A ‘pause button’ in human development

In some mammals, the timing of embryonic development can be adjusted to increase the chances of survival for both the embryo and the mother. This process, known as embryonic diapause, typically occurs at the blastocyst stage, just before the embryo implants in the uterus.

During diapause, the embryo remains free-floating, extending the duration of pregnancy. This dormant state can last weeks or months until conditions improve and development resumes. While not all mammals use this strategy, scientists have found that it can be triggered experimentally. However, whether human cells could also respond to these diapause triggers remained unclear.

Researchers at the Max Planck Institute for Molecular Genetics and the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences have found a potential “pause button” in the early stages of human development. This discovery addresses a long-standing debate about whether humans can control the timing of their development.

The study indicates that this “pause button” can be activated in human cells. These findings have important implications for our understanding of early human life and could enhance reproductive technologies.

Scientists identified that the molecular mechanisms controlling embryonic diapause also seem actionable in human cells.

In their research, the scientists used human stem cells and stem cell-based models called blastoids, which act as a scientific and ethical alternative to research. The researchers found that modulating a specific molecular pathway known as the mTOR signaling pathway could induce a dormant state in these stem cell models that closely resemble diapause.

Aydan Bulut-Karslioğlu said, “The mTOR pathway is a major regulator of growth and developmental progression in mouse embryos. When we treated human stem cells and blastoids with an mTOR inhibitor, we observed a developmental delay, which means that human cells can deploy the molecular machinery to elicit a diapause-like response.”

This dormant state is marked by reduced cell division, slower development, and a decreased ability to attach to the uterine lining. Notably, the ability to enter this dormant phase appears limited to a short developmental window.

Shared first author Dhanur P. Iyer said, “The developmental timing of blastoids can be stretched around the blastocyst stage, which is exactly where diapause works in most mammals. Moreover, this dormancy is reversible, and blastoids resume normal development when the mTOR pathway is reactivated.”

The authors concluded that humans, similar to other mammals, might have an inherent mechanism to temporarily slow down development, even if this mechanism isn’t actively used during pregnancy. This potential could be a remnant of the evolutionary process scientists have yet to understand or utilize fully.

Nicolas Rivron said, “Although we have lost the ability to enter dormancy naturally, these experiments suggest that we have retained this inner ability and could eventually unleash it. For basic research, the question arises as to whether human and other mammalian cells enter the dormant state via similar or alternative pathways and use it for the same purposes, such as pausing or timing their development and implantation.”

“The team’s discoveries could have implications for reproductive medicine: On the one hand, undergoing faster development is known to increase the success rate of in vitro fertilization (IVF), and enhancing mTOR activity could achieve this. On the other hand, triggering a dormant state during an IVF procedure could provide a larger time window to assess embryo health and to synchronize it with the mother for better implantation inside the uterus.”

Overall, the new findings offer valuable insights into the processes that govern our earliest development, potentially opening new pathways for improving reproductive health.

Heidar Heidari Khoei, a postdoctoral fellow in Nicolas Rivron’s lab and the study’s co-first author, said, “This exciting collaboration is a testimony to how complex biological questions can be tackled by bringing together respective expertise. I believe this work not only underscores the importance of collaboration in advancing science but also opens up further possibilities for understanding how various signals are perceived by cells as they prepare for their developmental journey.”

Journal Reference:

1. Dhanur P. Iyer, Heidar Heidari Khoei, Vera A. van der Weijden, Harunobu Kagawa, Saurabh J. Pradhan, Maria Novatchkova, Afshan McCarthy, Teresa Rayon, Claire S. Simon, Ilona Dunkel, Sissy E. Wamaitha, Kay Elder, Phil Snell, Leila Christie, Edda G. Schulz, Kathy K. Niakan, Nicolas Rivron, Aydan Bulut-Karslioğlu. mTOR activity paces human blastocyst stage developmental progression. Cell, 2024; DOI: 10.1016/j.cell.2024.08.048