Optical Micrograph of a Human Egg Cell After Fertilization
CC Studio/Science Photo Library
In 2018, a Chinese researcher faced global condemnation after announcing he had used CRISPR technology to create three gene-edited children. The scientific community’s primary concern revolved around the risks of using CRISPR, particularly its potential to cause harmful mutations.
Recent advancements in gene editing show promise, particularly with a refined version of CRISPR called base editing. This technique allows researchers to edit healthy embryos with a significantly reduced risk of unwanted mutations. However, ethical and scientific hurdles remain before considering its broader application.
Human DNA consists of double strands, and the original CRISPR method employs a protein known as Cas9. This protein utilizes a guide RNA to target specific genomic locations, where it creates cuts in both strands. Unfortunately, such repairs by cells can lead to small mutations that may disrupt gene function.
Thus, even when the CRISPR-Cas9 system is successful, its inherent risks include major mutations and chromosomal abnormalities due to incorrect DNA repair.
Improvements, such as CRISPR base editing, now allow for more precise modifications by changing a single DNA base and cutting only one strand. Such advancements have demonstrated life-saving potential in ongoing clinical trials, particularly as treatments for conditions like hypercholesterolemia.
However, gene editing in embryos differs vastly from treating diseases in adults. In adult therapies, successful editing in just a fraction of cells may suffice. Yet, in an embryo, precise editing is critical, as every cell in the body will derive from it.
In 2017, a Chinese study explored base editing in abnormal human embryos, yielding positive results with minimal unintended changes.
More recently, Columbia University’s Dieter Egli and his team conducted a larger study using healthy two-cell embryos, achieving varied results. They found that one modification succeeded in three-quarters of cells without unintended changes, while another, less effective modification caused problems in about half of the cells.
The researchers attribute these discrepancies to the design of their guide RNA, emphasizing the need for better optimization to minimize off-target effects.
One critical challenge remains: the issue of mosaicism. If only some cells in an embryo undergo the intended gene edit, diseases still risk manifesting. This raises concerns, as evidenced by the potential mosaicism in the three gene-edited children from China.
Currently, there’s no foolproof way to confirm the absence of mosaicism in gene-edited embryos. Genetic testing can detect issues, but may fall short with mosaic embryos, necessitating more comprehensive approaches to ensure accurate results.
While recent findings are encouraging, regulators continue to demand solutions to mitigate the mosaicism issue before considering the safety of germline gene editing.
Potential strategies include utilizing gene-edited sperm or eggs, where modifications made prior to fertilization could eliminate mosaicism. Although applications in humans are still pending, innovations such as lab-generated sperm from stem cells could pave the way for safe genetic modifications.
Such advances could eventually lead to safe gene editing in future generations, but ethical questions about the implications of gene editing remain unresolved.
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Source: www.newscientist.com
