My research interests are driven by a desire to make pregnancy and parturition safer. My group conducts enquiries into the fundamental structure and function of the materno-fetal interaction and has carried out research into pathologies of pregnancy such as hydatidiform mole, failed implantation, poor placentation, intrauterine growth retardation, auto-immune diseases of pregnancy, preterm rupture of fetal membranes and pre-eclampsia. In a regulatory setting the scholarship required to carry out research into the scientific basis of human early development allows insight into the toxicity and teratogenicity of chemicals in the environment such as pesticides and I give scientific advice in that area.
Morphogenesis of the Placenta
The placenta is largely composed of a chorionic villous tree with a branching organisation. In humans this is covered by a syncytium (a layer of fused cells). This cell layer is epithelial and over 10 m² in area by the end of pregnancy. The syncytialising process may be brought about by viral fusion proteins expressed by human endogenous retro-virus gene-sequences (HERVs) that merged with the human genome at early stages of primate evolution. As cells merge their initially separate cytoskeletons take up new configurations and their role in morphogenesis is constrained. We have made several experimental and descriptive studies to analyse these processes. In so doing we have established a number of proteins as markers of cell lineage at the maternofetal interface which are widely used by placentologists. We are investigating the effects of these viral genes.
Pathology of the placenta
In human development implantation is interstitial and an invasive process establishes a nutritive and respiratory placental surface composed of fetal tissue in contact with maternal blood. In pregnant women the depth of invasion is greater than in many other mammalian species and limited invasion may lead to failed implantation, poor placentation and significant diseases of pregnancy.
We are currently focussing our efforts on the condition pre-eclampsia which untreated can cause maternal and fetal fatalities. Of interest are the binding of hormones of pregnancy and molecules associated with proteolysis to caveolae (endocytosis related intuckings of plasma membrane) which may permit extremely localised effector function in the very carefully choreographed mechanisms of implantation and placentation. We are doing this to resolve a proteolysis paradox which can be simplified in the following question. How does a tiny proteinaceous embryo implant by digesting a path into a massive proteinaceous uterus without self-destruction by autolysis? Transport of passive immune antibodies across the placenta by selective receptor mediated endocytosis has been a subject of research in our lab. Tony Whyte and I were the first to identify the coated vesicle protein clathrin in the human body. Nick Bright and I showed that cytotrophoblast was non-permissive, establishing the reason for the delay in antibody transport from mother to fetus until towards the end of the first trimester when that layer becomes incomplete.
Survival of the Fetus as an allograft
Since the 1950s there has been widespread awareness of the avoidance of transplant rejection mechanisms by the "partly genetically foreign" fetus. This awareness, owing to the writings of immunologist and Nobel prize-winner Sir Peter Medawar, has encouraged biomedical scientists to strive to understand the mechanism(s). Our research into "the interface" between the mother and her fetus has been shown there to be a series of interfaces. These are anatomically complex and still incompletely understood. Our recent work has identified a mosaic unicellular sheet of cells lining the basal plate (the allo-epi-endothelium). This has required a reanalysis of the extent of co-operation at the materno- fetal lining of the large blood-filled sinus (the intervillus space) essential to fetal well-being. Major diseases of pregnancy such as pre-eclampsia have an immunological and genetic component and we are entering these fields presently.