Base editing in human embryos: Why patient voices matter

In our recent study published in Nature, my colleagues and I make use of novel genome editing techniques to better understand human embryology (see BioNews 1345 and 1349). There has already been speculation about the future applications of this work, but any discussion of potential clinical use must be firmly grounded in meaningful patient and public engagement.

In September 2022, a small village just outside Cambridge became the setting for an experience that fundamentally changed the direction of my research. I had been invited to take part in a citizens' jury – a public engagement exercise involving people affected by genetic disease. The jury was asked to consider whether editing the genomes of human embryos could be justified, if this was done to treat inherited genetic disease (see BioNews 1180).

My role was to explain the genetics, embryology and genome-editing methods involved. At the time, I was halfway through my PhD in the laboratory of Professor Kathy Niakan at the University of Cambridge, where I was using genome editing in human embryos – not to improve fertility or develop treatments, but to answer fundamental questions about early human development. I used CRISPR/Cas9, effectively a pair of molecular scissors that can cut DNA at precise locations. I was using this to cut out genes and see how this affected the first week of human embryo development. It was fundamental biology, basic and interested in 'how'. The word 'treatment' never came to mind.

The gene I was studying, NANOG, produces a protein that binds DNA and regulates the activity of dozens of other genes during the first week after fertilisation. In doing so, NANOG helps to establish the population of cells that will ultimately form the embryo itself.

CRISPR/Cas9 was ideally suited to this work. By providing a target DNA sequence together with the Cas9 enzyme, it was possible to make a precise cut in the genome, allowing us to switch off NANOG and see the effect of its loss. However, much like cutting a page from a book, making a DNA break can leave a scar. Such unintended changes at the cut site have raised concerns about the therapeutic use of CRISPR genome editing. For basic research, we considered this to be an acceptable limitation because our aim was to understand biology rather than to develop treatments.

At the citizens' jury, listening to patients, carers, charity representatives and families describe their lived experiences profoundly affected me. They spoke about the challenges of genetic disease, their hopes for future treatments, and the prospect of having children. Although opinions differed, there was broad agreement that embryo editing might one day be justified for treating serious genetic disease, but only if it could be shown to be safe.

During my presentations, I discussed emerging technologies including base editing (see BioNews 848, 924, 1035 and 1285). Unlike traditional CRISPR/Cas9 approaches, base editing does not cut DNA. Rather than a 'cut and paste' approach, it works more like 'find and replace', changing a single DNA letter without breaking the DNA strand. At the time of the citizens' jury, base editing had hardly been used in human embryos (see BioNews 920 and 964), and so this approach was largely theoretical.

I left the citizens' jury invigorated, motivated and wondering whether we could apply these emerging technologies to our own research. Traditional CRISPR/Cas9 would almost certainly have answered our biological questions about NANOG, but I became increasingly interested in technologies that might one day have therapeutic relevance. Scientifically, the greater precision of base editing also promised cleaner and more interpretable experimental results.

Adopting a new technology halfway through my PhD had considerable risks. Base editing might simply fail, leaving me no closer to understanding NANOG. Fortunately, my supervisor loved the idea and supported me through the lengthy optimisation process required to make it work.

Three years after pivoting to base editing, we published our results in Nature. Our findings are twofold.

First, biologically, we showed that NANOG is a master factor in human embryo development, vital for laying down the foundations of the embryonic body. We found that NANOG acts differently in human embryos than it does in mice, where it has been extensively studied. In mice, NANOG signals to cells that will form the yolk sac, and without NANOG the yolk sac fails to form. In human embryos, by contrast, the yolk sac can still form without NANOG – a stark contrast in cell dynamics just days after fertilisation, which emphasises the importance of studying human biology directly rather than relying on mice alone.

Second, technologically, we showed that base editing is highly efficient – capable of targeting DNA effectively and precisely, while avoiding some of the complications of previous CRISPR/Cas9 approaches. This doesn't mean that base editing is ready to be used in human embryos in clinical work or treatment at this stage, but it represents a major step forward for our understanding.

I started my PhD in 2020, following one of the most controversial events in the history of modern genetics. In 2018, He Jiankui revealed that twin girls – known by the pseudonyms 'Lulu' and 'Nana' – had been born after pregnancies were established with embryos that had been genetically altered using CRISPR technology (see BioNews 977a, 977b, 978a, 978b, 982, 984, 986, 987, 989, 1000, 1010 and 1027). This was met with widespread international condemnation, with scientists and ethicists describing the work as unethical, irresponsible and in breach of accepted scientific and regulatory standards. He Jiankui was later sentenced to three years in prison (see BioNews 1029, 1030, 1033, 1135, 1179 and 1308) and the case intensified global calls for a moratorium on heritable human genome editing (see BioNews 991, 1247 and 1333).

At that time, conversations about embryo genome editing were dominated by ethical concerns. Over time, there has been more of a focus on technical safety and on the development of more precise editing technologies. Although the science of genome editing has advanced rapidly, major questions remain – not only about safety, but also about the fundamental biology of early human development and the societal and clinical implications of applying these technologies.

Our study shows that base editing can be used effectively to investigate human embryo development, and provides encouraging evidence that this overcomes several limitations of traditional CRISPR/Cas9. However, extensive preclinical research, continued studies of early human development and public engagement will be essential to assess the safety and appropriateness of the approach, before any clinical applications can be considered.

Overall, this work highlights the value of rigorous basic biological research, and demonstrates how meaningful public engagement can influence both researchers and the direction of scientific inquiry. Although clinical applications may be years away, it is a reminder that scientific research should be guided not only by technical progress, but also by the priorities and concerns of the people whom the research is ultimately intended to benefit.

Our findings provide an important proof of principle for future research – both for further studying human development, and for comprehensively studying the safety and efficacy of these tools in relation to potential future treatments.