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A taste of our apprenticeships

As part of Science Oxford’s ‘STEM World of Work Programme’, on the 24 August 2015 we hosted a student interested doing an apprenticeship for a week so she could get a taste of what it’s like. 

MRC Harwell welcomed our first Science Oxford apprenticeship placement student, Chloe Manning from Wood Green School in Witney, on the 24 August 2015 for a week. Chloe gained a valuable insight into what it’s like to be a laboratory technician apprentice at MRC Harwell, and says her experience has made her want to come back during October half term.

The placement is part of Science Oxford’s STEM (science, technology, engineering and maths) World of Work Programme, which in partnership with Oxfordshire County Council is seeking to provide young people in Oxfordshire with information and opportunities on careers in their local area. One way they are doing this is to set up STEM apprentice placements, which enable 17 year olds considering an apprenticeship gain experience at a local organisation during their summer holiday. It’s a great chance for them to see if an apprenticeship in a STEM career is right for them.

During her time at Harwell, Chloe learnt many of the bread-and-butter techniques that are vital for our research. These included making up agar plates and buffer solutions, autoclaving glassware, using a microtome to slice up tissues embedded in paraffin wax, light and confocal microscopy and setting up Polymerase Chain Reaction (PCR). She was particularly intrigued by the robot arm we use to set up PCR plates, which can be pre-programmed for mass pipetting.    

As well as trying out these techniques herself, she got to see how and why they were used. On the Tuesday, she had a trip out to see how the microscopy she had learnt about were used for research at Rutherford Appleton Laboratories, just down the road from us. Chloe’s final day was spent in the Mary Lyon Centre, which houses our animal facilities. After she had changed into scrubs and passed through the air shower, to prevent the entry of any potential disease-causing agents, she was taken on a tour, where she got to see how the mice are kept.

Chloe says she really enjoyed her week at Harwell, and is looking forward to coming back. This has been the first time we have hosted one of these apprenticeship placements, and since it was so successful we hope it will provide a great taste of our apprenticeship scheme for others in the future.

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Discussing diabetes at Diamond open day

On 26 August 2015, we joined up with Diamond Light Source to discuss our research into hearing loss and type 2 diabetes. Our activity ‘Just a spoonful of sugar’ definitely had a few surprises!

We regularly team up with Diamond Light Source during their open days to showcase our work and highlight our collaborative projects. As visitors enter, they are met with a selection of stands where they get a flavour of the work done at Diamond and the wider campus. They then hear a lecture about the facility and are taken on a tour. This year our stand revolved around two big challenges currently facing medicine; antibiotic resistance and the rise in type 2 diabetes.

Type 2 diabetes is a growing problem in the UK - there are currently 3.9 million people with diabetes, double what it was in 1996 and estimated to rise to five million by 2025. Type 2 diabetes is most common in old age, and is due to an inability of the body to control sugar levels, either because the body does not produce enough insulin or because the person’s cells stop responding to it. The rise in cases of type 2 diabetes is thought to be partly due to an increase in unhealthy diets.

We were interested in whether visitors were aware of how much sugar there was in their diet, as in the UK we’re eating and drinking far too much of it. To illustrate how important it is to keep a careful eye the amount of sugar in our diet to prevent type 2 diabetes or keep it under control, we laid out a selection of foods with their sugar content represented in sugar cubes, hidden in front of each item. We asked them to pick an item, guess how much sugar they thought it contained, and lift up the cover to see if they were right.

Considering that the recommended amount for an adult is 30g per day, about 7 sugar cubes, the results were quite shocking. A 500ml bottle of coke had double this, nearly 14 cubes, while a 125g Galaxy bar had 15 cubes. Possibly more worrying was the ‘hidden’ added sugar in places where you wouldn’t necessarily expect it – 7 cubes in a 500g jar of pasta sauce, nearly 3 cubes in a reduced-fat yogurt, and a staggering 18 and a half cubes in a 1.5L bottle of Volvic touch of fruit flavoured water, something that many visitors thought looked quite healthy. It was easy to see how so many of us are going so far over the recommended sugar limit each day.

At the other end of the stand, we had a researcher talking about his work on otitis media, a very common condition in children that causes inflammation inside the ear. It is the most common reason for a child to visit their doctor in the UK, who normally prescribe antibiotics, and in severe cases can require surgery. If these cases are left untreated, it can cause hearing problems and delay language development. With the rise of antibiotic resistance, where bacteria are no longer killed by antibiotics, there is an urgent need to find alternative treatments for otitis media. Using our model ear, he spoke about the possible alternatives we’re investigating, including antimicrobial peptides, which we’re looking into in collaboration with researchers at Diamond.

It was a great day, and we had a lot of interest from the visitors, with some excellent questions. It would be interesting to know if they changed their eating habits when they got home!

MRC Harwell ‘trailblazer’ for apprenticeships

MRC Harwell has been chosen to design the blueprint for two new biotechnology apprenticeships, as part of a Government initiative to provide 3 million new apprenticeships by 2020. 

In the past, apprenticeships have varied greatly in quality, and were generally set up by schools and colleges. This meant that apprentices did not always leave with the skills that employers seek.

To address this issue, the Government has chosen 26 new Trailblazer groups to lead the development of a new set of standardised apprenticeships. This will help to ensure that apprentices gain the skills that employers look for, ensuring more apprenticeships can deliver their goal of increasing employability. The apprenticeships developed by these Trailblazers will provide the blueprint for other employers across the UK to adopt, helping the Government to meet its target of creating 3 million new apprenticeships by 2020.

By becoming a Trailblazer employer, MRC Harwell will establish two new standardised apprenticeships - a Licenced Animal Technician and a Named Animal and Welfare Officer – after discussion with around 20 other organisations working in the field. We have already seen success with our animal technician apprenticeship, and becoming part of this scheme will allow us to build upon this success. As the champion for the biotechnology sector, we will play a key role in defining the shape and structure of future apprenticeships in the field. 

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Phenoview: a new tool to compare IMPC data

The IMPC has developed a new, innovative way to display data so that you can compare knockout mouse lines for different genes that share the same trait, or all phenotypes for one gene.

‘Data is only as good as the tools available to analyze it.’ So starts the latest paper from the International Mouse Phenotyping Consortium, which is aiming to create a catalogue of mouse traits that shed light on the functions of 20,000 mammalian genes. Published in Nature Methods, Gagarine Yaikhom and the other authors from MRC Harwell’s Biocomputing team describe their latest tool, designed to maximise the potential of IMPC data – Phenoview.

Phenoview has been specially developed for the IMPC, and is therefore carefully tailored to make sifting through, viewing and comparing large swathes of genotype-phenotype data as effortless as possible. It is publically available and can be accessed via the sidebar of the IMPC website.

The first thing you see as you enter Phenoview is a heatmap. This huge grid gives an overview of all IMPC results, with phenotyping tests listed down the side and the genes laid out along the top. There are many additional features; for example, you can choose to only see results from certain centres, adjust the statistical stringency using a slider scale, or just show significant results. There are two ways of finding data – either browse for genes of interest by selecting the genes, procedures and parameters you are interested in from the relevant lists, or use the search box to go straight to the results for a specific gene.

By selecting the genes and parameters you are interested in, you can then add them to the basket, just like with online grocery shopping. Once you have all the data you need, you can then click ‘visualise’ to compare all of the results side-by-side. In most cases this is represented graphically, but for some, such as X-ray results, it is displayed as images – the appropriate method for each test is chosen automatically.

This mix-and-match approach means you can easily investigate the data you care about, see for yourself how strong a phenotype is in that line, compare the data for multiple lines and choose the appropriate knockout mouse lines for your research. It enables you to filter out the relevant IMPC data, whether it be genes for a particular phenotype, or phenotypes for a particular gene. And if you want to delve even deeper into the data, it is also possible to download the raw results.

The beauty of Phenoview lies in its apparent simplicity, yet it covers a massive amount of data and still allows in-depth investigation. As the IMPC accumulates ever more data, this tool will allow researchers to find the connections between genes and phenotype they require with ease. 

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EUMODIC: paving the way for the IMPC

The European Mouse Disease Clinic was the first mouse genetics project of its kind, and set the stage for an international effort to investigate the functions of 20,000 mammalian genes.

Sequencing the human genome was an enormous achievement, but it was just the start. The functions of most genes still remain unknown, so the next big challenge is to be able to understand how this DNA code makes us who we are. What exactly do these genes do, and how do faults in our genes lead to disease?

One of the best places to start to understand our own genetics is by investigating the mouse genome, since mice share over 90% of our genes. The European Mouse Disease Clinic (EUMODIC), a consortium set up in 2007, brought together scientists from many nations to investigate the functions of over 300 genes in mice. Over half of these genes had no previously known role. The consortium’s findings have now been published in Nature Genetics.

EUMODIC was the first step along the way to creating a database of all mouse gene functions, a vision now being realised by the International Mouse Phenotyping Consortium (IMPC). Covering 20,000 genes, carried out by 18 centres from across the globe and estimated to take 10 years, this enormous research endeavour is taking the groundwork established by EUMODIC to an entirely new level.       

Laying the foundations

In order to study gene functions, the EUMODIC consortium produced mouse lines which each had a single gene removed. They could then assess the traits of these mouse lines, using a specially developed set of tests, to deduce what the  role of the missing gene would normally be. In total, 449 lines were produced and data obtained on the functions of 320 genes.  

This was the first time such a project had been attempted on this scale, with multiple centres in different countries. The consortium therefore had to establish their own standard set of procedures, a pre-defined language to describe their results, and a central database to store all of the data. This laid the foundations on which IMPC protocols and procedures were built.

Understanding our genetics  

The EUMODIC project was the start of an incredible journey to discover more about the functions of our genes and how faults in our genes could lead to disease. It demonstrated how much can be accomplished by individual centres joining forces to achieve a common goal, and set in place the groundwork for IMPC to apply the same principles on an international scale.

Since all of the findings from the project have been made publically available, and all the mouse lines stored in the EMMA biorepository, other scientists can use it to advance their own research. This will not only allow us to understand  genes we currently know very little about, but will also open up new avenues for research into the genetics of human diseases and potential treatments.    

EUMODIC leaves a legacy that will live on in the IMPC and in the resources it provided for science, and will be truly transformative for genetic and medical research.    

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Science Up Close at Harwell Campus

A busy week for Harwell Campus saw 1,600 school students visit the STFC on Wednesday 8 July 2015, the simultaneous opening of two new space centres by the European Space Agency and RAL Space on Friday 10 July, and culminated in 16,000 visitors attending the Harwell Campus Science Up Close open day on Saturday.

Science Up Close was the first event of this scale in over a decade on the Campus, and allowed visitors to learn about much of the research on site, from tours of the Diamond Light Source and STFC’s Central Laser Facility, to the opportunity to get up close and personal with a huge cast of a Gorgosaurus dinosaur skeleton or taste samples of ice cream snap-frozen using liquid nitrogen. MRC Harwell was present at the schools event on Wednesday and the Open Day on Saturday, demonstrating aspects of our work for the public.

On Wednesday a group of our PhD students ran a workshop at the Research Complex at Harwell (RCaH) for two groups of 20 A-Level pupils. The pupils took part in our Diagnosis DNA activity, first pioneered at the British Science Festival last September. After loading their agarose gels, the pupils waited for the gel electrophoresis experiment to run so they could diagnose which children in our fictional family had inherited their father’s faulty copy of the Huntington’s gene. Whilst they waited to see the results, we carried out the ever-popular strawberry DNA extraction procedure with them, answered their questions, and discussed their potential career choices. We were impressed by how intelligent the questions we were being asked were, although it did mean we had to answer some of them with “let’s Google that”! The feedback from the schools was equally pleasing, with one pupil saying that the event had “actually made me rethink my future”.

The main event of Science Up Close was undoubtedly the open day on Saturday. Of the 16,000 members of the general public who came along to the campus to see what the resident scientists were up to, around 1,500 made their way to the RCaH lobby, where MRC Harwell volunteers awaited. Here, we ran a stand with two main activities: a jigsaw puzzle to explain the work of Mary Lyon, and a variety of sand-filled plastic fruits which we used to demonstrate the weight of certain animals' brains. Did you know that the brain of a dolphin weighs about the same as an adult human’s brain, and that both weigh the same as a pineapple? The tortoiseshell cat puzzle was particularly popular once again, and visitors also thought that “it was great to see so many women in science”.

Of both events, Nanda Rodrigues said “it was fantastic to meet such enthusiastic members of the public and young people who wanted to pursue science as a career”. 

 
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Discussing cilia research with PCD patients

On 6 June 2015 Dominic Norris spoke to a support group for Primary Ciliary Dyskinesia, a genetic disorder of cilia, about a link between cilia and a reversed organ arrangement.

Dominic Norris, the leader of our cilia, development and disease research group, spoke to a room full of patients and their carers on 6 June at the annual general meeting of the Primary Ciliary Dyskinesia (PCD) Family Support Group. His talk focused on the role of cilia in defining the arrangement of our internal organs, and how this process can be disrupted in PCD patients.

Motile cilia are tiny, hair-like structures that protrude from many different cell types. Their roles vary, but probably the best known example is the ‘muco-ciliary escalator’ – the movement of mucus and any debris caught in it out of the lungs by the sweeping motion of the cilia that line the airways.

PCD is a rare inherited disorder caused by dysfunctional motile cilia. This means patients have trouble clearing their lungs, ears and sinuses, making them prone to recurring bacterial infections. If left untreated, chest infections can lead to a type of severe lung damage known as bronchiectasis. They may also have fertility problems, and around half have ‘situs inversus’, where the internal organisation of the left and right sides of the body are the opposite way around to normal.

While the human body is largely symmetrical, there are certain organs that have a preferred orientation. In those with situs inversus, it is as if a mirror was held up to the body - the heart, for example, is over to the right rather than its normal position on the left. Perhaps surprisingly, this total reversal of a person’s organ arrangement causes few problems, and accounts exist of the condition only being discovered during an X-ray, operation or post-mortem.

Situs inversus is the result of cilia malfunctioning during the third week of embryonic development. A small dimple forms at one end of the embryo, known as ‘the node’, filled with cilia. These cilia normally swirl around in a circular movement, driving a leftward flow across the node, which is detected by cells around the rim. This leads to differences in gene expression on the left and right side of the embryo, resulting in the baby being born with a normal organ arrangement. In PCD patients these cilia are faulty, meaning the flow is disrupted, which leads to situs inversus 50% of the time.

Dominic spoke about this link between PCD and situs inversus, and how his team investigate the genes involved in this process of left-right patterning by studying it in mice. The session went down well with the audience, with the majority saying they found it interesting, useful and informative.

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Conditional transgenesis training course

We ran our Conditional Transgenesis training on 8 June 2015, which introduced participants to the key concepts for work with mouse lines in which genes can be temporally or spatially modified.

Being able to inactivate a gene and see the effect in a living mouse is remarkable. Yet global inactivation of a gene in every gene in the body is a blunt tool and can pose problems such as lethality and viability. This is why we have set up a new one day training course to teach participants about more refined conditional transgenesis methods.

For example, if you are a researcher interested in a gene essential for embryonic development, total inactivation may be lethal, but you might want to study the gene’s role in the adult. Using conditional techniques, you can selectively modify the gene later on in life, once the mouse is fully grown, or limit the inactivation to a particular cell-type or organ.

The best known of these techniques is the Cre-lox system. In this case, a mouse line is bred so that it the gene of interest flanked by two lox P sites. These sequences and the targets of action for the enzyme Cre recombinase, which can be expressed specifically in an individual cell-type or induced at a specific time point (e.g. in the adult). The action of the Cre recombinase results in the loss of the sequence between the lox P sites, and therefore gene modification, in the target tissue or at the target time.

The course was aimed at PhD students and early career postdocs, and was intended as an introduction for those just beginning to use these techniques. It included an overview of a variety of conditional mutagenesis techniques, the challenges associated with them, the generation and breeding of conditional mutant mouse lines, and a workshop on designing experiments with conditional mutant mouse lines. The course was limited to around 20 participants for the workshop in the afternoon, which was based on what the participants had learnt in the morning.

Overall, the course went down very well, with 18 of the participants saying they would recommend it to others. Due to the popularity of the course, we are investigating the possibility of running it again. For more information on this course and others, please email training@har.mrc.ac.uk or view our full range of training courses on the training section of our website.

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IMPC embraces ethical guidelines

The ARRIVE guidelines, developed in 2010, aim to assure reproducibility and transparency in animal research. The IMPC reports on how it ensured it meets them.

Reproducibility is fundamental to the success of scientific experimentation – the results of an experiment can only if be considered sound if they can be reproduced. Where animals are concerned, this is a particularly pressing issue. Solid science is based on sound ethics, and good experimental design leads to a reduction in animal numbers and improved animal welfare.

The Animal Research Reporting of In Vivo Experiments (ARRIVE) guidelines, created by the National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs), provide a checklist of 20 items that scientists use ensure their experiments are designed correctly and to report the details other scientists would need to obtain the same results.

The ARRIVE guidelines were originally intended for those seeking to publish their findings in a peer-reviewed journal, but they can also be applied to large-scale databases. The International Mouse Phenotyping Consortium (IMPC), which is phenotyping over 20,000 mouse lines, follows these guidelines in the interest of maximising the transparency and reproducibility of their data. A detailed account of how is published in PLOS Biology.

The consortium members began by distributing a survey to all of the IMPC centres, helping them assess how each centre carried out the experimental procedures. All details on how the data was obtained, such as the allele structure used and the genetic background of the mouse, were made available for download from the IMPC web portal.

IMPC created a standardised language for key terms so that all centres could describe phenotypes in the same way. This allows cross-comparison of the data. They designed bespoke software packages for collecting IMPC data, and carrying out statistics to shed light on human disease. These measures ensured the IMPC’s work is in line with the ARRIVE guidelines.

By following the ARRIVE guidelines, IMPC is doing all it can to remain a trustworthy, reliable source of phenotyping information for years to come.

Karp NA, et al. (2015) Applying the ARRIVE guidelines to an In Vivo database. PLoS Biology. DOI: 10.1371/journal.pbio.1002151

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Steve Brown made a Fellow of Royal Society

Professor Steve Brown was elected a Fellow of the Royal Society on 30 April 2015 for his work in mouse genetics. 

The Royal Society was founded in 1660 and is the oldest scientific academy in continuous existence. It is a fellowship of the world’s most eminent scientists and aims to recognise, promote and support excellence in science. Election as a Fellow of the Royal Society recognises the achievements of those who have made an exceptional contribution to science.

Each year, up to 52 new fellows are elected by the Royal Society from around 700 candidates. They join around 1,600 fellows and foreign members, including 80 Nobel laureates. Past Fellows of the Royal Society have included many extremely influential scientists, such as Isaac Newton, Charles Darwin, Ernest Rutherford, Albert Einstein, Dorothy Hodgkin, Francis Crick and James Watson. Current Fellows include Stephen Hawking, Tim Berners-Lee and Paul Nurse.

Professor Steve Brown, Director of the Mammalian Genetics Unit at MRC Harwell, has now been elected a Fellow of the Royal Society for his pioneering work in mouse genetics and genomics. More information can be found on his page on the Royal Society website.

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