PhD opportunities in 2017
There are four vacancies available at the MRC Harwell Institute for 4 year MRC funded PhD/DPhil Studentships starting in October 2017.
The MRC Harwell Institute 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.
There are several research themes offering PhD projects at the MRC Harwell Institute for 2017:
- Genetic basis of type 2 diabetes
- Genetics of circadian rhythms and sleep in health and disease
- The genetics and pathology of deafness
- The role of cilia in development and disease
- Disorders of sex development
- Bioinformatics of mouse models of disease
- Statistical genomics
- Investigating Novel Stress Response Pathways in Neurological Disease
- Novel and bespoke mouse models for dissecting neurodegenerative disease
Click here for more information and details about how to apply.
Closing date Tuesday 7th February.
Royal Society hosts tribute to Mary Lyon
In tribute to the eminent geneticist Mary Lyon and her role in developing the theory of X chromosome inactivation, a process implicated in disease inheritance, 100 researchers from nine countries attended a scientific meeting hosted by the Royal Society. As part of the event researchers attended a one day meeting at the MRC Harwell Institute where Mary developed her theory. The event brought together worldwide experts in this dynamic field to discuss the latest research advances and reflect on the life and work of Mary Lyon, who first proposed the theory of X chromosome inactivation 55 years ago.
The meeting marked the opening of a brand new Mary Lyon exhibition at Harwell. The exhibition includes a timeline of Mary’s life surrounded by panels exploring her education, career at Harwell, and major discoveries. A map of the world pinpoints the many places she visited during her career, bringing to life her global network of researchers.
Mary’s career at Harwell spanned a period of more than 50 years and it was during this time that she made many remarkable discoveries. Mary developed the theory of X chromosome inactivation in 1961 while studying mice with different coloured patches of fur. She hypothesised that one of the two X chromosomes in the cells of female mammals is randomly inactivated during early development so that females don’t have twice the number of X chromosome gene products as males, a potentially toxic double dose. Her hypothesis, now accepted and supported by subsequent research, has had profound implications in understanding the genetic basis of X-linked diseases as well as being one of the first descriptions of epigenetic phenomena.
Mary went to Cambridge in the early 1940s, at a time when women were not official members of the university. Despite taking the same courses as men women were awarded a ‘titular’ degree. In 1998 Mary and other women from her era were officially awarded a full undergraduate degree. WW2 served to change the position of women in the world and had a strong influence on Mary’s career. Much of her research involved looking at the effects of radiation in mice as result of the events of WWII. Most of the important discoveries Mary made were offshoots of studying radiation induced mutations in mice.
Speaking at the event Dr Sohaila Rastan, one of Mary’s PhD students commented: “Now 55 years after the hypothesis was first described, Mary Lyon would have found it very gratifying to see how much research it has spawned. Although the X inactivation field has advanced so significantly some basic questions still remain unanswered.”
Professor Steve Brown, Director of the MRC Harwell Institute, said: “Mary would have relished the cut and thrust of the scientific discussion at the meeting, and would have joined in the excitement of the many new developments that were reported. She laid the groundwork for all that has followed, and the meeting was a fitting tribute to her scientific legacy.”
Age-related disease genes discovered
In the first ever study of its size, scientists at the MRC Harwell Institute, led by Paul Potter, have conducted a large-scale genetic screen in mice to discover genes involved in
age-related disease. The findings so far have been published in Nature Communications.
Advancing age is a risk factor for many diseases. As we get older the risk of getting dementia, diabetes, and cardiovascular disease increases, and we are also more likely to experience other health problems such as age-related hearing loss. As the age of the UK population continues to rise (1 in 3 babies born in the UK in 2013 are expected to celebrate their 100th birthday) it is increasingly important to devise new therapies and approaches to treatments. Our genetic makeup is known to play a significant part in susceptibility to age-related disease – yet very little is known about these underlying genes.
What was done
In order to identify novel genes and biological pathways associated with age-related disease, changes or "mutations" were introduced into the genomes of mice. The mice were then aged and regularly screened throughout their lives to find any effects of the genetic mutations. Phenotypes or characteristics detected after 6 months were identified as late-onset phenotypes and therefore may be related to ageing. Once a phenotype was found whole genome sequencing was carried out to pinpoint the gene responsible.
What has been found so far
To date, 27 late-onset phenotypes have been identified across a wide disease spectrum. Of these, the responsible defective genes have been found in 12 cases. Already this research has led to some interesting findings. Ageing the mice has revealed phenotypes and genes which would not have been seen otherwise.
Slc4a10 – a novel late-onset hearing loss gene
One example of a novel gene that has been uncovered, and a highlight of the screen so far, is the gene Slc4a10. Late-onset hearing loss was seen in mice which had a mutation in Slc4a10. In humans, very little is known about what causes this type of hearing loss. Impaired hearing was seen in mice at 9 months, it was then further impaired at 12 months, suggesting a progressive late-onset phenotype.
The expression of the Slc4a10 gene was localised to a specific part of the inner ear. On closer examination, it was found that the surface area of the stria vascularis was significantly reduced in mice with the mutation. The stria vascularis is important for maintaining ion concentration in the fluid of the inner ear, and this ionic balance is critical for auditory transduction – the process of turning sound vibrations into electrical signals. This gene had not been previously related to hearing loss in mice or humans and may provide a new insights into how this gene is involved in hearing.
Why is this study important?
The Slc4a10 findings illustrate how a large-scale screen can be used to uncover and characterise novel genes related to ageing. Many other genes have been found and further investigations begun.
The genomes of mice and humans are remarkably similar, sequencing of the mouse genome so far has found that we share 99% of our genes with mice. This study is a vital springboard for a better understanding of the genes in humans which may be involved in these diseases. It will enable new and more accurate preclinical animal models of late-onset human disease to be developed, which more closely resemble diseases in human patients. Several of the genes identified in this programme are now being studied in humans.
This study has also prompted a late-onset screen to be done by the International Mouse Phenotyping Consortium (IMPC). The IMPC aims to remove (knock out) every single gene in the mouse genome and phenotype the mice to produce a comprehensive catalogue of gene function.
Professor Steve Brown, Director of the MRC Harwell Institute, commented: “For the first time, we have been able to use the mouse to shed light on the diverse set of genes involved with late-onset disease in the human population. The work demonstrates that there is much that we don’t know about the genetic basis of late-onset disease, but the models that we have generated and the genes that we have identified are providing a powerful insight into disease mechanisms that will ultimately improve the prospects for new therapeutic interventions.”
This story has also been reported on by the MRC.
Diabetes gene mechanism discovered
Dr Roger Cox and colleagues at MRC Harwell have uncovered a new mechanism for how the diabetes gene SOX4 may be working, revealing a potential new therapeutic target for diabetes therapy.
Normally, after you have eaten a meal or sugary food the levels of sugar or glucose in your blood increase, this stimulates release of the hormone insulin which allows cells in the body to absorb this glucose and use it for energy, or store it for future use. Type 2 diabetes can occur when there is reduced insulin secretion in response to these increased glucose levels. Type 2 diabetes typically affects older people, but it is increasingly becoming common in younger people and has been associated with obesity.
Large scale genomic studies looking for common gene variations across lots of people have helped to identify many regions in our genome which may be involved in increasing the risk of type 2 diabetes, one of the genes in these regions is SOX4. In new research published in Diabetes, scientists at MRC Harwell and the Oxford Centre for Diabetes, Endocrinology & Metabolism have revealed a potential molecular mechanism underlying one aspect of how SOX4 may be involved in the pathology of type 2 diabetes.
How insulin is normally released from cells
Ordinarily, insulin and other materials that need to be transported out of the cell are packaged into ‘granules’. When the granule makes contact with the outer surface of the cell, the two fuse together and a fusion gap or pore forms allowing the contents of the granule to exit the cell – this process is known as exocytosis. For effective ‘full fusion’ exocytosis the pore initially opens, rapidly expands, then after a short delay collapses after the cargo has been released. Sometimes this process does not work properly and the pore expansion is halted during the initial opening, it may then eventually close, this is known as ‘kiss-and-run’ exocytosis.
Investigating Sox4 in mice
The SOX4 gene codes for a transcription factor, a protein that regulates whether other genes are activated or not. Scientists compared exocytosis in mice which had the typical or ‘wild type’ gene with mice that had a mutation in the gene, an incorrect version. Cells with wild type Sox4 followed the typical pattern suggestive of full fusion exocytosis taking place. In comparison, in cells with mutant Sox4 the pattern suggested kiss-and-run exocytosis, in other words that fusion pore expansion was impaired.
Scientists then carried out a gene expression microarray to see what genes Sox4 is involved in regulating, most notably the gene Stxbp6, which has been previously linked to faulty fusion pore expansion in other cells. Analysis in rat cells found that in both mutant and wild type Sox4 cells there was also increased expression of Stxbp6, but that the effect was stronger in the mutant.
Investigating SOX4 in humans
Scientists then extended these findings to human cells. There was higher SOX4 expression in cells from donors who had type 2 diabetes.
Why are these findings important?
These findings together suggest that increased SOX4 expression leading to increased STBP6 expression may be causing impaired expansion of the fusion pore, and consequently be involved in reduced insulin secretion in type 2 diabetes. Uncovering this mechanism paves the way for new therapeutic targets to be explored, for example to promote full fusion and release of insulin.
MRC Festival 2016
As part of the MRC’s inaugural Festival of Medical Research, both of our units at MRC Harwell opened their doors to the general public on Saturday 18th June for a ‘Your genes and you’ open day.
“I have enjoyed expanding my knowledge on genes and getting involved with hands on activities” – just one of the comments we received at our first MRC Festival. The rain just about held off for a jam packed day of activities and tours. Members of staff from all areas of our institution got involved on the day and ran activities. Visitors had the opportunity to use complex microscopes, extract DNA from a strawberry, watch a laser in action, learn about the latest research at MRC Harwell, and much more!
The Mary Lyon Centre (MLC) ran tours of its world-class animal facility throughout the day giving visitors a rare chance to see how an animal facility is run. MLC staff also showcased a range of phenotyping equipment to visitors and talked to them in more detail about mouse welfare.
Visitors were able to learn about the techniques and procedures used to analyse genes and proteins during tours of our working laboratories, as well as speak to scientists in our histology and clinical chemistry laboratories.
Our colleagues from the Research Complex at Harwell (RCaH) joined us with some very sophisticated equipment, including a 3D printer. Visitors had a go at protein crystallisation and mapping the positions of molecules in a cell using super-resolution.
We were lucky to have some VIP guests attend, including the Mayor and Deputy Mayor of Didcot Steve Connel and Jackie Billington and the Didcot and Wantage MP Ed Vaizey. It was fantastic to have them attend and engage with them about the important research we are doing at MRC Harwell. In addition, Agnes Jawara from the organisation Understanding Animal Research attended, Agnes interviewed people before and after their tour of the MLC to see what their opinions of animal research were.
Watch this video to see some of the action from the day!
Cross word answers for lab book:
Scientists shed new light on organ positioning in early embryos
An international team of scientists from the UK, the USA, and Japan have revealed new aspects of how developing embryos establish a left and a right hand side.
While we are externally mirror symmetrical between left and right, our internal organs are asymmetrically positioned and patterned (the heart lies towards the left and the liver towards the right side of the body). This asymmetry is established between 19 and 22 days of development in humans, often before the mother even knows that she is pregnant. If this process goes wrong, it can lead to birth defects and is particularly associated with congenital heart disease. New research, published in the journal PLoS Genetics provides insight into how this process happens and the ways in which it can go wrong.
The earliest known event in mammalian left-right (L-R) patterning, surprisingly, is not an asymmetry in where a gene functions, but a physical flow of fluid (from right to left) within a short-lived pit in the embryo. This tear-shaped pit is known as the node. The direction of this ‘nodal flow’ determines which side of the embryo will develop as the left. This leftward 'nodal flow' is driven by the action of motile cilia, hair-like structures protruding from the cell surface within the node. Exactly how nodal flow is detected by the embryo remains unclear: we know that the cells directly surrounding the node (the crown cells) are required to detect nodal flow; that the crown cells must each have an immotile cilium and that they must contain the putative calcium channel protein Polycystin-2 (PKD2). Previously the research team implicated a second Polycystin protein, PKD1L1, in this pathway.
Describing these new findings, Dominic Norris, Programme Leader here at MRC Harwell explains, “Firstly, we have been able to define a genetic pathway in which each element represses the next. This controls the early steps of L-R patterning: ‘nodal flow’ represses the gene Pkd1l1, which in turn represses Pkd2; this represses Cerl2 which encodes a known repressor of NODAL signalling (an important pathway in development of the embryo). Secondly, we demonstrate that PKD1L1 (the protein which is encoded by the Pkd1l1 gene) can mediate a response to flow. Finally, we have shown that a portion of the structure of PKD1L1 that sits outside of the cell is critical both for detecting flow and for proper L-R patterning. Together, these exciting findings reveal a genetic pathway operating at the level of flow sensation and demonstrate that PKD1L1 is able to act to elicit flow-induced chemical signals, thereby supporting the ‘mechanosensation model’ of nodal flow sensation (i.e. that the force of fluid flow itself can be directly detected by the node crown cells during the establishment of L-R asymmetry)”.
This research has emerged from an international collaboration that has made it possible to combine genetics, biophysics, and structural biology. In the UK, Rohannah Hussain and colleagues at Diamond Light Source, the UK synchrotron science facility, made it possible to understand the nature of structural changes caused by a point mutation in PKD1L1. This work took place on Diamond’s Circular Dichroism beamline, B23. Surya Nauli and colleagues at Chapman University, USA, allowed the role of PKD1L1 in flow detection to be assessed in cells. Hiroshi Hamada and colleagues in Osaka, Japan, provided novel techniques that allowed the team to more precisely analyse ‘nodal flow’.
This work provides a greater understanding of how genes interact with a physical flow of fluid to reproducibly establish a left and right hand side in the developing embryo. This knowledge underpins our ability to understand how the process of L-R patterning can go wrong, leading to congenital diseases, including congenital heart disease.
Rodent Little Brother: A new way to study mouse behaviours
Scientists at MRC Harwell have been working closely with Actual Analytics, Edinburgh as part of the NC3Rs’ CRACK IT initiative to develop a novel system for studying the behaviour of mice in their home cage.
Mice are used widely in research because they are mammals and are similar to humans in the way their bodies function and the genes they carry. Genetically altered mouse models are commonly used to investigate central nervous system disorders such as autism and neurodegenerative diseases such as Huntington’s disease.
How mice are studied in the lab
Mice are social animals and typically in a laboratory setting they are housed in small groups where they carry out their daily activities such as eating, sleeping, drinking, and grooming. In these ‘home cages’ they can interact with each other and often establish social hierarchies. A range of different ‘phenotyping’ tests have been developed to study the behaviour of mice in a quantifiable way. These tests, however, usually involve placing a mouse in a novel environment and in social isolation, which act as stressors and may confound the outcome of a test. Some tests require longer periods of social isolation which can adversely affect the wellbeing of the mouse, and even influence disease progression. Central nervous system and neurodegenerative diseases are often characterised by multiple phenotypes that are present over longer periods of time and can impact on social behaviour.
Improving the science
Scientists at MRC Harwell have been working closely with a technical development team at Actual Analytics to test new software which is capable of tracking the movements of three individual mice in group housed conditions. This method of studying mice is minimally invasive, only the insertion of a microchip is required (similar to microchipping household pets). The home cage is then placed in the ‘Home Cage Analysis System’ (HCA). The cage is placed on top of a base plate resembling a chess board, each ‘square’ connects to an antennae which can detect the movement of the microchipped mouse in that area. An infrared light source and camera is also used to record and analyse a range of additional behaviours in the home cage. The ultimate aim will be to record a collection of biologically meaningful home cage behaviours.
In pilot studies, mice from three different strains were recorded over a number of days. Initial results have already revealed new insights into the behaviour of mice, particularly about their behaviour at night which is not normally recorded. For example, mice were most active just before dawn and for several hours into the light phase, which is not something seen in individually housed mice. It was also possible to see how external events, such as movement of a cage position by the handler, can affect the mice. Scientists were also able to visualise social interactions between the mice.
Going forwards, this technology could help improve our understanding of the processes underlying complex central nervous system disorders, particularly when there is social impairment or more progressive changes at play. From a welfare perspective, HCA is minimally invasive and allows mice to be studied within their established social groups.
Find out more
To see the first paper on the Home Cage Analysis System click here
Pump Priming Awards for preliminary research using IMPC knockout mice
The MRC has just announced that pump priming awards are to be made available for scientists to support their work with mouse models generated and phenotyped through the International Mouse Phenotyping Consortium (IMPC). The IMPC aims to investigate the function of every gene in the mouse genome. 10–25 awards will be distributed in September of 2016 and 2017. These will be between £20–40k in value.
Applications are invited from UK-based research groups to receive knockout mice and carry out further investigations into their phenotypes.
The aims of this initiative are to help focus the research community’s attention to the importance of using mouse knockout lines that are well validated and comprehensively phenotyped. These mouse knockout lines are available through the IMPC and here at MRC Harwell in the Mary Lyon Centre (MLC). The initiative is also a way of raising the profile of IMPC as a resource to minimise the duplication of mouse knockout work, and therefore the number of animals used in scientific research.
This announcement is an exciting opportunity to highlight the important work being done by the IMPC and here at MRC Harwell. Funding smaller, pilot studies will help pave the way for more substantial studies in the future.
More information about the scheme, and details about how to apply can be found on the MRC website.
Saturday 18th June 2016, 10am-4pm
MRC Harwell, near Oxford, will be opening our doors to families on Saturday 18th June. We are leaders in genetic research, working towards improving medical knowledge and treatments by studying genetic traits in mice. It will be a great day out for all the family, with the chance to explore our labs, meet our scientists and find out what we really do. Discover how your genes make you who you are, see what it’s like to be a scientist by doing your own genetics experiment, find out why we’re investigating what genes do on a massive scale, take a guided tour of our labs, and even challenge yourself to do the same tests as our mice!
Booking required, for tickets please visit: https://www.eventbrite.co.uk/e/mrc-festival-your-genes-and-you-tickets-24995924483