Light micrograph of a human egg cell after fertilisation
CC STUDIO/SCIENCE PHOTO LIBRARY
In 2018, a researcher in China announced the creation of three gene-edited children using CRISPR, drawing widespread criticism from the global scientific community. The primary concern was not the concept of gene-editing itself, but the safety risks associated with the CRISPR technique, which could lead to harmful mutations.
Recently, a team in the United States has employed a refined version of CRISPR, called base editing, to modify healthy embryos without causing unwanted mutations. However, despite these advances, the question of whether this technique is ready for broader application remains unanswered due to significant challenges.
DNA is composed of two strands. The original CRISPR method involves a protein called Cas9, which pairs with a guide RNA to locate a specific genomic sequence. Cas9 then cuts through both DNA strands. When the cell repairs this break, errors often occur, leading to small mutations that can disrupt genes.
Thus, CRISPR-Cas9 is inherently risky, as it can result in DNA ends being reattached incorrectly, causing major mutations and chromosomal issues.
Several improved CRISPR variations have been developed. Base editing, for example, alters a single DNA base and only cuts one strand of DNA, allowing for more accurate repairs with reduced error risk. This method has already been life-saving, with ongoing trials for conditions like high cholesterol.
However, editing embryos is far more complex than treating diseases. In adults, incomplete gene editing in every cell is often acceptable, as only a fraction of cells need modification to treat a condition. In embryos, gene editing must be flawless, as every cell in the body originates from the embryo.
In 2017, a Chinese team reported encouraging results from a small study using abnormal human embryos discarded from IVF. They found that base editing achieved desired genetic changes in nearly all embryos with minimal unintended alterations.
Dieter Egli and colleagues at Columbia University in New York have conducted a larger study using healthy two-cell embryos donated by parents, yielding similar results. They attempted two genetic changes; one succeeded in three-quarters of cells without unwanted changes, while the other was successful in only about half of the cells, often resulting in unintended changes.
The researchers attribute the varying success to the guide RNAs used. They believe that improved design and testing of these guide RNAs could reduce off-target effects.
The principal challenge remains that base editing does not uniformly affect every cell in each embryo, a phenomenon known as mosaicism. In a mosaic embryo that develops into a child, only some cells will carry the intended genetic change, potentially allowing the targeted disease to develop. It is possible that the three gene-edited children in China are mosaics.
Currently, there is no reliable method to confirm whether a gene-edited embryo is a mosaic. While a single cell can be extracted from IVF embryos for genetic testing to assess disease risk, this approach is insufficient for mosaic embryos.
Although the latest findings are promising, they are unlikely to convince regulators that germline gene editing is safe. The issue of mosaicism must be addressed first.
One potential solution is to use gene-edited sperm or eggs. If editing occurs before an egg is fertilized and begins to divide, mosaicism could be avoided. While this has not yet been done in humans, a start-up claims to have the ability to produce sperm in the lab from sperm stem cells, which could potentially be gene-edited.
Such advancements may lead to the possibility of safely editing genes in children. However, whether this should be pursued is an entirely separate debate.
Topics:
