MRC WIMM PRIZE STUDENTSHIPS 2022
We study the cellular interactions and molecular events that lead to the development of high affinity and protective antibodies during humoral immune responses. Our main focus is the germinal centre reaction.
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.
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).
We study how iron and anaemia influence immunity and infectious diseases. Our research inspires therapies that control iron physiology to improve immunity, combat infections and treat disorders of iron metabolism. We work across the disciplines of immunology, haematology and global health, utilising in vitro, in vivo and human studies, and collaborate extensively to translate our mechanistic discoveries into clinically relevant progress.
De novo mutations (DNMs) are a significant contributor to human disease, affecting ~1:300 new births. We study the mechanisms by which these spontaneous mutations arise in the first instance, concentrating on the tissue where most originate, the human testis. We aim to understand why some pathogenic mutations arise more frequently than others and how the mechanisms regulating the production of sperm influences this process.
Using state-of-the-art laboratory and computational approaches to understand how mammalian genes are switched on and off during development and differentiation and how this goes awry in human genetic diseases.
The Haematopoietic Stem Cell Biology (HSCB) Laboratory is focused on understanding how the normal haematopoietic stem/progenitor hierarchy is disrupted during the development of myeloid malignancies. Our overarching aim is to improve the management of myeloproliferative neoplasms and related conditions through better monitoring and therapeutic targeting of malignant stem cell populations.
Nerlov Group - Single Cell Biology of Hematopoietic Stem- and Progenitor Cells in Blood Cancer and Ageing
The focus of the Nerlov laboratory is combining single cell biology (single cell RNAseq, ATACseq and functional analysis) with advanced mouse genetics to study hematopoietic stem– and progenitor cells in normal development and during ageing.
Our work has shown that metabolism both generalized and intrinsic to blood stem cells unleashes reactive metabolites such as the aldehydes – formaldehyde and acetaldehyde. Such metabolites damage DNA causing the stem cells to die or to accumulate cancer causing mutations. Fortunately, a two-tier protection mechanism ensures that these aldehydes do not irreversibly damage these stem cells.
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.
Leukaemia is the commonest childhood cancer and occurs when blood formation (haematopoiesis) is perturbed because of a genetic/molecular abnormality in haematopoietic stem and progenitor cells (HSPC). Human haematopoiesis is a dynamic process that starts in utero at 2-3 post-conception weeks (pcw) becoming established sequentially in the yolk sac, aorto-gonado-mesonephros (AGM), fetal liver (FL), and finally fetal bone marrow (FBM), which becomes the dominant haematopoietic organ at birth and remains so throughout postnatal life. Determining the characteristics and regulators of site- and stage-specific variation in haematopoiesis is key to understanding childhood blood disorders that originate before birth.
Our work is focused on the causes of skull malformations, particularly craniosynostosis, the premature fusion of one or more sutures separating the bones of the skull vault. A complex network of developmental mechanisms is involved in patterning and maintaining this complex system of bones, and a variety of genetic mutations can affect these processes to cause serious skull malformations. Oxford is a leading national referral centre in the surgical treatment of these malformations, enabling us study the entire process by which these arise from patient to mutation, and from mouse model to molecular pathogenesis.
Wilkinson Group - From basic biology to novel translational applications of haematopoietic stem cells
The Wilkinson group focuses on the biology and translational applications of blood-forming haematopoietic stem cells (HSCs). In cancer evolution and its therapy, HSCs may play the part of the villain or the hero. As a long-lived stem cell population, HSCs gradually accumulate genetic mutations and are therefore thought to be a cell-of-origin for several haematological malignancies. This has recently been strikingly seen in the clinical observation of Clonal Haematopoiesis of Indeterminate Potential (CHIP), where the peripheral blood cells become increasingly derived from a single HSC clone. CHIP is considered a pre-malignant state because it increases the risk of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), and it is also a major risk factor for therapy-related myeloid malignancies. The genetics of this pre-malignant state are now well characterized, however, the cellular and molecular mechanisms are still incompletely understood.