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Genetic Basis of Disease

Barts and The London has one of the most significant groupings of medical genetic researchers, seeking to find and study the genetic causes of human diseases; including skin disease; diabetes; coeliac disease; obesity; Down’s syndrome; cancer; motor-neurone disease; hypertension, and heart disease.

In the 2008 Research Assessment Exercise, the Blizard Institute of Cell and Molecular Science, returned in Hospital Subjects, was ranked joint 1st in the UK with Cambridge and Edinburgh in terms of 3* and 4* outputs and was joint 7th overall out of 28, ahead of Manchester, Newcastle and Southampton.

The William Harvey Research Institute, returned in Preclinical and Human Biological Sciences, was ranked 3rd in terms of 3* and 4* outputs, and 4th overall out of 13, ahead of Kings College London, Bristol and Nottingham.

Some leading Barts and The London Genetic Basis of Disease researchers

 Hypertension and Heart Disease

The aims of research in this area are to understand the basic underlying pathogenic mechanisms associated with the initiation and development of vascular diseases, eg, atherosclerosis and hypertension.

Professor Mark Caulfield, director of the William Harvey Research Institute is a pre-eminent figure in the genetics of cardiovascular disease. He is national co-ordinator of the MRC British Genetics of Hypertension Study. With Dr Patricia Munroe he co-ordinates this study on behalf of five other UK universities (Aberdeen, Cambridge, Glasgow, Leicester and Oxford). He published the largest genome screen in human hypertension on 2010 sib pairs highlighting four regions that may harbour susceptibility genes for essential hypertension in The Lancet during 2003.

The BRIGHT study is an active member of the MRC Human Sample Collection Initiative. With the Wellcome Trust Case Control Consortium, BRIGHT is partnering Oxford, Cambridge and the Sanger Centre to undertake pathfinder experiments for genome-wide association. Professor Caulfield is co-grant holder with Imperial, Cambridge and Oxford on the Wellcome Trust Functional Genomics Programme (£5.4 million) to develop observations on metabolic syndrome and translate these from experimental models to man. Professor Caulfield is also Deputy Chair of the London Biobank Regional Collaborating Centre and a member of Biobank UK Sample Storage Committee, Chair of Biobank UK Ethnicity Sub-Group, member of Biobank UK Measurement Sub-Group.

 Skin diseases

The main focus is hyperproliferative skin diseases such as the palmoplantar keratodermas (PPK) and ichthyoses. Professor David Kelsell’s team in the Blizard Institute of Cell and Molecular Science has identified the important role of proteins involved in the regulation and formation of epidermal cell junctions responsible for cell-cell adhesion, cell signalling and communication, key properties to maintain the normal cellular phenotype and tissue architecture.

Profile: Professor David Kelsell

Additional research programmes include the investigation of genetic and molecular events occurring in Basal Cell Carcinoma.

A prominent success which has received extensive media attention is the identification of the gene that causes the debilitating skin condition Harlequin Ichthyosis. Many children born with the disease die within two days of birth: those that survive endure painful rituals of scrubbing and applying cream to their skin at intervals to prevent it from cracking and becoming infected. The research group’s findings will facilitate the prenatal DNA diagnosis of this life-threatening disorder, and also pre-implantation genetic testing. With further research, more effective treatments could also be designed for Harlequin children.

 Diabetes and periodic fevers

Barts and The London is at the forefront of the international gene discovery programme in diabetes, related disorders, and periodic fevers (including genomewide association scans, candidate genes, functional genomics and applied physiology) and can count among its achievements a number of seminal discoveries.

Research is led by Professor Graham Hitman and an exciting new development is the recruitment of Dr Vardhman Rakyan to bring his groundbreaking work on epigenetics into our research portfolio.

Profile: Dr Vardhman Rakyan

The current research programme focuses on genes important to inflammation and pancreatic beta cells in a number of major resources including British/Irish as part of the Diabetes UK/MRC Warren2 collections, and from the South Asian subcontinent including younger adult patients from Bangladesh. The cell biology links to the genetic work with major interests in pancreatic beta cell metabolism and insulin secretory granule trafficking. Researchers here recently discovered that calpain-10 is a trigger for insulin release; current studies are extending to actions on the cytoskeleton and into other endocrine cell types.

The strength and uniqueness of this research is the clinical focus of the work, spanning from basic science to clinical application. An emerging interest is in the prevention of diabetes that is especially relevant to the School’s local Whitechapel community. Clinical translational research that interfaces with the NHS has been strengthened by several initiatives including the setting up of the North East London Local Diabetes Research Network (co-led by Graham Hitman) and a recent award of an MRC, National Prevention Research Initiative grant to pilot methods for identification of people at risk of diabetes and prevention strategies in the local Bangladeshi population.


Professor Graham Hitman was among a team of scientists to have identified a genetic link to obesity through a genomewide study of 2,000 people with type 2 diabetes and 3,000 controls. This study was part of the Wellcome Trust Case Control Consortium, one of the biggest projects ever undertaken to identify the genetic variations that may predispose people to or protect them from major diseases.

Through this genome-wide study, the researchers identified a strong association between an increase in body mass index (BMI) and a variation, or "allele", of the gene FTO. Their findings were published in the journal Science. The study found that people carrying one copy of the FTO allele have a 30 per cent increased risk of being obese compared to a person with no copies.

However, a person carrying two copies of the allele has a 70 per cent increased risk of being obese, being on average 3kg heavier than a similar person with no copies. Amongst white Europeans, approximately one in six people carry both copies of the allele.

 Coeliac disease

Research led by Professor David van Heel has recently identified eight new genetic risk factors for coeliac disease - a disease affecting one in 100 of the population - which is caused by an excessive immune response to wheat in the gut wall.

Funded by the charity Coeliac UK, and the Wellcome Trust, and published in Nature Genetics, the studies have revealed that those suffering have a different spectrum of genetic risk variants in multiple genes that control the nature of the immune system response.

Profile: Professor David van Heel

Behind its success is the Human Genome Project - a massive international research project to reveal the entire sequence of genes of all the human chromosomes. Exploiting technological advances that have enabled comparison of variations across the human genome in large numbers of people, researchers studied over seven thousand individuals with and without coeliac disease, amongst British, Irish and Dutch populations.

One of the key findings is that healthy individuals more often have a protective DNA sequence in the interleukin-2 and interleukin-21 gene region than individuals with coeliac disease. Interleukin-2 and interleukin-21 are cytokine proteins secreted by white blood cells that control inflammation. It is likely that the protective DNA sequences leads to different amounts of these cytokines being produced providing defence against intestinal inflammation. Professor Van Heel has recently been awarded £1 million by the Wellcome Trust to continue this work.

 Down’s syndrome

A world leader in Down’s leukaemia research is Professor Dean Nizetic from the Institute of Cell and Molecular Science. He is part of a London based team which achieved a genetic engineering first when it created a strain of mouse with an almost complete copy of chromosome 21. This unusual genome mimics the genetic makeup of people with Down’s syndrome. The research was published in Science.

The modified mouse will make it easier to understand the effects of Down’s syndrome, which is linked with types of leukaemia, heart disease and Alzheimer type symptoms relatively early in life. Researchers have spent over a decade trying to engineer a Down’s mouse – their efforts complicated by the fact that the mouse versions of the genes on human chromosome 21 are awkwardly scattered across three mouse chromosomes. About two-thirds lie on mouse chromosome 16, the rest on chromosomes 10 and 17. Professor Nizetic and his colleagues - along with Elizabeth Fisher of the UCL’s Institute of Neurology and Victor Tybulewicz of the MRC’s National Institute for Medical Research – rather than trying to duplicate regions of the mouse genome corresponding to human chromosome 21, radically tried instead to put the human chromosome into mice.

That strain of mice, called Tc1, has about 92 per cent of DNA of the human chromosome 21. It also has a unique set of several characteristics of Down’s syndrome not seen in any other mouse model. Although there are no tests for mental retardation in mice, the Tc1 mice have deficits in spatial learning and memory, fewer brain cells with altered functions, as well as skeletal changes similar to those found in Down’s syndrome patients and, most significantly, they have heart defects like those found in Down’s syndrome patients.

The research could have major implications in understanding these conditions in people with Down’s and, in the longer term, in aiding efforts to understand and perhaps ameliorate other effects of Down’s. The research also has implications concerning cell proliferation, cell differentiation, neurodegeneration, and protection from cancer, by identifying the molecular pathways and proteins which are altered by trisomy 21. Professor Nizetic’s work is supported by a programme award from the Leukemia Research Fund.

This research has a strong local history because Downs syndrome was first discovered at The London Hospital by John Langdon-Down in 1859.

Profile: Professor Dean Nizetic

 Bone Marrow Failure

Professor Inderjeet Dokal, with close colleague Dr Tom Vulliamy, has pursued a research interest in the biology of aplastic anaemia and bone marrow failure, a group of paediatric disorders characterised by the inability to make adequate numbers of red blood cells. The conditions may lead to early death from infection or bleeding if adequate treatment is not given.

Scientifically, the studies on this rare disease have made a connection with aplastic anaemia and the key enzyme telomerase, which maintains the telomeric ends of all chromosomes. It has been discovered that several key components of the enzyme are also mutated in different genetic subtypes of anaemia.

These findings have not only shown the importance of telomerase in humans but have also provided the platform for better diagnosis and future treatment strategies The immediate and future research aims are to establish the genetic basis of many uncharacterised cases of aplastic anaemia, determine their functional significance in aplastic anaemia, and explore how these may be manipulated for future treatment strategies.

This work is supported by a Wellcome Trust Programme Grant which has recently been renewed for another five years and many of the papers have been published in Nature Genetics.

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