An increasing number of patients in the UK develop heart failure. Heart failure accounts for approximately 20% of all hospital admissions amongst people over 65 and in the past 10 years the hospitalization rate has increased by ~160%. The mortality for patients treated with drugs continues to be very high with annual rates between 20 and 45%.In over 70% of patients heart failure is secondary disease of the coronary arteries, the vessels which carry blood to the heart muscle. In these patients heart failure is due the loss of contraction resulting from scar tissue and/or hibernating myocardium, a condition in which cardiac muscle does not contract properly, but is still alive. Reopening these vessels by surgery or catheters improves function of hibernating myocardium, heart failure symptoms and patients live longer.||Our research has significantly contributed to improve the diagnosis and treatment of heart failure. We have validated a new imaging tool based on a special scan of the heart which permits the identification of myocardial hibernation. We have established a diagnostic service here at the Hammersmith and referrals are received from Greater London and Southern England. Identification of this condition contributes to the decision of whether or not to procede with surgery. Therefore, this scan can contribute to significantly reduce the number of unnecessary operations.

Drugs are an important category of treatment for mental health disorders, but existing drugs do not work for everybody and often have undesirable side effects, so there is a need for new drugs with better properties. Many first-in-class drugs were discovered by observing the effects of compounds on humans or animals and using those effects to come up with potential applications. For example, when a new antihistamine was found to have a calming effect on patients, related compounds were tested in rats and humans leading to the discovery of chlorpromazine, the first antipsychotic. We believe there are many more potentially useful neuroactive compounds to be discovered and that natural sources, including the helpful microbes that grow in and on all of us, are particularly promising. To try to find them efficiently, we use large-scale imaging and automated computer analysis to test large numbers of microbes and microbial natural products for their effects on a tiny nematode worm called C. elegans. Because these worms are small and grow quickly, we can test thousands of compounds per day for behavioural effects, increasing our chance of discovery. Furthermore, because worms are our distant evolutionary cousins, they share many of our neurotransmitters (including dopamine and serotonin among many others) and so the compounds we discover, or related ones, may be useful as human drugs.

After fertilization, a single zygote proceeds through a series of cleavage steps to develop into a multicellular embryo, called a blastocyst. The cells of the blastocyst are capable of generating all adult cell types, a phenomenon known as pluripotency. The inner cell mass (ICM) of the blastocyst can moreover be cultured in a dish as pluripotent embryonic stem cells (ESCs). ESCs have become invaluable tools in regenerative medicine and to study development itself. With 1 in 8 couples experiencing infertility in the UK, it is ever more important to understand the factors contributing to healthy embryo development. Transposable elements (TEs) are parts of our DNA that are currently or historically mobile, -i.e. having the capacity to 'paste' themselves into new places in the genome. Many TE sequences used to be thought of as simply 'junk DNA'; however, we are beginning to understand that TEs have evolved to play new and unexpected roles in development and disease. For example, uncontrolled TE activity has been implicated in neurodegeneration and cancer. However, the expression of many TEs is also high in normal development, suggesting that they may also have beneficial roles in cells. This proposal focuses on exploring the function and regulation of a particular TE, called mouse endogenous retrovirus type L, MERVL. MERVL is the earliest expressed TE, and is transiently upregulated in mouse embryos at the 2-cell stage. This stage, conserved in human in 4-8 cell embryos, encompasses an essential process called Zygotic Genome Activation, when the embryo begins to turn on its own genes for the first time. These embryos are also considered "totipotent", meaning that they can not only generate embryonic tissues but also extra-embryonic tissues (like placenta). Interestingly, a small proportion of ESCs transiently become "2C-like" in normal culture, also possessing enhanced developmental potency. Here, we will use mouse ESCs and mouse embryos to investigate how and why MERVL regulation is important in early development. Using these tools, we will identify and characterize key factors required to activate and repress MERVL. In turn, we will investigate how these factors regulate the 2-cell stage, and affect ZGA and totipotency. To understand how MERVL and other TEs are directly regulated, we will combine genome-editing systems, called CRISPR/Cas9, with recent biochemical tools to pull out sets of proteins that bind MERVL. Lastly, we will explore the conservation of MERVL function and regulation in human cells, where a similar TE, HERVL, is known to play a conserved role. We aim to a) understand how HERVL regulates the 4-8 cell stage and human ZGA b) investigate how new HERVL regulators might contribute to specific cases of disease. These studies will significantly increase our understanding of how TEs contribute to early development, and will shed insight on how such processes are perturbed in disease.

The group investigates blood clotting mechanisms and particularly the causes of thrombosis and haemophilia. Our research includes the biochemistry and structure of coagulation proteins, the molecular genetics of thrombophilia and haemophilia and the cellular biology of blood vessels. Diseases of blood vessels and thrombosis are among the most prevalent causes of premature death in Western society. Advances in the basic science of these conditions are urgently needed to find ways of preventing the onset of disease and to improve the treatment of affected individuals.

Our programme aims at understanding how growth and cell size interact with gene expression and phenotypic variability. Having the right size is crucial for cell function and requires a careful balance between two opposing forces: how fast a cell accumulate mass, or grows, and how often it divides. Surprisingly, whereas cell division has been extensively studied, much less is known about what regulates cell growth. Yet, this is a very important problem because de-regulated growth is at the heart of pathologies such as cancer. We approach this problem combining state of the art experimental and computational systems-biology approaches in a simple unicellular eukaryote called fission yeast (Schizosaccharomyces pombe). It is a versatile and powerful model organism that enabled the discovery of many mechanisms controlling cell division. Recent technical developments have made systems-biology techniques more quantitative and more sensitive, permitting to analyse amounts of material as tiny as the content of a single cell. We exploit these recent advances to investigate how growth impacts on cell-to-cell phenotypic heterogeneity. This is an important aspect of our work because phenotypic heterogeneity contributes to rapid resistance to drugs such as antibiotics or chemotherapy. Ultimately our work will help understanding mechanisms controlling eukaryotic cell growth, and contribute to understanding how de-regulated growth can lead disease.