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: