New evidence shows that modifying human embryos brings doom to DNA. Three studies conclude that the CRISPR gene-editing method is not safe.
A few months ago, in June 2020, the findings of a group of scientists from Britain showed that the CRISPR gene-editing tool can cause unintended damage to DNA when used in human embryos. The results raised serious concerns about how safe it is to create genetically modified embryos.
Subsequently, even more evidence emerged that CRISPR can cause unexpected genetic mutations in the embryo. After June, two American research teams published papers with corresponding findings on bioRxiv (an online repository of biological research that is under review). The three papers have not yet undergone the peer-review process, but all three equally conclude that CRISPR is not safe enough to be used in human embryos with the aim of preventing the occurrence of genetic disorders and diseases.
“This is not even a simple signal for caution. It is a full-scale biological disaster hazard sign, placed right in front of embryo genetic modification,” says Fyodor Urnov, a geneticist specialist and professor of molecular biology at Berkeley, who had no involvement in any of the three studies.
In each of the studies, the researchers had the goal of modifying just one gene in the human embryo. But each team found that CRISPR not only altered the gene which was supposedly the target; it also caused unpredictable changes in other parts of the genome as well. Gene modification specialists, who have no involvement in the three studies, argue that unplanned interventions in DNA can cause miscarriages, cancer, or other health problems in babies born as a result of embryo DNA intervention.
In the first study, which was posted on bioRxiv on June 5, developmental biologist Kathy Niakan and her team at the Francis Crick Institute in London successfully managed to delete a gene called POU5F1, which is associated with embryo development. However, the findings showed that applying CRISPR to remove the gene also caused large alterations and rearrangements in the nearby DNA segment.
In the second study published on June 18, a team from Columbia University led by stem cell biologist Dieter Egli used CRISPR on human sperm cells to correct a mutation in the EYS2 gene that causes blindness. They then used the modified sperm cells to fertilize eggs in the laboratory and create embryos. When they examined the embryos, they observed that in about half of the 23 modified embryos, large segments of DNA on the chromosome containing EYS2 had been deleted.
A third group, led by reproductive biologist Shoukhrat Mitalipov of Oregon Health & Science University, used CRISPR on 86 embryos to correct a mutation in a gene called MYBPC3 that causes a hereditary heart condition that can be fatal. The researchers found that the modification caused mutations in large segments of the chromosome where the gene is located. The authors posted their research results on bioRxiv on June 20.
It is unclear whether the three groups had coordinated the publication of their work. But the results, if they pass the peer review stage, will significantly affect the discussion on the method of modifying the germline – that is, modifying sperm, eggs and embryos – with the aim of preventing genetic diseases. Germline intervention is controversial because it can cause genetic mutations that will be hereditary. Thus, if scientists make a mistake, this genetic error will continue to be passed from generation to generation.
Achieving pregnancy with a genetically modified embryo is prohibited in many countries, while in others there are formal regulations that directly or indirectly ban genetic intervention on embryos, but in many countries there is no such provision and theoretically it is not prohibited. The WHO has appointed a committee to regulate the procedures and restrictions on genetic modification of the germline, and in July 2019 issued a statement saying that “it would be irresponsible at this time for anyone to proceed with clinical applications of human germline genetic modification.” A second committee, formed by the U.S. National Academy of Medicine, the U.S. National Academy of Sciences, and the U.K. Royal Society, is examining ways in which safe germline intervention could be achieved and the cases in which this might be permissible. Both committees were formed after the November 2018 revelation that a Chinese researcher, Jiankui He, had used the CRISPR method to intervene in human embryos and had achieved pregnancies with these embryos, which led to the birth of the first genetically modified babies. The two committees are expected to announce their recommendations by 2021.
Paula Amato, assistant professor of obstetrics and gynecology at Oregon Health & Science University and member of Mitalipov’s research team, posted on twitter supporting that the use of CRISPR in human embryos to prevent the occurrence of certain diseases “could be unsafe and ineffective at this stage.” However, she suggested that safe correction of genetic diseases in embryos could be possible with a new version of CRISPR called base editing.
The established CRISPR method works by using a molecule as a guide to search for a specific DNA sequence in the genome. Once it finds it, the modification mechanism takes over and cuts this sequence by breaking the DNA double helix. Subsequently, the DNA tries to self-repair, but does not always do so successfully. The result is the appearance of mutations such as those described in the three studies.
Base editing, developed in 2016, is more precise than the original CRISPR method first described in 2012. Instead of cutting pieces of DNA, base editing changes just one DNA letter into another. In this way, it could potentially avoid the collateral damage caused by breaking DNA. A Chinese research team has already reported since 2018 that base editing in human embryos produced few unexpected modifications. But the base editing method is not yet problem-free. A 2019 study found that this technique produced a significant number of unintended mutations in mouse embryos. But even if researchers proceed with this or some other method of genetic modification of human embryos, the question will remain as to how many unchecked mutations will arise from them.
translation: Hurry Tuttle
original title: New Evidence Shows Editing Human Embryos Wreaks Havoc on DNA