Gene editing techniques could cure all sorts of diseases but could also cause genetic abnormalities in the Embryo as shown by a new study.
What is the fundamental nature of being human? Are we defined by our thoughts and emotions? Are we shaped by our actions, achievements, successes, and failures? Or are we simply products of genetic interactions, specifically the approximately 25,000 genes within the human genome, which instruct cells to create proteins?
While we encompass all of these aspects, it is undeniable that our genetic makeup, our genome, resides at the very core of our existence—the “master code” of our species. Advances in technology have now granted us the ability to manipulate and refine this master code, to edit it, and potentially enhance nature itself. This has raised the prospect of eradicating genetic disorders like cystic fibrosis, as well as improving cognitive abilities and extending life expectancy.
This concept is undeniably enticing. However, it is crucial to heed the call for caution made by some of the world’s leading researchers from the University of Oxford.
They reveal that the cells in early human embryos often struggle to repair DNA damage. Researchers assert that this has significant implications for the proposed use of gene editing techniques to eliminate severe inherited diseases from embryos, as well as for in vitro fertilization (IVF) procedures in general.
Presenting their research at the 39th annual meeting of the European Society of Human Reproduction and Embryology (ESHRE), Dr. Nada Kubikova from the University of Oxford issued a warning.
She stated, “Gene editing holds the potential to rectify faulty genes, a process that typically involves first breaking and subsequently repairing the DNA strand. Our recent findings caution against the application of commonly-used gene editing technologies to human embryos, as they may yield unintended and potentially perilous consequences.”
“Gene editing has the potential to correct defective genes, a process that usually involves first breaking and then repairing the DNA strand.”
But, these “new findings provide a warning that commonly-used gene editing technologies may have unwanted and potentially dangerous consequences if they are applied to human embryos.”
She outlined her assessment of the gene editing tool, CRISPR-Cas9, as a means to remove and replace specific segments of DNA within early embryo cells.
“Our results show that the use of CRISPR-Cas9 in early human embryos carries significant risks,” she remarked. “We have found that the DNA of embryo cells can be targeted with high efficiency, but unfortunately this rarely leads to the sort of changes needed to correct a defective gene. More often, the strand of DNA is permanently broken, which could potentially lead to additional genetic abnormalities in the embryo.”
Children and adults with genetic disorders including cystic fibrosis, cancer, and sickle cell disease are now being treated through gene editing. Many more hereditary illnesses may be averted if gene editing could be performed on embryos before they implant in the womb, since this is the only period of development during which CRISPR-Cas9 technology can be assured to reach every cell of the embryo. But because it could change the human DNA in a way that would be passed down through the generations and because we don’t know if it’s safe, its use in fetuses is banned in most countries around the world.
Dr. Kubikova said, “We wanted to evaluate whether CRISPR-Cas9 could be an effective method for correcting genetic mistakes in human embryos and to shed light on whether such methods would be safe to use.”
Dr. Kubikova and her colleagues created 84 embryos in an ethically accepted trial by fertilizing donated eggs with donated sperm by intracytoplasmic sperm injection (ICSI). They employed CRISPR-Cas9 to produce DNA double-strand breaks, or breaks in the two strands of the DNA molecule, in 33 of the embryos.
They “used CRISPR to target areas of the DNA that don’t contain any genes,” added Dr. Kubikova. “This is because we wanted to learn what is always true about how CRISPR affects embryo cells and their DNA, and not be distracted by changes caused by disrupting a particular gene.”
The remaining 51 embryos served as a control group.
All of the body’s cells have very effective methods for mending DNA damage. The ends of damaged DNA strands are often swiftly repaired. This is crucial because unrepaired DNA damage prevents cells from functioning normally and may even be fatal. The most frequent method that cells repair DNA is by reuniting the two ends of the strand, albeit this process often results in the deletion or duplication of a few genetic code letters at the location where the strands are reattached. Genes may be disrupted and mutations cannot be fixed as a result.
“This is known as non-homologous end joining,” according to Dr. Kubikova.
Cells can also repair a DNA break by using an intact copy of the afflicted region as a template, copying it, and replacing the damaged area as they do so. DNA fragments with slightly different DNA sequences, such as those with a normal sequence rather than a mutation, may be given to the cells. When the CRISPR break is repaired, the cell may employ these templates to do so by deleting the damaged DNA while also duplicating the remaining portion of the provided sequence.
“This is known as homology directed repair and is the process required for correcting a mutation,” she added.
In 24 out of 25 embryos, the researchers found changes at the targeted DNA locations, showing that CRISPR is quite effective in the cells of human embryos. Only 9% of the targeted locations were, however, repaired utilizing the therapeutically beneficial homology guided repair technique. Non-homologous end joining occurred on 51 percent of the broken DNA strands, resulting in mutations where the strands were rejoined. 40% of the damaged DNA strands were not successfully repaired. Large sections of chromosomes that run from the break site to the end of the chromosome were ultimately destroyed or duplicated as a result of the unrepaired breaks in the DNA strands. This kind of abnormality affects embryo viability, and if impacted embryos were transferred to the uterus and gave birth to a baby, they would be at significant congenital risk.
In early human embryos, homology guided repair is rare, and during the first few days of life, human embryonic cells struggle to repair damaged DNA strands, according to the results of this research. Using CRISPR-Cas9 to target the DNA site was incredibly effective. However, the majority of cells used non-homologous end joining to repair the DNA damage brought on by CRISPR, which results in new mutations rather than the removal of old ones. If efforts were made to employ CRISPR-Cas9 to treat genetic illnesses in human embryos, this would be challenging since the evidence shows that most attempts to do so would fail, according to Dr. Kubikova.
Although the findings warn against the use of genome editing in human embryos, there were some encouraging outcomes, showing that dangers may be reduced and the success rate of mutation removal can be raised by changing the method genome editing is carried out. This raises the prospect of technological advancements in the future.
On average, only around 25% of IVF-created embryos are successful in conceiving a child. Before being transplanted to the womb, half of them stop growing in the lab. According to this research, some IVF embryos fail to grow because they are unable to effectively repair DNA damage. This knowledge might result in better IVF procedures.
Now that early embryos are being protected from DNA damage, researchers are focusing on developing new methods to enhance fertility therapies. Additionally, they want to investigate gentler gene editing techniques that don’t damage DNA strands, which could be easier for embryos to handle.
According to Dr. Kubikova, “In the future, such methods may offer the possibility of reversing mutations that have blighted families for generations, preventing the inheritance of catastrophic disorders.”
Professor Karen Sermon, the chair-elect of ESHRE and the Head of the Reproduction and Genetics Research Group at Vrije Universiteit Brussel in Brussels (Belgium), who was not directly involved in the research, said, “I think it’s likely that gene editing will become a useful tool at some point in the future for preventing babies from being born with serious genetic diseases in a restricted number of cases where preimplantation genetic testing would not apply.”
She added: “However, this research shows one of the ways that it can go wrong. It will be some time before we can be confident that we really understand how to use it successfully without any unwanted and unexpected surprises. It will require stringent regulation.”
He Jiankui, a Chinese scientist, claimed in 2018 that he had successfully developed the first gene-edited kids to shield them against HIV. Scientists were worried about the safety of the work, and in December 2019, Jiankui was sentenced to three years in prison for breaking a Chinese law that says you can’t change the genes of human babies.
Source: European Society of Human Reproduction and Embryology
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