Clinical Research in Obstetrics & Gynaecology
Clinical research led by Gordon Smith (Professor of Obstetrics & Gynaecology) is focused on the analysis of clinical, biochemical and ultrasonic factors predictive of subsequent adverse outcome of pregnancy. Many of these outcomes are relatively uncommon and informative analysis requires large sample sizes, which are potentially very costly to collect. This problem is addressed by creative utilisation of secondary analysis of data. Key findings include: (1) the relationship between low maternal levels of a placentally derived protein (PAPP-A) in early pregnancy and the later risk of poor fetal growth, pre-eclampsia and stillbirth; and (2) the relationship between maternal serum levels of alpha-fetoprotein in the first half of pregnancy and the risk of the infant subsequently dying from sudden infant death syndrome in the first year of life.
Angiogensis and reproduction
The work of Dr Steve Charnock-Jones (Non-clinical Reader, Obstetrics & Gynaecology) focuses on the biology of the lining of the womb (the endometrium). This programme of work studies the role of the development of new blood vessels in the physiological control of menstruation and in the development of pathological conditions, such as endometriosis. Through this work, he has developed a new model of endometriosis which is being exploited for the assessment of novel medications for the treatment of this condition. This area of work has also extended into studying the implantation of the developing embryo in the womb and in the role of angiogenesis in the formation and development of the placenta. This has led to a successful collaboration with Graham Burton (Professor, PDN) who has interests in early placentation and the effect of varying levels of oxygen in early pregnancy in determining placental function.
Immunology of Pregnancy
The work of Dr Francesco Colucci (MD, PhD, Non-clinical Senior Lecturer, Obstetrics and Gynaecology) aims at understanding how immune cells impact on reproduction, cancer and transplantation. The common denominator of these three themes is the study of Natural Killer (NK) cell biology (including uterine NK cells, in collaboration with Professor Ashley Moffett’s group, Dept Pathology). NK cells have taken centre stage in modern medicine because they have a broad recognition system that detects molecules within the individual, between individuals and across genomes, such as: self-MHC during NK cell maturation; stress-inducible molecules during infections or tumour transformation; allogeneic antigens on tissue grafts and the placenta; viral products. The nature of these interactions sets the threshold for the activation of diverse functions, which vary with the subset of NK cells and their surrounding microenvironment and span from swiftly killing abnormal cells, to releasing growth factors that participate in placental development, and to making inflammatory factors that help fighting infections. The programme of work has three specific objectives:
- define how maternal recognition of paternal antigens is related to reproductive success;
- characterize the key signals immune cells use to recognise tumours;
- determine the signalling pathways within immune cells responsible for the outcome of cell transplantation.
Genomic Imprinting in Reproductive Biology
Genomic imprinting is a form of epigenetic gene regulation in mammals which results in the copy of either the mother or the father being turned off. The “imprinted genome” includes less than 1% of the human genes but is essential for normal development and influences key physiological pathways that impact on the health of the mother and the baby. Research by Dr Miguel Constancia (Non-clinical lecturer, Obstetrics & Gynaecology) and Dr Anne Fergusson-Smith (Reader, PDN) aims at unravelling how imprinting works at the various levels, using multi-disciplinary approaches that include genetics, molecular biology, developmental biology, physiology and animal modelling. Researchers want to know how imprinted genes control pre and postnatal nutritional resources in several organ systems, from the placenta to the brain, and in the context of the developing organism. Other main interests include the study of imprinting defects during pregnancy that impact on the growth trajectory of the baby and the wellbeing of the mother (e.g. intra-uterine growth restriction and overgrowth, maternal metabolism, pre-eclampsia, cancer). Research is also being focused on the dynamics of epigenetic marking systems, how these are influenced by environmental factors, and links with early growth programming, metabolism and disease risk in later life.
Fetal growth and metabolism
Work by Prof Abigail Fowden, Dr Dino Giussani and Dr Alison Forhead (Professor, Reader and Lecturer, respectively, PDN) has shed light on the role of the hormonal system producing cortisol (the hypothalamo-pituitary adrenal axis) in both fetal preparation for birth and in the control of the onset of labour. Epidemiological studies around the world have suggested that the environment in the womb may be a critical determinant of cardiovascular and metabolic predisposition towards a range of diseases in later life, in particular those of the cardiovascular system. Biological studies of the mechanisms that link the intra-uterine environment have suggested that the explanation may lie in activation of the HPA axis by acute and chronic physiological stressors, in particular arterial hypoxaemia. Studies have also addressed the association between oxidative stress and cardiovascular and endocrine function in later life.
The mechanisms that allow growth of the antigenically foreign conceptus without stimulating rejection by the mother’s immune system is one of the most fascinating questions in immunology. The work of Dr Ashley Moffett and Dr Andrew Sharkey takes this further by studying the role of the maternal uterine immune system in regulating the process of placentation. Specifically, they address how the dominant population of uterine leukocytes, Natural Killer (NK) cells recognise MHC Class I ligands on fetal trophoblast cells and how might this result in altered trophoblast function. Hence, their view of the maternal-fetal relationship does not consider the placenta as akin to an allograft that must avoid rejection by maternal T cells. Instead, they have defined several molecular recognition systems whereby cells of the innate immune system discern and respond to the placenta.
Cancer of the Female Reproductive organs
Over 80% of patients with ovarian cancer respond to primary chemotherapy treatment. However, the majority of patients develop recurrence within two years of diagnosis and die from chemotherapy-resistant disease. Work led by Dr James Brenton (Cambridge Research Institute and Department of Oncology), is focused on understanding clinically relevant mechanisms of drug resistance by combining translational clinical trials with in-vitro functional studies. Work by Mr Ahmed Ahmed (Oncology and Obstetrics & Gynaecology), has identified a novel pathway of clinical paclitaxel resistance in ovarian cancer. Dr Helena Earl (Department of Oncology) and Dr Brenton have designed translational ovarian cancer studies in which gene expression analysis of serial biopsies was used to identify predictive markers of treatment response. Dr Evis Sala (Department of Radiology) has ongoing studies to advance the understanding of in vivo response to chemotherapy in ovarian cancer or radiotherapy in cervix cancer using dynamic contrast MRI. Professor Bruce Ponder (Department of Oncology), in collaboration with Professor Doug Easton (Department of Public Health) have set up large international collaborations in breast and ovarian cancer to identify novel genetic associations. Their work on whole genome association study for breast cancer resulted in the identification of novel susceptibility loci that were independently validated in large case-control studies. Paul Pharoah, Department of Oncology, is the leader of the Ovarian Cancer Association Consortium to conduct a genome wide association study in ovarian cancer.
Research led by Professor Margaret Stanley (Department of Pathology) has unraveled important insights into the in vivo mechanisms of cervical cell-mediated immunity against HPV infections. Dr Nick Coleman (Department of Pathology) has discovered novel protein biomarkers to improve early diagnosis of pre-malignant stages of cervical cancer. Prof Carlos Caldas (Department of Oncology) is Research Director of the Cambridge Breast Unit. Work led by Prof Caldas has resulted in the discovery of novel genetic prognostic signatures in ER positive breast cancer. He leads the CancerGRID national project that is aimed at developing software tools to combine clinical and molecular data to facilitate high quality translational studies. Dr Helena Earl leads a national translational trial in breast cancer in which gene expression analysis of serial biopsies will be used to indentify novel predictive markers of chemotherapy response. Paul Edwards (Department of Pathology) has discovered the first balanced chromosomal translocation in breast cancer involving the neuregulin gene. Dr Luke Hughes-Davies, Department of Oncology, is studying the role of the interaction between EMSY and BRCA2 in breast cancer.