Reacción a "A new version of CRISPR, base editing, reveals a key factor in human embryo development"

In 2015, just two years after the world learned of the enormous potential of CRISPR-Cas9 gene-editing tools, a team of Chinese researchers published the first paper demonstrating that it was possible to edit human embryos using these tools, just as we had been doing with mouse embryos. That first paper drew a great deal of criticism, especially from those who believed that a single-celled human embryo—a zygote—is already a person and possesses the identity of a person. The researchers anticipated this criticism by using triplonuclear embryos (with three nuclei), which result from the abnormal fertilization of an egg by two sperm. This is something that commonly occurs when applying in vitro fertilization techniques.

These three-nucleated embryos cannot continue developing beyond a few cell divisions; they eventually degenerate and die, and are therefore routinely discarded. These were the embryos used by the researchers. In doing so, they were conveying the idea that they had no interest in implanting the edited human embryos (if they had done so, no child would ever have been born from them) and could explain that they were only interested in determining whether CRISPR-Cas9 tools could be successfully used on preimplantation human embryos—which they did confirm.

In Europe, it took researchers two years to conduct a similar experiment. It was carried out by a researcher named Kathy Niakan, then at the Francis Crick Institute in London, who went a step further and decided to use CRISPR to investigate the possible differences between human and mouse embryos in the preimplantation stage—that is, before implantation in the uterus.

Much of what we know about early human embryology comes from studies conducted on mouse embryos. Naturally, these experiments were based on the assumption that these two mammalian species would have similar, equivalent genetic and cellular development. But Kathy Niakan suspected that this was not entirely true. She decided to apply to the UK’s Human Fertilization and Embryology Authority (HFEA) for permission to use surplus human embryos from in vitro fertilization procedures to inactivate, using CRISPR, the same gene (POU5F1, which encodes the OCT4 transcription factor) in both mouse and human embryos simultaneously, to analyze whether the consequences were comparable. And they were not. In 2017, when he published the study’s results in the journal Nature, he demonstrated that inactivating OCT4 in human embryos blocked embryonic development, preventing them from reaching the blastocyst stage. In contrast, inactivation of the same gene (Pou5f1) in mice did not appear to affect the early development of mouse embryos, which successfully reached the blastocyst stage without any problems, apparently without needing Oct4.

Niakan’s work demonstrated to us, beyond a shadow of a doubt, that we could not use mouse embryos to understand the early stages of human embryonic development prior to implantation, because they were significantly different.

From that work, it could be inferred that we had to continue researching human embryos—not mouse embryos—if we wanted to understand the embryology of the initial stages in humans.

Nine years after that milestone, Kathy Niakan’s own laboratory—now leading the Loke Centre for Trophoblast Research at the University of Cambridge—in collaboration with other researchers and institutions, has used second-generation CRISPR tools, base editors (designed by David R. Liu of the BROAD Institute in 2016, which are more specific and carry a lower risk of unexpected modifications elsewhere in the genome), to inactivate another early-expressed gene: NANOG.

The research results are published in the journal Nature this week. Once again, the study was conducted on surplus human embryos derived from in vitro fertilization and on mouse embryos. And, once again, the results were surprising. Inactivation of the NANOG gene in human embryos directly affects the epiblast (the inner cell mass)—the cluster of pluripotent cells from which all cell types and tissues of the developing fetus will derive— but apparently leaves intact the tissues that will form the placenta and the yolk sac, derived from the trophoblasts (the cells surrounding the blastocyst). In contrast, inactivation of the homologous Nanog gene in mouse embryos disrupts both the epiblast and the trophoblasts that will give rise to the placenta and the yolk sac. This provides new evidence from the same researcher, Kathy Niakan, that the early stages of human and mouse embryo development are not equivalent. It also confirms that the NANOG gene is essential for the development and differentiation of the embryo’s pluripotent cells.

It is also further confirmation that we must continue researching human embryos—surplus to in vitro fertilization processes—with the necessary permits from the authorities, precisely to understand the early stages of human embryo development. This could provide new insights to improve the implantation rate of human embryos and increase the likelihood of a successful pregnancy—one of the most delicate stages of assisted reproductive technologies, where many human embryos still fail to implant and, unfortunately, do not reach full term, forcing women or couples to begin a new cycle of in vitro fertilization. This is the potential impact of this new research by researcher Kathy Niakan.

This is the second paper to use base editors in human embryos, following the one deposited on the bioRxiv preprint server—which has not yet been published but was nonetheless discussed in the journal Nature a few weeks ago. In that study, American researchers, led by Dieter Egli, demonstrated how these base editors could be used to mutate various genes for therapeutic purposes with high efficiency and with virtually no associated problems in other parts of the genome.

Both papers demonstrate that it is now possible to genetically edit human embryos safely and effectively using base editors, unlike first-generation CRISPR-Cas9 tools, whose use in human embryos (as well as in mice or any other species) is associated with multiple unpredictable alterations in the genome. This is something we unfortunately witnessed following He Jiankui’s ill-fated experiment in 2018, which resulted in the birth of the first three girls with edited genomes but with unforeseen genetic modifications—compelling the Chinese government to medically monitor these girls in anticipation of potential pathologies that might arise.