlier this month. They voiced their concerns that new gene-editing techniques using RNA-guided endonuclease (RGEN), such as the CRISPR/Cas system, will result in an explosion of poor science that cannot be reproduced. While current methods require considerable skill in a range of genetic techniques, this technology opens up the possibility that labs entirely new to the field - without the wider expertise necessary to deliver a high quality and standardised mouse mutant - could start editing mouse genomes.

It is possible that these labs will use outbred mice, or mice of a mixed or unknown genetic background, introducing unwanted genetic variability into the mutant line created. It then becomes extremely difficult to discern what phenotypes are simply due to the genetic background and which are actually due to the specific genetic alteration. The advantage of the IMPC is that it is systematically targeting every gene, creating a knockout mouse using the same inbred background every time, so that they are all produced exactly the same way. It is this consistency and quality that is the reason why the IMPC is still so important.

“The IMPC has set the highest standards in mouse genetics as it works towards a comprehensive catalogue of the function of all mouse genes,” commented Professor Steve Brown, director of the Mammalian Genetics Unit. “We have defined unprecedented standards and quality control mechanisms to generate the IMPC library of mouse mutants. Moreover, we have also defined robust experimental procedures for determining the phenotype of our mutant lines along with rigorous scrutiny and quality assurance of the data produced. All of this ensures that we will generate a very reliable catalogue of gene function with high levels of reproducibility - a critical resource that will underpin biomedical sciences for decades to come.”

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Oxford Brookes careers event 2014

We took part in a speed-dating style careers event at Oxford Brookes University last Thursday, where we advised biological science students on options for their future career.

Students often reach a crisis as the end of their degree looms. What should they do next? What jobs can they do? Should they take further study? We went along to Oxford Brookes University on 27 March to help explain the opportunities out there and answer their numerous questions.

Over a hundred students registered for the Oxford Brookes Health & Life Sciences Careers Event, and there were over 40 employers and experts there to offer advice. In order to ensure that all students had the opportunity to talk to all of these employers in the short window from 6.30pm to 8pm, it was run as a ‘speed-networking’ event, with groups of three rotating around the companies, and were given just seven minutes to speak to each employer. It therefore resembled speed-dating, with a strict time limit that you could spend talking to each person.

The hall was laid out as it would be for an exam – rows of tables in neat lines, grouped into separate faculties. MRC Harwell had two tables, with our ‘double act’ working together to cover all of the major career routes that the students might want to consider. It was an intense experience, with almost constant talking for the full hour and a half.

At the first table, the students met Dr Nanda Rodrigues, who worked as a postdoctoral researcher at Oxford University and is now our Head of Scientific Business and Administration. She told them about career routes that require a PhD, including those of a postdoctoral researcher, clinical fellow, senior scientist, project manager and director. While first year students found this somewhat useful for decisions such as whether to take a placement, it was the second and final year students who said they benefited from these discussions most.

Students then moved onto the other table, where Jeremy Sanderson explained to them about science career routes that do not require a PhD. His first job was as a careers advisor, and he still takes an interest in offering guidance to students. Jeremy’s own career in science began as a biomedical scientist in the NHS, after which he switched to working in academia. He has a particular interest in microscopy is now our Bio-imaging Facility Manager.

Together, these experiences gave the students the chance to hear about two very different sides of the same coin and provided an insight into the major career routes they can take in science. Whether to commit the next three or four years of their life to a PhD is a major decision, and by no means an easy one to make. We hope that the advice and experiences we shared will equip them with the information they need to make the right choice.

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Cryopreservation training course

Last week we held our popular four day cryopreservation course, designed to give animal technologists hands-on experience of embryo and sperm freezing and in vitro fertilization.

Cryopreservation allows long-term storage of embryos and sperm, providing a convenient way to preserve, protect and transport mouse lines for use in research. Here at MRC Harwell we have extensive experience of using cryopreservation techniques. By providing this course we aim to share our expertise with the wider scientific community.

The course runs over a period of three and a half days, this year from Monday 10 to Thursday 13 March, and is worth ten continuing professional development (CPD) points. It is led by MRC Harwell’s Frozen Embryo and Sperm Archive (FESA), part of the European Mutant Mouse Archive (EMMA), a collective effort by centres all across Europe to create a genetic archive for use by the international scientific community.

On Monday, the participants learnt how to freeze sperm in liquid nitrogen using plastic semen straws. While embryos can be stored ready to use, sperm cryopreservation has the advantage that, as long as you have enough oocytes for fertilisation, you can potentially recover over a thousand mice from the sperm of just one male.

Tuesday was all about embryo cryopreservation. The embryos were harvested, loaded into straws and frozen in the morning, and after lunch the group learnt how to thaw them out again. At the end of the day, everyone had the chance to get to know each other a little better at the course dinner.

The final day and a half of the course was set aside to give participants experience of a straightforward and robust in vitro fertilisation (IVF) procedure, with a demonstration of how these embryos can then be transferred into recipient females to establish a new pregnancy. The course concluded with a final review and recap.

In this way, the course allowed participants to gain experience of the entire process, from harvesting the embryos and sperm, to conducting IVF and transferring embryos into the female mouse. After a productive and enjoyable few days, they left fully equipped to put their newly acquired skills to use.

We will be running another cryopreservation course later in the year on 6-9 October 2014. Please contact Martin Fray (m.fray@har.mrc.ac.uk) for more details.

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