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- Generating new data through our Experimental Programme
+Linking targets and diseases
- We have developed a portfolio of experimental projects designed to provide new information in our key therapy areas - to enable target identification and prioritisation. We generate target-centred data in human, physiologically relevant - systems to improve the strength of causal links between targets and diseases in our focus therapeutic areas of Oncology, - Immunity and Inflammation and Neurodegeneration. We combine whole genome approaches and high throughput methods to - address the full range of relevant targets in disease most relevant cellular systems. We use the expertise of all our - partners in emerging and established technologies including: + Our research programme generates and analyses data to connect targets to diseases, assess the strength of this evidence, and help identify and prioritise targets for drug discovery. This includes evidence that causally links targets and diseases, as well as foundational data that helps us understand biological processes and disease progression more deeply. +
++ Within the research programme, we combine whole genome approaches and high throughput methods to address the full range of relevant targets in disease in the most relevant cellular systems. We use the expertise of all our partners in emerging and established technologies, focusing on three therapy areas to generate new understanding:
- - Gene editing (CRISPR) - -
- - Induced pluripotent stem cells - -
- - Single cell genomics - -
- - Organoid and tissue culture + Oncology
- - Large-scale genetics, genomics and epigenomics + Neurodegeneration
- - Genome-wide sequencing + Immunology and Inflammation
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- Oncology
-- Our projects in Oncology utilise resources and expertise within the Wellcome Sanger Institute's - Cancer, Ageing and Somatic Mutations Program, - which has played an important role in understanding the genetic basis of cancer. A shared theme is the use of accessible cancer - resources to curate and analyse clinical genomic datasets to identify driver genes (mutations, amplification, deletions - and gene fusions) across multiple cancer sub-types. A key resource is the unique collection of >1000 human cancer cell - lines at the Sanger Institute along with their drug sensitivities. Genomic information including RNA-seq and synthetic - lethality from genome editing in model systems that best reflect the biology of tumours can identify many new target - opportunities as exemplified in - Behan et al 2019. We are expanding our gene editing approaches to both tumour based cancer targets for instance by - identifying potential combination targets, and immuno-oncology targets by identifying targets that modify the tumour - microenvironment or alter cell killing in co-culture. -
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- Immunology and Inflammation
-- We focus on explaining the genetic basis of immune-mediated diseases including inflammatory bowel disease (IBD) and SLE where there - is a strong interest from our partners and expertise on the Genome Campus. We developed a state of the art meta-analysis for the - existing IBD cohorts, and we are moving candidate targets into CRISPR-cas9 knockouts in gut epithelium organoids for validation. - In addition, we are generating eQTL datasets including at the single cell level that can be used to resolve the causal genes at - loci implicated from genetics for IBD and SLE. We are probing the roles of targets either in well-defined immune cells through - gene editing and single cell transcriptomics and epigenetic profiling (for instance in microglia, macrophages, dendritic cells and - T cells in response to various stimulations, - or in disease such as asthma using single cell genomics. - We also have projects that intersect with oncology including identification of receptor ligand pairs in NK cells with application to - immuno-oncology as well as intersections with the role of the immune system in neurodegenerative disease. -
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- Neurodegeneration
-- In Neurodegeneration we are using the collective expertise of our partners and through collaboration with UCL and the Cambridge Dementia - Research Institute we have built a set of projects based on the use of iPSC derived neurons particularly in Alzheimer's and Parkinson's disease. - These projects use CRISPR-cas9 gene editing to identify modifiers of the response to oxidative stress, mechanisms of Tau uptake and the - effects of Alzheimer's disease specific mutations in neurons. We also characterise these neurons using single cell transcriptomics. We have - established protocols for similar analysis of enteric and sensory neurons including the effect of rare monogenic mutations - for pain. We are using fine mapping of GWAS in Alzheimer’s (AD) and Parkinson’s (PD) disease to identify and test potential targets in the - same neuron systems and using functional approaches to model the effect of common variants on relevant phenotypes. -
-- The recent discovery of the relevance of neuroinflammation in neurodegeneration has led us to develop projects at the intersection with - immunity and inflammation. We have profiled microglia from trauma patients for eQTLs,and are using IPSc-derived microglia for genetic and - gene editing screens. -
- Finally, we have recently started to profile the effect of chromatin modifying mutations of neural progenitor cells and neurons, focussing - on targets identified in the - Deciphering Developmental Disorders project. + Take a look at our publications to read about our recent work.
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