Earlier this month, Denis Rebrikov went to an old mansion in Moscow that now houses the Russian Academy of Sciences’s (RAS’s) Institute of Philosophy to confront his critics and set the record straight. Rebrikov was a well-regarded but little-known geneticist across town at the Pirogov Russian National Research Medical University when a June news article in Nature revealed his controversial plan to alter the DNA in human embryos with CRISPR, the powerful genome editor, and then implant them so they could develop into babies. He has subsequently become the focus of worldwide attention—and widespread condemnation in Russia and elsewhere as a reckless self-promoter.
At the opening of the meeting, attended by bioethicists, geneticists, and clinicians, Rebrikov lamented that the group wanted to debate the merits of his proposed experiment before he had a chance to describe it in detail. “People are discussing my thoughts and my intentions as if I’m not here,” Rebrikov said. “In Russia, we have a saying, ‘I have not read Pasternak, but I have my opinions about him,’” he added, referring to the author of Doctor Zhivago. “That’s my case.”
The fury that Rebrikov has faced builds on the outrage surrounding He Jiankui, the Chinese scientist who startled the world in November 2018 when news broke that he had stealthily used CRISPR to edit human embryos in an attempt to make them resistant to HIV and then implanted them, leading to the birth of twin girls. Not only had He proceeded with flimsy regulatory review, but the girls were not facing any immediate risk that could outweigh the potential harm the editing could cause. As a result, He lost his university job, got booted from a biotech he started, and is subject to ongoing government investigations. He’s experiment also sparked new calls for a moratorium on any further germline editing—making DNA changes that can be passed to future generations, which is what He did and what Rebrikov’s embryo edits would do as well. Two high-level panels were formed with representatives from several countries—but not Russia—to examine the ethics of such work and how to regulate it.
Yet unlike He, Rebrikov has been open about his intentions. He plans to seek rigorous ethical and regulatory review. He would use the technology to treat inherited deafness, addressing a medical need that is arguably more compelling than the theoretical one He chose. Rebrikov says he has a detailed research plan to assess the risks of altering embryos with CRISPR before he makes any attempt to implant them. And whereas He had no expertise in reproductive medicine, Rebrikov works as the chief geneticist at the country’s largest government-run in vitro fertilization (IVF) clinic.
Rebrikov’s critics have made a bevy of assertions about his motivations, suggesting he wants fame and glory, grants for his institution, wider acknowledgement that Russian scientists do cutting-edge research, or to prod the country’s strict regulators to loosen up control on many fronts. A stocky 43-year-old who is a former champion in sambo, a Russian martial art that combines judo and wrestling, Rebrikov deftly ducks those charges and counter punches; he calls them speculations and dismisses the claims with a “ha ha” or a shrug. Rebrikov stresses his belief that germline editing has great promise to help people. “When I see a new technology come forward, I want to see how it works and how I can improve it. I am doing research at the speed that natural biological factors allow.”
Some highly respected scientists in Russia who know Rebrikov well openly support his efforts. Sergey Lukyanov, a molecular biologist who heads the Pirogov medical school—and is Rebrikov’s former Ph.D. adviser and frequent collaborator—agrees that germline editing is premature for now. But he supports Rebrikov’s step-by-step approach. “[Rebrikov] is one of these people who takes action towards any imperfection of the universe that can, from his point of view, be corrected. For him, this is an opportunity to give happiness to parents to have healthy children.”
Rebrikov takes the sharp criticism in stride. “People are usually very conservative, and that’s normal,” he says. Rebrikov, in contrast, says he has a high tolerance for risk if there’s a substantial benefit at stake. “In sports school, we were taught to win without thinking about the magnitude of the problem,” he says.
Some opposition he suspects comes from the many scientists who are religious. “For me, it’s strange that some people believe in God and make experiments with DNA,” he says, asserting that these people have “cockroaches in their brains”—a Russian phrase meaning they are confused, if not delusional.
Critics, even after learning the details of Rebrikov’s plans at the meeting, think he is the one with cockroaches in his brain. “The clinical use for gene editing is like taking something out of the air, it’s imagined,” Sergey Kutsev, a clinician who heads Moscow’s Research Centre for Medical Genetics and is the top genetic adviser to the Ministry of Health, told the gathering. Aside from reservations about whether the deafness mutation Rebrikov has targeted is a good choice, Kutsev insisted that the chance of causing harm with CRISPR germline editing is too great for any genetic condition. “I’m absolutely sure the technology’s not ready, the same as every other doctor.”
Rebrikov acknowledges the scientific consensus that a bright red line now prohibits germline editing because the young CRISPR technology remains too error prone. Yet to the utter dismay of many colleagues, he has put his toes right on the line. And he is forcing Russia and the world at large to confront the key question: How, exactly, do you responsibly cross it?
Cowboy or Careful?
Rebrikov first discussed editing embryos at a conference in Kazan, Russia, on “postgenome” technologies in October 2018, nearly 1 month before the He story would explode. “I was really surprised that in the full auditorium of 500 people he was freely speaking about this issue,” says Egor Prokhortchouk, a genomics specialist at RAS’s Research Center of Biotechnology in Moscow. Even though Rebrikov’s study didn’t violate Russian regulations, Prokhortchouk still thought it was pushing the limits of what the strict science and health ministries would allow.
Working with nonviable embryos made at his IVF clinic—part of the Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology—Rebrikov and his co-workers used CRISPR to introduce a deletion into a gene for a protein, CCR5, that studs the surface of white blood cells. People who naturally inherit a defective CCR5 gene from both parents are highly resistant to HIV and suffer no dramatic ill effects from the protein’s absence; this is the same gene that He tried to cripple in the twin girls. But Rebrikov’s experiment—which joined about a dozen such human embryo-editing studies published to date, mainly from Chinese researchers—simply explored the efficiency of CRISPR. He did not discuss implanting edited embryos. “Everybody was interested in technical details and nobody asked questions about ethical things,” Prokhortchouk says.
In February, however, Rebrikov disclosed his greater ambitions to Prokhortchouk and his medical students. Rebrikov and his colleagues had described the CCR5 embryo study in the Bulletin of RSMU, which led Prokhortchouk to invite him to a student journal club to discuss the paper and He’s experiment. “Rebrikov insisted that he wants to create CCR5-edited babies and that this will protect them from HIV infection from their mothers,” says Prokhortchouk, who was—and remains—opposed to such plans.
Rebrikov says from the outset he was not interested in preventing a specific medical ailment, but rather to prove that he could safely help people with germline editing, which he believes will one day be widely used. He wanted to build his case by finding people with rare medical situations that would warrant the risk. He hoped to identify, for example, women who were living with HIV and wanted babies but were not responding to marketed antiretrovirals, which powerfully reduce the risk of mother-to-child transmission. Using IVF to create embryos homozygous for the CCR5 mutant in theory could help prevent infection from their mothers.
"The clinical use for gene editing is like taking something out of the air, it’s imagined." -Sergey Kutsev, Research Centre for Medical Genetics
Rebrikov’s initial CRISPR embryo experiments aimed to better gauge the risks and challenges. Ideally, when CRISPR is introduced right after an egg is fertilized, it will make its desired edit at the one-cell zygote stage, so that as the embryo divides, all cells are corrected. But if CRISPR enters at the two-cell stage or later, it may create a child who has the desired change in some cells but not others. This mosaic child could still be vulnerable to HIV. But out of eight embryos edited using CRISPR, Rebrikov’s team found evidence of mosaicism in only three of them at the blastocyst stage, when they are 5 days old and have about 250 cells. Still, the study did not assess the equally concerning possibility that the editing would create accidental, “off-target” mutations; theoretically, these could trigger a cancer or cause other health problems. Rebrikov’s publication attracted little attention: A Chinese team had published similar work 2 years earlier—and Bulletin of RSMU is obscure.
Only when Nature ran its news story, which said he hoped to implant an edited embryo within 6 months, did Rebrikov’s plan begin to draw more widespread scrutiny. Leading CRISPR scientists and bioethicists outside of Russia slammed Rebrikov’s plans as “irresponsible,” “unsettling,” and “a slippery slope,” charging that he was a “cowboy” who had “weak data” and was trying to “grab some attention.” Rebrikov rejects assertions that he hyped his plans and stresses that he didn’t seek any of the media attention. “If somebody called me and asked, ‘Would you answer my questions?’ OK, well, why not?” he says, noting that he has stopped replying to most media requests.
But the attention led to a July meeting, instigated by Prokhortchouk and hosted by Kutsev. “It was strange to me that Russian scientific society was not reacting at all,” Prokhortchouk says. Among the 10 attendees, to Prokhortchouk’s surprise, was a pediatric endocrinologist, Maria Vorontsova. She is widely reported to be Russian President Vladimir Putin’s daughter, although no one in the family has confirmed that. (Putin has demanded that his private life remain private but has acknowledged having daughters and grandchildren.) Vorontsova’s presence prompted a Bloomberg story on 29 September with the headline: “Future of Genetically Modified Babies May Lie in Putin’s Hands.” It suggested the meeting was “secret” and, with little evidence, that Vorontsova might influence Putin’s position on germline editing and, in turn, its fate in Russia. “The meeting was not secret,” retorts geneticist Igor Korobko, a Ministry of Health official who attended. “And we have rules and laws: It’s not the president’s decision.”
A Detailed Plan
Rebrikov couldn’t find any HIV-infected women who didn’t respond to antiretrovirals and also wanted to get pregnant. So he recently switched gears and sought hearing-impaired couples who are homozygous for a mutation known as 35delG in a gene, GJB2, that produces a protein in gap junctions, the channels that help move chemical signals like potassium between cells, including in the inner ear. The 35delG mutation, in which a single incorrect DNA base cripples the protein the gene codes for, is one of the most common genetic causes of hearing loss. Rebrikov wants to use CRISPR to replace the aberrant DNA base with the correct one.
Rebrikov told Science that he plans to do extensive safety checks before seeking approval to implant an edited embryo. First, he wants to sequence the entire genomes of each parent to get a baseline for assessing off-target mutations in their edited embryos. He then wants to stimulate the woman’s ovaries, obtain about 20 eggs, fertilize them with her partner’s sperm, and finally add the mutation-fixing CRISPR. He’ll grow these embryos for 5 days, at which point they will have about 250 cells and be in the blastocyst stage. Then he will do repeated rounds of whole-genome sequencing of 10 of these blastocysts, which aims to reveal all mutations that differ from the genomes of the parents.
If the number of new mutations is in the range seen normally in unedited embryos—about 100 per embryo—he will move to the next stage with the remaining edited embryos: a preimplantation test, commonly done in IVF, in which five to seven cells are removed from an early embryo and their genomes analyzed. In this case, he will check the cells for many types of genetic defects and for mosaicism for the CRISPR edit. But there could be other cells in the blastocyst that have unaltered GJB2 genes or off-target changes. “We always will have some limits of the technology,” Rebrikov says.
With help from a Moscow hearing clinic, this summer Rebrikov identified five couples who are homozygous for 35delG and certain to have a deaf child. He has met one—though the husband and wife have yet to decide whether they want to participate in his experiment.
Several clinicians and researchers who specialize in hearing loss say they do not believe such couples should take the risk of editing their embryos. For one thing, 35delG homozygotes sometimes only have mild hearing impairment. They also note that a proven alternative is available: a cochlear implant, an electronic device that stimulates auditory nerves. It can restore some hearing and is particularly successful when young children undergo the surgery. People homozygous for 35delG mutations “do really well with cochlear implants,” says Richard Smith, an otolaryngologist and researcher at the University of Iowa in Iowa City. Smith and others question Rebrikov’s decision to focus on deafness, a condition that some people with hearing loss do not see as a disability. Smith says he would pick something more “lethal.”
David Corey, a neurobiologist at Harvard Medical School in Boston who specializes in the molecular basis of hearing loss, adds that several biotech companies are trying to develop therapies that can correct the mutation in children after they’re born. “If I were a parent, I’d wait for a gene therapy delivered only to the affected cells,” Corey says.
It was strange to me that Russian scientific society was not reacting at all."-Egor Prokhortchouk, Russian Academy of Sciences Research Center of Biotechnology
Rebrikov counters that potential parents, properly informed of the risks, should make the decision. “How do they estimate the quality of life of their babies?” he asks “Yes, hearing is not a life-or-death issue, but parents can say, ‘Well, we think that we very strongly want our child to have hearing.’”
Pavel Tishchenko, a bioethicist at the RAS Institute of Philosophy who organized this month’s meeting there with Rebrikov, strongly challenged this idea at the gathering. “Just agreement of some patients is not enough for many reasons,” he said. “What will you tell the patients? The whole truth or just a part of it?” Will they know, Tishchenko asked Rebrikov, that germline editing was declared premature by an expert committee from the World Health Organization (WHO) and, separately, a prominent group of scientists who wrote an editorial in Nature? (Rebrikov says he will make his informed consent documents public.)
Tishchenko questioned whether Russian society is ready for germline editing, and he worried that Rebrikov’s proposal will not get close scrutiny from regulators. The Ministry of Health has a competent ethical committee, he told the gathering, but he has less faith in other levels of review within Russia. “We have a lot of ethical committees who will say yes to any innovations,” he said.
The ultimate question, Tishchenko said, is who is accountable if the child suffers a bad outcome? Rebrikov said that if regulators OK an experiment and something goes wrong, the researcher should be absolved. But Tishchenko recalled the story of a man at a sporting event in ancient Greece who threw a lance that killed a spectator. “Who is responsible? The one who threw the lance or the organizer of the lance-throwing competition?” he asked. “The question is not answered until this day.”
Such larger questions won’t be resolved anytime soon. But will Rebrikov’s proposed experiment even clarify the safety of germline editing? Science asked several researchers who have expertise in DNA sequencing about Rebrikov’s plan to search for off-target effects in blastocysts. To a person, they argued that his team would likely miss too many mutations caused by CRISPR.
Spotting these unintended edits “is not trivial,” says Fyodor Urnov, scientific director of the Innovative Genomics Institute at the University of California, Berkeley, who has opposed editing of human embryos even for research purposes. Even with state-of-the-art sequencing machines like the one Rebrikov says he will use, it would take sophisticated bioinformatics to detect the rare mutations in the 250 cells of a blastocyst. Urnov, a native of Russia, says it would be “very impressive” if Rebrikov could develop the necessary customized computational algorithm to compare the genomes in an embryo to its parents and detect these mutants.
Urnov notes that other groups that have edited human embryos with CRISPR have found troubling levels of off-target mutations. If Rebrikov developed a convincing way to identify such mutations and found that they were few, would that alter Urnov’s confidence in germline editing? “Yes it would,” he says. “From its current state of zero confidence.”
The day before the Institute of Philosophy meeting, the Russian Ministry of Health broke what many had seen as its curious silence about germline editing. “Issuing permission to edit the human genome in clinical practice would now be a premature and irresponsible measure,” it said in a press statement, noting that this was in line with the WHO expert committee on human genome editing. Korobko, who heads the ministry’s department of science, innovation, and biomedical health risks, says the statement came in response to yet another media account of Rebrikov’s plans, this one in Kommersant, an influential Russian newspaper.
Legally, Korobko says, Rebrikov’s work could fall under existing IVF regulations that make it illegal to create embryos for research purposes, but now, “It’s not prohibited.” Rebrikov’s earlier studies were on discarded IVF embryos, and his future plans arguably would not strictly be fundamental research but a clinical trial that aims to help a couple have a healthy baby. Still, Korobko doubts an ethics committee at the ministry would approve a permit for a clinical trial of germline editing. “The recommendation of the WHO means a lot to the Russian Federation,” he said.
His openness to the subject is really a plus to shift the responsibility from a simple scientist or an institution to the shared responsibility where all of society is included." -Elena Grebenschikova, Russian Academy of Sciences Institute of Scientific Information on Social Sciences
RAS has not spoken publicly about human germline editing, even though many science academies around the world have called human germline editing premature. One reason may be that many Russian scientists did not take Rebrikov’s pronouncements seriously. “When I first heard about this proposal, I considered this a bad joke because our country overregulates research,” says Raul Gainetdinov, a psychiatrist who heads the Institute of Translational Biomedicine at St. Petersburg State University. “We stumble like hell. We cannot push anything through the Ministry of Health.” Gainetdinov adds that only a handful of labs in Russia even do germline editing in animal models.
Elena Grebenshchikova, a bioethicist at RAS’s Institute of Scientific Information on Social Sciences, told the Moscow meeting attendees that she is glad Rebrikov pushed these issues into the public arena in Russia. “There’s a lack of communication between scientists and the society,” she said. “His openness to the subject is really a plus to shift the responsibility from a simple scientist or an institution to the shared responsibility where all of society is included.”
Rebrikov has grown weary of the frenzied media, some of which has badly misrepresented his work and plans. He will no longer offer a timeline when asked when he might be ready to seek approval to implant an edited embryo. “That’s a very strange question because now, we’re not making babies, we’re just proceeding in a scientific way.”