Russian biologist plans more babies edited by CRISPR

A Russian scientist announced that he was planning to produce genetically modified babies, which would make him only the second person known to have done so. It would also defeat the scientific consensus that such experiments should be prohibited until an international ethical framework has agreed on the circumstances and security measures that would be required. justify them.

Denis Rebrikov, a molecular biologist, said Nature he plans to implant in the female embryos modified by a gene, perhaps before the end of the year if he can get an approval by then. Chinese scientist He Jiankui sparked an international outcry by announcing last November that he had made the first baby in the world to be edited by a gene, binoculars.

The experiment will target the same gene, called CCR5, which he did, but Rebrikov says his technique will offer greater benefits, be less risky, and more ethically justifiable and acceptable to the public. Rebrikov plans to disable the gene, which encodes a protein that allows HIV to enter cells, into embryos that will be implanted in HIV-positive mothers, reducing the risk of transmitting the virus to the baby. in utero. In contrast, he modified the gene in embryos created from fathers with HIV, which, according to many geneticists, brings little clinical benefit, because the risk that a father passes HIV to his children is minimal.

Rebrikov heads a genome-modification laboratory at Russia's largest fertility clinic, the National Center for Medical Research in Obstetrics, Gynecology and Perinatology of Kulakov, Moscow. He is also a researcher at the Russian National Medical University Pirogov, also in Moscow.

According to Rebrikov, he has already made an agreement with an HIV center in the city to recruit HIV-infected women who wish to participate in the experiment.

But scientists and bioethicists contacted by Nature are disturbed by Rebrikov's plans.

"The technology is not ready," says Jennifer Doudna, a molecular biologist at the University of California at Berkeley, who has developed the CRISPR-Cas9 genome-modification system that Rebrikov envisions as "the best way to do it." use. "This is not surprising, but it is very disappointing and disturbing."

Alta Charo, a researcher in bioethics and law at the University of Wisconsin-Madison, says that Rebrikov's projects are not an ethical use of technology. "It's irresponsible to follow this protocol at this point," adds Charo, a member of a World Health Organization committee that develops ethical governance policies for the editing of the human genome.

Rules and regulations

The implantation of embryos modified by genes is prohibited in many countries. Russia has a law that prohibits genetic engineering in most cases, but it is unclear whether and how the rules would be applied regarding the editing of genes in an embryo. And the Russian regulation on assisted procreation does not explicitly refer to gene editing, according to a 2017 analysis of this regulation in various countries. (The law in China is also ambiguous: in 2003, the Ministry of Health had banned genetically modifying human embryos for breeding, but the ban did not involve any sanctions and its legal status was and was not allowed. is still not clear).

Rebrikov expects the Ministry of Health to clarify the rules for the clinical use of embryo editing in the next nine months. Rebrikov says that he feels the urgent need to help HIV positive women and that he is tempted to continue his experiments even before Russia eliminates regulations.

To reduce the chances of him being punished for his experiments, Rebrikov plans to seek the approval of three government agencies, including the Ministry of Health. It could take anywhere from a month to two years, he says.

Konstantin Severinov, a molecular geneticist who recently helped the government design a funding program for gene editing research, believes that such approvals could be difficult. The powerful Russian Orthodox Church is opposed to gene editing, said Severinov, who splits his time between Rutgers University in Piscataway, New Jersey, and the Institute of Science. and Skolkovo technology, near Moscow.

Before attempting to implant embryos containing modified genes in women, a transparent and open debate about scientific feasibility and ethics is needed, said geneticist George Daley of Harvard Medical School in Boston, Massachusetts. who also heard about Rebrikov's plans. Nature.

One of the reasons that gene-modified embryos have created a huge global debate is that, if they are allowed to become babies, the changes can be passed on to future generations – a large-scale intervention called germ line modification. Researchers agree that one day, technology could help eliminate genetic diseases such as sickle cell anemia and cystic fibrosis, but additional tests are needed before they can be used to alter human beings. .

Following the announcement of its announcement, many scientists have renewed their calls for an international moratorium on germ line modification. Although this has not happened yet, the World Health Organization, the US National Academy of Sciences, the Royal Society of the United Kingdom and other leading organizations have all been discussing ways to end dangerous and unethical uses, often defined as unnecessary or excessive risk. genome editing in humans.

HIV-positive mothers

Although he was widely criticized for his experiments using sperm from HIV-positive fathers, his argument was that he just wanted to protect people from the infection. But scientists and ethicists have argued that there are other ways to reduce the risk of infection, such as contraceptives. There are also reasonable alternatives, such as drugs, to prevent HIV transmission by the mother, says Charo.

Rebrikov is in agreement and therefore plans to implant embryos only in a subset of HIV-positive mothers who do not respond to standard anti-HIV drugs. Their risk of transmission of infection to the child is higher. If the edition succeeds to disable the CCR5 gene, this risk would be greatly reduced, says Rebrikov. "It's a clinical situation that calls for this type of therapy," he says.

Most scientists say that there is no justification for editing the CCR5 gene in embryos, even in this case, because the risks do not exceed the benefits. Even if the therapy goes as planned, and both copies of the CCR5 gene in the cells are turned off, there is still a chance that these babies become infected with HIV. Cell surface protein encoded by CCR5 It is thought that 90% of HIV infections are the gateway, but their removal will not affect other routes of HIV infection. Gaetan Burgio of the Australian National University of Canberra still has many unknowns about the safety of gene editing on embryos. And what are the benefits of editing this gene, he asks. "I do not see them."

Hit the target

The safety of gene editing in embryos in general is also causing concern. Rebrikov says that his experience – who, like He, will use the CRISPR-Cas9 genome editing tool – will be safe.

One of the main problems raised by his experience – and more generally by editing genes on embryos – is that CRISPR-Cas9 can cause unwanted "untargeted" mutations of the target gene, and that these could be dangerous if, for example, out of a tumor suppressor gene. But Rebrikov says he is developing a technique to ensure that there are no "off target" mutations; He plans to publish his preliminary results online within a month, possibly on bioRxiv or in a peer-reviewed journal.

Scientists contacted by Nature were skeptical about the possibility of making such assurances about untargeted mutations or another known challenge related to the use of CRISPR-Cas 9, the "targeted mutations", in which the correct gene is modified, but not in the intended manner.

Rebrikov writes, in an article published last year in the Bulletin of the RSMU, which he is the editor, that his technique disables both copies of the CCR5 gene (by removing a section of 32 bases) more than 50% of the time. He stated that the publication in this newspaper did not constitute a conflict of interest because the reviewers and editors are blinded by the authors of an article.

But Doudna is skeptical about these results. "The data I've seen indicates that it's not so easy to control the functioning of the DNA repair." Burgio also thinks that the changes have likely resulted in a number of things. 39; other deletions or insertions difficult to detect, as is often the case with gene editing. .

Misplaced changes may mean that the gene is not properly disabled, and therefore that the cell is still accessible to HIV, or that the mutated gene could function in a completely different and unpredictable way. "It can be a disaster," says Burgio.

In addition, non-mutated CCR5 has many functions that are not yet well understood, but that offer advantages, say scientists critical of Rebrikov's projects. For example, it seems to offer some protection against major complications following infection with West Nile virus or influenza. "We know a lot about it [CCR5’s] role in the entry of HIV [to cells]but we do not know much about its other effects, "says Burgio. A study released last week also suggested that people without a working copy of CCR5 could have a shortened life.

Rebrikov understands that if he continues his experiment before the implementation of updated Russian regulations, he could be considered a second He Jiankui. But he says he would only do it if he is sure of the safety of the procedure. "I think I'm crazy enough to do it," he says.