Joan Hunt Senior award lecture: New tools to shed light on the ‘black box’ of pregnancy

Correct establishment of the placenta is critical to the success of a pregnancy, but many of the key events take place during or shortly after implantation and are inaccessible for study. This inaccessibility, coupled with the lack of a suitable preclinical animal model, means that knowledge of human early placental development and function is extremely limited. Hence, the first trimester is often referred to as the ‘black box’ of pregnancy. However, recent advances in the derivation of trophoblast stem cells and organoid cultures of the trophoblast and endometrium are opening new opportunities for basic and translational research, providing for the first time cells that faithfully replicate their tissue of origin and proliferate and differentiate in culture in a stable and reproducible manner. These cells are valuable new tools for investigating cell-lineage differentiation and maternal-fetal interactions, but become even more powerful when combined with advances in bioengineering, microfabrication and microfluidic technologies. Assembloids of the endometrium comprising various cell types as model systems to investigate events at implantation, and placentas-on-a-chip for the study of nutrient transfer or drug screening are just two examples. This is a rapidly advancing field that may usher in more personalised approaches to infertility and pregnancy complications. Many of the developments are still at the proof-of-principle phase, but with continued refinement they are likely to shed important light on events that are fundamental to our reproduction as individuals and as a species, yet for ethical reasons are hidden from view.