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Oxford Brookes ‘speed networking’ event

We took part in a speed-dating style careers event at Oxford Brookes University on 20 April 2015, where we gave biological science students advice on the careers available to them. 

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 Monday to help explain the opportunities out there and answer their numerous questions.

The Oxford Brookes Health and Life Sciences Careers Event is designed to introduce students to relevant job roles, provide career guidance and stimulate thinking about future employability. By speaking to over 30 employers, they can gain unique insights into the career paths they may wish to take. The main feature of the event is “speed networking”, where students are given just seven minutes to speak to each employer, moving from table to table like speed dating.

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. She also gave them tips about what a good CV and covering letter should contain. Students who were unsure about registering directly for a PhD after their degree could explore the options of working for a year or two before making up their mind.

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 and 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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Role of Fto gene in obesity revealed

New research led by Roger Cox shows how overexpression of the Fto gene makes mice fat, which could explain why there is an association between an FTO variant and obesity in people.

 Fat cells (stained red) produced abundantly in mice where the Fto gene is highly activated

While the role of a healthy diet and plenty of exercise in preventing obesity is well known, the influence of our genetic makeup is less clear. We all know some people who struggle to keep their weight under control and others who eat to excess, yet never seem to gain any weight. The answer to why there is such a difference could lie in the role of genes such as FTO.

The fat mass and obesity-associated (FTO) gene was the first gene shown to play a role in human obesity on a large scale. Initially, an association was found between obesity and a specific variant of the FTO gene in humans, but this did not show cause and effect. However, it was followed by studies in mice that showed an overexpressed Fto gene resulted in excessively fat mice, particularly when they were fed a high fat diet. Conversely, mice lacking a functional Fto gene were found to be especially lean.

However, the mechanism by which Fto acted remained elusive, and many questions remained regarding the role it played in regulating fatness and weight gain. The process of generating new fat cells, or adipocytes, is referred to as adipogenesis. Roger Cox’s team at MRC Harwell, together with researchers at the University of Oxford, have now shown that Fto acts upon key processes that occur during the early stages of adipogenesis, causing more fat cells to be produced. The work, jointly funded by the Medical Research Council and Wellcome Trust, is published in Nature Communications.  

Understanding the obesity ‘epidemic’    

In the west we are currently in what many are calling an obesity ‘epidemic’ (although not infectious), with more people being classed obese than ever before. To figure out why this is happening, we need to understand every aspect of it, including how our genes could make some of us more prone to getting fat. While so far in people we only know there is an association between a variant of FTO and being obese, how the variant predisposes to obesity is poorly understood.

Many early studies on FTO function focussed on food intake, but this study adds to a growing number of studies pointing to a functional role in fat itself. This study suggests Fto has a major influence on our propensity to gain weight, by influencing the amount of fat cells we produce in response to overeating, and could help to explain why people are becoming obese.    

“It has emerged that a number of genes in the FTO locus may co-ordinately be involved in determining obesity,” said Samantha Laber, a DPhil student joint first author on the study, “but our work and that of others clearly shows a central role for FTO in adipogenesis.”

Elucidating the role of Fto

The Fto gene product is a nucleic acid demethylase, an enzyme which removes methyl groups from DNA and RNA. It is known to regulate splicing of mRNA from many genes by affecting the ability of the splicing factor to bind to it. One of these genes is RUNX1T1, which as others have shown can be spliced differently to give either a long or short form. The short form promotes adipogenesis. The researchers therefore sought to determine whether Fto acts via RUNX1T1 to increase fat production in mice.

                    The proposed role of FTO – boosting an early stage of fat cell production via the short form of RUNX1T1

Mice with Fto overexpressed (causing an abundance of the FTO enzyme) gain weight easily, but only become noticeably bigger when they are older, as it takes time for the fat to accumulate. However, the researchers found that the fat of younger mice looked different under the microscope, with lots of little fat cells, an indication that an early stage of adipogenesis was already taking place.        

To study how Fto activity affects adipogenesis, the researchers took mouse embryonic fibroblasts and early ‘preadipocytes’ from mice with Fto overexpressed and knockout mice (which lack Fto). These were cultured in a special cocktail that caused them to develop into mature adipocytes. Genes with a key role in adipogenesis were less active than normal in the cells from the knockout mice, but were overly active in the cells from the mice with overexpressed Fto.

As they saw in the fat tissue from the mice, the cells cultured from the mice with overexpressed Fto produced lots of little adipocytes, a sign of an early stage of fat production known as ‘mitotic clonal expansion’. At this stage, preadipocytes are induced to proliferate, increasing their numbers. Later they accumulate a fat reservoir, growing in size to become mature adipocytes.

As the levels of the short form of RUNX1T1 were much higher in the cells from the mice with Fto overexpressed, the researchers suggested that FTO must swing the balance so that more of the short form is produced. This in turn leads to a chain of events that result in more mitotic clonal expansion, more fat cells being produced and ultimately a mouse that gains weight more easily. Their work has therefore revealed a new function for FTO - increasing fat production.

“Many early studies on FTO function focused on food intake,” Dr Dyan Sellayah, a senior author on the paper commented, “but this study is one of a growing number now that suggest that FTO may function in adipose tissue, independently of food intake.”

Understanding Animal Research Open Labs

On Monday 23 March 2015, we had a visit from a group of science 13-14 year old students at Didcot Girls' School, as part of the Open Labs initiativeMost students who took part said that their experience of visiting MRC Harwell had changed their attitude to animal research and helped them see why it was important.​

Open Labs is organised by Understanding Animal Research (UAR), an organisation dedicated to improving understanding of the humane use of animals in medical research, and tends to take place around the same time as British Science Week. The aim is to give school children the chance to look around an animal facility, so that they can see for themselves how animals are used in scientific research. This helps to dispel the myths surrounding animal research, giving them a solid basis on which to form their own opinions. 

The first part of their visit was a tour around the Mary Lyon Centre. Before they were allowed into the facility, they had to undergo our measures to prevent disease causing agents being brought in -  changing into a sterile boiler suit, wearing a hairnet and putting on shoe covers. They then entered one-by-one through the air shower, which encapsulates each person and blows off any remaining bacteria, dust or debris that could potentially lead to disease being transferred to the mice. Once inside, they were shown how the mice are kept in specially designed cages, complete with their own ventilation system, saw how we house the mice them with others to keep them company, and got a chance to see some of the procedures taking place at the time. They heard how someone must come in to check on them every single day of the year, including Christmas Day, Boxing Day and bank holidays. We explained how we are studying these mice to discover the function of every gene in the mouse genome, as part of the International Mouse Phenotyping Consortium (IMPC)

Next, they had a tour of our research facilities, based in the Mammalian Genetics Unit. Here, they saw the other side of our research - analysing how genes are involved in diseases such as type 2 diabetes, sleep disorders and various forms of deafness. They got to get a feel for what it's like to be a medical researcher in our visitors' lab, where we set up an activity where they had to use gel electrophoresis to separate out DNA fragments and work out which children had inherited the gene for Huntingdon's disease from their parents. Although these weren't real patient samples, this is a very commonly used technique in genetic research and is also used in genetic testing for patients. It gave them the chance to see what it's like to work in medical research, and how improving our understanding of our genes can help to give patients the information they need to make life-changing decisions.

It was great to welcome such an enthusiastic group of students for the day. We hope that the experience will have informed their view of animal research, helping them to understand what is is we do and why it is so important for improving our understanding of genetics in mammals, advancing healthcare and providing better treatments.

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Diamond Light Source open days

MRC Harwell was at Diamond Light Source's open days this weekend, 14-15 March 2015, talking about the work we do at Harwell Campus and it's impact, including Dr Mary Lyon's work on X-inactivation.

The Diamond Light Source synchrotron is one of the first things that you see as you turn into Harwell Campus, and it is quite a sight. The huge, donut-shaped building is designed to accelerate tiny, sub-atomic particles called electrons around in a loop. Rooms known as 'beam lines' radiate out from this central circle, stationed so that they can use the 'light' given off by these electrons as they whizz around it. This light isn't visible light, but other parts of the electromagnetic spectrum such as X-rays or infrared. Diamond hosts an eclectic mix of research into diverse applications, covering almost all areas of science - one beam line could be used for deciphering the structure of proteins, another for investigating the materials in an archeological artifact, yet another for designing new materials to improve solar power, and so on. Rolls Royce even donated an aeroplane fan blade they used the synchrotron to design, which Diamond now keep on display as a statue.

For the weekend, Diamond opened its doors to the public. Visitors entered into the entrance foyer, which was lined with stalls such as ours. At regular intervals during the day, they were invited to attend a 40 minute talk on Diamond Light Source, which as 2015 is the International Year of Light, included a short history of research into light. After this, the visitors were taken on a guided tour of the facility, complete with enormous magnets, vacuum pumps and lead-lined rooms. In between the tours, visitors moved around the stands, allowing them to find out more about applications of the technology at Diamond and other research going on at Harwell Campus.

Our stand was based around the work of Dr Mary Lyon, who used to work at MRC Harwell. She proposed the theory of X-inactivation, which revolutionised our understanding of how genes are inherited in female mammals. As females have two X- chromosomes, while males only have one, one of these is switched off at an early stage in development to prevent females from having a double dose of these gene products. However, this process is random, so is different in different cells. As these cells grow, they develop into patches, meaning that all female mammals are 'mosaics', with different X chromosome gene expression in different parts of their body. We illustrated this with the classic example of the tortoiseshell cat.

These open days provided us with a wonderful opportunity to discuss our research with the public, particularly adults from other scientific disciplines whose only knowledge of biology came from their half-remembered school days. It was great to join together with one of the most influential organisations on campus to deliver our public enagagement, something which we will be doing again on a much larger scale at the Harwell Campus open day on the 11th July. We hope you can come!    

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Oxfordshire Science Festival 2015

We were in Oxford’s Bonn Square on Saturday 7 March, explaining how X-inactivation gives us tortoiseshell cats with colouring sheets and jigsaws!

 

Dr Mary Lyon, who first proposed her theory of X-inactivation while working at MRC Harwell, sadly passed away at Christmas. We therefore decided to base our stand at this year’s Oxfordshire Science Festival on X-inactivation, using the example of tortoiseshell cats. Our stand was part of ‘Science in Your World’, which ran from 10am to 4pm on Saturday 7th March. We had two main activities - a tortoiseshell cat jigsaw and a colouring sheet puzzle.

X-inactivation occurs in all female mammals. As they have two X chromosomes, they are at risk of having a double 'dose' of these gene products compared to males. To prevent this, one of the X chromosomes is inactivated early in development, effectively switching off the vast majority of genes. However, which of the two chromosomes is inactivated is random, and is different for each cell in the early embryo. As this ball of cells develops, the original cells give rise to patches. All female mammals are therefore 'mosaics', with different X chromosome genes active in different parts of their body - as you can see with the orange coat gene in tortoiseshell cats. And once this X-inactivation has happened, it lasts for the animal's entire life.   

For the jigsaw, we had two bags of plastic Xs and Ys, one for each parent. First, we asked them to pull out one sex chromosome out of the 'Mum' bag and one out of the 'Dad' bag, and we asked them whether they thought the kitten was a boy or a girl, and what colour it would be. They tried this until they pulled out an orange X and a black X, the ingredients required to make a tortoishell cat. They then got to have a go at the jigsaw, turning over each part to find out what colour it would be and placing it in the correct position. No two cats made during the day were the same, showing how the process of X-inactivation 'turning off' the orange coat colour gene on the X chromosome in different cells is random. Later in the day we could even show all of the other cats people had made, so they could see how each and every tortoiseshell cat was different.

The colouring sheets gave them a problem to solve - if you have a Dad cat who is orange and a Mum cat who is black, what colour will the kitten be? There were two sheets, one where the kitten was a boy and one where it was a girl. We helped them work it out, starting by showing the parents' sex chromosomes would be and getting them to work out what the kitten's ones would be. This led them to the answer of either a black male cat or a tortoiseshell female cat, which they used to colour in the cat outline.

When we asked if they'd ever seen a tortoiseshell cat, lots of children said their cat was one. This provided a great lead-in, as we could ask if it was a boy or a girl. They always said it was a girl, allowing us to explain why tortoiseshell cats are nearly always female. However, one man did raise the point that in very rare cases you can get an XXY cat, which would mean a male cat could have a tortoiseshell coat! This led to talking about Mary Lyon's work and how X-inactivation gives us a better understanding of X-linked diseases like haemophilia and Duchenne Muscular Dystrophy.

It was a great day, with both families and adults trying the puzzles and asking some excellent questions. Thanks to all those who came along and took part!

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Learning the art of cryopreservation

Last week, from the 2-5 March 2015, participants came to MRC Harwell to take part in our Mouse Embryo and Spermatozoa Cryopreservation training course, a technique in which we have particular expertise. 

Our extremely popular Mouse Embryo and Spermatozoa​ Cryopreservation course ran this year from 2-5 March. This three and a half day long course is intended to give animal technologists practical, hands-on experience of murine embryo and spermatozoa freezing techniques routinely used at MRC Harwell, as well as a simple, robust in vitro fertilization procedure. It led by MRC Harwell’s Frozen Embryo and Sperm Archive (FESA), part of the European Mutant Mouse Archive (EMMA), and is worth ten continuing professional development (CPD) points.

The course allows participants to gain experience of the entire process, including harvesting embryos and sperm, conducting IVF and transferring embryos into the female mouse. Participants learnt how to freeze sperm and embryos in liquid nitrogen using plastic semen straws, gain experience of a straightforward and robust in vitro fertilisation (IVF) procedure, and watched a demonstration of how these embryos can then be transferred into recipient females to establish a new pregnancy. While embryos can be stored ready to use, sperm cryopreservation has the advantage that you can potentially recover over a thousand mice from just one male. The course included a dinner on the second evening, providing a great chance for everyone to get to know each other a little better

The course runs twice a year, and the next one will take place on the 21-24 September 2015. To register your interest in this course, please contact the course convenor Martin Fray (m.fray@har.mrc.ac.uk) or email training@har.mrc.ac.uk.

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IMPC article in 'International Innovation'

An interview with the chair of the IMPC, Professor Steve Brown, has been published in the science magazine International Innovation, a global dissemination resource that provides insight and analysis on current scientific research trends. In the article, he explains the consortium's achievements to date, our intentions for the future, and why it will be an unparalleled resource for research into mouse genetics and human disease. You can read the full article in the attachment below.

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New ALS mouse model discovered

Dr Acevedo-Arozena led research on a mouse with the same mutation as a familial form of amyotrophic lateral sclerosis, which may provide new insights into the how the disease develops.

Indicators of neurodegeneration (red, green) seen in the lumbar spinal cord of 52 week old Sod1 mutant mice.

Amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, is a neurodegenerative disease that affects motor neurons. It causes muscle weakness and paralysis, and gradually worsens over time, typically lasting for around three to five years before death. People with ALS have a weak grip, difficulty moving and walking, and problems breathing and swallowing. The condition worsens over time, and there is no cure.

A newly discovered mouse line, which shares the same gene mutation as found in a type of ALS, has been described for the first time by a team led by Abraham Acevedo-Arozena together with collaborators from the UCL Institute of Neurology. It provides a new mouse model for ALS research. Their findings are published in Human Molecular Genetics.

Familial ALS accounts for around 10% of all cases, caused by gene mutations that can be inherited. Mutations in the gene for superoxide dismutase 1 (SOD1) are known to cause a large proportion of these familial ALS cases, and some research has indicated that defects in SOD1 may also underlie other forms of sporadic ALS. Normally, the main function of SOD1 is to remove superoxide radicals, preventing their accumulation from causing oxidative damage to the cell. However, the mutant variety of SOD1 takes on a new, toxic function that ultimately leads to the death of the motor neurons that control muscle movement.

While there are already numerous mouse models of SOD1 ALS in existence, all overexpress the human gene, producing excessive amounts of the mutant protein. Yet overexpression of the non-mutant SOD1 gene can result in an ALS-like syndrome. This raises concerns about whether the neurodegeneration and other effects seen in these models are actually due to the mutation, or just the fact that the gene is overexpressed.

The aim of the researchers was to create the best possible model of SOD1 ALS. They identified a mouse line with a chemically induced point mutation in the mouse gene Sod1, and found it to be exactly the same as one seen in patients with a type of familial SOD1 ALS. As the mice aged, they developed signs of reactive gliosis (an indicator of damaged neurons), gradual degeneration of their motor neurons, and a loss of nerve contact with muscles in the hind limbs. The mice lost grip strength, developed tremors and an odd gait, and become severely hunched as their back muscles weakened. However, mutant mice do not progress to end-stage disease, and therefore do not become paralysed. The researchers also found indicators that the mitochondria in their motor neurons were malfunctioning, often considered an important factor in the development of ALS in patients.  

This is the first mouse model described that has the equivalent of a human ALS mutation in the mouse Sod1 gene. It provides a new model, which can be used to study the early stages of ALS and develop new treatments to reduce the burden of this terrible disease.

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Down’s syndrome sleep disturbances in mice

Disrupted sleep patterns are a common feature of Down’s syndrome. New research by Pat Nolan’s group shows this is shared by Tc1 mice, providing a model for future studies. Image credit: Wellcome Images.

Down’s syndrome is an extremely debilitating condition, caused by the whole or partial presence of a third copy of chromosome 21. It affects about 1 in 700 babies born, and comes with a whole host of health issues, including intellectual disability, early onset dementia and heart and gut problems. A less well known feature of Down’s syndrome is an unusual sleep pattern - patients with Down’s syndrome tend to be sleepier during the day, wake more during the night and take longer to get to sleep.

While there are many mouse models of Down’s syndrome, none fully replicate all of the symptoms, so different models are used to study different aspects of the condition. Pat Nolan led research at MRC Harwell and the Nuffield Department of Clinical Neurosciences, published in Genes, Brain and Behavior, to investigate whether the Tc1 mouse model could be used to study these sleep disturbances.

The Tc1 model is trans-species, expressing most of human chromosome 21, which adds to the two copies of the equivalent chromosome that mice already have. It is the most complete genetic model of Down’s syndrome, with many characteristics of someone with the condition, including learning and memory problems. It also avoids the confounding issue found in other models of additional, irrelevant chromosome regions also being duplicated. However, no one had looked into whether Tc1 had unusual sleep patterns.

The researchers used two complementary methods, circadian wheel running and video tracking, to monitor a group of male Tc1 mice and compare their behaviour to a set of ordinary male mice. The circadian wheel method tracks when they are running on their wheel and uses this as measure of their activity, whereas video monitoring tracked when they were immobile and took this as a measure of sleep. During circadian wheel running,  mice were monitored during a normal day/night cycle of 12 hours light and 12 hours darkness, followed by 12 days of constant darkness and 14 days of constant light, whereas for video tracking mice were tracked for one normal day/night cycle and one day in constant darkness.

Mice are nocturnal, so naturally sleep more during the day and are more active at night. During the night, the Tc1 mice displayed an initial period of total hyperactivity, barely stopping at all for the first six hours and had a lower number of sleep episodes (our equivalent of a nap) during their active phase. When the researchers later added a 3 hour pulse of light in the middle of the night, which normally triggers sleep, they found it had little effect in inducing sleep on the Tc1 mice - they stayed active and took much longer to settle down and go to sleep.

Taken together, these findings point towards Tc1 as a model that could prove extremely useful for future research into the sleep patterns of those with Down’s syndrome, helping us understand why so many people with the condition have trouble getting a good night’s sleep.

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MRC Mouse Network Meeting 2015

Our annual MRC Mouse Network Meeting was held at The Westminster Conference Centre in London on the 23 January 2015. Every year, network members meet to hear about the latest IMPC developments at MRC Harwell. The day included updates from MRC Harwell on mouse line availability, production and phenotyping, as well as presentations by mouse network members, a poster and networking session, and talks on the future of the IMPC and our planned developments at MRC Harwell. It is an exciting time for the IMPC, with over 1,500 lines now phenotyped and big plans being put in place for Stage 2, and it was great to catch up with mouse network members from all over the UK.

Members who could not attend the meeting can download the agenda and slides on our MRC Mouse Network Meeting 2015 page. 

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