Debate rages on first gene-edited babies, drives to eliminate diseases
A statement released by the organizing committee of the Second International Summit on Human Genome Editing in Hong Kong, on November 29, 2018, noted: “We heard an unexpected and deeply disturbing claim that human embryos had been edited and implanted, resulting in a pregnancy and the birth of twins,” “Even if the modifications are verified, the procedure was irresponsible and failed to conform with international norms.”
Similar criticism has rained down since the revelation last week that He had used the CRISPR–Cas9 genome-editing technique to modify the CCR5 gene in two embryos, which he then implanted in a woman.
The gene encodes a protein that some common strains of HIV use to infect immune cells.
CRISPR-Cas9 is a unique technology that enables geneticists and medical researchers to edit parts of the genome by removing, adding or altering sections of the Deoxy ribonucleic Acid (DNA)/genetic material sequence.
It is currently the simplest, most versatile and precise method of genetic manipulation and is therefore causing a buzz in the science world.
CCR5 is the main coreceptor used by macrophage (M)-tropic strains of human immunodeficiency virus type 1 (HIV-1) and HIV-2, which are responsible for viral transmission. CCR5 therefore plays an essential role in HIV pathogenesis.
Meanwhile, the WHO has said it is creating a panel to study the implications of gene editing after a Chinese scientist controversially claimed to have created the world’s first genetically-edited babies.
“It cannot just be done without clear guidelines,” the head of the United Nations health agency, Tedros Adhanom Ghebreyesus, told reporters in Geneva on December 3.
“WHO is putting together experts and we are working with member states…to discuss the standards and guidelines that can cover the ethical and social safety issues,” added Tedros, a former Ethiopian health minister.
Tedros made the comments after a medical trial, which was led by Chinese scientist He Jiankui, claimed to have successfully altered the DNA of twin girls, whose father is HIV-positive, to prevent them from contracting the virus.
Also, United Nations (UN) has rejected a proposal to temporarily ban the release of organisms carrying gene drives — a genetic-engineering technology designed to spread mutations rapidly through a target population.
Dozens of scientists, on November 29, at a meeting of the United Nations Convention on Biological Diversity (CBD) in Sharm El-Sheikh, Egypt, opposed the moratorium proposal, although numerous environmental and activist groups supported it.
A gene-drive moratorium was never likely to succeed in the face of opposition from biotechnology-friendly countries, because changes to the CBD must be accomplished by reaching consensus among the convention’s almost 200 parties.
Instead, representatives at the two-week-long meeting agreed to changes to the treaty that were vague enough that both proponents and sceptics of gene-drive technology are touting victory.
Signatories to the treaty, which has been ratified by most of the world’s countries and influences national laws that affect biodiversity, agreed on the need to assess the risks of gene-drive releases on a case-by-case basis. They also said that local communities and indigenous groups potentially affected by such a release should be consulted.
The journal Nature raises six big questions on gene-edited babies that are still unanswered.
1. Is He Jiankui in trouble?
On November 27, a day before He gave his talk at the summit, China’s national health ministry called on the government of Guangdong — where He’s university, the Southern University of Science and Technology is — to investigate He.
Two days later, the science ministry ordered him to stop doing any science; He had already said the experiments were on hold.
How the Guangdong investigation will proceed is not clear. He is accused of transgressing a 2003 health-ministry guideline, which is not a law and has no clear penalties attached to it.
Whether He’s university will take any action against him is also unclear.
A university spokesperson told Nature that he “cannot disclose such information at this moment” and to wait for official statements “at an appropriate time.”
He has been on leave since February 2018 and this is scheduled to last until January 2021; this week, the university criticized his claims and distanced itself from his work.
On November 27, the laboratory web page hosted by the university — to which He has been referring people for information about the gene-edited babies — went down, although another site for He’s lab remains.
Several statements praising He Jiankui’s accomplishments have also disappeared from government sites.
A post on the science ministry’s site describing a genomic-sequencing technology that He developed, and a post praising He’s genomic sequencing technology on the website of the Thousand Talents Plan — a prestigious scheme to bring leading academics back to China — are both now inaccessible.
It’s not clear if these actions are related to the week’s events, but both posts were still accessible until recently.
He went back to Shenzhen, where he lives, after his talk at the summit, according to a statement provided by He’s spokesperson, Ryan Ferrell, and missed a planned appearance at the summit on November 29. “I have returned to Shenzhen and will not attend the conference on Thursday. I will remain in China, my home country, and cooperate fully with all inquiries about my work,” the statement said.
2. Are He’s claims accurate?
Many scientists have said that an independent body should confirm He’s scientific claims by performing an in-depth comparison of the parents’ and children’s genes.
The problem is, almost everyone agrees that the babies and their parents should remain anonymous.
“He has kept them secret, and for good reasons,” says Nobel-prizewinning biologist David Baltimore, chair of the summit’s organizing committee and former president of the California Institute of Technology in Pasadena.
“We haven’t even laid out how that independent investigation will happen.”
He’s team could supply anonymised samples. Outside scientists could also visit He’s laboratory to analyse the data.
In a statement released by his spokesperson, He said that he would invite other researchers to do an independent investigation. “My raw data will be made available for third-party review.”
He also says that he has submitted studies on his human gene-editing research to journals for publication.
He has told some scientists that a paper will be published by the end of the year, but has not specified in which journal. But even if this happens, strict Chinese genetic-resources laws would prevent He from publishing the gene sequences of the parents or the children, and without those, scientists would have a difficult time verifying his claims.
3. How exactly did CRISPR edit the twins’ genomes?
In the absence of a peer-reviewed publication or preprint describing He’s gene-editing work, some scientists are parsing his presentation to try and understand how the twins’ genomes were edited — and any potential consequences of these changes.
A geneticist at Australia National University in Canberra, Gaetan Burgio, who works on CRISPR gene editing, says that the raw sequencing data that He presented in his talk suggests that the babies’ cells harbour multiple edited versions of the CCR5 gene, with different-sized DNA deletions.
Such ‘mosaicism’ can be caused when CRISPR edits some early embryo cells differently to others, or fails to edit some. Other researchers have reported mosaicism in efforts to edit human embryos for research purposes.
RNA researcher Sean Ryder, at the University of Massachusetts Medical School in Worcester, pointed out additional concerns in a Twitter post.
He Jiankui told the gene-editing conference that he targeted the CCR5 gene because some people naturally carry a mutation in CCR5 — a 32-DNA-letter deletion known as delta-32 — that inactivates the gene. But Ryder says that that the CCR5 deletions that He claimed to introduce into the babies’ cells by CRISPR gene editing are not identical to the delta-32 mutation.
“The point is that none of the three match the well-studied delta 32 mutation, and as far as I can tell, none have been studied in animal models.
Unconscionable,” Ryder wrote in the post.
He Jiankui, seated, looks up as he answers questions during his presentation at the human genome-editing summit on 28th November
4. When will there be another gene-edited human?
As Jennifer Doudna, a pioneer of the CRISPR-Cas9 genome-editing tool, listened to He present his work at the summit, one idea kept coming back to her.
“The thought I kept having was the potential for rogue scientists to use this in unethical ways. It’s a real risk,” says Doudna, a biochemist at the University of California, Berkeley, United States.
Before He’s revelation, many scientists were already worried about the prospect that someone was on the brink of creating a gene-edited person.
Biologist George Daley, dean of Harvard Medical School in Boston, Massachusetts, and a member of the summit’s organizing committee, pointed to a procedure that replaces diseased mitochondrial DNA in an embryo with healthy mitochondrial DNA from another person, eliminating the embryo’s original disease-causing mutation.
Although mitochondrial-replacement therapy lacks the approval of the biomedical community or the US Food and Drug Administration (FDA), doctors based in New York City used it to produce a baby in Mexico in 2016. “Similar premature practice of embryo editing by CRISPR-Cas9 is likely despite our calls for caution,” Daley said.
At the Hong Kong summit, scientists discussed whether another announcement of human-germline editing — the modification of genes passed on to future generations — is nigh.
“We do have reason to be concerned,” said Baltimore. “If anyone working in the field gets indications that it is happening, it is important they let authorities know.”
5. Will He’s revelations hamper ethical efforts to do germline editing?
Many researchers fear that He’s revelation could hamper the future of germline editing. “In the US some are suggesting draconian bans, which is antithetical to goals of science,” says Baltimore.
In the wake of the revelations, FDA Commissioner Scott Gottlieb made comments that raised concerns among scientists.
“Governments will now have to react,” he told the news site BioCentury. And on November 28, the US National Institutes of Health (NIH) director Francis Collins said in a statement: “The need for development of binding international consensus on setting limits for this kind of research, now being debated in Hong Kong, has never been more apparent.”
The statement released at the summit’s close makes a plea to keep open a path for safely translating gene-editing technology into treatments: “Germline genome editing could become acceptable in the future if these risks are addressed.”
But the debacle has focused worldwide interest on germline genome editing and fears of a chilling effect may be overstated.
“There might be some women excited by the possibility of taking part in this research,” said Judith Daar, at the University of California Irvine School of Medicine and School of Law, at a summit satellite session when asked whether the controversy might dissuade women from donating eggs for research in the future.
“The instinct is to say this is a debacle and could suppress participation. But I’m always amazed by the diverse reactions,” she added.
6. How will scientists ensure better oversight of germline editing in future?
“We don’t have a blueprint, but we have been asking academies,” said Baltimore. “It is a challenge to the world.”
The statement released by the summit’s organizing committee suggests that science academies around the world make recommendations to their own governments, while coordinating with each other.
It also suggests the creation of an international forum that would funnel research and clinical trials through an international registry, and discuss issues such as equitable access to the benefits of gene editing. But genome editing in human embryos potentially has an unwieldy range of users, and that could make maintaining such an organization difficult. “Virtually every lab doing molecular biology is using this technique,” said Daley.
The committee also suggested the need for a “translational pathway” that would provide a rigorous and responsible way for researchers to take germline gene editing to the clinic.
Organizing-committee member Alta Charo, a bioethicist at the University of Wisconsin Law School in Madison, said expectations have to be realistic.
“You can’t expect perfection. What you can do is try to minimize these incidents with enforcements that punish rogue behaviour.”
The next human genome-editing summit will take place in London in 2021.
Meanwhile, an evolutionary geneticist at Imperial College London, Austin Burt, in an e-mail to the press, said: “The final agreement here recognises the value of the enormous opportunity that gene drive research represents as well as the safeguards necessary to ensure its responsible development.”
Burt leads Target Malaria, a project that intends to test gene-drive-carrying mosquitoes in sub-Saharan Africa as early as 2024.
The project’s director of stakeholder engagement, Delphine Thizy, says that the team is already conducting community outreach in sub-Saharan African countries, such as Burkina Faso, where they hope to release the engineered mosquitoes. “For our work, it won’t change anything,” she says.
Jim Thomas, co-director of the ETC Group, an environmental advocacy organisation in Ottawa, sees it differently.
“This is a very cautionary and concerned decision about gene drives,” he says.
“There is nothing whatsoever in the text that talks about so-called benefits of gene drives — only risks. It’s not a formal moratorium, but it gets pretty close.”
In particular, Thomas thinks that the treaty text sets a high bar for seeking the approval of communities potentially affected by the release of an organism carrying a gene drive.
“This is a decision that gives the power back to communities to decide whether or not their lands and territories should be experimented on — and rightly so.”
A biotechnology-policy specialist at North Carolina State University in Raleigh, Todd Kuiken, who is part of an expert panel that advises the CBD on gene drives, says that it will take time to parse the language agreed today.
The countries that will ultimately license any gene-drive release must interpret the text — and thus he sees no quick end to the debate.