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New PhD studentships available

Open for applications: Closing date Friday 6th March 2015 (deadline extended)

MRC Harwell is an International Centre for Mouse Genetics at the forefront of studies in mouse functional genomics and mouse models of human disease. We are engaged in lifetime studies – from developmental abnormalities through to diseases of ageing.

We are offering PhD projects in these areas at the Mammalian Genetics Unit at MRC Harwell for 2015:

  • Cilia, Development & Disease
  • Neurobehavioural Genetics
  • Genetics of type 2 diabetes
  • Genetics of Deafness
  • Biocomputing
  • Statistical Genomics
  • Age-related disease

Our doctoral training programme:

MRC Harwell offers first class opportunities for PhD students including a formal training programme. Students join a 4-year PhD programme that includes an initial six-month induction and rotation across two laboratories of their choice before selecting and embarking on their research project. Students register with either the University of Oxford or the Open University. Currently we have 24 doctoral training students. Together the many junior members of the Unit contribute to a vibrant atmosphere providing a supportive environment for the development of future leaders in mouse genetics and the life sciences.

The Mary Lyon Centre at MRC Harwell is one of the best state-of-the-art SPF mouse facilities in Europe. Supporting core facilities include: Bioimaging, Transgenics/Genome Editing, Frozen Embryo and Sperm Archiving (FESA), Genomics, Phenotyping, Clinical Chemistry, Proteomics, Histology and Pathology. MRC Harwell has strong collaborative basic and clinical science links with the University of Oxford and many other UK biomedical research centers.

More information about potential supervisors and research interests can be found on our research pagesInformal inquiries can be made to the Director of Graduate Studies Professor Roger Cox by emailing  r.cox@har.mrc.ac.uk.

Apply Now:

Award of an MRC-funded studentship within the Unit is conditional on achieving a first-class or 2.1 honours degree, or equivalent, in a biological science or related discipline. Graduates in 2015 please indicate in your cover letter the predicted class of your degree. Applicants will please send to studentapplications2015@har.mrc.ac.uk the following files (1) a one page covering letter, (2) a CV with the names and contact details of two referees and (3) a completed application form (attached below).

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‘Social jetlag’ linked to obesity-related disease

Being out of sync with your body clock may affect your metabolism, leading to obesity and disease. Credit: JD.

Just as travelling to a different time zone can make you feel more inclined to curl up in bed at midday than grab a bite for lunch, you can get ‘social jetlag’ from living slightly out of sync with your body clock on a weekly basis. While this may have less of an obvious effect than travel jetlag, in the long term it could harm our health. Research by Parsons et al., published in the International Journal of Obesity, suggests those with social jetlag run a higher risk of developing obesity-related diseases.

Social jetlag occurs when you have a mismatch between the times that you sleep during the working week and on your days off. Perhaps you prefer to lie in at the weekends, but during the week you have to get up early for work. This mismatch is thought that to set your circadian clock off kilter, which not only controls when you fall asleep and wake up, but also keeps your metabolism in check. And while most people recover from travel jetlag within a day or two, social jetlag can continue for a person’s entire life, so could have long-lasting effects on your health.

While the rise of obesity in the West is generally attributed to high calorie diets and a sedentary lifestyle, there is growing evidence that disruptions to our internal body clock such as those caused by social jetlag may also play a role. To investigate the effects of social jetlag on obesity and risk factors for associated diseases such as type 2 diabetes, Michael Parsons and Pat Nolan joined forces with researchers in London, the USA and New Zealand. They gave 815 New Zealanders who were part of the Dunedin Longitudinal Study a questionnaire to fill in to assess their sleeping habits.

When they were 38 years old, these participants underwent a series of tests to assess their BMI, fat mass and girth, as well as indicators of inflammation and diabetes, used to determine if they were obese and showed any signs of obesity-related disease.  The researchers found a correlation between social jetlag and being obese with warning signs of related diseases. This could be due to many different factors – perhaps these people just have a greater tendency to eat a poor diet and do less exercise, or maybe social jetlag causes changes in the expression of genes that regulate our metabolism.

While more research is required to determine the underlying cause for this correlation, this research suggests that cutting down on social jetlag could help us stay healthy. This adds to growing evidence for a link between social jetlag and obesity, and particularly highlights how social jetlag could increase our risk of obesity-related diseases. Since these diseases include some of the biggest killers in the western world, cutting down on social jetlag and working in sync with our body clock could help us live a long and healthy life.

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Mary Lyon, discoverer of X inactivation, dies

It is with great sadness that we have learnt of the death of Mary Lyon, aged 89, on Christmas Day.

Mary was a colleague and friend to all of us, and was pivotal in leading and developing mouse genetics at Harwell. She was one of the foremost geneticists of the 20th century, and with the discovery of X inactivation and her work on the t complex, she brought fundamental and profound insights to mammalian genetics and the genetic bases of disease. Her accomplishments were widely recognised by many international honours and prizes, and she was a formidable icon to all woman making their way in science.

In her own quiet way, she was a tremendous inspiration and supporter of young scientists and all those who were starting out in a career in genetics. She would never fail to give good advice and forthright opinions to all who sought her counsel.

Her legacy will be recognised through the Mary Lyon Centre and the continuing work in mouse genetics at MRC Harwell. She remained very involved in science after retirement, and continued to follow and contribute to current developments in mammalian genetics. We celebrate her life and contributions to genetics - she was one of the greats of British science.

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A combined approach to hearing loss research

So far, genetic research into age-related hearing loss in patients has yielded little insight. A reciprocal approach, combining patient data with results from mouse models, could provide the answer.

Loss of hair cells in the inner ear of the trombone mouse model aged 6 months (left) and 9 months (right).

It is now possible to study the genetics of large cohorts of patients using techniques such as genome-wide association studies and exome sequencing, which enable links to be made between gene variants and disease. However, these approaches only indicate which genes might be involved, and cannot tell us how these could lead to the disease. We therefore need animal models to fully investigate the causes of the condition.

This is especially true for age-related hearing loss, where the results from such studies with patients have been difficult to interpret. While these studies have identified possible contributory genes, none of the associations have been particularly pronounced. By taking a human-to-mouse approach, it is possible to see whether mice with the same genes as those identified in patients develop the disease symptoms, therefore proving that the disease is caused by these genes.  Conversely, a reciprocal mouse-to-human approach, starting with mouse models such as those in the Harwell Ageing Screen, can be used to investigate how the genes could cause the human condition and identify potential ways to treat it.

A mini review by Mike Bowl, published in Gerontology, has investigated how we can combine our knowledge from mouse and human studies to further research into the genetics of age-related hearing loss. Establishing good mouse models will allow researchers to investigate the onset and progression of the disease at the cellular level, something which is not possible in patients. This will improve our understanding of the causes of one of the most common forms of hearing loss.

What is age-related hearing loss?

Often mistakenly assumed to be an inherent part of the ageing process, progressive hearing loss in old age is the most common kind of sensory loss experienced by the elderly. Age-related hearing loss, also known as presbycusis, affects 31% of people in their sixties and 63% of those over 70, and our ageing population means that these are expected to rise.

Beginning with high-pitched noises and progressing to deeper sounds, the person gradually loses the ability to hear. Less able to hear conversations, people with age-related hearing loss can experience social isolation, depression and cognitive decline. The only treatment is a hearing aid.

When we hear a sound, pressure differences in the air cause the ear drum to vibrate. These vibrations are transferred along a chain of tiny bones, causing the last in the chain to knock against a small window in a fluid-filled structure shaped like a snail’s shell. This is the cochlea, which houses the tiny hair cells that detect the vibrations and transmit the signal to the brain to interpret.

During age-related hearing loss, these vital hair cells are lost and the person loses the ability to hear. However, we lack detailed knowledge of the underlying processes that cause these hair cells to be lost, meaning more research is needed to understand exactly how and why this happens.

Such knowledge is crucial for developing better treatments, such as gene therapy, antioxidant treatments or stem cell therapy, which hold the potential to prevent, lessen or even reverse hearing loss in old age.

Why is a model required?

Research into age-related hearing loss presents a number of challenges, not least of which is that all of the interesting changes happen in the cochlea, which is encased within the temporal bone - the hardest bone in the body. This means that the inner ear can only be examined post-mortem in patients, making it difficult to determine if what you see is the primary cause of the hearing loss or a secondary event occurring much later.

To add to this, age-related hearing loss is extremely complex and likely to have multiple causes, including a variety of genetic and environmental factors. However, if you have a good model, every mouse within that line should have the same genetic makeup and live in the same environment, so should develop hearing loss in the same way. This means that you can investigate the progression of the disease at various stages, from the initial trigger to the end result, and record the effect it has on their ability to hear.

This reciprocal, integrated approach, combining our knowledge from studies in both patients and animals, has the potential to reveal new insights into this complex and common disease. Perhaps, with our ageing population, it will lead to new treatments at a time when we need them most.

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Sleep in old age mimicked in mice 

Old age affects our circadian clocks, disturbing our sleep at night and increasing the frequency of daytime naps. Investigating these parameters in mice could reveal the part played by genetics.

 Why do elderly people need more naps? Credit: Deutsche Fotothek.‎

It’s well known that old people have a tendency to drop off in their armchair and stir during the night, but exactly why this happens is still somewhat puzzling. And because we are now living so much longer than previous generations, it’s in all our interests to discover what is really going on.

One way in which we can investigate it is to use the mouse, specifically strains that are tested over their lifetime to monitor the ageing process. Pat Nolan has led research, published in Neurobiology of Aging, which compared how the sleep patterns of four inbred mouse strains change as they age, and identified how these can model sleep in human ageing.

The mammalian circadian clock will continue to maintain a sleep-wake cycle in the absence of any cues, but it is only really useful when it is ‘entrained’ to work in response to light. While daylight is the trigger for us to wake up, mice are nocturnal, so it instead results in them falling asleep. Despite this, in all other respects the sleep pattern of mice closely resembles that of humans, making them an excellent model to study the effect of ageing on this system.

To assess the circadian system in the mouse strains, the researchers used a variety of methods. They tested the visual health of the mice by placing them in enclosure surrounded by computer monitors and measuring how well they could track a pattern that rotated around them. They also tested for cataracts and the ability of the pupil to constrict in response to light. Alongside this, they used a novel 24 hour video tracking system to measure when the mice were awake or asleep, in a normal day/night cycle. Finally, they monitored the animals’ activity on running wheels, firstly in a day/night cycle and then in constant darkness, to track their circadian rhythms. This was done at five different stages of their life, and the results were used to determine what happened to their circadian system as they got older.

As all of the mouse strains aged, their sleep became more fragmented and they woke more often. In addition, two of the strains had more naps during the night (their day). One strain in particular, C57BL/6J, was found to provide the best model of human ageing, as its eyesight gradually got worse and it developed cataracts, just like people.

This strain could therefore be used to study exactly what happens to alter our circadian system as we age, and potentially develop a way to alleviate the more disruptive aspects, allowing people to make the most of their golden years.

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Cilia growth regulator essential for lung development

Researchers at MRC Harwell have shown stumpy cilia in mice lacking a functional Atmin gene prevent proper lung development. This could have important implications for human ciliopathies.

Nodal cilia from wild type mice (left), compared to Atmin and Dynll1 mutants (middle and right). Shortened, stumpy cilia can be seen in the Atmin mutant, while Dynll1 cilia bulge at their base.

Ciliopathies are diseases that all share a common cause - defective cilia. Research led by Dominic Norris, published in Development, into the underlying genetics of mouse lines with short cilia and underdeveloped lungs has helped explain the essential role of the Atmin gene in lung development.

What are cilia?

Cilia are small hair-like protrusions that extend from the surface of cells, and are known to play diverse roles in the body, from being required for certain kinds of cell-to-cell signalling to acting as flow sensors. Some cilia are motile, such as those lining the wind pipe, which beat so as to clear mucus from the lungs. With these varied roles, it is perhaps unsurprising that the symptoms of ciliopathies can vary considerably. However, they often include developmental abnormalities.

Cilia consist of a central microtubule scaffold surrounded by the cell membrane. In order for cilia to grow, proteins must be carried to the tip, where they are added onto the cilium. Molecular motors ‘walk’ up and down the cilium to transport these proteins as cargo - kinesin transports cargo up to the tip (‘anterograde’ transport), whereas cytoplasmic-dynein-2 transports cargo down to the base (‘retrograde’ transport).

Atmin’s role in cilia

Atmin encodes a protein that regulates the transcription of the Dynll1 gene. This study revealed that DYNLL1 protein is an important component of cytoplasmic-dynein-2.  

Both Atmin and Dynll1 mutant cells had fewer and shorter cilia than normal, and any present appeared stunted. Yet when functional DYNLL1 protein was added to Atmin mutant cells, the cilia were ‘rescued’. They deduced from this that Atmin acts via Dynll1 to regulate cilia growth.

To explain how the stunted cilia in these mutant mice lead to abnormal lung development, the researchers considered their role in signalling. Normal development and patterning of the embryo requires various signalling pathways. One of these, the ‘hedgehog’ signalling pathway, is known to require fully developed cilia. This pathway and was found to be working less efficiently in their lungs, and deficient signalling due to stunted cilia almost certainly interfered with normal lung development in these embryos.

Baffling bulges   

Some questions still remain. Particularly puzzling was the bulges they observed at the bottom of the Dynll1 mutant cilia – if retrograde transport is disrupted, you would expect everything to get stuck at the tip of the cilia, and therefore would expect to see a bulge at the top. They suggest that this might be due to another motor protein component taking up the slack, or possibly that the only aspect disrupted is the release from the base of the cilium. Whatever the cause, it merits further investigation.

This discovery has begun to unravel the vital role of cilia in mammalian development and disease. As similar defects in retrograde transport are known to occur in the human skeletal ciliopathies, it potentially provides an important step in understanding these complex diseases. 

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Cause of patient’s paralysis deciphered

Research led by Dr Abraham Acevedo-Arozena has determined the cause of muscle stiffness and periods of paralysis in a patient, using a mouse line with exactly the same mutation.

A patient’s attacks of muscle stiffness and weakness have been attributed to a novel mutation in the SCN4A gene, using a mouse line identified at MRC Harwell with the equivalent mutation. The research, published in Brain, gives us new insights into the important role of this gene.  

A remarkable likeness

The patient considered in this study was a 70-year-old man who had been having periods of paralysis since he was eight. His muscles would stiffen, particularly after exercise, and after this his muscles would become weak. He was diagnosed with hyperkalemic periodic paralysis with paratonia congenita, a type of muscle channelopathy, and had a family history of the condition. The researchers discovered he had a mutation in the SCN4A gene never described before.

SCN4A encodes a key subunit of voltage-gated sodium channels in muscles, responsible for initiating and propagating the electrical signal that moves along nerves to trigger the muscle to contract. Mutations in this gene have previously been linked to a subset of muscle channelopathies, conditions where patients experience attacks of muscle stiffness and weakness due to prolonged muscle contraction, the result of faulty sodium channel inactivation.

A mouse line identified at MRC Harwell had the exact same mutation in SCN4A. It also had remarkably similar traits, with attacks of hind limb immobility that caused the mouse to drag its hind limbs along behind it, lending it the name ‘draggen’. They found evidence of pathology in their muscles, with strange structures that are not normally seen.

Skewing the energy balance

The researchers noted that male draggen mice failed to gain weight after 12 weeks old, suggesting an overactive metabolism. As muscles use large amounts of the body’s energy and so have a big effect on overall metabolism, the researchers suspected this might be linked to their muscle traits.

They investigated a possible link between energy use in muscles and immobility attacks by measuring activation of AMP-activated protein kinase (AMPK). When a muscle contracts, it breaks down ATP to generate the energy it requires and the by-product AMP, which activates AMPK. You can therefore use AMPK as an indicator of the amount of ATP being used by the muscle.

They found more AMPK was activated at resting levels than normal, and after the muscles had contracted a lot, as they would during exercise, AMPK activation was blunted. So this SCN4A mutation upsets the balance of energy expenditure in draggen mouse muscles, which could potentially underlie the periods of paralysis – if all the energy is used up in one go, none would be left for later.

This study gives us a new insight into the causes of SCN4A channelopathies, highlighting a mutation not previously associated with these conditions. In addition, it provides a new mouse model to support future research into potential causes and treatments, highlighting for the first time a potential link between specific muscle mutations and whole body metabolism.

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Third method for mitochondrial donation

In June 2014, MRC Harwell’s Dr Andy Greenfield chaired a panel that reviewed two potential mitochondrial replacement therapies. New evidence has now prompted them to consider a third. 

             A polar body alongside the egg, which could be used in mitochondrial replacement therapies. Credit: Spike Walker, Wellcome Images

Mitochondria are the ‘powerhouses’ of cells and generate the energy they need to function. What makes them unusual cell components is that they contain their own DNA, separate from the main bulk of DNA found in the cell nucleus, which contains additional genes they need to function.

In patients with mitochondrial disease, a mutation in their mitochondrial DNA means that their cells lack the energy they need to function. As mitochondria are maternally inherited, these mutations can be passed down from a mother to her children. 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.

Mitochondrial replacement techniques offer the chance to prevent the inheritance of mitochondrial disease. Through a process similar to current IVF techniques, these methods could allow mothers with mitochondrial disease to give birth to healthy children.

Earlier this year, in June 2014, Dr Andy Greenfield chaired a review by the Human Fertilisation and Embryology Authority (HFEA) on the safety and effectiveness of mitochondrial replacement methods. This was used to produce a report on two techniques – mitochondrial spindle transfer and pronuclear transfer – and their potential use in fertility treatments. After reviewing the available evidence, they found that these techniques were likely to be effective and that they had no cause to consider them unsafe. This report was given to the Government, who have announced that they intend to proceed to propose relevant regulations to Parliament.

After the report was published, new data by Wang et al. 2014 emerged that provided evidence for the potential use of a third technique for mitochondrial transfer, known as polar body transfer (PBT). The HFEA panel therefore reconvened in October 2014 to produce an addendum to the original report, which considered the merits of this third potential method for mitochondrial replacement therapy.

As with the other two methods they reviewed, the panel found no reason to consider PBT unsafe. However, they suggested a minimum set of experiments, particularly in human cells, they deemed necessary before it can be considered safe and ready for use in patients.

Expert panel chair Andy Greenfield said that PBT should be seen as a promising, if emerging, development in this field: “Having reviewed the latest data on this new technique – data which appeared too late for our previous review - it is the panel’s view that PBT has the potential to provide another treatment option for eradicating mitochondrial disease for future generations.

"There is still more work to be done, and it is perhaps at an earlier stage of development than its sibling techniques, but we believe PBT represents an exciting new development in this area.”

Why use polar body transfer?

A polar body is produced either during the maturation of the egg (the first polar body) or just after fertilisation (the second polar body). It contains a nucleus, just like the egg or early embryo, but very little else. Both polar bodies could potentially be used for mitochondrial replacement therapy.

Unlike other techniques that require the nuclear DNA from the mother’s egg to be extracted, PBT simply inserts the whole polar body into a donor’s egg that has had the nucleus removed. A polar body can therefore be thought of as a pre-packaged nucleus ready for transfer into a cell with healthy mitochondria.

PBT could either be used on its own or in combination with either mitochondrial spindle transfer or pronuclear transfer as a mitochondrial replacement therapy. While the research into this method is at an early stage compared to the other two methods, it could potentially offer advantages, such as lower risks of leaving nuclear DNA behind or carrying over faulty mitochondria.

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Microscopy training course a success

We held a new training course on the 2-3rd October, 'Understanding and Using the Light Microscope', which introduced participants to microscopy and taught them to use it effectively.

Unlike other scientific instruments, which will not work unless they are adjusted properly, the light microscope will give an image at the flick of a switch, however badly it is set up. For this reason, superficially the microscope appears simple, but scientific journals are replete with examples of poor quality images.

We therefore decided to run a new course at MRC Harwell to teach participants the basic principles of light microscopy, equip them with the skills required and enable them to use the light microscope to its full potential. The course was led by Jeremy Sanderson, our Bio-imaging Facility Manager, who has had twenty years of experience teaching the principles of light microscopy with the Royal Microscopical Society. He was therefore extremely well placed to provide tailored teaching and advice on the operation of both basic microscopes and advanced research instruments.

Course numbers were limited to a maximum of just four participants for the two days, which meant that participants were not fighting over microscopes and could receive more individual tuition. It also gave ample time for the participant’s individual questions and problems to be addressed.

At the end of the course, the participants were given a booklet and USB stick to take back with them, with additional information to refer back to at a later date. This was also tailored to some extent, with the information included adapted to suit each participant’s interests, ability and needs.

The feedback from the course was excellent, with participants agreeing that they found the course useful, that there was a good balance between introductory talks and practical sessions, and that they would definitely recommend the course to others. One participant praised the high level of expertise and knowledge of the tutor, combined with the ability to get it across, while another said, “It covered everything I needed. It was more deep than I expected.”

This course is repeated on the 27-28th October 2014. If you are interested in applying, please email training@har.mrc.ac.uk.

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MRC Harwell at the british science festival

We travelled to Birmingham to run our ‘DNA Diagnosis’ workshop at the British Science Festival on Thursday 11th September, which focused on the tricky topic of genetic testing.

The British Science Festival is one of the largest science festivals in Europe, and every year it attracts a host of spectacular science shows, deep discussions and thought-provoking talks. MRC Harwell’s workshop was designed to give sixth-form and college students an insight into medical research by asking them to use DNA samples to make their diagnosis.

We presented the students with the scenario of a family where the father had Huntington’s disease, a devastating genetic condition caused by an autosomal dominant mutation within the HTT gene. The most common symptom is Huntington’s chorea, uncontrolled involuntary writhing movements caused by neurodegeneration in the brain, but can also be accompanied by changes in mood, coordination and gait. Genetic testing is currently available at various stages, including before having children, as part of a selection process during IVF, during pregnancy and after the child is born. It raises a multitude of ethical questions, and anyone who undergoes such testing must first receive genetic counselling.

As the mutation within the HTT gene introduces more CAG (cytosine-adenine-guanine) repeats, the mutant allele is longer than the healthy allele. Because of this, the mutant HTT allele can be detected by separating the gene DNA based on its size. This is done using two very common laboratory techniques; polymerase chain reaction (PCR) and gel electrophoresis.

So we set the students a challenge – can you use these two techniques to work out which of the children in the family have inherited their Dad’s mutant HTT gene? We gave them an instruction sheet, the DNA and reagents, and they got stuck in. While a few had been lucky enough to have done similar experiments on work experience, for many of the students it was the first time they had ever picked up a pipette. It gave them a great introduction to life in a lab, and we made our way around the tables to ask them about their career aspirations and offer a little advice.

Once each group had loaded their gel, we set it running for 15 minutes. While they waited, we struck up a discussion about the ethics of genetic testing – would they really want to know if they had the mutant HTT gene, considering that we have yet to find a cure? At what age can a child decide to get tested? Can parents make the decision on their child’s behalf? Is it right to select embryos for IVF or abort an affected foetus? Of course, these are tough questions and we weren’t expecting any clear-cut answers, but it got the students thinking about this whole ethical maze.

However, they could answer one question – which family members had Huntington’s disease? One band meant they just had the healthy allele, whereas two bands meant they had a copy of the mutant version and would go on to develop the condition later in life, just like their dad. The results were as expected, with the mutant allele present in two of the four children’s DNA. Thankfully, these samples weren’t taken from real patients, but it could just as easily have been a true diagnosis. Would you want to know?

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