The 2019-20 intake of GW4-CAT Fellows:
Dr James Fasham
Clinical Specialty: Clinical Genetics
James is an Academic Clinical Fellow in Clinical Genetics, with a background in paediatric medicine. His research focuses on understanding the gene causes of rare inherited conditions, particularly those which include learning disability. James has undertaken further training in bioinformatics, specifically related to next-generation sequencing. He is using bioinformatic approaches to address the challenges involved in investigating diseases that have a large number of potential genes as causes. He plans to undertake a cross-disciplinary PhD including clinical phenotyping, big data techniques and molecular biology to robustly prove novel gene-disease associations, for the benefit of the patients and their families and to improve our understanding of the place of genes within biological pathways
Mr Mark Gormley
Clinical Specialty: Dentist
Mark is a dentist with an interest in genetic epidemiology and the application of human genetics to study disease relevant to the mouth, head and neck. Since graduating from the University of Dundee with distinction, he completed longitudinal dental foundation training, followed by core training in oral and maxillofacial surgery, before taking up an oral surgery NIHR Academic Clinical Fellow post at the University of Bristol Dental School.
During his academic fellowship, Mark spent time in the MRC Integrative Epidemiology Unit, using population-based approaches to identify novel risk predictors for head and neck squamous cell carcinoma in UK Biobank. He was awarded the Association of British Academic Oral and Maxillofacial Surgeons research bursary in 2017 for this work. Over the past year Mark has also completed a Postgraduate Certificate in Genomic Medicine at the University of Cambridge and is currently writing his dissertation for a Masters in Medical Education.
Dr Alice Hughes
Clinical Specialty: Obstetrics and Gynaecology
Alice is a specialty trainee in Obstetrics & Gynaecology with a particular interest in Maternal and Fetal Medicine. Her interest in research began whilst studying for her medical degree at the Universities of Exeter and Plymouth and she became interested in Genetics during a BSc in Reproductive and Developmental Sciences at Imperial College London. She went on to work as an Academic Foundation Doctor in Exeter and completed a MSc in Genomic Medicine alongside her research work. Following an Academic Clinical Fellowship in Cambridge, Alice is returning to the South West to complete a PhD and build upon her previous research in Exeter, focusing on birth weight, genetics and fetal insulin.
Mr Dmitri Shastin
Clinical Specialty: Neurosurgery
Dmitri is a specialty trainee in Neurosurgery with an interest in brain imaging and epilepsy surgery. His commitment to academic neuroscience began during undergraduate training at the University of Tartu, Estonia, where he engaged in neuropharmacology research investigating the effects of antidepressant drugs in a rodent model of kainate-induced epilepsy. Following his graduation in 2011 he moved to the United Kingdom. After securing a training number in Cardiff and gaining experience in multicentre clinical trials in neurology and neurosurgery he subsequently became a Welsh Clinical Academic Track (WCAT) fellow, being introduced to diffusion weighted imaging-based research in epilepsy in his first year. He hopes to continue to investigate epileptogenic networks by combining neuroimaging approaches, magnetencephalography and stereotactic electroencephalography-based signal analysis techniques and computational modelling in his PhD.
Dr Nick Thomas
Clinical Specialty: Endocrinology
The 2018-19 intake of GW4-CAT Fellows:
Dr Kate Burley
Clinical Specialty: Haematology
Kate is an NIHR Academic Clinical Fellow in haematology, with a long-standing interest in genomic medicine. She graduated from the University of Birmingham in 2009, having also completed an intercalated BMedSci funded by the Wolfson Foundation. Kate’s ACF has been based at University Hospitals Bristol and involved projects within the NIHR BioResource – Rare Diseases and NHS 100,000 Genomes Project. She has focused on the deep phenotyping of selected pedigrees with rare heritable bleeding and platelet disorders.
The overlapping genetic architecture of blood cell granularity and neurodevelopmental disorders
Platelets are blood cells needed for clot formation. Neurons are brain cells which transmit information through chemical signals. Although they have different roles in the body, platelets and neurons both function by releasing tiny substance-filled packages called granules. Previous research has shown that similar genes control this process in both types of cell.
Autism is a neuronal disorder which affects the way individuals interact with the world. The genes causing autism are poorly understood but are thought to be involved in the formation of neuron granules. Platelet genes are better understood. I plan to use the similarities between platelet and neuron granules to identify new genes causing autism. In the longer term, we hope this research leads to improvements in diagnosing and treating the disorder.
My research builds on data showing that differences between healthy people in the number of granules in platelets are linked to subtle changes in genes. I will analyse lists of these genetic changes and select those most likely to be involved in both platelet granule formation and autism. For the most promising genetic change, I will alter this gene in cells in the laboratory to see if this affects granules, and therefore could contribute to autism.
Dr Majd Protty
Clinical Specialty: Cardiology
Majd is an academic-clinical registrar in cardiology with an academic interest in atherothrombotic disease.
His clinical academic career continued with a cardiovascular-themed academic foundation programme in Wales where he also completed a Masters degree in therapeutics (awarded with distinction). Subsequently, he was appointed to the prestigious Wales Clinical Academic Track (WCAT) where he continued to refine his academic and clinical interests in “clotting cardiology” and to prepare for a PhD.
He is excited to join the ranks of the GW4CAT fellows to pursue his academic interests in inflammatory-driven atherothrombotic cardiovascular disease with leading experts.
Characterising the role of inflammatory procoagulant phospholipids in acute coronary syndrome
Heart (cardiovascular) disease is the number one cause of death in the UK. Patients with heart disease who experience a heart attack (also known as acute coronary syndrome, or ACS) are at a higher risk of dying from recurrent heart attacks or stroke. Heart attacks happen as a result of blockages in the heart arteries. These blockages are caused by an inflammatory state, which is triggered by damage to abnormal fatty areas (atherosclerotic plaques) inside blood vessel walls. This damage leads to activation of blood cells such as white cells (responsible for fighting infections and wound healing) and platelets (responsible for blood clotting and wound healing) which in turn lead to abnormal clotting and blockages in heart arteries.
Blood clotting is normally mediated through interactions of blood proteins with fats (lipids) called phospholipids that are present on the surface of blood cells. These phospholipids are linked to inflammation of blood vessels and are elevated in conditions with abnormal clotting. Their potential role in driving abnormal clotting events in heart attacks is unknown and will be characterized in this programme of work.
I will characterize the phospholipid profile generated by blood cells and components in patients with heart disease, with the aim of identifying the drivers of clotting in these patients, and new treatment targets.
Dr Emily Milodowski
Clinical Specialty: Veterinary Surgeon
Emily is a veterinary surgeon with an interest in immunology, particularly in understanding immune dysregulation in cancer and the potential to manipulate this for cancer therapy. She hopes to continue to investigate this during her GW4 CAT fellowship.
Emily graduated as a veterinarian from the University of Bristol in 2015, having previously undertaken an intercalated degree in the School of Cellular and Molecular Medicine. Following a year in general practice, Emily completed a small animal internship at the Royal Veterinary College, where she was awarded a Post Graduate Diploma in Clinical Veterinary Practice. Emily began her research career with an Elizabeth Blackwell Institute Clinical Primer at the University of Bristol, which provided the grounding for her on going interest in cancer immunology.
Elucidating mechanisms of tumour escape from checkpoint blockade
Our immune system contains cells capable of detecting and killing cancer. These are called Tumour Infiltrating Lymphocytes (TILs). When cancer cells are detected, TILs are sent into tumours to stop the cancer developing. However, cancers have evolved many ways of evading TILs, including delivering “off” signals. These “off switches” are co-inhibitory receptors on the surface of TILs which, when activated, stops the immune cell from recognising and destroying the tumour, allowing it to progress.
Blocking co-inhibitory receptors (such as PD-1 and CTLA-4) on TILs can reverse this off signal, and has been successful in improving outcomes in certain cancers, such as Malignant Melanoma, where other traditional treatments have failed. Unfortunately, some patients do not respond to co-inhibitory blockade, while other cancer types demonstrate little response to PD-1 or CTLA-4 blockade in any patients. My project aims to explore alternative inhibitory pathways that can be targeted in these patients. If we find that alternative co-inhibitory pathways appear more important in blocking TIL function in some tumours, then we may identify new targets for anti-cancer drugs.
Clinical Specialty: Clinical Genetics
Claire is an Academic Clinical Fellow in Clinical Genetics, with a background in paediatric medicine. Her interests include understanding the biomolecular pathways underlying normal human development and the errors that can occur in these processes to result in childhood disease. This vital information can then be utilised to optimise and personalise disease management strategies for affected individuals and their families.
As a GW4-CAT fellow, Claire plans to undertake a collaborative PhD in developmental genetics, aiming to define the causes of uncharacterised rare developmental disorders in order to explore novel treatment options in these and related diseases.
Determining the molecular basis of newly discovered developmental disorders identified in genetically-isolated communities
Neurodevelopmental disorders (e.g. learning difficulties) are common, yet unfortunately many families never receive an explanation for their child’s difficulties as each individual disorder is often rare and complex.
A proportion of these disorders arise due to misprinted genes. Genes act as our body’s instructions for normal human growth and development. If a misprint occurs, normal development may become disordered, resulting in specific medical problems. However, genetic studies to identify genes responsible for developmental disorders are challenging.
Certain ‘isolated’ communities, such as the Amish, are populations descended from small numbers of ancestors. By not intermixing with outsiders, the Amish have become ‘genetically isolated’ and have a unique genetic make-up, whereby certain genetic disorders have become more common and others rare/absent. This enables genetic studies that are not possible in other populations.
We aim to find the genetic causes of neurodevelopmental disorders in Amish and other isolated communities as part of established research programmes in these populations. This will provide important health benefits, including diagnosis, and optimised treatment and family planning advice. Importantly, this will enable similar benefits for families affected by overlapping neurodevelopmental disorders worldwide, whilst also aiding medical-scientific research more generally to understand brain development and function, and neurodevelopmental disease.
Clinical Specialty: Psychiatry
Chantelle Wiseman is a psychiatry trainee with research interests in the epidemiology of psychiatric disorders, particularly post-traumatic stress disorder (PTSD). Chantelle graduated from the University of Leicester in 2012, and undertook an Academic Foundation Programme in the Wales Deanery. She has continued her clinical training there since, and developed her academic interests by being appointed to the Clinical Academic Mentorship Scheme at Cardiff University, and subsequently being awarded an Institutional Strategic Support Fund grant for a primer research project.
Chantelle is enthused that the GW4 CAT programme will allow her to focus primarily on her research interests for a few years, which will be an expansion of her primer research into the predisposing risk factors of PTSD.
Exploration of the relationship between social cognition and PTSD in the pre, peri and post-trauma period.
Post-traumatic disorder (PTSD) is a disabling psychiatric illness that can occur following a very distressing event, such as sexual assault or war. People with this illness experience very upsetting and intrusive memories and nightmares, have a heightened sense of threat, and avoid reminders of the event. However, not everyone who experiences a traumatic event will develop PTSD; this project tries to better understand why that is, by examining the role of social cognition in both the onset and recovery of PTSD.
Social cognition is the ability to understand emotions in yourself and others, and it has been put forward that difficulties with social cognition may increase the risk of developing PTSD. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a large cohort study of children born in 1991/1992, I will examine whether difficulties with social cognition in childhood lead to an increased risk of developing PTSD in adults. I will then study around 50 adult patients with PTSD and assess their social cognition and review their progress after several months to see if social cognition difficulties affect recovery from PTSD. This study could have implications for the way that we understand and treat PTSD.
The 2017-18 intake of GW4-CAT Fellows:
Dr Michael Ambler
Clinical Specialty: Intensive Care
Mike is an intensive care registrar, with an interest in the physiology of hibernation and torpor and its potential application in the setting of critical illness.
Before medical school, he completed a degree in physiology and psychology and is pursuing a neuroscience interest in his research, which aims to identify the neural circuits that control entry into torpor.
Animal studies show that lowering body temperature protects against organ damage. This has resulted in the use of physical cooling techniques in critical care and operating theatres, to protect the brain when blood flow is impaired. Unfortunately, these physical cooling techniques trigger reflexes that attempt to correct the temperature back to a normal level. These reflexes probably limit the effectiveness of the treatment and may even cause harm to the patient.
Laboratory mice actively enter a protective state of torpor in response to reduced ambient temperature and poor food availability. During torpor, the animal’s body temperature and metabolic rate drop dramatically and there is a suppression of compensatory reflexes. I aim to understand how the mouse brain triggers torpor, and to investigate the relationship between torpor and sleep. I will use this knowledge to test whether it is possible to induce a torpor-like state in the rat, which is an animal that does not naturally enter torpor. This will demonstrate the principle that species that do not naturally enter torpor can be made to enter a similar state by activating the appropriate brain circuits.
Eventually, I aim to induce an organ-protective torpor-like state in humans on intensive care units.
Dr Sarah Clarke
Clinical Specialty: Paediatrics
Sarah is a Paediatrics registrar and her research interest is in juvenile idiopathic arthritis (JIA) and its associated uveitis. She graduated from the University of Oxford Medical School in 2011, having previously completed an undergraduate degree in immunology. Her NIHR funded Academic Clinical Fellowship was spent within in the ocular immunology groups at the University of Bristol (UK) and National Institutes of Health (US).
Sarah is excited to be moving into a new field for her GW4 Fellowship and will be investigating population-based approaches to further risk stratify children with JIA.
Juvenile idiopathic arthritis (JIA) is the most common rheumatological condition of childhood. Significant numbers of JIA patients (up to 30%) develop complications with their eyes (uveitis, JIAU) and are at risk of blindness. We do not know why uveitis is so common in JIA, why only some children get uveitis or what causes more severe disease. Current research suggests our genes and our environment are involved but their exact contributions are unclear. This project will look at how genes related to similar autoimmune conditions may be involved in JIA and systematically assesses the evidence for environmental factors associated with JIA and JIA-U. This project will then look for genes specifically associated with JIA-U in a genome-wide association study. However, we know from similar diseases that having predisposing genes is insufficient alone to cause disease.
Epigenetics studies how genes are switched on/off (our “epigenome”) and helps explain how genes and the environment act together to cause disease. Thus, this project will also examine whether the epigenome mediates JIA and JIA-U disease risk. Finally, all of this information will be used to identify key elements of the epigenome of JIA patients and test whether changes to these can predict development of JIA-U.
Clinical Specialty: Psychiatry
Rebecca is an Academic Psychiatrist with a clinical and academic interest in mood and anxiety disorders. She began her research career with a Wellcome Trust Clinical Primer scheme at Bristol University, and subsequently was awarded an NIHR Academic Clinical Fellowship in Psychiatry. During these posts, she developed skills in large scale quantitative data analysis and epidemiology.
Rebecca’s plan for the GW4 CAT Fellowship is to investigate the emerging field of Nutritional Psychiatry, undertaking her PhD on ‘Micronutrients and Mood Disorders’, with a particular focus on magnesium. As part of this work she aims to investigate the evidence for an association between magnesium and depression, and use genetic methodologies to explore potential causality.
Depression and anxiety disorders are becoming increasingly common. There is some research suggesting that our diet, (what we eat) might make us more likely to become depressed and anxious. This type of research is called ‘Nutritional Psychiatry’ research. Many research studies have shown that people with depression and anxiety disorders do not have enough of certain ‘micronutrients’ either in their food, or in their blood. One example is magnesium, which is contained within green leafy vegetables, and is lacking in processed foods. It is possible that our society is not consuming enough magnesium, which could be increasing the number of people with depression and anxiety. However, it is difficult to say whether a low magnesium in depressed people was the cause of their depression. It may be because people with depression eat less healthily, or because people with other problems (e.g. alcohol use or long-term illnesses) are more likely to get depressed.
This research will aim to get around these difficulties by using our DNA or genetic code to look at whether genetic differences that result in having lower magnesium, are also linked to our risk of depression.
Clinical Specialty: Psychiatry
Judith is a higher trainee in psychiatry. She studied Medicine at the University of Dundee and began psychiatry training on the Maudsley Hospital rotation. She was funded by the Cardiff MRC Clinical Academic Mentorship scheme and the Welsh Clinical Academic Training scheme before joining the Wellcome GW4-CAT. Judith is fascinated by the biology of neuropsychiatric diseases. Her other interests include improving physical health outcomes for people with mental illness. She is a Trainee Editor for the British Journal of Psychiatry, and tweets in a personal capacity as @drjudeharrison.
As part of the GW4-CAT she is undertaking a PhD on genetics and magnetic resonance imaging in Alzheimer’s Disease.
Studies have identified lots of small genetic changes associated with Alzheimer’s disease. They relate to disease processes like immunity, inflammation cholesterol metabolism.
I aim to:
– Examine small changes in groups of genes related to disease processes. I will do this by creating ‘genetic scores’ for different processes.
– Explore associations between the ‘genetic scores’ and changes on brain scans, blood tests for inflammatory markers and cholesterol, and memory function.
I will use information from large groups of people which has already been collected from other large studies: an in-house cohort, the Avon Longitudinal Study of Parents and Children, and UK Biobank.
These include different age groups, so I can potentially identify the earliest events in the disease. My project will have the ability to detect differences because the total number of participants is so big. The findings of this study could help us to identify those who might benefit from particular treatments in clinical trials. This will help to focus efforts to find new therapies for Alzheimer’s disease.