Professor Gordon Smith
Clinical Research in Obstetrics & Gynaecology
Clinical research led by Gordon Smith (Professor of Obstetrics & Gynaecology and Honorary Consultant in Maternal-Fetal Medicine) is focused on the analysis of clinical, biochemical and ultrasonic factors predictive of subsequent adverse outcome of pregnancy. Many previous studies have used secondary analysis of diverse data sources, including research datasets (such as the ALSPAC and MoBa cohorts), administrative datasets (such as Scottish national birth registries, and routine NHS data) and record linkage. Although such studies are on-going, a current major focus is a prospective cohort study of unselected nulliparous women who attended the Rosie Hospital for antenatal care between Jan 2008 and July 2012. A total of 4,500 women were recruited. They had ultrasound scans performed at booking, ~20, ~28 and ~36 weeks gestational age and blood was obtained at the same time. At the time of birth, the placenta and membranes were systematically sampled. Following birth, the case record was reviewed and the outcome of the pregnancy ascertained. The study has led to assembly of a database and biobank and a number of projects are on-going to use this resource to develop improved methods of Obstetric risk assessment.
Angiogensis and reproduction
The work of Prof Steve Charnock-Jones (Professor of Reproductive Biology, Obstetrics & Gynaecology) focuses on the biology blood vessels and oxygen in of the lining of the womb (the endometrium) and the placenta. This includes studies of the role 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 also extends to studying 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 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 Reader, 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.
Epigenetics and 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 senior lecturer, Obstetrics & Gynaecology) and Dr Anne Ferguson-Smith (Professor, Genetics) aims at unravelling how imprinted genes and more globally epigenetic mechanisms of gene regulation work to sustain an healthy pregnancy 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 Development
Intrauterine growth and development have important roles in determining life expectancy. They affect not only neonatal viability but also health and disease risk much later in adult life. Research by Professor Abigail Fowden, Professor Dino Giussani and Dr Alison Forhead (all of PDN) investigates the biological mechanisms regulating fetal growth and development during normal and sub-optimal intrauterine conditions common in compromised human pregnancies. They are also interested in the long term physiological consequences of changes in the intrauterine environment that may explain the early life origin of adult disease. In particular, their work focuses on the developmental effects of altering fetal availability of oxygen, nutrients and hormones and on the outcomes that these changes have on the phenotype of the offspring and its risk of developing cardiovascular, metabolic and endocrine diseases in later life. The research takes a comprehensive approach to development from the gene to the systems levels, integrating the maternal, placental and fetal contributions to pregnancy outcome. Most recently, the research has concentrated on the roles of oxidative stress and stress hormones in programming development with particularly emphasis on the treatments that may alleviate some of the worst health outcomes of a poor intrauterine environment.
Reproductive immunology
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 Prof Ashley Moffett and Dr Andrew Sharkey in collaboration with Dr Colucci 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 (Cancer Research UK Cambridge Institute and Department of Oncology), is focused on identifying predictive biomarkers for personalized therapy for women with ovarian cancer. By carrying out molecular studies on translational clinical trials and in-vitro functional studies his group identified that TP53 mutations are ubiquitous in the commonest form of ovarian cancer and has developed personalized assays of response and recurrence based on circulating tumour DNA. Dr Helena Earl (Department of Oncology) and Dr Brenton have designed translational ovarian cancer studies in which genomic analysis of serial biopsies was used to identify predictive markers for response to the chemotherapy drug paclitaxel, and methods for measuring intratumoural heterogeneity which may predict worse outcome.
The Centre for Cancer Genetic Epidemiology hosts three research programmes investigating the inherited basis of breast and ovarian cancer. Professor Easton and Professor Pharoah and Dr Antonis Antoniou set up and lead the Breast Cancer Association Consortium, the Ovarian Cancer Association Consortium and the Consortium of Investigators of BRCA1/2. These multi-centre international consortia have been successful in identifying over 70 genetic loci associated with an increased risk of breast cancer, 12 loci associated with ovarian cancer risk and several loci that modify the breast and ovarian cancer risks due to deleterious mutations in BRCA1 and BRCA2.
Research led by Professor Margaret Stanley (Department of Pathology) has unravelled 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.. Dr Helena Earl leads a national translational trial in breast cancer in which gene expression analysis of serial biopsies will be used to identify 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.
Understanding normal and abnormal function of the placenta
The Centre for Trophoblast Research (CTR) is an initiative that serves to promote and integrate research into maternal-fetal interactions across the University and with the Babraham Institute. Primarily a virtual centre, it embraces over 20 Principal Investigators (some of whom are listed above) and their research teams embedded within various basic science and clinical departments. Together, these constitute an unparalleled breadth of expertise that ranges from the earliest stages of blastocyst differentiation through implantation and immunological interactions to placental development and function, large and small animal models of feto-placental physiology, and the epidemiology of complications of pregnancy. We are therefore able to take a uniquely comprehensive and integrated approach to the underlying mechanisms for, and assessment of, placental dysfunction. For example, members recently identified that interactions between paternal antigens on the invading trophoblast cells and receptors on the maternal immune cells affect the blood flow to the fetus, and hence pup weight, in the mouse.
The CTR has also provided a national and international lead in high-quality training of new investigators through its programme of Next Generation Fellowships and graduate studentships, along with running an annual course in Placental Biology aimed at post-doctoral researchers. It also organises an annual scientific meeting that acts as a UK focus for researchers in this area of reproductive biology, and strategic workshop meetings that bring together international experts from different fields to discuss key topical concepts in an innovative manner.
Full details of the CTR’s activities and scientific advances can be found at www.trophoblast.ac.uk.
