One of the leading Russian specialists in the field of molecular biology and genetic engineering, Denis Vladimirovich Rebrikov, in an interview with the journal Nature, spoke about plans to conduct an experiment to create children with edited genes. He stated that he was ready to repeat the experience of the Chinese geneticist He Jiankui, during which the twins Lulu and Nana were born. According to Rebrikov, he is considering the possibility of implanting genetically edited embryos by the end of the year, if he receives the appropriate approval of three departments, including the Ministry of Health of the Russian Federation.
What is CRISPR-Cas9?
CRISPR-Cas9 is a genome editing technology based on the principles of the immune system of bacteria (they are able to find and eliminate viral DNA). CRISPR-Cas9 includes a targeting RNA molecule that finds the desired piece of chromosome, and a Cas9 enzyme that cleaves DNA. If you add a normal copy of the gene at this point, it will be inserted in the right place. The process resembles text editing, when part of the sentence is deleted and other words are inserted in its place.
Gene editing in Russia
The purpose of the Russian biologist's experiment will be to modify the same gene that the Chinese genetic engineer worked on - CCR5. In an interview with Nature, Rebrikov said he was going to disable a gene in embryos that encodes a protein that allows HIV to enter the cells of the body. The embryos will subsequently be implanted in HIV-positive mothers who do not respond to standard therapy. It is noted that the risk of transmitting the infection to the child in this case will be higher, but if during the procedure it is possible to successfully disable the CCR5 gene, then this risk will be significantly reduced.
Recall that He Jiankui, in turn, took cells from HIV-positive fathers, and then transplanted the resulting embryos to HIV-negative mothers. There was no practical sense in this, which in turn, among other things, was another reason for the criticism of the Chinese geneticist by the world community of scientists. He's work drew a barrage of criticism from the scientific community and led to an open letter in which scientists called for a moratorium on experiments on gene editing of embryonic cells. Rebrikov argues that his method of gene modification will be more useful, less risky, and more ethically justified and acceptable to society.
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Rebrikov adds that he has already reached an agreement with a local HIV center, where he intends to attract female volunteers to take part in his experiment.
The journal Nature asked other researchers for comment on the planned experiment of the Russian scientist, who, as expected, expressed concern about Rebrikov's plans. For example, Jennifer Doudna, a molecular biologist at the University of California at Berkeley and one of the pioneers of the CRISPR-Cas9 gene editing method, says the technology is not fully understood and is not ready for use in clinical situations.
Even if the experiment is successful, there will be little risk of infection. And until now we do not know exactly how this will affect the life of a person as a whole. For example, in a recent study, carriers of both copies of the mutant CCR5 were at risk of earlier death compared to carriers of the normal gene.
Russian experts also expressed their disagreement with such experiments.
Molecular geneticist Konstantin Severinov, who was contacted by the authors of Nature, noted that it would be very difficult to get approval for such experiments in Russia. After all, you will have to take into account not only the opinion of government agencies, but also the church, which opposes gene editing. And this greatly reduces the chances of getting approval - at least in the coming years.
And yet the most important question is how realistic is the perspective that Rebrikov is drawing?
Dolotovsky believes that the experiment is technically possible, but the problem lies in the ethical part of the question.
According to Rebrikov himself, to whom the editors turned for comments, the ethical side of the issue is an extremely important aspect.
Why are people afraid of genetic experiments?
One of the reasons why the topic of genetically modified embryos has caused such heated debate in the world community is due to the fact that if such experiments are allowed now, the resulting "GMO children" will grow up and be able to pass on their modified genes to subsequent generations. Scientists generally agree that gene editing technology may one day help eliminate genetic diseases such as sickle cell disease and cystic fibrosis, but much more research is needed to date.
In addition, there are concerns about the safety of gene editing of embryos more generally. Rebrikov says his experiment, in which he, like the Chinese geneticist He, is going to use the CRISPR-Cas9 genome editing method, will be completely safe. However, scientists believe that using CRISPR-Cas9 in its current form could cause "off-target" mutations in other genes without capturing the desired ones, which are the target of the editing process. Thus, it is possible that genes, for example, those responsible for suppressing tumor growth, may be disabled.
According to Rebrikov, he is developing a method that can guarantee such misses. The scientist plans to publish preliminary results of this work within a month, possibly in the online bioRxiv scientific preprint repository or in a peer-reviewed journal.
When asked to comment on this statement to our portal, the author of the project replied as follows:
In turn, the scientists to whom the authors of Nature turned for comments were skeptical about Rebrikov's claims about solving the problem of non-target mutations and the possibility of implementing only target ones, in which only the necessary genes will be edited and exactly as planned.
Last year, in the journal Vestnik RSMU, where he is the editor-in-chief, Rebrikov published an article in which he argued that he had developed a method that could disable both copies of the CCR5 gene (by removing a portion of 32 base pairs) in more than 50 percent of cases.
However, Jennifer Doudna, a molecular biologist at the University of California, Berkeley, expressed skepticism about these results.
Australian National University geneticist Gaetan Burjo agrees with her, noting that during the editing process, possible deletions and insertions are difficult to determine.
Incorrect editing can cause a gene to be disabled inappropriately, leaving the cell still unarmed against HIV, or mutating a gene that functions in a completely different and unpredictable way, Burjo says.
Moreover, notes Burgio, the unmutated CCR5 gene has many useful functions that are still not fully understood. For example, scientists have previously determined that the gene appears to provide some protection against complications from infection with West Nile virus, as well as influenza.
Prospects for CRISPR in Russia
We also asked Denis Vladimirovich about the prospects for the CRISPR-Cas9 technology and whether it is capable of defeating all genetic diseases.
Denis Vladimirovich Rebrikov (photo by Nature).
“Hereditary diseases will not be defeated by CRISPR-Cas9, but by preimplantation genetic diagnosis (PGD). The fact is that, as indicated above, editing is justified only if all four alleles are broken (for a given pair of parents). These are extremely rare situations. One in a million. But children with hereditary diseases are born very often (almost 1% of newborns!) And it is very easy to defeat this: for a couple of parents who have the risk of having a sick child (because we know their genetics in advance (from somewhere)) carry out IVF and PGD in order to select a healthy embryo. And no CRISPR-Cas9 is needed! For some reason, few non-specialists understand this."
When asked how things are generally going with the CRISPR-Cas9 studies in Russia, and what role the state plays in them, Rebrikov replied that, on the whole, so far everything is fine.
About how he would describe the CRISPR-Cas9 technology and what his attitude to it is, Rebrikov replied:
Nikolay Khizhnyak