Base editing reveals gene essential for human embryo formation

Using base editing, a highly precise method of genome editing, scientists have investigated the role of the NANOG gene in human embryos for the first time with this approach.

During the earliest stages of development, cells become committed to different lineages that later form either the fetus itself or supporting tissues such as the placenta and yolk sac. These lineage decisions are thought to be controlled by so-called master regulator genes, first identified through studies in mice. A study led by researchers at the University of Cambridge has now investigated the role of one such regulator, NANOG, directly in human embryos donated following IVF treatment, with informed consent.

'A better understanding will help stem cell research and regenerative medicine, and that could have a transformative impact that can affect all of our lives,' said  Professor Kathy Niakan, corresponding author of the study published in Nature, emphasising the importance of the research beyond developmental biology.

Using base editing (see BioNews 848, 920, 924 and 1285) to disrupt NANOG, the researchers found that embryos failed to form the epiblast – the group of cells that gives rise to the fetus itself – while cells destined to become supporting tissues continued to develop. The findings also revealed important differences between human and mouse embryos, highlighting the value of studying human development directly.

'This study is a fantastic example of how the latest advances in genome editing can help us understand how human embryos develop. In particular, the study deepens our insight into why only a modest proportion of all embryos implant in the uterus, and result in an ongoing pregnancy,' said Sarah Norcross, director of PET (the Progress Educational Trust). 'The study also shows the value of enabling patients to donate their unused IVF embryos – and also sperm and eggs – for use in research. It is regrettable that only a minority of UK clinics enable patients to donate embryos to research, and we would like to see regulations changed so that more clinics are able to offer this (see BioNews 1219, 1220, 1243, 1268 and 1334). Every IVF patient should be given the option of donating unused embryos to research.'

NANOG was originally named in the early 2000s by stem cell researchers working on mouse embryonic stem cells, who drew on the Celtic myth of Tír na nÓg – the 'land of eternal youth' – to reflect the gene's role in helping embryonic stem cells maintain a self-renewing, pluripotent state (see BioNews 210).

The researchers note that base editing is more precise than earlier CRISPR/Cas9 approaches and can reduce unintended off-target genetic changes, raising the possibility of future clinical applications (see BioNews 1035). They suggest that, in the longer term, genome editing could help prevent the inheritance of serious single-gene disorders, such as cystic fibrosis, in cases where current IVF approaches cannot produce an unaffected embryo for transfer. However, they emphasise that extensive further research would be required before any clinical use.

Although the authors emphasised that reproductive use of this technology remains a distant prospect, the study has renewed discussion about the ethics of heritable genome editing.

However, first author Dr Oliver Bower told Nature News that attention should not be focused on heritable genome editing at this stage. 'The conversation shouldn't be about clinical work.... There is a huge amount of basic biology and pre-clinical work needed before that step,' he said.