What is being done? We will study patients with a life-threatening condition called cardiogenic shock. This type of shock happens when the heart is suddenly unable to pump sufficient blood around the body to meet the needs of vital organs such as the brain, lungs, liver and kidney, thereby impairing their ability to function normally. Cardiogenic shock is often a consequence of a sudden and unexpected event, for example a heart attack Our study is aimed at understanding how the body responds to the inadequate blood supply caused by cardiogenic shock and to find out how and why this response varies from one patient to another. Our long-term goal is to improve survival from cardiogenic shock by developing a better understanding of which patients will benefit from specific treatments and how we can ensure that the right patients are getting the right treatment at the right time. We also hope to identify new targets for drug treatment aimed at modifying the body's response to cardiogenic shock. Why is this needed? Every year across Europe over 50000 patients are diagnosed with cardiogenic shock. Despite improvements in how we deliver care to patients with acute heart problems, death rates from cardiogenic shock have remained unacceptably high at between 30% and 50% for the last two decades. Current treatments use drugs and mechanical pumps to temporarily restore or replace the function of the heart, to "buy-time" for the heart to recover. Most of the patients who die, do so due to failure of other vital organs, often despite some recovery of heart function. We believe that in many cases death is a consequence of inflammation caused by a dysfunctional response of the immune system to the initial insult. Of those who survive, 30% will suffer the effects of long-term heart damage (heart failure), as well as the consequences of critical illness, including extreme weakness, fatigue, depression, chronic ill health with repeated hospital attendances and admissions, being unable to return to work and a poor quality of life. How will this be done? We believe that a dysregulated and inappropriate immune response to cardiogenic shock results in widespread inflammation, organ failure and often death. Further we think that the nature and drivers of the patient response to cardiogenic shock differ between individuals. We will take a novel approach to studying cardiogenic shock by measuring the levels of gene activity and mediators of inflammation in blood from patients with this condition. Using these data, we will: - better understand the reasons why people develop cardiogenic shock and die from it - identify why there is variation between patients in severity of disease and the response to current therapies - work out which patients are likely to benefit most from current and new treatments and why - work with doctors undertaking clinical trials of new treatments for cardiogenic shock to use the knowledge gained from this study to improve the design of such trials Where will the work be done? The work will be undertaken at Queen Mary University London, the University of Oxford and the Wellcome Sanger Institute using blood samples from patients in the UK and Germany. When will this work take place? We will complete this work between 2022 and 2025.

The importance of the lymphatic circulation to human biology and health is hugely underestimated. A major reason for this is an absence of ways to investigate the lymphatics in humans. Veins on the back of the hand are easily seen, but the lymph vessels are invisible. Standard methods of analysing them such as x-ray, ultrasound, CT and MRI cannot easily detect the lymphatic vessels. Consequently, the lymphatic system has been largely underrated and its role in disease not widely appreciated. Through cellular and animal research we now know that the lymphatics play an important part in heart disease, cancer, infection, and fat metabolism; the four main challenges in healthcare today. Knowledge of how lymphatics do and do not work in humans has not kept pace, largely because of difficulties with investigation. While circulating blood is the main supply system for the body (providing water, nutrients, and oxygen to all cells), lymphatics are the returning, recycling and cleansing system. Lymphatic vessels are like veins but instead carry lymph fluid from tissues to lymph glands. The lymphatic system houses most of our immune cells such as lymphocytes. Infections, including Covid, must enter the lymph vessels and reach the lymph glands to activate lymphocytes. This develops effective immunity against that infection. The main consequence of a failure of lymphatic function is a condition called lymphoedema - where swelling occurs due to fluid accumulation, often in a limb and more commonly the legs. People with the condition also have reduced circulation of immune cells, which leads to an increased risk of infection that can be recurrent and life threatening. Lymphoedema is common (with 400,000 people in the UK, and 250 million people affected worldwide) but is not often diagnosed due to lack of awareness amongst clinicians. There are two different types - secondary lymphoedema (a result of damage to a previously healthy lymphatic system), and the much rarer primary lymphoedema (due to a genetic fault). Unlike cardiovascular disease and cancer, not one drug is licensed to treat lymphoedema and no universally successful surgical treatment exists. Thus, currently, lymphoedema cannot be cured and is managed through a range of physical therapies such as massage and compression to improve swelling. At St George's Hospital we operate a primary and paediatric lymphoedema clinic to which patients are referred from across the UK. More than 20 years of seeing patients with primary lymphoedema and lymphatic malformations, collectively known as primary lymphatic anomaly (PLA), has resulted in the discovery of several causal genes. Consequently, the St George's Hospital lymphoedema clinic is internationally renowned and has been appointed a Centre of Excellence, and has the largest collection of patients with lymphoedema anywhere in the world. The research proposed here is designed to improve our understanding of the mechanisms that lead to lymphoedema in humans through use of newly developed and more powerful investigatory methods. Patients with PLA - because of an inborn fault in lymphatic function caused by a gene mutation - will be studied so we can piece together how these faults are a driver of lymphoedema. This process has already begun in one type of PLA where the gene (PIK3CA) fault is not inherited but develops only in some cells and tissues of the body, a so-called somatic mosaic disorder. A drug now exists to block the effects of the faulty gene causing this lymphatic problem. Trials using this drug are now underway with St George's as one of a few centres for recruitment. Knowledge of other causal genes and the mechanisms producing the lymphoedema as planned in this research project, will create opportunities for new treatments. We believe the results of our work can be extended to other types of lymphoedema, such as those secondary to for example breast cancer treatment.

Each cell in our body contains an identical DNA blueprint inherited from our parents (excepting sperm and eggs that contain half a copy). The decoding and expression of these genes needs to be finely regulated to make different cell types and govern cell metabolism. This is achieved by 'epigenetic' modifications to the DNA. One form of epigenetic regulation is achieved by marking certain regions of the genome with methyl groups that tend to block gene expression. Most of this DNA methylation is faithfully inherited every time cells divide and so acts as a semi-permanent regulator of how genes operate. When sperm fertilises egg the methylation marks on each are largely erased in the first few days after conception and a new 'methylome' is created for the embryo. We have studied a seasonal experiment of nature in rural Gambia whereby conceptions occur against very different dietary and nutritional conditions. We have shown that certain 'environmentally-sensitive hotspots' across the genome are very sensitive to the baby's season of conception. These hotspots have a characteristic signature indicating that they are permanently altered in the very early embryo. We believe that they may have evolved to SENSE the mother's (nutritional) environment, RECORD that information, and ADAPT the developing fetus to be best suited to the predicted future conditions. If the future conditions are different these changes may become maladaptive and cause disease. We have already shown that certain of these variable regions may be linked to diseases such as obesity, cancer and thyroid disease. In this grant, we seek to better understand HOW diet affects the laying down of these methylation marks, WHICH areas of the methylome are especially sensitive to such influences, HOW they influence the development of the placenta and fetus, and ultimately WHAT effects these changes have on the baby's development and life-long health. To achieve this, we will follow rural Gambian families planning to conceive and collect data and blood samples within +/-15 days of conception to much better characterise the environmental factors that are driving the epigenetic changes we study. We will use advanced metabolomic methods to measure differences in the pathways required for DNA methylation and search for possible factors beyond diet (including pesticide and other toxic exposures, pharmaceuticals, etc). We will also search for seasonal differences in the mothers' gut microbiome to see if that may be influencing the changes we see. We will use new finely-targeted epigenetic arrays to study our hotspots of interest and learn how and why they might have evolved, playing special attention to how these changes affect genomic processes (such as imprinting) that are crucial for placental (and hence fetal) development. Finally we will examine the effects of these changes on the babies born in the new cohort and follow them into the future. This will create an open, accessible 'Early Developmental Epigenetic BioResource' for researchers worldwide.

Free text scientific literature has the potential to be an incredibly valuable source of data for uncovering the often hidden relationships between genes, diseases and phenotypes. Phenotypic descriptions cover abnormalities in anatomical structures, processes and behaviours. For example 'growth delay' and 'body weight loss'. Such descriptions form the basis for determining the existence and treatment of a disease but, because of their inherent complexity, have previously received less attention by the text mining community. In recent years, significant effort has been spent by a small number of expert curators to create coding systems for phenotypes (called "ontologies"), such as the Human Phenotype Ontology (HP) [1] and the Mammalian Phenotype Ontology (MP). The PheneBank project proposes to support and speed up curation using terms discovered directly from the literature and to automatically integrate them with such standard ontologies There are three major challenges we seek to address: (1) knowledge brokering: to develop state of the art text mining approaches to identify phenotypic descriptions in scientific texts; (2) knowledge management: to create a structured resource of phenotype terms used in scientific texts and link them to existing coding systems; and (3) adding insight to evidence: to work with domain experts to utilize statistical association algorithms to identify meaningful phenotype-disease / phenotype-gene profiles. The disease profiles will be evaluated against hand curated standards in human disease databases (e.g. Online Mendelian Inheritance of Man and OrphaNet) with a focus on rare diseases. Mined data will be provided in a machine understandable database - a definitive output of the project - to support clinicians and scientists. At the technological level the project will pioneer new methods for text mining that exploit machine learning (ML). Scientific texts remain a challenging area for a variety of reasons: descriptive naming, high levels of ambiguity/out of vocabulary words, use of complex sentence structures and an evolving vocabulary. Current techniques in term recognition employ ML in pipelines to search for continuous sequences of words that represent genes, proteins and cells etc. State of the art models include conditional random fields using feature sets based on dictionaries as well as the local and topical context where the term is located. However, phenotype descriptions are often represented by discontinuous sequences, such as 'growth in the patient was delayed'. One key aspect not previously addressed is in the capture of such non-canonical terms. This requires a different paradigm based on grammatical parsing algorithms that capture structural relations as well as joint learning techniques that can leverage large numbers of features simultaneously and optimise these across the diverse contexts in which phenotypes are mentioned. The project also seeks to harness texts for extracting statistically significant associations between phenotypes, diseases and genes. Earlier approaches have suffered from not providing deep semantic descriptions of the relations they tried to target. This means that association scores merge notions of genetic, pharmacological, and epidemiological relations etc. without distinction. Our parsing-based approach is an attempt to overcome this issue by discovering more precise relationships. The approach follows ground breaking work at the Wellcome Trust Sanger Institute (WTSI), including terminology alignment of phenotypes using pairwise scoring of the conceptual elements that make up the phenotype. An exciting aspect of this project is inter-disciplinary collaboration across stakeholders to build a resource of phenotype-disease profiles: (a) computer scientists from the Universities of Cambridge, Colorado and Manchester; (b) bioinformaticians and life scientists from the WTSI, McGill University and EMBL-EBI, and (c) clinicians from the NIHR Bioresource.