The Genetic Component to Infertility and Early Developmental Failure

Our goal is to elucidate the genetic causes of failure of human early embryo development. We will integrate human embryology, genetics and stem cell biology, fields in which we are internationally recognized experts, to achieve breakthroughs that will overhaul the way we look at our own early development. We currently investigate the DNA of patients that never have embryos of good enough quality to transfer after IVF. The effect of the DNA variants we identify in these patients will be investigated in embryos; furthermore, we will search for the causes of chromosomal abnormalities, as well as the effect of changes in the mitochondrial DNA on embryo development and fertility. In the first and second work package of the project, we will unveil why embryos fail to develop during the first four days of development, in embryos donated as well as created especially for research. We will apply techniques that have not been used on embryos before to discover which genes are important for early development. For the first time, we will trace proteins that we suspect are involved in embryo growth, while watching the live embryos grow. In the third work package, we will investigate embryo loss at the next developmental stage (day 4 to day 6) using advanced gene manipulation. We will do this in human preimplantation embryos and in so-called ‘stem-cell derived’ embryos, which are obtained by allowing stem cells to aggregate into cell clumps mimicking embryo development. Finally, in the fourth work package we will study implantation using endometrial organoids, made from stem cell aggregates that mimic the inside of the uterus. We will then allow (stem cell derived) embryos to implant in the organoids to study implantation. As the legal boundary for culture of human embryos is
14 days, we will study embryo development beyond that point using stem-cell derived embryos. The
unique advantages we hold as a group are (1) a large stem cell biology lab with a unique collection of human embryonic stem cell lines, and the know-how to obtain induced pluripotent stem cells from patients; (2) our intense collaboration with the CRG UZBrussel, one of the largest Belgian IVF centres, to obtain embryos for research as allowed by the liberal legal Belgian framework, and (3) with the Brightcore DNA and RNA sequencing facility. The answers reached will improve diagnosis of infertility, which nowadays often remains unexplained, and significantly change fertility treatments such as IVF. Our novel implantation model will help us gain important new knowledge about why implantation fails and early pregnancy is repeatedly lost, which at present remains poorly understood.