MRC Mammalian Genetics Unit
Unit profile from the MRC Network publication issued December 2003.
It is now widely known that animals share many genes with humans and can suffer from the same diseases, for example diabetes or deafness. Investigating these diseases in animals can provide vital leads to understanding both their causes and ways to treat them in humans. This approach to medical research lies at the heart of work at the MRC Mammalian Genetics Unit (MGU) at Harwell in Oxfordshire.
Professor Steve Brown (right), Director, MRC Mammalian Genetics Unit
Harwell reaches critical mass
Harwell has been a site of MRC research activity since 1947, when the MRC Radiobiology Unit was opened alongside the Atomic Energy Research Establishment, now the headquarters of the UK Atomic Energy Authority. A former RAF base, the site is now a hotbed of science and technology, and home to a cluster of high-tech organisations which will soon be joined by the UK's new Synchotron, the Diamond Light Source. In 1995 the MRC Radiobiology Unit was reconstituted to form two new units, the Radiation and Genome Stability Unit and the MGU. These opened in January 1996, together with the UK Mouse Genome Centre which is now part of MGU, making MRC Harwell a unique campus for multi-disciplinary genetics research.
Since MGU's Director Steve Brown took the reins in 1996, the unit has dramatically expanded its scientific scope and increased its personnel from 40 to over 100. It now has 13 research programmes encompassing molecular genetics, genomics, genetic manipulation and data analysis at all levels, from single genes to the whole genome. With a combination of cutting-edge facilities and expertise unrivalled in Europe, MGU Harwell has become firmly established as one of the world's leading academic centres for mouse genetics.
From mouse to man
Network spoke to Steve Brown to find out more about the MGU's research and the latest developments at Harwell. The mouse, he explained, is pivotal to investigating human disease. Not only is this long-standing favourite of geneticists easy to breed and work with, but more importantly it was the first mammal to have its genome entirely characterised. The full DNA sequence, which was published in Nature a year ago and to which the MGU contributed through its role as coordinating centre of the UK mouse genome sequencing consortium, showed that nearly all human genes have a mouse counterpart. However, hunting for rare naturally occurring genetic diseases in mice that happened to exactly mirror human ones would be akin to looking for hens' teeth, so the bulk of the MGU's work is built around a systematic approach to creating mouse models. MGU researchers look for abnormal inherited physical characteristics, or phenotypes, that might correspond to human diseases in the offspring of male mice that have been treated with N-ethyl-N-nitrosourea (ENU), an organic chemical that induces genetic mutations in sperm. After rigorous analysis to find out exactly what is wrong, they use molecular genetics to pinpoint the faulty gene and then search for its human equivalent.
A sticky problem
The approach has most recently paid dividends in the discovery of genes that might be involved in glue ear, or otitis media.This distressing condition causes partial deafness in two out of three young children at some time, and is the most common reason for childhood operations. It is caused by a chronic inflammation that leads to a build-up of sticky fluid which blocks the middle ear and impairs hearing. At best this is uncomfortable, but in severe cases it can delay children's speech and social development and lead to hearing problems later in life. Although glue ear is known to run in families, its genetics are poorly understood.
Steve Brown has long had an interest in the genetics of deafness. A test for hearing loss was part of the intensive battery of screens that MGU researchers used to seek out new disease models among tens of thousands of ENU-generated mice. While most of the mutations they found affected the workings of the inner ear, in one mouse line the middle ear was full of thick pus, just like glue ear seen in children. The MGU team went on to isolate two disrupted genes called Jeff and Junbo and are now looking to see whether they have defective human counterparts in families prone to glue ear.
The Mary Lyon Centre
But what about medical conditions that are much more difficult to detect? There is a clear need to develop even more sophisticated and comprehensive tests to pick up subtle new phenotypes. And as we learn more about the genetics of disease in mice, it becomes increasingly important to find out what is happening physiologically, so that we can compare disease processes in mice and humans. This is where the new Mary Lyon Centre at Harwell fits in. Named in honour of Dr Mary Lyon, who has worked at Harwell since joining the Radiobiology Unit in 1955 and discovered the phenomenon of X-chromosome inactivation, it will house specially designed mouse phenotyping facilities and create a new centre of excellence in mouse anatomy, physiology and pathology. The Mary Lyon building was commissioned and handed over to the MGU in November and will officially open in June 2004. Professor Bob Johnson has been appointed to head the new Centre. It has the capacity to house all of Harwell's mice as well as the MRC's Frozen Embryo and Sperm Archive. In the first appointment of its kind in the UK, Michael Cheeseman, a member of the Royal College of Veterinary Surgeons, has been tasked with building expertise in mouse pathology, which will be disseminated to the research community through residencies and externships.
Innovative to the core
As the MGU has expanded, its research programmes have been integrated around a number of broad themes to make the most of existing strengths and to develop new synergies. These are: basic genetics mechanisms such as imprinting and development; functional genomics; neurobehavioural and neuromuscular genetics; and the molecular genetics of deafness and type-2 diabetes. The work is supported by five 'core' facilities, soon to be augmented by the new Mary Lyon Centre. As well as supporting existing MGU research, the cores' own innovations contribute to developing new approaches and methods at Harwell.
Harwell United
One of the major challenges facing genetics is to integrate genetic information with biology, from the level of DNA to the whole organism. This requires multidisciplinary working, not just at the MGU but also through external collaborations. The MGU's location is ideal for this. It provides access to other major scientific facilities at Harwell – for example, a CRAY supercomputer at the neighbouring Rutherford Appleton Laboratory – and positions the Unit within the wider campus of Oxford University. The MGU's first joint appointment with Oxford, in statistical genomics, highlights the strong links that the two institutions have forged. The appointee will lead the MGU's computational biology programme to manage and analyse large-scale functional genomics data. Harwell's thriving research community is also a draw for many of Oxford's graduate and post-graduate students.
The MGU is the leading partner in EUMORPHIA (European Union Mouse Research for Public Health and Industrial Applications), a pan-European project to improve our understanding of human physiology and disease by developing informative mouse models. The consortium brings together 17 partners in eight European Union countries. Steve Brown is its coordinator and the MRC's Human Genetics Unit and Functional Genomics Unit are among the UK partners. EUMORPHIA was highlighted as an model integrated research programme at the launch of the sixth EU Research Framework Programme (FP6) a year ago.
EUMORPHIA partners have already completed their first task, to develop and agree standard ways to work with mice, and are now tackling the second, to devise a standardised and comprehensive range of phenotype tests. Other high priorities include developing and testing new IT tools for collecting, sharing and analysing data from these tests, and finding new ways to create and characterise informative mouse genetic variants.
Over the last seven years, the MGU has firmly established its role as a leading international player in mammalian genetics research. Working with partners at Harwell, Oxford, in Europe and worldwide it will continue to make a significant contribution to meeting one of the 21st century's major challenges – translating genetic knowledge into improved human healthcare.