When the powerful and simple-to-use CRISPR/Cas9 gene-editing system was invented just over six years ago, its inventors knew it would be only a matter of time before someone, somewhere, would attempt to create the world’s first gene-edited babies. Now, a scientist in China, previously unknown to many experts in the field, claims to have done it.
In a series of YouTube videos released on Nov. 25, He Jiankui of the Southern University of Science and Technology explained that he used CRISPR to introduce a mutation in a gene called CCR5. The goal: replicate a naturally occurring mutation that appears to confer resistance to HIV. Some of those edited embryos were implanted in a woman’s uterus, leading to the birth of twin girls just weeks ago, He says.
“The girls are [as] safe and healthy as any other babies,” He claims. He goes on to denounce calling the girls “designer babies” and says his technique should be used only for healing, not to alter traits like eye color, sex, or intelligence. “I understand my work will be controversial, but I believe families need this technology, and I’m willing to take the criticism for them,” He says.
If the fallout is any indication, He underestimated just how controversial his project would be. Scientists and ethicists are united in a state of alarm over the experiment’s secrecy; its questionable consent practices; He’s decision to tiptoe the lines between healing and enhancement, given that HIV is preventable and treatable in other ways; and the fact that the editing affected the babies’ germ lines, so the mutations will be carried all through their development and passed on to any children they may have.
On Nov. 29, the Associated Press (AP) reported that China’s government ordered He’s work halted and investigated. Chinese Vice Minister of Science and Technology Xu Nanping called the work illegal in an interview with China state media, AP reported. On Nov. 30, the Chinese Clinical Trial Registry was updated to indicate that He’s embryo editing trial has been withdrawn.
“This work represents a deeply disturbing willingness by Dr. He and his team to flout international ethical norms,” US National Institutes of Health director Francis Collins says in a statement.
He’s announcement came two days before CRISPR experts were due to gather in Hong Kong for an international genome-editing summit Nov. 27 to 29. The move resembled an “attempt to seize headlines,” says Peter Mills, assistant director of the Nuffield Council on Bioethics, a UK policy group. “If the claims are true, it is a premature, inexplicable, and possibly reckless intervention that may threaten the responsible development of future applications of genome editing.”
On Nov. 28, at the summit in Hong Kong, He addressed a room packed with scientists and media teams. “First, I must apologize. This leaked unexpectedly,” He said. The work has been submitted to a journal for scientific review, He said, and the conference organizers did not know of He’s study before the news broke.
He proceeded to explain his work in mouse, monkey, and human cells. He aimed to make a particular mutation in the gene for CCR5, a protein that HIV uses to infect cells. Other groups, including Sangamo Therapeutics, are developing therapies to edit CCR5 in immune cells of adults with HIV. But doing this in embryos “is totally absurd,” says Bryan Cullen, a virologist at Duke University. “It’s irresponsible. We don’t know enough to do that.”
Underpinning the broader ethical questions is the fact that mutating CCR5 could have unanticipated effects on the girls’ development. The mutant CCR5 could leave them more susceptible to other diseases, including malaria and the flu. And if CCR5 wasn’t edited in every cell in the embryos, normal versions of CCR5 could remain, leaving them susceptible to HIV infection.
He’s experiment recruited eight couples of men with HIV and women without. One couple dropped out. According to the AP report, He used 11 edited embryos for in vitro fertilization before a pregnancy was established. At the summit in Hong Kong, He said another woman is in the early weeks of pregnancy.
In a Chinese document explaining the study, signed on March 2017, He writes that he hopes to implement strict industry quality-control standards and stand out in the increasingly competitive international gene-editing field. He goes on to say that the work would be a groundbreaking study to surpass the in vitro fertilization technology that won a 2010 Nobel Prize and would bring dawn to the treatment of countless major hereditary diseases.
A common safety concern about CRISPR gene editing is the risk of off-target effects when an edit or cut is made in places beyond the intended DNA site. He sequenced a single cell from the growing embryos to search for off-target cuts, found one that appeared insignificant, and went on to implant the embryos for pregnancy, he says. He plans to continue to monitor the girls’ health and DNA at least until they turn 18.
At the meeting, Wensheng Wei, a genome-editing scientist at Peking University, said that there is no reliable way to fully sequence the whole genome of a single cell and asked He how he could be confident there weren’t more off-target effects. With “current state-of-the-art” techniques, He said his team could fully check about 80–85% of the embryo’s genome. “His answer was not convincing at all,” Wei later told C&EN. Around 15–20% of those embryos’ genomes weren’t confidently checked for off-target effects, Wei estimates.
The work goes against ethical guidelines advanced by multiple organizations internationally. The precise laws and associated consequences in China are unclear, but many Chinese scientists condemned the work. “Why have you chosen to cross this red line? Why did you perform these clinical trials in secret?” Wei asked He at the meeting.
Wei didn’t get a satisfactory answer to these questions either. He said he presented preclinical work at a Cold Spring Harbor Laboratory conference. He’s presentation also indicated that he consulted CRISPR scientist Mark DeWitt from the University of California, Berkeley, and bioethicist William Hurlbut of Stanford University. According to articles from STAT, neither supported He’s experiment. And according to the AP, He’s former PhD adviser, Michael Deem of Rice University, was involved in the project and was present when the babies’ parents consented to the experiment.
When questioned about his understanding of informed consent, He revealed that only four people reviewed the informed consent document before it was used in the trial. The document refers to He’s work as an “AIDS vaccine development project,” and CRISPR is mentioned only twice. He says he personally explained the document to participating couples line by line.
Many scientists were also perplexed at He’s decision to edit CCR5. David Liu, a chemist who has invented new versions of CRISPR at Broad Institute of MIT and Harvard, pointed out that although the fathers were HIV positive, their sperm was washed before fertilization, and thus infection was unlikely. Furthermore, prophylactic drugs can suppress the virus in infected individuals. “I don’t see the unmet medical need for these girls,” Liu said when questioning He in Hong Kong.
In response, He explained the stigma of AIDS in China, saying children are given to relatives to prevent potential transmission of HIV. He believes that by protecting children genetically, parents will have new hope. “I feel proud,” He said.
Just days before the news broke, He published a paper claiming the field “lacks concise and plain-language ethics statements” on using gene-editing technologies such as CRISPR in the clinic. He proposed five principles for embryonic editing, including that it should be only “for serious disease, never vanity” (CRISPR J.2018, DOI: 10.1089/crispr.2018.0051).
But several organizations, including the United Nations Educational, Scientific, and Cultural Organization (UNESCO); the Nuffield Council on Bioethics; and the US National Academies of Sciences, Engineering, and Medicine, have already issued embryonic editing guidelines. The UNESCO guidelines call for a moratorium on human genome editing. The Nuffield Council and National Academies don’t go that far, but the National Academies’ first criterion for heritable germ-line editing is an absence of reasonable alternatives, which He’s work fails to meet. “There may be a future in which embryo editing is justified following a careful analysis of potential benefits, risks, and ethical issues, but the recently reported work does not meet these standards,” Liu says in a statement.
Ethics committees have generally looked favorably on using CRISPR in children and adults to fix an inherited or spontaneous genetic mutation that causes disease. Several companies are preparing to launch clinical trials testing CRISPR in this way. In those cases, edited individuals won’t pass on their altered DNA to their offspring, because their germ-line cells—eggs and sperm—remain unedited.
Benjamin Hurlbut, a professor of biology and society at Arizona State University, who attended the Hong Kong summit, says He’s purported achievement “simply leapfrogs completely over anything that would count as treatment into something that is much more unequivocally in the territory of enhancement.” Hurlbut adds, “These two lives are now an experiment, a matter of scientific curiosity, which is an outrageous way to relate to human lives.”
CRISPR researchers, many of whom are developing CRISPR therapies to treat or cure a variety of genetic diseases and cancers in a way that doesn’t involve germ-line editing, worry that He’s experiment will mar public perception of gene editing. “It would be a shame if enthusiasm and support for this work is negatively impacted by the recent news,” says Sam Sternberg, a CRISPR scientist at Columbia University.
Chinese scientists are also concerned that the news could hurt the country’s reputation. More than 100 Chinese scientists signed an online letter opposing He’s work. The Genetics Society of China and the Chinese Society for Cell Biology condemned gene editing in embryos intended for reproductive purposes and said that He’s project was “against the law, regulation, and medical ethics of China.” And SUSTech, He’s university, says He “has seriously violated academic ethics and codes of conduct.”
One of CRISPR’s inventors, Feng Zhang of Broad Institute, called for a moratorium on implanting gene-edited embryos until a list of safety requirements is constructed. But in Hong Kong, George Daley, dean of Harvard Medical School and one of the summit’s organizers, told the audience that “it’s time for us to at least consider a responsible pathway for clinical translation.”
At the end of He’s session, another summit organizer asked if He would have done the experiment with his own baby. He replied, “If it was my baby, with the same situation, I would try it first.”
This story was revised on Dec. 1, 2018, to indicate that the Chinese government has halted He’s research and that his clinical trial has been withdrawn. Several hyperlinks were also corrected.