BY DAVID SYRANOSKI
A Russian scientist says he is planning to produce gene-edited babies, an act that would make him only the second person known to have done this. It would also fly in the face of the scientific consensus that such experiments should be banned until an international ethical framework has agreed on the circumstances and safety measures that would justify them.
Molecular biologist Denis Rebrikov has told Nature he is considering implanting gene-edited embryos into women, possibly before the end of the year if he can get approval by then. Chinese scientist He Jiankui prompted an international outcry when he announced last November that he had made the world’s first gene-edited babies — twin girls.
The experiment will target the same gene, called CCR5, that He did, but Rebrikov claims his technique will offer greater benefits, pose fewer risks and be more ethically justifiable and acceptable to the public. Rebrikov plans to disable the gene, which encodes a protein that allows HIV to enter cells, in embryos that will be implanted into HIV-positive mothers, reducing the risk of them passing on the virus to the baby in utero. By contrast, He modified the gene in embryos created from fathers with HIV, which many geneticists said provided little clinical benefit because the risk of a father passing on HIV to his children is minimal.
Rebrikov heads a genome-editing laboratory at Russia’s largest fertility clinic, the Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology in Moscow and is a researcher at the Pirogov Russian National Research Medical University, also in Moscow.
According to Rebrikov he already has an agreement with an HIV centre in the city to recruit women infected with HIV who want to take part in the experiment.
But scientists and bioethicists contacted by Nature are troubled by Rebrikov’s plans.
“The technology is not ready,” says Jennifer Doudna, a University of California Berkeley molecular biologist who pioneered the CRISPR-Cas9 genome-editing system that Rebrikov plans to use. “It is not surprising, but it is very disappointing and unsettling.”
Alta Charo, a researcher in bioethics and law at the University of Wisconsin-Madison says Rebrikov’s plans are not an ethical use of the technology. “It is irresponsible to proceed with this protocol at this time,” adds Charo, who sits on a World Health Organization committee that is formulating ethical governance policies for human genome editing.
Rules and regulations
Implanting gene-edited embryos is banned in many countries. Russia has a law that prohibits genetic engineering in most circumstances, but it is unclear whether or how the rules would be enforced in relation to gene editing in an embryo. And Russia’s regulations on assisted reproduction do not explicitly refer to gene editing, according to a 2017 analysis of such regulations in a range of countries. (The law in China is also ambiguous: in 2003, the health ministry banned genetically modifying human embryos for reproduction but the ban carried no penalties and He’s legal status was and still is not clear).
Rebrikov expects the health ministry to clarify the rules on the clinical use of gene-editing of embryos in the next nine months. Rebrikov says he feels a sense of urgency to help women with HIV, and is tempted to proceed with his experiments even before Russia hashes out regulations.
To reduce the chance he would be punished for the experiments, Rebrikov plans to first seek approval from three government agencies, including the health ministry. That could take anywhere from one month to two years, he says.
Konstantin Severinov, a molecular geneticist who recently helped the government design a funding programme for gene-editing research, says such approvals might be difficult. Russia’s powerful Orthodox church opposes gene editing, says Severinov, who splits his time between Rutgers University in Piscataway, New Jersey, and the Skolkovo Institute of Science and Technology near Moscow.
Before any scientist attempts to implant gene-edited embryos into women there needs to be a transparent, open debate about the scientific feasibility and ethical permissibility, says geneticist George Daley at Harvard Medical School in Boston, Massachusetts, who also heard about Rebrikov’s plans from Nature.
One reason that gene-edited embryos have created a huge global debate is that, if allowed to grow into babies, the edits can be passed on to future generations — a far-reaching intervention known as altering the germ line. Researchers agree that the technology might, one day, help to eliminate genetic diseases such as sickle-cell anaemia and cystic fibrosis, but much more testing is needed before it is used in the alteration of human beings.
In the wake of He’s announcement, many scientists renewed calls for an international moratorium on germline editing. Although that has yet to happen, the World Health Organization, the US National Academy of Sciences, the UK’s Royal Society and other prominent organizations have all discussed how to stop unethical and dangerous uses — often defined as ones that pose unnecessary or excessive risk — of genome editing in humans.
Although He was widely criticized for conducting his experiments using sperm from HIV-positive fathers, his argument was that he just wanted to protect people against ever getting the infection. But scientists and ethicists countered that there are other ways to decrease the risk of infection, such as contraceptives. There are also reasonable alternatives, such as drugs, for preventing maternal transmission of HIV, says Charo.
Rebrikov agrees, and so plans to implant embryos only into a subset of HIV-positive mothers who do not respond to standard anti-HIV drugs. Their risk of transmitting the infection to the child is higher. If editing successfully disables the CCR5 gene, that risk would be greatly reduced, Rebrikov says. “This is a clinical situation which calls for this type of therapy,” he says.
Most scientists say there is no justification for editing the CCR5 gene in embryos, even so, because the risks don’t outweigh the benefits. Even if the therapy goes as planned, and both copies of the CCR5 gene in cells are disabled, there is still a chance that such babies could become infected with HIV. The cell-surface protein encoded by CCR5 is thought to be the gateway for some 90% of HIV infections, but getting rid of it won’t affect other routes of HIV infection. There are still many unknowns about the safety of gene editing in embryos, says Gaetan Burgio at the Australian National University in Canberra. And what are the benefits of editing this gene, he asks. “I don’t see them.”
Hitting the target
There are also concerns about the safety of gene editing in embryos more generally. Rebrikov claims that his experiment — which, like He’s, will use the CRISPR-Cas9 genome-editing tool — will be safe.
One big concern with He’s experiment — and with gene-editing in embryos more generally — is that CRISPR-Cas9 can cause unintended ‘off-target’ mutations away from the target gene, and that these could be dangerous if they, for instance, switched off a tumour-suppressor gene. But Rebrikov says that he is developing a technique that can ensure that there are no ‘off-target’ mutations; he plans to post preliminary findings online within a month, possibly on bioRxiv or in a peer-reviewed journal.
Scientists contacted by Nature were sceptical that such assurances could be made about off-target mutations, or about another known challenge of using CRISPR-Cas 9 — so-called ‘on-target mutations’, in which the correct gene is edited, but not in the way intended.
Rebrikov writes, in a paper published last year in the Bulletin of the RSMU, of which he is the editor in chief, that his technique disables both copies of the CCR5 gene (by deleting a section of 32 bases) more than 50% of the time. He says publishing in this journal was not a conflict of interest because reviewers and editors are blinded to a paper’s authors.
But Doudna is sceptical of those results. “The data I have seen say it’s not that easy to control the way the DNA repair works.” Burgio, too, thinks that the edits probably led to other deletions or insertions that are difficult to detect, as is often the case with gene editing.
Misplaced edits could mean that the gene isn’t properly disabled, and so 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 real mess,” says Burgio.
What’s more, the unmutated CCR5 has many functions that are not yet well understood, but which offer some benefits, say scientists critical of Rebrikov’s plans. For instance, it seems to offer some protection against major complications following infection by the West Nile virus or influenza. “We know a lot about its [CCR5’s] role in HIV entry [to cells], but we don’t know much about its other effects,” says Burgio. A study published last week also suggested that people without a working copy of CCR5 might have a shortened lifespan.
Rebrikov understands that if he proceeds with his experiment before Russia’s updated regulations are in place, he might be considered a second He Jiankui. But he says he would only do so if he’s sure of the safety of the procedure. “I think I’m crazy enough to do it,” he says