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Over two weekends, RDM researchers talked about their work to visitors of all ages at Oxford IF.
Wilkinson Group - From basic biology to novel translational applications of haematopoietic stem cells
Haematopoietic stem cells (HSCs) support blood system homeostasis and are also used clinically in cell and gene therapies. We are interested in studying the biology of this important stem cell population and developing new HSC-based therapies.
Our group is interested in developing novel immunotherapeutic approaches for leukaemia. Clinical approaches currently used include allogeneic haematopoietic stem cell transplantation, chimeric antigen receptor T cell therapy and immune checkpoint inhibitors. While each of these approaches can be successful, they also fail in many patients as a result of tumour adaptations or diminished function of immune cells. Enhanced immunity can also lead to immune-related adverse events due to on- or off-target effects. We are exploring the mechanisms that underpin these failures and using this information to devise new strategies that can be translated into early phase clinical trials.
Our focus has been on the cell biology of the T-cell surface. We developed general methods for crystallizing glycoproteins and determined the structures of key T-cell surface proteins including the first adhesion protein (CD2) and its ligand CD58, the costimulatory receptor CD28 and its ligand CD80, and the large tyrosine phosphatase CD45. We also worked out how weak, specific recognition is achieved by these types of proteins and obtained the first insights into the overall composition of the T-cell surface. Most importantly we proposed, with PA van der Merwe, one of the most complete and best-supported explanations for leukocyte receptor triggering, called the kinetic-segregation model (youtube.com/watch?v=HygSTSlycok). Please see http://davislab-oxford.org/ for more details of our lab’s activities.
Genomic instability (GI) is a hallmark of cancer that plays a central role in its initiation and development. GI can arise as a result of germline and somatic mutations that compromise a cell’s ability to accurately sense, signal or repair DNA damage. GI can also arise as a result of errors in chromosome segregation during mitosis, or when chromosome breakage events result in the transmission of chromosome rearrangements, and/or gains and losses to daughter cells during cell division. These catastrophic events are not only linked to tumour initiation, they also play a central role in cancers ability to evolve and acquire new aggressive traits, such as the ability to metastasize, or become resistant to anti-cancer therapies. However, in some specialised cell types, genome rearrangements must occur as programmed, highly orchestrated events, where they function to bring about genetic diversity: the B and T lymphocytes of our immune systems deliberately induce and repair DNA breaks in a mutagenic fashion to diversify antibody and antigen receptor encoding genes. Research in the Chapman laboratory aims to better understand the biological pathways that allow for genome diversification as a physiological process, and those that lead to GI in cancer. We also work towards devising strategies to exploit the GI-driving pathways as vulnerabilities to selectively kill cancer cells.
The most common childhood cancer is acute lymphoblastic leukaemia (ALL). There has been amazing progress in treating childhood ALL, but unfortunately a subset of childhood ALL continues to be refractory to treatment. In addition, even for children who are cured, conventional therapies are often quite toxic and can cause long lasting life-altering effects. In the Milne lab, we are trying to better understand how normal gene regulation is disrupted in childhood ALL so that we can better design targeted therapies. Recent work in our lab has focused on a subset of childhood ALL that is caused by rearrangements of the Mixed Lineage Leukaemia (MLL) gene, which create MLL fusion proteins (MLL-FPs). MLL-FPs can directly alter gene expression in the cell through aberrant epigenetic regulation of genes. Work in the lab mainly focuses on gene regulation, specifically using genome wide techniques such as RNA-seq, ATAC-seq, ChIP-seq and 3C techniques to analyse the 3D genome.
The Hughes group is interested in the basic mechanisms which control the activities of genes and how sequence changes in the regulatory non-coding portion of the genome alter gene expression and underlie common human diseases. The sequences which codes for protein only represents ~2% of the human genome and this small fraction has been the focus of the majority of scientific scrutiny over the last 30 years. However, work over the last decade and a half has shown that the vast majority of sequence changes that underlie most common human diseases, such as diabetes, cardiac, cancer, neurological and autoimmune diseases, lie in the non-coding rather than coding portion of the genome. The development of complex multicellular organisms is completely dependent on the exquisitely orchestrated expression of gene networks, as is our cells’ abilities to react to stimuli from our environment. It is therefore suspected and, in some cases, confirmed, that these changes in our non-coding genome alter the behaviour of embedded regulatory elements and so effect the “how” and “where” such genes are expressed, rather than the structure of the proteins themselves.
My lab is interested in understanding how the genome functions and leveraging this to develop genome editing strategies to treat human disease.
Our work focuses on understanding how obesity drives the development of type 2 diabetes and cardiovascular disease. Specifically, it aims to decipher molecular determinants of adipocyte number and distribution within the body; key factors of susceptibility to obesity-associated cardiometabolic diseases. To achieve this, we employ human genetic and physiological approaches, coupled with functional studies in human adipose cells and model organisms.
Our work has shown that metabolism both generalized and intrinsic to blood stem cells unleashes reactive metabolites such as the aldehydes – formaldehyde and acetaldehyde.
Our aim is to obtain a mechanistic insight into the birth of hematopoietic stem and progenitor cells in embryonic development and determine the contribution of these cells to the emerging hematopoietic and immune systems of the embryo.
My group focuses on the biology of megakaryocyte cells - large, rare cells found in the bone marrow that release blood platelets into the circulation and also produce many growth factors and other proteins that regulate blood cell development and the bone marrow microenvironment. We apply state-of-the-art single cell multi-omic approaches to clarify the cellular pathways by which megakaryocytes arise from haematopoietic stem cells. This is important as in certain malignancies, such as myeloproliferative neoplasms (MPNs), megakaryocytes develop abnormally and drive the key pathological features of the disease, including the harmful scarring that destroys the bone marrow in myelofibrosis, the most severe of the MPNs.
Single Cell Biology of Hematopoietic Stem- and Progenitor Cells in Blood Cancer and Ageing
Working closely with the craniofacial teams based in Oxford and other UK units, we specialise in the application of whole exome and genome sequencing to children born with a serious malformation of the skull termed craniosynostosis.
Our laboratory studies the mechanisms regulating normal blood stem and progenitor cell differentiation and how these are perturbed in blood cancers such as Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndromes (MDS). Our aim is to not only to understand fundamental biological principles about cell fate choice and differentiation and how they are corrupted in disease, but also to improve therapies for patients. We combine molecular and cellular studies on primary normal and leukaemic human blood stem/progenitor cells with studies in appropriate models. We use state-of the art genetic screens, transcriptional, epigenetic and immunological assays on highly purified cells and single cells. The PhD projects in our laboratory will provide a strong foundation in stem cell and cancer biology using leukaemia as a model, and in immunology and training in cellular, molecular and computational analyses with a focus on single cell methods.
Molecular Immunology, Immunity to Influenza and Ebola viruses
Combining computational biology, computational chemistry, and machine learning techniques with biological big data to unravel the higher genomic code of life.
Virus infection is a constant threat to the cells of all living organisms. To counter this threat, cellular receptors detect virus presence and activate potent antiviral immune responses. Some of these sensors of virus presence signal for the activation of innate immune genes, which in humans include type I interferons. These cytokines then alert neighbouring, uninfected cells and induce the expression of hundreds of genes, many of which encode proteins with direct antiviral function. Viruses in turn have developed strategies to counteract and evade detection and control by the innate immune system. As such, cells and viruses are in a dynamic arms race in which host defence mechanisms and viral counter-measures rapidly co-evolve. Our aim is to investigate the molecular mechanisms by which mammalian cells recognise and respond to infection by viruses.