Human eggs that contain too many or too few chromosomes can lead to miscarriage, IVF failure and conditions such as Down鈥檚 syndrome. Now, researchers have found that giving the eggs a single injection can substantially reduce the risk of chromosome error. The approach could eventually boost the chances of success for older women undergoing IVF.

鈥淚t really seems like a big deal,鈥� says at Nilo Frantz Reproductive Medicine in Porto Alegre, Brazil, who wasn鈥檛 involved in the new research. 鈥淭o my knowledge, this is the first [therapy] to show such clinical potential for correcting this major cause of IVF failure.鈥�

During a process called meiosis, egg and sperm cells eject exactly half of their genetic material. This means that when egg and sperm combine during fertilisation, they form an embryo with a complete genome. Sometimes, however, a sperm or egg cell has slightly more or slightly less than the half genome it should contain. This is a condition known as aneuploidy.

Aneuploidy affects about in the early 30s and becomes more common with age. 鈥淎lready in the late 30s, more than 65 per cent of all eggs are aneuploid,鈥� at Ovo Labs, a biotechnology company in Germany, told the audience at the conference in London on 6 July.

Clinicians sometimes screen IVF embryos for aneuploidy when treating couples at greater risk of miscarriage or IVF failure. , conditions caused by the genetic error 鈥� which include Down鈥檚 syndrome 鈥� are only detected via blood tests and ultrasound scans taken during the first trimester of pregnancy. Until now, there have been no ways to reduce the risk of aneuploidy occurring in the first place, says Zielinska.

Now, Zielinska and her colleagues have found that the level of a protein called shugoshin-1 is substantially lower in older mouse and human eggs than in younger ones. Shugoshin-1 helps with a stage of meiosis in which two copies of each chromosome line up along the middle of an immature egg cell. The protein maintains the molecular glue that holds each pair together.

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When sperm penetrate an egg, the two copies of the egg鈥檚 chromosomes separate and move to opposite sides of the cell. One end ultimately forms the final egg cell, and the other end is discarded.

But in older eggs, the glue holding the chromosome pairs together degrades, which can cause the two copies of each chromosome to separate before fertilisation. When this happens, the chromosomes spread unevenly throughout the cell 鈥� which means the resulting egg may be aneuploid.

To explore whether replenishing shugoshin-1 could prevent aneuploidy by helping to hold chromosome pairs together, the team collected 111 spare, immature eggs from more than 30 women aged between 22 and 43 who were banking eggs or undergoing IVF.

The team injected the genetic code for shugoshin-1, in the form of mRNA, into one or more of each donor鈥檚 eggs, and left other eggs from the same donor untreated.

A few hours later, chromosomes had prematurely separated in 53 per cent of the untreated eggs, whereas this figure was nearly half 鈥� 29 per cent 鈥� in the treated ones. In eggs from nine donors who were aged over 35, aneuploidy rates were 65 per cent, on average, in untreated eggs. But in treated eggs, the average figure was just 44 per cent. This reduction wasn鈥檛 statistically significant, although this is probably because of the study鈥檚 small sample size, according to the researchers.

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Further experiments showed the approach could prevent aneuploidy in mouse eggs, which were then successfully fertilised to produce healthy offspring.

No side effects were seen in the mouse or human studies. 鈥淲e鈥檝e achieved live births in mice, so, from that perspective, we鈥檙e confident that this approach is not interfering in the mouse model with any steps of embryo development, and it doesn鈥檛 interfere with pup health and pregnancy health,鈥� Zielinska told the conference audience.

The researchers are now working towards testing the effects of shugoshin-1 in people. This would involve tweaking standard IVF to use immature eggs rather than mature ones, but this change would be fairly easy to implement, says Zielinska.

She hopes the therapy, which the team calls EmbryoProtect, will provide an affordable way to improve IVF for older women. 鈥淲e anticipate that the treatment will cost a fraction of the cost of a full IVF cycle,鈥� says Zielinska. 鈥淏y meaningfully improving IVF success rates, especially for women over 35 where baseline success is low, we hope that fewer attempts will be needed to conceive.鈥�

We now know the master gene that controls embryonic development in people. Called NANOG, its role has been identified by making precise changes to the DNA of fertilised eggs using a technique called CRISPR base editing.

The discovery might lead to ways to boost the success rate of IVF and help treat non-fertility-related conditions. 鈥淭he other reason we study these early stages of human development is that it has really profound importance for stem cell biology,鈥� says at the University of Cambridge. 鈥淎 better understanding will help stem cell research and regenerative medicine, and that could have a transformative impact that can affect all of our lives.鈥�

It鈥檚 long been known from animal studies that NANOG plays a role in embryonic development. The gene was named after the Celtic world of the ever-young, T铆r na n脫g, because its activation is what makes stem cells immortal. Crucially, though, the team鈥檚 work shows that NANOG has a different role in people than in other animals, such as mice.

When a fertilised egg starts developing, the cells take on one of three different roles 鈥� forming the placenta, the yolk sac, which is also in mammalian embryos, or the embryo itself. When the team used base editing to disable NANOG in fertilised mouse eggs, none of the resulting cells developed into yolk sac progenitors. Base editing is a modified form of CRISPR that changes a single DNA letter at a time. By contrast, the original form of CRISPR slices through DNA strands, resulting in various kinds of mutations. 鈥淭he precision of the technique reduces the likelihood of unintended chromosomal abnormalities, which can occur with the original version,鈥� says Niakan.

But when the team disabled NANOG in human eggs donated by women undergoing IVF treatments, none of the cells developed into those that form the embryo. In other words, the activation of NANOG is what initiates the developmental programme that results in cells forming a human body.

These embryos still appeared normal under a microscope, however, and the selection of IVF for implantation is based largely on shape, Niakan says. 鈥淥ne out of two times, even though from the shape it looks like the embryo is developing well, it doesn鈥檛 have the potential to implant,鈥� she says. 鈥淪o perhaps by identifying key markers or genes like NANOG, that knowledge could help improve on these rates.鈥�

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Niakan鈥檚 team isn鈥檛 the first to base-edit human embryos. It was , but using embryos discarded because of abnormalities, so the results might not reflect what happens in healthy embryos. Then last month, at Columbia University in New York and his colleagues released , describing base editing of two-cell embryos.

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鈥淲hat we were trying to achieve was fundamentally different. Our study is about understanding key genes 鈥� this is the first time that the technique has been used to study gene function in human embryos,鈥� says Niakan. 鈥淒ieter鈥檚 study was evaluating the use of the technology in disease-associated mutation correction.鈥�

Egli says Niakan鈥檚 study聽shows that NANOG has an important role in human development that is different to its role in mice.

All three studies suggest that CRISPR base editing of human embryos is much safer than editing them with the original form of CRISPR, as was done with three children. However,聽 at Monash University in Melbourne, Australia, who was part of Niakan鈥檚 team, stresses that we are still far from the point where CRISPR base editing could be used to create gene-edited children, for example, to prevent inherited conditions. 鈥淭he technology is not ready for that,鈥� says Herbert. 鈥淚 think there is unanimous agreement on that.鈥�

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A major obstacle to this is that, often, only some of the cells in an embryo are successfully gene-edited, known as mosaicism. This means if gene editing was used to correct disease-causing mutations in an embryo, the resulting child might still develop that condition.

For instance, with one edit that Egli鈥檚 team tried to make, 80 per cent of embryos were mosaics. Niakan鈥檚 team did its editing at a much earlier stage, injecting the gene-editing machinery into eggs along with the sperm used to fertilise them. This reduced mosaicism, but not by much: half of the eggs were still mosaics. 鈥淸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,鈥� says at the Francis Crick Institute in London.

Niakan says it would be really unethical to try to base-edit children at the moment, but she鈥檚 not ruling it out in the future: 鈥淚 would also hugely advocate for much more basic research that鈥檚 publicly available and publicly discussed.鈥�