For the first time, scientists have used base editing, an ultra-precise form of genome editing, to study gene function in human embryos. The study has revealed the role of a “master gene” that is essential for forming the human body during embryo development.
While human embryo base editing has been previously reported, this is the first time that this technique has been used to study gene function in human embryos. The results show that the extreme precision of the technique reduces the likelihood of unintended chromosomal abnormalities, which can occur with the more widely used CRISPR/Cas9.
“Base editing represents a significant advance on conventional CRISPR/Cas9 because it carries a far lower risk of causing unintended chromosome errors,” said lead study author Kathy Niakan, professor at the University of Cambridge Loke Centre for Trophoblast Research. “Base editing can precisely change a single nucleotide base pair to another in an entire human genome of around 3 billion base pairs—that’s an incredible feat.”
In this study, published in Nature, researchers used base editing to block the “master gene”— called NANOG—in very early-stage human embryos. They found that, without it, embryonic cells failed to develop into the epiblast, the pluripotent cell layer that later forms every tissue in the human body. Notably, the embryos could still form the cells that go on to become the placenta and yolk sac, meaning NANOG's role appears specific to body-forming cells rather than the entire embryo.
Pluripotent cells can develop into any other type of cell in the body and are widely used in biomedical research, from drug testing to disease modeling. Human embryonic stem cells, which are pluripotent, arise in a part of the developing embryo that has high levels of NANOG activation. This has caused scientists to suspect that NANOG plays an important role in their creation.
“By pinpointing how genes like NANOG control the development of pluripotent cells, we can make stem cell systems for biomedical research more predictable and reliable,” said first author Oliver Bower, also a researcher at the University of Cambridge’s Loke Centre for Trophoblast Research.
From mouse to human
The findings complicate assumptions carried over from decades of mouse research, which first identified NANOG as a likely key player in early development.
In previous mouse studies, loss of NANOG disrupted both the epiblast and the yolk. However, in this human embryo study, loss of NANOG primarily affected the epiblast.
Until now it has not been possible to directly investigate the function of NANOG in human embryos because the genome editing techniques available, like conventional CRISPR/Cas9, cause too much unintended damage to the DNA.
“We had predicted that the gene called NANOG would have a really important role in human development, given its importance in the development of mouse embryos. What we found was that NANOG functions somewhat differently in humans to mice, which means our assumptions about the role of this gene don’t transfer neatly across species,” said Katarina Harasimov, a researcher at the University of Cambridge’s Loke Centre for Trophoblast Research who was also involved in the study.
Looking ahead
The researchers say a better understanding of genes like NANOG could eventually help improve IVF success rates and shed light on causes of early pregnancy loss.
Base editing could also potentially be used in the future to edit specific genes in human embryos for debilitating inherited conditions, like cystic fibrosis and Huntington’s disease, to prevent the conditions being passed on to future generations. Currently, this is not legally permissible.
Before any future clinical use, extensive safety testing, further development of the technique and broad public debate and support would be required.