2022-23 Intake of GW4-CAT HP Fellows
Dr Kathryn Fleming
Specialty – Haematology
Specialty – Orthoptics
Daniel is an orthoptist aiming to understand how a common childhood eye disease – strabismus – affects mental health. Poor mental health is one of the largest causes of disability worldwide. Affected individuals are more likely to experience physical and social symptoms and disadvantages. People with strabismus may be more likely to have a mental health condition such as depression and anxiety. This fellowship will use population and genetic epidemiology techniques to find out if strabismus causes poor mental health and what social and physical mechanisms underpin the relationship.
In 2014, Daniel completed training as an orthoptist in the University of Sheffield, UK. He worked as an orthoptist in University Hospital Southampton and completed an NIHR Pre-Doctoral Clinical Academic Fellowship at the University of Southampton, gaining the Gift of Sight Clinical Research Award for work stemming from that fellowship. Today, Daniel is an advocate for patient and public involvement in clinical research. He will use his GW4 CAT HP fellowship to build a clinical academic career throughout which he will continue to champion, and improve care for, children with eye disease.
2021-22 Intake of GW4-CAT Fellows:
Dr Giles Dixon
Clinical Specialty – Respiratory Medicine
I am a Specialist Trainee in Respiratory Medicine and will be investigating how we can predict and track the course of Interstitial Lung Disease (ILD). ILD is a devastating condition which causes scarring on the lungs and results in 1% of all deaths in the UK. I aim to understand how we can predict who will develop worsening (progressive) disease and how we can track the course of the disease over time.
My interest in respiratory disease began at The University of Sheffield when I completed an undergraduate BMedSci at the MRC Centre for Developmental Biology. I achieved a 1st Class Honours research degree investigating novel imaging techniques to visualise neutrophil biology in a zebrafish model of inflammation. Through my Academic Foundation Programme at the University of Bristol I worked at the Academic Respiratory Unit, investigating the role of pleural fluid procalcitonin and lymphocyte subset analysis in pleural effusions.
Exploring the application of machine learning to characterise the driving mechanisms and predict the progression of fibrotic ILD
During my GW4 Wellcome Trust Fellowship I will try to understand why some people diagnosed with ILD will develop progressive disease whereas others will not. I am interested in how we can use machine learning to analyse CT scans using a process called quantitative CT (qCT) to provide additional insight into the mechanisms behind the disease.
I will collate a comprehensive anonymised database of patients with fibrosing ILD across the Southwest and collate lung function, blood test and novel imaging data. I will then utilise a machine learning approach to understand which factors can help to predict prognosis.
My retrospective work will inform the design of a prospective clinical study where I will monitor disease progression over time using qCT scanning and compare this to more traditional methods of monitoring the disease. I will also utilise novel imaging techniques including specific radiolabelled ligands and markers of endothelial health to understand the driving mechanisms of disease progression.
It is hoped by building a greater understanding of disease mechanisms that we can provide a more personalised approach to patient care and aid the development of novel treatments.
Dr Lowri Allen
Clinical Specialty – Diabetes and Endocrinology
Lowri Allen is a clinical trainee in Diabetes and Endocrinology in South Wales. During her medical training at the University of Edinburgh, she completed an intercalated degree in Pharmacology. After graduating with honours in 2013, she completed academic foundation training in South East Scotland, before moving to South Wales in 2015. As an academic core medical trainee she was awarded a grant from the Diabetes Research Wellness Foundation which she used to establish an e-cohort of just under 200, 000 pregnancies in Wales, to describe pregnancy outcomes in type 1 diabetes as compared with pregnancy outcomes in women without type 1 diabetes. She was subsequently appointed to the Welsh Clinical Academic Track (WCAT) programme, which has allowed her to further explore her interest in pregnancy in type 1 diabetes, and in particular to describe outcomes in teenage pregnancies in type 1 diabetes.
Through a PhD, Lowri hopes to further explore her interest in pregnancy in type 1 diabetes. She is particularly interested in understanding how the combination of genetics and the intrauterine environment influence the risk of the offspring of those affected by type 1 diabetes developing type 1 diabetes themselves during childhood.
A study of the relative protection against transmission of type 1 diabetes amongst the offspring of
mothers with type 1 diabetes
Type 1 diabetes is a lifelong, incurable condition associated with many possible complications,
especially if blood sugar levels are poorly controlled. Children with a family history of type 1
diabetes are at increased risk of type 1 diabetes. However, the risk is twice as high if the child’s
father has type 1 diabetes compared with if the mother has type 1 diabetes. The reasons for this
Using data from large cohorts, we will compare the genetic risk score for type 1 diabetes between
the children of mothers with type 1 diabetes who develop the disease themselves and other
children with type 1 diabetes. We will explore the impact of environmental factors on the risk of
type 1 diabetes in children of mothers and fathers with type 1 diabetes. We are particularly
interested in whether children of mothers with poorly controlled type 1 diabetes during pregnancy,
who are exposed to higher blood sugar levels, might be less likely to develop type 1 diabetes.
Understanding factors that increase the risk of developing type 1 diabetes may help us identify
strategies to reduce the likelihood of children at high risk of type 1 diabetes developing the disease.
Dr Naomi Cornish
Clinical Specialty – Haematology
I am a Specialist Trainee in Haematology. My enthusiasm for research began with an intercalated BSc in Medical Genetics at Cardiff University, which was supported by a Wolfson Foundation Award. I was subsequently able to develop my experience of genomics research as a result of the Wellcome Trust-funded Elizabeth Blackwell Institute Clinical Primer Scheme at the University of Bristol, when I undertook a project which investigated the mechanisms underlying a rare inherited blood disorder. I hope to use my GW4-CAT fellowship to explore the genetic basis of haematological disease in the context of other common health problems.
Genomic Insights into Cancer-associated Venous Thromboembolic Disease
People who have cancer are at significant risk of developing a venous thromboembolism (a blood clot) as a complication of their illness and this is a major cause of morbidity and mortality. However, the risk of cancer-associated venous thromboembolism (VTE) varies greatly between individuals due to a complex interplay between inherited and acquired risk factors.
While anticoagulant therapy (which thins the blood) can reduce the chance of these blood clots occurring; there is an increased risk of bleeding associated with these medications. It is therefore important to identify which patients with cancer are at highest risk of VTE, so that preventative therapy can be selectively offered to those who have the greatest potential benefit to gain from it.
During my PhD fellowship I aim to explore the genetic basis of cancer-associated VTE. I plan to undertake an epidemiological approach to identify new genes which may be implicated in this important health problem, followed by a laboratory-based analysis to study the biological function of some of these genes.
This work will hopefully contribute to our understanding of the mechanisms underlying cancer-associated VTE and help efforts to accurately risk-stratify and manage patients who may develop this condition.
Clinical Specialty – Intensive Care Medicine
Aravind Ramesh is a specialist trainee in Intensive Care Medicine in the Severn Deanery. During medical training at the University of Cambridge, he completed an intercalated degree in Neuroscience. After finishing his clinical studies at the University of Oxford, he completed the Academic foundation programme in London, during which he explored epigenetic mechanisms underlying Friedreich’s Ataxia. Having spent some time working abroad in New Zealand, he completed Core Medical Training in Newcastle upon Tyne before moving to Bristol to begin Intensive Care registrar training with an NIHR funded Academic Clinical Fellowship.
Through a PhD, Aravind hopes to explore an interest in immune function in critical illness, as alterations in immune function may be a key driver of outcomes after an initial critical insult. He will explore how T cell metabolism shapes T cell function in acute illness through a range of approaches, with a specific focus on arginine metabolism and effects on T cell proliferation
Arginine metabolism and T cell function in severe infection
I wish to understand why different patients with the same initial insult can have wildly different outcomes in Intensive Care. Poorer outcomes are associated with higher rates of hospital-acquired infection from ‘opportunistic’ organisms that cause disease in patients with defective immune systems. One example is the detection of herpesviruses in critically ill adults on ICU, viruses that don’t usually trouble patients with intact immune systems. Their presence strongly suggests a problem with T-cell immunity, immune cells that are critical for controlling herpesvirus infections. Defective T-cells are detected in sepsis (life-threatening infection), but also in other causes of critical illness including major trauma. I will investigate the mechanisms underlying impaired T-cell function in order to identify future drug targets to liberate this suppressed arm of the immune system. I will study the metabolism of the amino acid arginine because 1) this amino acid vital for normal T-cell function and 2) preliminary data suggests that sepsis is associated with increased arginine breakdown. I will use a combination of approaches to interrogate the hypothesis that increased breakdown of arginine by the enzyme arginase drives suppression of T-cell function in severe infection.
2020-21 Intake of GW4-CAT Fellows:
Dr Fergus Hamilton – University of Bristol Fellow
Clinical Specialty – Microbiology
Fergus Hamilton is a clinical microbiologist and infectious disease doctor. His interests are fundamentally, why although nearly all of us get infection, only a small number of us get serious infection, and even less die. Is this to do with our genes, our immune system, or the bugs? A combination of all three? I will investigate this question with a focus on host features that predict severe infection, or mortality from infection. In particular, I will use host transcriptomic (and other ‘omic) data to analyse pathways associated with host tolerance of infection, with a particular focus on heme degradation. On a broader level, the research will then use large databases (UK Biobank, ALSPAC), to perform large scale analyses of these pathways (and others) to investigate the genetic heritability of infection, and mortality associated with it. This work will be jointly supervised by Peter Ghazal FMedSci, Professor of Systems Immunity at the University of Cardiff, and Nic Timpson, Professor of Genetic Epidemiology and PI of ALSPAC.
Investigation of immune pathways and genetics underlying resistance and tolerance in severe infection
Infection is very common, but rarely deadly. For my PhD I want to explore the balance between ‘resistance’ to infection – the ability to kill and destroy invading pathogens like bacteria, fungi and viruses, with ‘tolerance’ to infection – the ability to bear an infection without adverse effects when these pathogens attack. Both these strategies are governed by immune pathways and are critical to survival from infection. For example, in the COVID-19 outbreak, it is clear that some patients bear the infection with mild or no symptoms while others suffer from immunopathology, an overactive immune system – perhaps representing an imbalance between resistance and tolerance. I will focus on whether we can use genetic data from large human studies and from model or in vitro work about the activity of genes when we do get infected and attempt to identify specific pathways that are a ‘trade-off’ between these two evolutionary strategies – tolerance and resistance . I will target my investigation on the haem degradation pathway, which controls iron transport and storage within humans. Iron is a critical nutrient for both hosts and pathogens, and has been shown to be important in determining infection outcomes. I will explore how this pathway is regulated in large gene expression data from sepsis patients and will also recruit new patients with infection to look at this pathway. I will also explore the balance between incidence and case fatality of infection using large genetic datasets, to explore whether genes that make you resist infection are more likely to make you die.
Dr Rachel Kwiatkowska – University of Bristol Fellow
Clinical Specialty – Public Health
Rachel trained in public health and works as an infectious disease epidemiologist, with a focus on developing surveillance systems in low/ middle income settings.
During her medical training in Liverpool she completed an MSc in molecular biology of parasites and disease vectors at the Liverpool School of Tropical Medicine; she also has a Masters in Public Health from the London School of Hygiene and Tropical Medicine.
As an academic clinical fellow in Bristol her research included epidemiological analyses of infectious disease outbreaks, and a feasibility study using electronic care records to monitor antimicrobial use in rural outpatient clinics in China: part of an interdisciplinary study investigating drivers of Antimicrobial Resistance (AMR) in Anhui province.
Through a PhD, Rachel hopes to explore new approaches to the surveillance of drug-resistant gut bacteria, combining genomic and epidemiological information to improve our understanding of how resistance spreads within the community.
Assessing the role of care homes as community reservoirs, and potential sentinel sites for the enhanced surveillance of infectious disease
The COVID-19 pandemic has had a devastating effect on care home residents, and shows how vulnerable they are to infection. Infections often spread ‘silently’ in care homes, since older people often don’t experience symptoms in the same way that younger people do. We need to identify bacteria and viruses in care homes quickly to stop them spreading, and do this without causing distress to residents. Taking samples like saliva or faeces rather than throat swabs is one way to reduce discomfort; viruses and bacteria can also be found on surfaces within the care home and even in waste water. This study will investigate how the SARS-CoV-2 virus that causes COVID-19 spreads into and around care homes. When a care home reports a COVID-19 infection, we will take regular samples from residents, staff and the environment to see where the virus can be found. Using findings from this study, we will build a mathematical model to explore the best way to monitor care homes for the SARS-CoV-2 virus and other viruses and bacteria.
Dr Simeng Lin – University of Exeter Fellow
Clinical Specialty – Gastroenterology
Simeng is a gastroenterology trainee in the South West Severn region, with an interest in inflammatory bowel disease (IBD). Her academic interest in gastroenterology began during her undergraduate studies at the University of Sheffield, where she published two papers on functional bowel conditions, and was a sub-investigator in a number of gastroenterology clinical trials during her gastroenterology specialty training. She was subsequently awarded a Wellcome-funded Clinical Primer at the Translational Research Exchange @ Exeter where she developed skills in data analytics and mathematical modelling of large datasets, alongside obtaining a Postgraduate Certificate in Genomics Medicine at the University of Exeter. Simeng hopes to utilise her clinical and data analytic skill sets to further understand the molecular mechanisms surrounding treatment outcomes in patients with IBD in her PhD.
Using genomic approaches to understand immunogenicity of biologic drugs in inflammatory bowel disease
Background: Inflammatory bowel disease (IBD) affects at least 115,000 people in the UK and millions worldwide. Symptoms include abdominal pain, diarrhoea and weight loss. These are often severe. Anti-TNF drugs are effective medicines. Unfortunately, not everyone responds to these drugs. Many people that do respond eventually lose response. One of the major reasons people lose response is the development of an immune response to the drug (immunogenicity), where the body produces proteins (antibodies) that fight against the drug. Currently, a limited number of alternative therapies are available. Many people face surgery as the next option. Therefore, it is important to understand why some people develop these proteins. Research Approach: We will analyse blood samples from people with IBD who have received anti-TNF drug. We will use the latest techniques to understand the relationship between a person’s genes, the environment, and the way the body reads the gene. We will compare the messages from specific blood cell types in people who have developed these proteins to those who did not. Expected Impact: By better understanding the immune pathways that lead to the development of these proteins, doctors can target the safest and most effective therapy for individual patients.
Dr Jack Underwood – Cardiff University Fellow
Clinical Specialty – Psychiatry
Dr Jack Underwood trained at Peninsula Medical School before commencing Foundation and Core Psychiatry Training in South Wales. After initial support from the MRC Centre for Neuropsychiatric Genetics and Genomics Clinical Academic Mentorship Scheme, he spent time out-of-programme as a Clinical Research Fellow at the Neuroscience & Mental Health Research Institute, Cardiff University, funded by a Wellcome Trust Clinical Primer. During this time he worked on projects examining the genetics and epidemiology of Autism Spectrum Disorder (ASD), presenting internationally and authoring a number of publications. He was subsequently appointed to the prestigious Welsh Clinical Academic Track (WCAT) training programme, focusing on cross-disorder overlap and phenotyping in ASD. His passion for neuroscience combines with an interest in medical teaching, as a lecturer and facilitator at Cardiff University, as the Neuroscience Trainee Editor for RCPsych’s Online Learning (TrOn) modules, and RCPsych Neuroscience Champion for Wales. As a GW4-CAT Fellow, he plans to investigate evidence for subgroups within ASD based on genetics and cross-disorder pathophysiology.
Psychiatric Comorbidity in Autism Spectrum Disorder
Autism Spectrum Disorder (autism) is a long-term condition which affects 1-2% of people . It includes difficulties with social skills and communicating with other people, repetitive behaviour and having a small range of hobbies or interests. It can affect how people perceive the world. Some autistic people see, hear and feel the world differently. More autistic people are being are being identified, as people become more aware of the condition.
Mental health problems are common in autistic people, but we don’t understand why. This project will look at this, and what effects genetics or lifestyle have. We will study the rates of mental health problems in a group of people taken from the National Centre for Mental Health (NCMH) Database, as well as two large datasets taken from anonymised health records. A small number of autistic people with anxiety will then be seen and assessed more deeply. Through this we will assess the effects of genetic risk and life choices on mental health.
2019-20 Intake of GW4-CAT Fellows:
Dr James Fasham – University of Exeter Fellow
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.
Clinical and molecular delineation of neurodevelopmental disease within genetically isolated communities.
Inherited neurodevelopmental disorders affect brain development and function and occur as result of changes to the genetic code, which may be passed down through families. The causes of these disorders remain poorly understood, and they present an immense healthcare burden worldwide. This means that affected families may often undergo multiple investigations in search of a diagnosis.
Some neurodevelopmental disorders, which are otherwise rare in the general population, may occur more commonly in certain communities such as the Amish and Palestinian populations. The unique genetic make-up of these communities makes it easier for scientists to identify the genetic causes of inherited neurodevelopmental disease, which in turn greatly aids scientific understanding of brain growth, development and function. This project aims to identify new genetic causes of human inherited neurodevelopmental disease within these community settings. Studying the biological function of these genes will help us understand more about human health and the medical problems which arise when the genes involved do not function properly. This knowledge is ultimately important to develop better treatments for these disorders. Crucially, this work will also provide diagnoses for patients and their families, not just in these communities, but also worldwide.
Dr Mark Gormley – University of Bristol Fellow
Clinical Specialty: Dentistry
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.
The effect of statins on the risk and progression of head and neck squamous cell carcinoma (HNSCC).
Background – People taking statin drugs to reduce blood cholesterol, may also have a lower risk of getting certain cancers, but the evidence surrounding head and neck cancer is inconclusive.
People being prescribed statins have abnormal levels of circulating blood factors such as cholesterol, hormones and metabolites, which provide the signals, sources of fuel and building blocks essential for cells to grow. This results in the exposure of cells to an environment which may alter the chances of a cancer developing. We want to determine whether the use of statins to modify the metabolic environment also influences the likelihood of developing and dying from head and neck cancer.
Research approach – 1) Analyse large patient datasets to determine if statin use is causally involved in protecting against head and neck cancer development and progression.
2) Explore how changes in cholesterol, hormones and metabolite levels as a result of statin use might mechanistically prevent head and neck cancer using laboratory studies.
3) Identify potential targets for prevention or therapy in head and neck cancer.
Expected impact – This project will investigate the link between statin use and head and neck cancer, which could help inform targeted cancer screening, prevention and intervention for these patients.
Dr Alice Hughes – University of Exeter Fellow
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.
Investigating the importance of fetal insulin in birth weight and early postnatal growth
Background – Babies born very small or very large are at risk of short and long-term complications. Women with diabetes in pregnancy are more likely to have large babies because the fetus produces more insulin in response to glucose crossing the placenta. How other factors may affect insulin-mediated fetal growth and what impact this might have are not known.
Research approach – This project will investigate how much of birth weight is due to fetal insulin, at what point in pregnancy it becomes an important contributor to growth and how it influences early growth after birth. We will use monogenic (single gene) disorders which influence fetal insulin to study this, and look at whether we can tell how big the baby will be if we know whether they have a certain genetic change before they are born. We will also look at what genetic and environmental factors influence fetal insulin using polygenic (multiple common genes in the population) data, including participants from large international studies.
Expected impact – This project will improve understanding of the role of fetal insulin in birth weight and how it contributes to complications from low and high birth weight. We hope this work will provide the basis for ways we could prevent and predict complications from being born very small or very large.
Mr Dmitri Shastin – Cardiff University Fellow
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.
An investigation of white matter fibre tract topology, connectivity and microstructure to uncover the ictogenic network in focal epilepsy
Epilepsy is the most common serious neurological disorder and one-third of those affected continue to experience disabling seizures despite taking regular medications. It is thought that there are abnormal cortical areas in the brain that, together with the white matter connections that join them, form pathological circuits responsible for seizures. These circuits vary between subjects in their properties, location and spread. Modern medical imaging and other investigations do not fully detect the abnormal circuits, leaving the majority of patients unsuitable for surgery or vastly reducing their chances of seizure freedom post-operatively. Using state-of-the-art imaging hardware and methodology I will obtain high quality brain scans of 20 patients with epilepsy. I will look at the multiple qualities that can tell us about the state of the brain connections, producing very detailed maps of abnormalities. I will then test contribution of these abnormalities by mathematically simulating seizures and comparing my simulations with the real seizure activity we record from the same patients. This will help us describe the circuits or give us information about how these circuits work. My approach will allow us better understand the exact mechanisms that drive epilepsy and may help develop better treatments for these patients.
Dr Bnar Talabani – Cardiff University Fellow
Clinical Specialty: Nephrology
Bnar is a clinical-academic trainee in nephrology with an interest in diabetic kidney disease (DKD), which is the commonest cause of end stage renal failure.
She graduated from Cardiff Medical School in 2013, having also completed an intercalated BSc in Clinical Epidemiology. Prior to her appointment onto the Academic Core Medical Training Programme, Bnar generated a number of publications on acute kidney injury and has won prizes at national conferences for presenting this work.
She was awarded a prestigious Wellcome Trust Clinical Primer Award to conduct laboratory based research in macrophage populations in DKD. Subsequently, she was appointed onto the prestigious Wales Clinical Academic Track (WCAT) programme where she will continue to refine her research interests. As a GW4-CAT fellow, she hopes to expand our understanding of the role played by macrophages in driving the progression of DKD, with a view to later identifying new therapeutic targets for this common and debilitating disease.
Macrophages in Kidney Disease
Background – Diabetes consumes approximately 10% of total NHS resources. Diabetic Kidney Disease (DKD) affects 40% of people with diabetes, remaining the commonest cause of kidney failure in the UK and leading to increased mortality. While good control of blood-sugar and blood-pressure can slow the decline of kidney function, we are unable to stop or reverse it. Macrophages are immune cells important in the control of infection and injury. Recent advances suggest that Macrophages are important drivers of DKD. Understanding the behaviour of these cells, and how they may contribute to the development of DKD is a central focus of this project.
Research Approach – I will capitalise on advances made in Cardiff and Bristol Universities that have developed new, world-leading approaches to studying different macrophage populations and developed experimental models of DKD that closely model the pathology. I plan to identify and purify different types of kidney macrophages, and to perform an unbiased profiling of their gene expression patterns.
Expected Impact – I expect these studies to delineate the regulatory network underpinning renal macrophage biology in DKD, which I intend to study in depth. Ideally, this will lead to improvements in early diagnosis, stratification and treatment of patients likely to develop DKD.
Dr Nick Thomas – University of Exeter Fellow
Clinical Specialty – Endocrinology
Nick is a specialty trainee in Diabetes and Endocrinology. His interest in research in diabetes began with an academic F2 post at the University of Exeter where he was involved with work developing a novel urine test for measuring endogenous insulin production. He then completed an academic clinical fellowship around adult onset type 1 diabetes. This work used novel genetic stratification techniques to show that adult onset type one diabetes was more common than previously thought, work he presented internationally.
Building on this novel genetic stratification technique working alongside bioinformatician’s and mathematicians he completed a six month secondment within the Translational research exchange Exeter. During his PhD he intends to build on his previous work. He is conducting a clinical study to define the rate of progression of adult onset type 1 diabetes close to diagnosis as well as investigating novel markers of endogenous insulin production. The aim of this work is to increase participation in type 1 diabetes intervention trials as well as improve the diagnosis of type 1 diabetes close to disease onset given the difficulties of differentiating type 1 form type 2 diabetes at older ages of onset.
Defining the decline in endogenous insulin secretion in type 1 diabetes diagnosed after 30 years of age
Type 1 diabetes is associated with loss of insulin release, which results in high blood sugars. In children and young adults this loss of insulin is known to happen quickly. After just a couple of years of having type 1 diabetes, most of this age group will make almost no insulin. Research is trying to find new treatments to slow down and even stop this insulin loss. Those developing type 1 diabetes after 30 years of age are rarely included in these trials- despite making up nearly half of all cases of type 1 diabetes. This is because, in this age group, the rate of insulin loss is unknown. Finding out this rate and factors that effect it is an important step towards including older individuals in trials.
I also aim to test a new, simpler way of monitoring insulin loss by using a finger prick blood test. This will hopefully make it possible to conduct research from home rather than in hospital. Together, the answers to these questions aim to make it easier to develop new treatments for type 1 diabetes, as these studies could recruit many more people, using a much simpler and cheaper measure of insulin loss.
2018-19 Intake of GW4-CAT Fellows:
Dr Kate Burley – University of Bristol Fellow
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 – Cardiff University Fellow
Clinical Specialty – Cardiology
Majd is an academic-clinical registrar in cardiology with an academic interest in atherothrombotic disease.
His commitment to academia started at a young age, when he spent three gap years in a leading BHF-funded laboratory, generating a number of publications and presentations on platelet signalling in thrombotic and bleeding disorders. Following this, he completed his medical training at the University of Birmingham, graduating with honours, distinctions and several prizes including the prestigious Chancellor’s prize.
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 – University of Bristol Fellow
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.
Dr Claire Salter – University of Exeter Fellow
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.
Dr Chantelle Wiseman – University of Bristol Fellow
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.
2017-18 Intake of GW4-CAT Fellows:
Dr Michael Ambler – University of Bristol Fellow
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.
Life on Hold: Torpor as a Model of Resilience
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 – University of Bristol Fellow
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.
Applying ‘omics to understand and predict juvenile arthritis and its associated uveitis
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.
Dr Rebecca Carnegie – University of Bristol Fellow
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.
Micronutrients and Mood
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.
Dr Jude Harrison – Cardiff University Fellow
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.
Exploring Biological Pathways in Alzheimer’s Disease Using Polygenic Scores, MRI and Blood Biomarkers
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.