The second week of gestation is crucial for human development, as the growing embryo needs to implant in the mother’s womb to survive. Many early pregnancies fail at this point, but it has been difficult to determine exactly why. Lacking the proper tools, researchers haven’t been able to follow this stage of development in the lab.
A recent study analyzed some of these key molecular events in cultured human embryos between days 7 and 11. Among the findings: Genetic triggers signal the embryo to begin forming its head-to-tail body axis, the researchers found. This “symmetry-breaking” event is key because it commits one end of the embryo to turn into the head and the other the “tail.”
“We look here at the pattern of gene expression as embryos are establishing their body plan,” says Magdalena Zernicka-Goetz, an embryologist at the California Institute of Technology and the University of Cambridge, UK, who led the research. “We have been trying to identify the major critical phases of life and steps in the stages of development for years now.”
Published in Nature Communications, the study tracked the development of 16 human embryos left over from IVF treatment. The researchers could work with the embryos after the 7-day point–at which implantation is usually required–thanks to a culturing technique, developed by Zernicka-Goetz’s team, that uses a media that includes hormones such as progesterone.
The paper focuses on three stages of development. The first is how the embryonic cells lose their pluripotency: moving from an unrestricted state in which they could develop into any tissue to a defined pathway that determines how they will turn out. The second is the role of a family of cell signaling molecules, called the fibroblast growth factor (FGF), which is known from previous experiments to play a major role in embryo development in mice. The third is differences in gene expression across the human embryo that could signal the onset of symmetry breaking and the establishment of the main body axis. “Human embryos are very precious to work with,” Zernicka-Goetz says. “And therefore, it’s very difficult to gather a lot of these embryos to have such a detailed study.”
Looking at patterns of gene expression across the embryos, the research identified distinct clusters of cells. Along with a grouping known as the epiblast, which is the precursor of the fetus proper, there were clusters that would usually go on to develop into the yolk sac and the placenta, called the hypoblast and trophoblast, respectively. The study found significant interaction between these clusters within the developing embryos, similar to those seen previously in mice. Cells within the human hypoblast secrete signaling molecules, the results suggest, which encourage the nearest epiblast cells to break symmetry and start to develop into the head.
The study also offers some insights into why some embryos fail to implant, which is often a particular problem with assisted conception techniques such as in vitro fertilization. “We show in the paper that if there is not enough FGF signalling, then those embryos are the ones that develop wrongly,” Zernicka-Goetz says. “We cannot compromise on them at the time of pregnancy.”
Sanna Vuoristo, an embryologist at the University of Helsinki, Finland, who helped to develop the culturing technique for post-implantation stage embryos, says the results represent a significant technological advance. “Human embryo research has taken a huge leap forwards,” she says, while noting the important advances reported in a separate study from researchers in China. Published in late 2019, the study detailed the successful culturing of human embryos for up to 14 days—the maximum time allowed under current international guidelines.
The recent paper “highlights the importance of human embryo research” because it stresses “that there are differences between the mouse and humans,” Vuoristo says—pointing to the different molecular markers, for example. And while the signaling center in the human hypoblast does the same job as in the mouse, and so expresses the same genes, it is organized differently.
The new study results highlight the useful results that could come from studying human embryos beyond the current 14-day limit. “There has been discussion about extending this 14-day rule and I think there is a place for it now, at least to discuss clearly where we should really draw the line,” Vuoristo says.