International Business Department           Liu Bojia           September 30, 2024

  There is a complex process of embryonic development that takes place between a fertilised egg and finally becoming a full-fledged individual. One might think that once an embryo has begun to develop, it would be in a relentless rush to push through each step in a step-by-step fashion. In reality, however, embryonic development involves a series of cellular differentiations and special events, including a dormant period that suspends development.

  According to the Waddington model, the development of the embryo is like a small ball rolling down a hill, from an undifferentiated and unstable state at the top of the hill to the basin where it becomes a terminally differentiated form. However, this ball rolling down process can be paused, and many mammals have evolved mechanisms to temporarily retard embryonic development, allowing the embryo to stagnate at the blastocyst stage and preserving the embryo.

  This embryonic dormancy can be triggered by hormonal changes, starvation, and other factors, and under unfavourable conditions, the suspension of embryonic development can help to enhance the survival of both the embryo and the mother. During this time, the embryo is left free-floating, and when conditions are favourable the embryo restarts the developmental process again. Although scientists have observed this phenomenon in many mammals, the vast majority of studies have concluded that human embryos do not have a developmental ‘dormancy’ period.

  In the new study in Cell, scientists at the Max Planck Institute for Molecular Genetics made a bold attempt to artificially introduce some external intervention to see if they could trigger a pause in the development of human embryos. As it turns out, the molecular mechanisms that control the embryo's ‘dormancy’ could potentially work in human embryos as well, which means that in the future researchers could regulate embryo development in vitro and increase the success rate of in vitro fertilised embryos.

  According to the paper, due to ethical concerns, the new study did not directly use human embryos as experimental subjects, but rather explored the use of human stem cell-based blastocyst models. In previous studies, the authors had found that the mTOR pathway is a major player in mouse embryo development, and that simply inhibiting mTOR signalling in mouse blastocysts alone was sufficient to cause a developmental pause-like phenomenon in the embryos, and could even limit the developmental progress of the blastocysts within a few weeks.

  Based on these findings, the authors attempted to add an mTOR inhibitor to a human stem cell blastocyst model, and the mTOR downregulated blastocysts, which had smaller blastocysts along with a lower number of trophoblast-like cells, were found to be more resistant to the mTOR inhibitor compared to untreated controls. These differences indicate that the developmental process of blastocysts is retarded and inhibited.

  In addition to this, the down-regulation of mTOR reduced the expression of proteins associated with blastocyst implantation, reducing the chances of blastocyst implantation into the endometrial cell layer and further limiting the embryonic development process. ‘This means that we were able to trigger a dormancy-like phenomenon in human embryos by altering mTOR.’ Dr Aydan Bulut-Karslioglu, corresponding author of the study, said that this dormancy is reversible, and that by reactivating the mTOR signalling pathway, the blastocyst model goes through the normal developmental steps.

  The authors suggest that in humans, as in other mammals, there is still an internal mechanism to slow down the development of the embryo, except that it is not actively activated during human pregnancy. But as long as this ability exists, it is expected to have important implications for reproductive medicine, such as for embryos fertilised in vitro, where researchers can regulate mTOR signalling to trigger embryo dormancy, providing a longer window of time for assessing the health of the embryo and ensuring its survival and subsequent healthy development.