Reacción a "A new version of CRISPR, base editing, reveals a key factor in human embryo development"

We sometimes like there to be a sense of mystery, but little can be done to solve problems without knowledge; moreover, knowing how something works does not detract from wonderment, it adds to it. Given all the things that can go wrong between having a fertilised egg and a healthy baby (and happy parents), such that this path fails in about 70% of cases, the more understanding we have of the early steps of human embryo development, the better chance we have of reducing distress, disappointment and sometimes debilitating disorders.

The work from Oliver Bower and others associated with Kathy Niakan’s lab is an important example of both how the research should be done as well as uncovering new knowledge about the first week or so of our beginnings. They focussed on a gene called NANOG, known from studies carried out in mice to play an important role in both the early epiblast, a group of cells that will go on to form the embryo proper, and the yolk sac, which is one of the extraembryonic tissues that, along with the placenta, supports the former. The most direct way to study the role of a specific gene is to inactivate it, and methods based on the use of CRISPR/Cas9 provide a direct and efficient way to do this. However, standard CRISPR methods that create double strand breaks in DNA rely on cellular mechanisms of DNA repair that all too frequently lead to chromosome damage, as shown previously by the Niakan lab and others. This can make it both challenging to draw firm conclusions and wasteful of valuable human embryos. The authors therefore chose to use base editing, a precise method to alter single nucleotides (‘letters’ in the code). [N.B. this is not the first attempt, but it was carried out with a high degree of rigour and with statistically valid results.] Bower et al show that the methods are both precise and efficient in the context of human embryos.

Furthermore, by introducing the base editing components along with the sperm during IVF (by intracytoplasmic sperm injection), they also largely avoid mosaicism, where the editing occurs after the first cell division such that only a proportion of cells carry the edit, which can also complicate interpretation of results. With respect to NANOG function, they find that it is required for the epiblast, and it is therefore also essential for human embryo development at an early stage, but that it is dispensable for the development of the extraembryonic endoderm that gives rise to the yolk sac. This adds to the evidence that the genes and mechanisms operating during early mouse and human embryo development can be substantially distinct, making it inappropriate to rely too much on results obtained with the former to understand the latter.

Although focussed on the role of NANOG in the early embryo, the work does relate to the notion of heritable genome editing, specifically by showing that base editing is very efficient, precise (with rigorous choice of guide RNAs), and can be used in a way that reduces concerns about mosaicism. These are all parameters that need to be close to perfect if the methods were to ever be used to create edited babies. They are not there yet, and even if they were, this should not be attempted without appropriately robust review, oversight, and knowledge of the extent of public acceptance and qualifications, and it would have to be legal, which it is not in most jurisdictions.