NANOG gene activation found to drive human embryo formation

NANOG switches – Using CRISPR base editing, researchers disabled the NANOG gene in fertilised human eggs and found none of the cells went on to form the embryo itself—an essential role in the developmental programme of early human development. The work may help explain why man

In IVF clinics, the heartbreak often starts with the microscope. Embryos can look like they’re developing well—shape and growth appear reassuring—yet they still don’t take.

Now, work on early human development has put a specific gene at the center of that unseen shift. Researchers have identified NANOG. a “master” gene. as a switch that initiates the developmental programme that leads to formation of a human body. They reached that conclusion by making precise changes to the DNA of fertilised eggs using CRISPR base editing.

NANOG has long been implicated in embryonic development from animal studies. The gene’s name comes from the Celtic world of the ever-young. Tír na nÓg. because its activation is what makes stem cells immortal. But the new study shows something crucial: NANOG behaves differently in people than in other animals, including mice.

The team began with a familiar early fork in the road. When a fertilised egg starts developing, its cells take on one of three roles: forming the placenta, forming the yolk sac (which is also present in mammalian embryos), or becoming the embryo itself.

In fertilised mouse eggs, disabling NANOG using base editing produced a striking outcome. None of the resulting cells developed into yolk sac progenitors. The researchers point to an advantage of base editing itself: it is a modified CRISPR method that changes a single DNA letter at a time. rather than slicing through DNA strands and producing a range of mutations.

“The precision of the technique reduces the likelihood of unintended chromosomal abnormalities. which can occur with the original version. ” Kathy Niakan of the University of Cambridge says. For the mouse model. that precision still translated into a clear developmental consequence: when NANOG is switched off. yolk sac development fails to emerge.

When the same approach was applied to human eggs donated by women undergoing IVF treatments, the pattern flipped—at least in the specific fate of what emerged. Disabling NANOG in human eggs led to none of the cells developing into those that form the embryo.

The embryos still appeared normal under a microscope. But IVF selection for implantation is based largely on shape, Niakan says. “One out of two times. even though from the shape it looks like the embryo is developing well. it doesn’t have the potential to implant. ” she explains. Her argument is practical. and personal to the clinic: if markers or genes like NANOG can be identified. that knowledge could help improve these rates.

Niakan’s team isn’t the first to use base editing on human embryos. The first attempt came in 2017. using embryos discarded because of abnormalities. which meant the results might not reflect what happens in healthy embryos. Then last month, Dieter Egli at Columbia University in New York released a pre-print describing base editing of two-cell embryos.

Niakan draws a sharp line between the goals. “What we were trying to achieve was fundamentally different. Our study is about understanding key genes – this is the first time that the technique has been used to study gene function in human embryos,” she says. Egli, however, is not persuaded.

“It does not demonstrate an essential role [for NANOG in human embryogenesis]. There are no functional follow-ups or molecular mechanism,” Egli says.

Niakan counters that her team performed the additional work needed to make the claim about NANOG’s role.

There’s another thread running through all three studies, even amid disagreement about interpretation: CRISPR base editing of human embryos appears safer than editing them with the original form of CRISPR, as was done with three children. Still, safety isn’t the same as readiness.

Mary Herbert at Monash University in Melbourne, Australia, who was part of Niakan’s team, stresses how far the science is from gene-edited children. “The technology is not ready for that,” Herbert says. “I think there is unanimous agreement on that.”

The obstacle is mosaicism—when only some cells in an embryo are successfully gene-edited. That means a child could still develop the condition the editing was meant to prevent.

The risk shows up in real numbers. In one edit Egli’s team tried to make, 80 per cent of embryos were mosaics. Niakan’s team injected the gene-editing machinery into eggs along with the sperm used to fertilise them. aiming to edit earlier and reduce mosaicism. It helped, but not enough: half of the eggs were still mosaics.

“[This] would still be too high a rate of mosaicism in many circumstances if the methods were being used to correct a DNA variant that causes a genetic disorder,” Robin Lovell-Badge of the Francis Crick Institute in London says.

For now, Niakan draws the ethical boundary clearly. “I would also hugely advocate for much more basic research that’s publicly available and publicly discussed,” she says, and she describes it as unethical to try to base-edit children at the moment—while not ruling it out in the future.

Even if clinical translation is distant, the new findings land close to the present. In IVF, the embryo’s look can be misleading. The science here suggests that what matters may be written in the timing of a gene like NANOG—how quickly an early developmental programme is switched on. and whether those first instructions can ever lead to a body that can implant and grow.

NANOG CRISPR base editing IVF embryo development mosaicism stem cells Kathy Niakan Dieter Egli Mary Herbert Robin Lovell-Badge regenerative medicine