Newcastle Fertility Centre at Life in collaboration with University of Cambridge, Loke Centre for Trophoblast Research
Our over-arching goal is to improve outcomes of assisted reproductive technologies for the treatment of infertility and for the prevention of disease.
The three main aims of this research are:
- Develop and optimise clinical treatments to minimise transmission of mitochondrial DNA mutations (change in genes) from a mother to her child.
- Investigate how the mitochondrial DNA mutations are transmitted from mother to child following mitochondrial donation.
- Investigate the impact of the mitochondrial DNA mutations on fertility.
Cardiff University School of Biosciences
At fertilization, the sperm activates the egg to start development. We have previously shown that a sperm-specific protein, PLCzeta, causes a series of calcium pulses in the egg that trigger egg activation and embryo development after IVF and intracytoplasmic sperm injection (ICSI). PLCzeta may be deficient in the sperm of some men and this can explain many cases of failed fertilization after ICSI. In this project we aim to provide the basis for a solution to the problem of failed fertilization. We will make new versions of human PLCzeta and inject them in human eggs that have failed to fertilize after IVF or ICSI. We shall test their effectiveness in causing calcium changes and in activating embryo development. In addition, we have recently found that ability of human eggs to undergo calcium oscillations depends upon the activity of mitochondria. We shall also investigate ways of improving mitochondrial activity to make eggs more sensitive to PLCzeta and more sensitive to other agents such as strontium which can promote calcium oscillations and egg activation. In the course of this project we intend to provide new ways of causing multiple calcium changes in eggs to improve the efficiency and success rates of fertilization after ICSI.
Centre for Reproductive Medicine Coventry, University of Warwick, University of Edinburgh
We aim to understand differences between eggs and embryos that develop normally and those that do not. Many eggs and embryos have problems that interfere with development and limit IVF success rates. Basic scientific information is lacking but is essential to find out how to improve treatments. Our research focuses on how genetic and non-genetic information is structured and organised during egg maturation, fertilisation and embryo development. Having shown how error-prone these critical stages are, we are keen to understand how embryos respond to errors and recover from abnormalities that would be lethal in other cell types. To do this, we study eggs and embryos unsuitable for use in treatment, such as immature or unfertilised eggs, and embryos that do not develop well. We use frozen eggs and embryos, if patients change their minds and donate them to research. We also use occasional fresh eggs donated directly to research through egg sharing. In research, we use novel molecular techniques to show how cell parts are organised in eggs and embryos, and to analyse genetic and non-genetic content in embryonic cells. We also collaborate with others whose research tools give complementary approaches, such as endometrial organoids or electron microscopy.
Guys Hospital, London
Our work is aimed at both developing new approaches to diagnostic testing of preimplantation embryos and increasing knowledge of the biology and genetics of early embryo development. This is with a view to understanding the basis of successful pregnancies and improving the chances of healthy offspring for couples undergoing preimplantation genetic diagnosis (PGD) and IVF procedures. We intend to work over the next three years, further developing this approach. Our aims will be: a) To improve the chances of healthy offspring by introducing and developing better strategies and protocols for embryo culture and testing, b) To explore new avenues in modelling early human development to understand the biology and genetics of human embryos, c) To investigate the potential impact of air pollution on early embryo development and increased miscarriage rates.
Living Systems Institute
One week after fertilization the embryo implants into the uterus and prepares to produce the different tissue layers that will make the body. This formative period is inaccessible and therefore remains very poorly understood. It is also the major period of pregnancy failure. Recently human embryonic stem cells have been shown to form structures called embryoids that appear very similar to the early embryo. Ongoing research is finding ways to support development of embryoids into the equivalent of the second week of embryogenesis. A critical question is how well do stem cell embryoids resemble actual human embryos? Our studies aim to answer this by: (i) side by side comparisons of embryoid and embryo cultures, using a series of techniques, including sequencing analyses of individual cells; (ii) combining embryoid and embryo cells to determine how well they intermingle and work together; (iii) creating specific genetic modifications to test functions identified in embryoids; (iv) deriving stem cells from different stages of cultured embryos which should correspond with stem cell types obtained from embryoids. These studies will lead to increased knowledge of human embryo development, and may enable improvements in assisted conception through better measures of embryo quality and optimization of culture conditions.
Francis Crick Institute Laboratory
The uterine environment suffers a radical remodelling during the implantation window, which is hypothesised to be essential for the attachment, invasion, and development of human embryos. While the cellular and biochemical changes in the uterus have received wide attention, the changes on its mechanical properties (stiffness and viscoelasticity) have remained unexplored.
Work from our laboratory and others shows that the mechanical properties of tissues are essential for their development. The aim of our study is to understand how the mechanical environment of the uterus interacts with the embryo for its correct development. We hypothesize that the changes in the uterus during the implantation window could provide a ‘mechanical gate’ for healthy embryos to develop.
To test our hypothesis, we developed a hydrogel that mimics the mechanical properties of the uterus and allows for the 3D development of human embryos peri-implantation. Our system is modular, which will allow us in the future to incorporate cells from the uterus or to mimic in the laboratory the uterine environment in conditions related to infertility. With this approach, we aim to go beyond the prevalent embryo-centric vision of implantation, to incorporate the complexity of its interactions with the dynamic and complex uterine environment.
University of Cambridge, Loke Centre for Trophoblast Research
The aim of this project is to understand how human embryo cells become specialised and organised into functional tissues at the time of implantation in the maternal uterus, which undergoes remarkable remodelling. Despite valuable research uncovering mechanisms responsible within animal models, differences between species make the process of implantation unclear within humans. Uncovering these mechanisms is essential to inform maternal and fetal health, pregnancy complications, developmental disorders, and stem and progenitor cells. In the past decade we have made advances in human genome editing, live imaging and multi-omics analysis, which have revealed fundamental mechanisms regulating the first and second cell fate decisions prior to implantation. More recently, we developed ex vivo models of human implantation into maternal endometrial tissue, and thus we are perfectly poised to decipher this next step of human development. We will map at unprecedented resolution the cell lineages of human embryos and provide transformative insights into genetic and epigenetic regulation, signalling crosstalk, tissue remodelling and morphogenesis. We aim to generate a developmental blueprint for the earliest stages of human life. A key outcome of this fellowship will be a preclinical ex vivo platform to accelerate development of safe and effective therapeutic interventions. This will enable systematic testing of emerging therapies, including safety and efficacy of heritable genome editing, refinement of mitochondrial replacement therapy, treatments for endometrial and placental disorders, and evaluation of drug toxicity. The physiological understanding of human embryogenesis will transform the next generation of stem cells, stem cell-based embryo models and organoids.
Hull and East Riding Fertility
Over 50% of women in the UK of reproductive age are overweight (BMI 25-29.9 kg/m2) or obese (BMI ≥ 30 kg/m2). These conditions have a negative impact on female reproductive health in terms of conception rates, miscarriage, maternal, fetal and neonatal complications (Balen & Anderson 2007) with possible long-term implications for the health of the offspring.
Such problems are apparent whether conception occurs spontaneously or following Assisted Reproductive Technologies (ARTs). An increase in BMI is associated with a reduced chance of conception even in regularly-ovulating women. Oocyte number (Maheshwari et al 2007) and quality assessed morphologically have also been reported as lower in overweight and obese women. Most reports indicate a decrease in embryo quality as BMI increases, though a recent study reported no change (Robker et al 2009) with the caveat that the number of patients was small.
Interestingly, Styne-Gross et al (2005) reported that BMI in 536 donor-oocyte recipients was not correlated with implantation rate, ongoing pregnancy or miscarriage, suggesting that BMI did not compromise endometrial receptivity but more likely, influenced embryo quality.
A fundamental problem with studies on embryo quality is their reliance on morphological assessment which is a notoriously unreliable procedure, and there is a need for objective, quantitative biomarkers of oocyte and embryo quality.
In our past research we have devised a range of non-invasive metabolic markers, notably, the depletion and appearance of key compounds from the culture medium, particularly glucose, pyruvate, lactate and amino acids as well as oxygen, the consumption of which provides a global marker of overall energy production. All these techniques may be applied to individual oocytes and embryos (e.g. Sturmey et al 2009a) and provide non-invasive quantitative markers of embryo health. For example, human embryos with a pyruvate consumption distributed in the mid to lower range are the most likely to give rise to a pregnancy following embryo transfer (Turner et al. 1994), while Lopes et al (2007) found that oxygen consumption predicted the viability of cattle embryos post-transfer.
Most notably, we have shown that the pattern by which amino acids are depleted or appear in the culture medium (non-invasive Amino Acid Profiling) is predictive of the capacity of human embryos to develop to the blastocyst stage in vitro (Houghton et al 2002) or give rise to a pregnancy following transfer in clinical IVF (Brison et al 2004).
We have subsequently demonstrated that metabolic activity is correlated with molecular damage (Sturmey et al 2009a); embryos with lower levels of damage have characteristically low metabolic activity. Thus, embryos with the highest viability show lower depletion and appearance of amino acids. This observation and other data were used to formulate the 'quiet embryo hypothesis' (Leese 2002; Sturmey et al 2009a) which proposed that viable embryos have less molecular and cellular damage than those which arrest and a reduced need to take up nutrients for repair processes.
Leese et al (2007) extrapolated these findings to animal models; especially domestic ruminants, which indicated that a high level of feeding prior to and during conception leads to adverse developmental outcomes; observations which have been linked to the metabolism of the early embryo. Furthermore, we have identified a metabolic role for endogenous triglyceride during oocyte and embryo development in domestic species (Sturmey et al 2003). Thus, we have shown that the amount and composition of triglyceride in the egg and embryo can be modified by the environment in which they develop; using an in vitro model, cattle embryos can be induced to take up significant triglyceride from the culture medium.
The long term implications of aberrant triglyceride accumulation in human eggs and embryos are unknown. On the basis of these data, we proposed that one consequence of the high plane of nutrition of obese women (and those with diabetes: Moley et al 2001) could be nutritional enrichment of the periconceptual environments (follicular, oviductal and uterine).
Strong evidence of such enrichment in the human has been provided by Robker et al (2009) who reported significant positive correlations between BMI and the ovarian follicular content of glucose, lactate, triglycerides, insulin and C-reactive protein. We hypothesise that periconceptual enrichment promotes an active embryo metabolic phenotype which may compromise embryo health and lead to the reduced fertility and increased miscarriage seen in OVOB patients.
In addition, there is strong evidence that nutritional stress on the embryo can have major consequences for fetal and neonatal health (Leese et al 1998) and long term health implications for the offspring. Of special concern is the recent report of Ceelan et al (2008), who found that IVF children had elevated blood pressure compared with those conceived naturally, which we hypothesise, indicates that a sub-optimal nutritional environment may have long term health consequences. Similar effects might be present if the embryo develops in the nutritionally enriched environment of OVOB women.
