Decoding the intrinsic programme of human embryo development

The human body consists of more than 250 specialised cell types. During embryonic development, this great diversity arises from a small group of equivalent cells known as the epiblast. In humans, the first specialised cell types develop from the epiblast over about 2 weeks, in a specific order and at specific time points. This period of development is critical for embryo formation and remarkably vulnerable as about 60% of pregnancies fail around this stage. Thus, a detailed understanding of this process is essential for both basic and applied research, yet remains limited due to restrictions on human embryo work. Decades of research in developmental biology have identified signalling molecules that instruct epiblast cells to become specialised. Nevertheless, these signals are often present well before the specialised cells emerge in the embryo, suggesting they are insufficient to fully explain how the human body develops. My key question is how cells respond to instructive signals at the right time during embryonic development. To address this, I established an experimental method reproducing early human development using pluripotent stem cells (hPSCs) in a dish. This is a simple and amenable for manipulations model to study human embryogenesis that avoids the use of actual embryos. Using my stem cell model, I discovered that the presence of a signal is insufficient to make them specialised. The stem cells must be prepared to respond to the signal (“competent”), otherwise they do not react or react wrongly. Moreover, they become responsive to different signals only at specific time points during development. Therefore, there must be a molecular mechanism “counting time” in stem cells that instructs them to become responsive at the right moment. I identified a cascade of regulatory proteins (transcription factors) sequentially activating each other with specific timing, acting as an internal timer in the human embryo. I propose that this internal timer instructs the epiblast to become responsive to the right signals at the right time. I hypothesize that the order in which the epiblast becomes responsive to different signals defines the timing when the respective specialised cell types emerge. In my project, I will reconstruct the molecular mechanisms that enable stem cells to respond to specialising signals at the right time. First, I will identify the components of the internal timer that instruct signal responsiveness. Second, I will investigate the instructive mechanism and how its failure leads to known human developmental defects. Finally, I will test how this system enables the stem cells to respond to signals inducing specialisation. Together, these mechanisms form an important developmental programme responsible for the formation of the human body, which has been difficult to study due to the lack of suitable experimental systems. My research will advance our understanding of early human development and developmental disorders. Importantly, knowledge of specialisation mechanisms will facilitate the establishment of efficient methods for generating specialised cells from stem cells in a dish for biomedicine, drug discovery, and disease modelling. Furthermore, my research will reveal the fundamental principles of cell specialisation that govern not only embryo development, but also physiological cell turnover and regeneration. Failures in these processes may contribute to degenerative diseases and age-related decline. Therefore, my work will facilitate the development of novel treatments and regenerative therapies. Ultimately, my research will contribute to fundamental and biomedical research for the benefit of society.