Human embryos make sperm and eggs by first forming primordial germ cells (PGCs), but lab-grown versions of these cells fail to follow the normal developmental script. The problem is that scientists cannot yet replicate the precise epigenetic changes—chemical marks on DNA that control gene activity—that human PGCs undergo in the body. When these marks go wrong, infertility or germ cell cancers can result. This project aims to identify the proteins that drive those changes and then use CRISPR to activate the right genes in cultured stem cells, forcing them to become faithful copies of human PGCs. If it works, the team will have a reliable, accessible lab model for studying human germline development. That model could eventually serve as a screening platform for environmental or pharmaceutical factors that harm male fertility. It could also help explain how germ cell tumours arise. For now, this is fundamental science—no one is growing human eggs or sperm in a dish tomorrow. But past work on gene activation in stem cells has already shown the approach can kickstart PGC development, so the path from understanding to application is clearer than it might seem.
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Summary In mammals, the process of creating sperm and eggs is essential for starting a new life cycle. The first step in this development is the formation of primordial germ cells (PGCs) in the early embryo. These cells undergo changes in gene expression and profoundly remodel the epigenetic information associated with their DNA before commencing development towards sperm or eggs. Disruptions in this process can lead to infertility or germ cell cancer. Previous research, including studies by myself and others, suggests that the unique epigenetic changes in human PGCs are crucial for normal gamete and embryo development. Despite this, our understanding of human PGC development, especially in terms of epigenetic remodelling, remains largely elusive. The main obstacle hindering progress in this area is the lack of an accessible and efficient model system that fully replicates human PGC development in a laboratory setting. This project aims to identify proteins promoting human PGC development, understand how they work, and use this knowledge to recreate human PGC development in cultured cells. In this project, my team and I will build upon my prior studies focusing on human PGCs and model systems used to derive in vitro human PGCs in the laboratory. In current model systems, in vitro-derived human PGCs only partially follow the normal developmental path and exhibit abnormal gene expression. Our research focus will be on genes active in human PGCs but inactive in in vitro-derived germ cells. We hypothesize that activating a combination of these genes will promote normal development of in vitro-derived human PGCs. To test this, we'll use a CRISPR technique to activate individual genes or combinations of candidate genes and observe the impact on in vitro human PGC development. We'll particularly focus on factors promoting human PGC-specific epigenetic changes. The gene combination found to most efficiently promote hPGC development will be used to establish a novel model system for in vitro human PGC development relying on CRISPR-mediated gene activation. Simultaneously, we'll study the DNA and protein interactions of the identified candidates to understand their function. Importantly, my past research shows that activation of key transcription factor genes through CRISPR can initiate human PGC development in cultured cells, highlighting the potential of this approach. Our goal is to overcome the limitations of previous in vitro models and create an accessible stem cell-based system faithfully recapitulating human PGC development. This system will deepen our understanding of human germline development and potentially serve as a platform for deriving gametes from cultured cells in the future. In medical and pharmaceutical research, the established system could be a valuable screening platform for identifying risk factors affecting male reproductive health globally. Additionally, our research into the function of proteins in the human germline will enhance the understanding of germ cell tumor types originating from human PGCs. This project aligns with the BBSRC strategic delivery plan by providing insight into a fundamental human development process and establishing a transformative technology to enhance our understanding of diseases.
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