A human embryo ‘base edited’ so that it can’t produce a key protein (right), fails to form the mass of cells that gives rise to tissues and organs. A non-edited embryo (left) shows the cells (cyan). Credit: Katarina Harasimov, Oliver Bower and Kathy Niakan, Loke Centre for Trophoblast Research, University of Cambridge
For the second time this month, a team of researchers has reported harnessing a precise gene-editing technique to alter the DNA of human embryos.
Precise genome editing of human embryos triggers praise and alarm
This time, the scientists used the method, called base editing, to study human development rather than to explore ways to prevent disease. However, the experiment’s success makes the need for ethical discussions around embryo editing even more urgent, some researchers say.
The results, published today in Nature1, show that a key protein called NANOG plays a part in embryo development that had not been seen in studies in mice. That finding highlights the importance of studying human embryos, rather than relying on animal models, says Janet Rossant, a developmental biologist at the Hospital for Sick Children in Toronto, Canada. “If you want to be able to improve reproductive technologies, then it is very important to have an understanding of the normal development of the embryo,” she says.
Such research has often been swept up in the public debate around gene-editing human embryos to prevent genetic disease or, more controversially, to alter traits such as intelligence. And there has been little progress on deciding when such gene editing would be acceptable, says Joy Zhang, a sociologist at the University of Kent in Canterbury, UK. “It’s frustrating.”
Surprise results
In the latest study1, researchers working with Kathy Niakan, a developmental biologist at the University of Cambridge, UK, used base editing to disrupt the gene that produces NANOG. The team worked with sperm, eggs, and embryos that were donated for research, and allowed the embryos to develop for only about a week.
The edited embryos failed to form a proper ‘epiblast’, the mass of cells that gives rise to the body’s tissues. But they did form cells that later give rise to supporting structures such as the placenta and the yolk sac. Studies have shown that mice can’t form the yolk sac without NANOG, so the result is surprising.
Niakan’s lab previously used the popular gene-editing technique CRISPR–Cas9 to disable production of an important protein called OCT4 in human embryos2. But CRISPR–Cas9 editing, which cuts both strands of DNA, is less precise than base editing, which replaces a single DNA base in a strand. That imprecision can make it difficult to interpret results, Rossant says: did the embryos stop developing because OCT4 was removed, or because of unwanted, harmful edits made by CRIPSR–Cas9?
In this high-speed video, a base-edited human embryo divides from one cell into many during the first week after fertilization.Credit: Oliver Bower, Katarina Harasimov and Kathy Niakan, Loke Centre for Trophoblast Research, University of Cambridge
By contrast, base editing seems to be less damaging to the genome, according to both of the studies reported this month1,3. This might allow researchers to get a clearer picture of the role of NANOG and, eventually, other proteins in human embryo development, Rossant says.
It might also mean that base editing will eventually prove safer than CRISPR–Cas9 for editing genes in embryos to prevent disease, says Alta Charo, a biotechnology ethics and policy consultant in Washington DC. Even so, she emphasizes, this would only be an “incremental step” towards making the technique safe enough for use in embryos destined for implantation in the womb.
Safety hurdles
Many safety improvements are still required, Charo says. For instance, researchers continue to grapple with the fact that gene-editing techniques such as base editing often work in some, but not all, of the cells in an embryo. As a result, the embryo becomes a mosaic, containing some modified and some unmodified cells, with unknown consequences for any resulting fetus.
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Such scientific hurdles have allowed researchers to postpone answering deeper questions about the ethics of heritable gene editing, Charo says. But, she adds, this month’s developments are making it clear that scientists can’t permanently avoid these questions — including whether and when it would be ethically appropriate to edit an embryo, and what it means to create mutations that will be passed down to future generations.
