鈥淚 FEEL proud, actually.鈥� So He Jiankui told his peers as he stood up to defend gene editing twins before birth at the Second International Summit on Human Genome Editing in Hong Kong on 28 November.
Two days earlier, He鈥檚 experiment 鈥� the world鈥檚 first reported births following genetic modification of human embryos 鈥� had been revealed by the Associated Press news agency. Working in China, He says he has been using the CRISPR gene-editing technique on human embryos to create people who are resistant to HIV. So far, this has resulted in two babies: twin girls, born in November.
The experiment flies in the face of widespread agreement among geneticists that it is too soon to be attempting trials like this. There have been more than 60 meetings and reports on gene editing humans in the past three years. Most have concluded it would be irresponsible to proceed with any clinical use of embryo editing until safety issues 鈥� which can include unwanted changes to DNA 鈥� have been resolved.
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While some researchers have used CRISPR to edit human embryos, these have all been destroyed. He is the first scientist to implant any into a uterus to cause pregnancy. The resulting babies could be the first humans to one day pass on intentional mutations to their own children.
Unknown impact
There hasn鈥檛 yet been any independent verification confirming He鈥檚 claims. But He鈥檚 presentation at the summit appears to have convinced many in attendance. 鈥淎mong the scientific community, we鈥檙e very sure,鈥� says Helen O鈥橬eill at University College London, who was there.
He told the packed audience that he picked a gene called CCR5 because it is already 鈥渨ell-understood鈥�. This gene makes a protein that allows HIV to infect cells. Some people 鈥� mostly Europeans 鈥� have naturally occurring mutations in the gene that make them resistant to some strains of HIV. He said that disabling the gene at the embryo stage may protect children from contracting HIV.
The approach was tested first in mice and monkeys, He told the summit, before he recruited eight HIV-positive men and their HIV-negative female partners for his trial. One pair dropped out, but He was able to make 30 embryos from the seven remaining couples.
He said he managed to edit 70 per cent of these using CRISPR to disable the CCR5 gene, and that he is proud of this work because there are millions of children at risk of contracting HIV (see 鈥�Why was HIV the first target of gene editing?鈥�).
In the question-and-answer session following He鈥檚 talk, David Liu 鈥� a researcher at Harvard University who was involved in developing CRISPR 鈥� remarked that the twins hadn鈥檛 needed gene editing to protect them getting HIV from their father. 鈥淚 just don鈥檛 see the unmet medical need for these girls.鈥�
CCR5 mutations are uncommon in the Chinese population, said Robin Lovell-Badge of the Francis Crick Institute in the UK, meaning we don鈥檛 know whether altering this gene could have unexpected effects in the twins. He also cited evidence that CCR5 mutations can increase susceptibility to other infectious diseases like influenza and West Nile virus.
The twins appeared 鈥渘ormal and healthy鈥�, He told the summit, and sequencing DNA from their cord blood and placentas hadn鈥檛 found any off-target mutations. He acknowledged that the twins 鈥� whose identity hasn鈥檛 been revealed 鈥� will need years of follow-up tests to know for sure.
He鈥檚 data also showed that in one of the twins, only one copy of the CCR5 gene was successfully disabled, meaning she is still susceptible to contracting HIV.
鈥淚 think there has been a failure of self-regulation by the scientific community,鈥� the chair of the summit, David Baltimore at the California Institute of Technology, later told the conference.
One of the main criticisms levelled at He is the secrecy under which he conducted his work. He didn鈥檛 register the trial with the voluntary Chinese Clinical Trial Registry until early November. And He told the summit that the university where he works 鈥� the Southern University of Science and Technology 鈥� was unaware he had used research money allocated to him to partially fund the trial.
It isn鈥檛 yet known at which institution or hospital He conducted the work, and it is unclear whether the participants were properly informed about the potential risks (see 鈥�A brave new world?鈥�). He said he asked four experts to review the informed consent process, including an unnamed professor in the US.
鈥淭he twins appeared normal and healthy, He said, but will need years of follow-up tests to know for sure鈥�
China鈥檚 vice minister for science and technology, Xu Nanping, told Chinese media on 29 November that He鈥檚 trial 鈥渂latantly violated China鈥檚 relevant laws and regulations鈥�. Xu said he has ordered the trial to be shut down and for the scientists involved to be investigated.
At the summit, He said that he has now submitted the details of his trial to a scientific journal so it can be subject to peer review.
The conference concluded with a statement from its organisers saying they continue to believe that using gene editing to make changes that could be passed on to future generations is 鈥渋rresponsible at this time鈥�.
However, the committee added that, should the risks be addressed, it may in future become acceptable when there is a compelling medical need and no reasonable alternative.
What the experts say
I am shocked and disgusted by this news. This work sets a dangerous precedent, unless there is broad global rejection of the clinical processes used. The global scientific community has reacted strongly [with] calls for verification and re-doubled efforts to put in place criteria for the clinical use of CRISPR.
Jennifer Doudna, at the University of California, Berkeley, who discovered a way to use CRISPR to edit genes
If the twins, and one more pregnancy in progress, are very healthy, then there will probably be additional germline editing clinical trials soon. We either allow or outlaw. If the latter, then we may drive it underground 鈥� just as it is moving from hypothetical speculation to rigorous testing.
George Church, at Harvard University, who helped develop the capability for CRISPR to be used in humans
It is appalling that the edited human babies were generated without the full engagement of independent scientific and ethics experts, relevant regulatory institutions and governing bodies. He鈥檚 naivety about multiple scientific, medical and ethical issues was very alarming to hear in person.
David Liu, at Harvard University, who helped develop the accuracy and versatility of CRISPR
The entire world faces the same challenge in regulating gene editing. This experiment is a mistake by one single researcher and doesn鈥檛 represent what we [in China] stand for. I believe all of us will learn from it and raise our awareness on the ethical rules and regulations around scientific research.
Linqi Zhang, HIV researcher at Tsinghua University in Beijing
This case may be the trigger for countries to develop better oversight. I am confident China will develop more effective oversight of gene editing. My own view is that China should adopt a licensing system similar to the UK, where certain procedures and research can only be carried out in certain institutions, and that such research has to be reviewed by approved ethics committees.
Reidar Lie, an expert on Chinese medical research ethics at the University of Bergen in Norway
What is CRISPR?
Michael Le Page
We have been modifying plants and animals for decades, but it has been done by simply chucking extra DNA into a cell, with no way of ensuring that it safely inserts itself into the genome. As a result, no one tried this in human embryos as there was no way to guarantee it was safe.
Then came CRISPR gene editing, discovered in 2012. At its heart, CRISPR is a way of searching through the 3 billion DNA letters in our genome to find a particular sequence. It used to take years and hundreds of thousands of dollars to design a custom protein to seek out a specific sequence. CRISPR proteins instead work with a guiding piece of genetic code to find the corresponding sequence in DNA. It is both cheap and easy to make new guides out of RNA, sending the CRISPR proteins to different target sequences.
The most widely used CRISPR protein, called Cas9, cuts DNA after binding to the target. When the cut is repaired by the cell, bits of DNA get added to or removed from the ends. The term genome editing is a bit misleading as CRISPR Cas9 is usually used to disable genes by inducing random mutations in this way.
But alternative forms of CRISPR Cas9 are being developed, including 鈥渂ase editors鈥� that chemically change one DNA letter to another one 鈥� true genome editing that enables precise changes.
This is crucial if CRISPR is to be used to treat conditions in adults. The first clinical trials of CRISPR are already under way in China, where immune cells are being altered to make them better at killing tumour cells in people with advanced cancer.
The potential power of such approaches was demonstrated in 2015, when a more expensive non-CRISPR form of gene editing saved the life of Layla, a 1-year-old girl in the UK who had leukaemia.
This article appeared in print under the headline 鈥淭he CRISPR bombshell鈥�
