Summary: Understanding the earliest hours of human life has long been a profound challenge in developmental biology. While decades of animal research in mice have provided general structural clues, directly mapping human embryonic genes has remained functionally impossible due to the collateral damage caused by conventional gene-editing tools. Standard CRISPR/Cas9 platforms frequently trigger unintended chromosomal abnormalities and double-stranded DNA breaks, rendering delicate human embryos unviable for precise genetic study.
In a new study, researchers successfully deployed an ultra-precise genome editing technique called base editing to investigate gene function in human embryos for the first time. By chemically altering a single nucleotide base pair out of approximately 3 billion within human embryonic cells, scientists cleanly deactivated a master regulator gene known as NANOG.
The results provide a remarkably detailed look at the first few days post-fertilization, revealing that while early mammalian pathways share a common vocabulary, the molecular blueprint of a human embryo diverges significantly from the classic mouse model.
Key Facts
- The Base Editing Revolution: Base editing represents a monumental technological leap over conventional CRISPR/Cas9. Instead of cutting both strands of the DNA double helix, it cleanly transitions a single target nucleotide base pair into another, virtually eliminating the risk of accidental chromosome errors.
- The Role of NANOG Unmasked: By deploying this hyper-precise tool to block the NANOG gene, investigators discovered that the gene is an absolute prerequisite for the formation of the epiblast, the specialized cluster of pluripotent cells that eventually builds the entire human body.
- Placental Independence: Interestingly, even in the complete absence of NANOG, embryonic cells destined to become supporting structural tissues, such as the placenta and the yolk sac, were still able to form and differentiate normally.
- Species-Specific Divergence: The study dramatically upends cross-species assumptions. While past mouse models showed that losing NANOG ruined both the body-forming epiblast and the supporting yolk sac, the human embryo trial proved that human NANOG is strictly, selectively tied to body-forming line development.
- Clinical Windows for IVF Success: Mapping how NANOG and its downstream networks govern early cellular choices provides a definitive framework to investigate early pregnancy loss and engineer highly targeted interventions to optimize human IVF success rates.
- Regulatory and Ethical Guardrails: Conducted with strict independent oversight from the UK Human Fertilisation and Embryology Authority (HFEA), all embryos were voluntarily donated from surplus IVF cycles, cultured strictly under a 6.5-day ceiling, and never transferred into a uterus.
Source: University of Cambridge
Research led by the University of Cambridge Loke Centre for Trophoblast Research has shown that a genome editing technique can be used to alter a single gene in human embryonic cells, enabling the study of very early human development in unparalleled detail.
The technique, called base editing, is a more precise version of the genome editing technique CRISPR/Cas9. It can change a single nucleotide base pair – the basic building block of DNA – within a human genome of approximately 3 billion base pairs.
Using base editing, the researchers blocked a gene called NANOG in very early-stage human embryos, and found that the cells of the early embryo could not develop into more specialised pluripotent cells called the epiblast – which later form the body.
The results reveal the crucial role of NANOG in the development of human embryos, and helps scientists better understand how human embryos develop in the first few days after an egg is fertilised.
Without NANOG, the cells that later become the placenta and yolk sac – the tissues that support the developing embryo – could still form.
While human embryo base editing has been previously reported, this is the first time that this technique has been used to study gene function in human embryos. The results show that the extreme precision of the technique reduces the likelihood of unintended chromosomal abnormalities, which can occur with another more widely used version of CRISPR/Cas9.
Understanding more about the role of genes required for human development, such as NANOG, could in future help to improve IVF success rates and better understand early pregnancy loss.
Base editing could also potentially be used in future to edit specific genes for debilitating inherited conditions – like cystic fibrosis and Huntington’s disease – in human embryos to prevent the conditions being passed on to future generations. However, this would not be legally permissible in the UK at present. Before any future clinical use, extensive safety testing, further development of the technique, and broad public debate and support would be required.
“Base editing represents a significant advance on conventional CRISPR/Cas9 because it carries a far lower risk of causing unintended chromosome errors. Base editing can precisely change a single nucleotide base pair to another in an entire human genome of around 3 billion base pairs – that’s an incredible feat,” said Professor Kathy Niakan at the University of Cambridge Loke Centre for Trophoblast Research, who led the study.
She added: “Our results indicate that the NANOG gene is critical for the development of pluripotent cells, the building blocks that are fundamentally important to human development.”
Pluripotent cells can develop into any other type of cell in the body and are widely used in biomedical research, from drug testing to disease modelling. Human embryonic stem cells, which are pluripotent, arise in a part of the developing embryo that has high levels of NANOG activation. This has caused scientists to suspect that NANOG plays an important role in their creation.
“The precision of base editing is a major step from the previous generation of genome editing techniques. This allows us to study early human development with greater confidence,” said Dr Oliver Bower, a researcher at the University of Cambridge’s Loke Centre for Trophoblast Research and first author of the study.
He added: “By pinpointing how genes like NANOG control the development of pluripotent cells, we can make stem-cell systems for biomedical research more predictable and reliable.”
Human development does not always follow the mouse blueprint
Decades of animal research, particularly in mice, were essential for identifying NANOG as a gene likely to play a major role in early development. But this study shows that NANOG does not function identically in human and mouse embryos.
In previous mouse studies, loss of NANOG disrupted both the epiblast and the yolk sac – a tissue that supports the developing embryo. In this human embryo study, loss of NANOG primarily affected the epiblast, the future body-forming line of cells.
Until now it has not been possible to directly investigate the function of NANOG in human embryos because the genome editing techniques available, like conventional CRISPR/Cas9, cause too much unintended damage to the DNA. This work underscores the importance of directly investigating human development.
“We had predicted that the gene called NANOG would have a really important role in human development, given its importance in the development of mouse embryos. What we found was that NANOG functions somewhat differently in humans to mice, which means our assumptions about the role of this gene don’t transfer neatly across species,” said Dr Katarina Harasimov, a researcher at the University of Cambridge’s Loke Centre for Trophoblast Research who was also involved in the study.
Ethical and legal compliance
The embryos, eggs and sperm used in the study were unused samples donated by couples who had undergone IVF treatment. Most donors had completed their family, and wanted their surplus embryos, eggs or sperm to be used for research.
The embryos were only cultured in the lab for up to six and a half days after fertilisation, and then allowed to perish.
The study was done under a research licence and strict regulatory oversight from the Human Fertilisation and Embryology Authority (HFEA), the UK Government’s independent regulator overseeing fertility treatment and research. The research was also reviewed and approved by Newcastle and North Tyneside Research Ethics Committee.
The study is published today in the journal Nature.
It was conducted by scientists at the University of Cambridge Loke Centre for Trophoblast Research in collaboration with colleagues at Monash University, Broad Institute of Harvard and MIT, Francis Crick Institute, MRC Laboratory of Molecular Biology as well as clinical collaborators at Bourn Hall Clinic, Newcastle Fertility Centre, Assisted Reproduction and Gynaecology Centre, Create Fertility, and Centre for Reproductive and Genetic Health.
Key Questions Answered:
A: Think of traditional CRISPR/Cas9 as a pair of molecular scissors that cuts straight through both strands of the DNA double helix. When the cell scrambles to glue those broken ends back together, it often introduces major, chaotic errors, such as deleting whole chunks of chromosomes. This random damage makes it impossible to isolate the effects of a single gene. Base editing, by contrast, acts like a ultra-precise pencil or text eraser. It never cuts the DNA backbone; instead, it uses a modified protein to directly rewrite a single chemical letter (a single nucleotide base pair) out of 3 billion, turning off a target gene with surgical precision.
A: In the first few days after an egg is fertilized, embryonic cells are completely unspecialized. They must rapidly choose whether they are going to form the actual human body or the external life-support systems like the placenta. By using base editing to turn off the NANOG gene, Cambridge researchers discovered that NANOG is the ultimate genetic master switch for the body-forming path. Without it, the embryo can still build a placenta and a yolk sac, but it completely loses the ability to form the “epiblast”, the core cluster of pluripotent stem cells that possesses the blueprint to grow our organs, limbs, and tissues.
A: For decades, mice have been the golden standard for medical research because editing human embryos was technically and ethically restricted. However, this study proves that mammalian development does not follow a universal template. In mice, losing the NANOG gene destroys both the future body and the yolk sac. But in the human embryos studied, losing NANOG only affected the body-forming cells, leaving the yolk sac untouched. This means our core genetic rules do not transfer neatly across species. Directly studying human tissue using precise, safe tools like base editing is the only way to accurately decode human fertility, tackle inherited diseases like cystic fibrosis, and find out why early pregnancies fail.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics and neurodevelopment research news
Author: Jacqueline Garget
Source: University of Cambridge
Contact: Jacqueline Garget – University of Cambridge
Image: The image is credited to Loke Centre for Trophoblast Research, University of Cambridge
Original Research: Open access.
“Base editing reveals an essential role for NANOG in human embryogenesis” by Oliver J. Bower, Ana E. R. Orsi, Riley McMahon, Desislava Staneva, Josephine Blagrove, Kashish Singh, Claire S. Simon, Afshan McCarthy, Patricia Garcia, Valerie Shaikly, Mohamed Taranissi, Martin Wilding, Paul Serhal, Rabi A. Odia, Mina Vasilic, Meenakshi Choudhary, Athanasios Papathanasiou, Kay Elder, Phil Snell, Leila Christie, Mandana Arbab, David R. Liu, Mary Herbert, Katarina Harasimov & Kathy K. Niakan. Nature
DOI:10.1038/s41586-026-10792-1
Abstract
Base editing reveals an essential role for NANOG in human embryogenesis
Understanding how the first cell lineages in human development are specified and maintained has fundamental importance and clinical implications for regenerative medicine, infertility and pregnancy loss. While mouse models have provided valuable insights into transcription factors regulating early development, translating these findings to human embryos has been limited by ethical, technical and biological constraints.
Functional studies of transcription factors in human embryos have been hindered by nuclease-based genome-editing approaches that induce genotoxicity. To overcome this, we applied adenine base editing (ABE8e) to precisely target an exon splice donor site, resulting in a splicing defect and functional knockout of NANOG, representing the first application of base editing to study a developmental regulator in human embryos.
This approach did not trigger genotoxicity and showed limited off-target editing. Loss of NANOG disrupts pluripotent epiblast specification and instead cells differentiate toward a primitive endoderm (yolk sac) or trophectoderm (placental) transcriptional programme.
Retention of primitive endoderm differentiation in NANOG-edited human embryos reveals a functional compensation distinct from mouse, underscoring the importance of directly investigating human development.
Our findings demonstrate an essential role for NANOG in human pluripotency and epiblast specification, and highlight the utility of base editing for functional interrogation of human development.
