Around 2018–19, there was not a bigger science and ethical story than the debate over heritable human genome editing (HHGE) and the scandal over the “CRISPR babies.” The scientist, He Jiankui, who attempted to engineer the germline of human embryos, resulting in the birth of twin girls in late 2018, was later jailed by Chinese authorities.
Even as groups of leading scientists called for a temporary moratorium, several distinguished scientific organizations, including the World Health Organization and the National Academies of Sciences, issued detailed reports from blue-ribbon committees proposing guidelines for the future clinical practice and governance of HHGE. Then in 2020, the COVID-19 pandemic hit, and the topic largely disappeared from the headlines. (The health of the CRISPR babies, three in all, remains unknown.)
Five years later, there are signs that the lull is over. A recent article in the Economist is headlined: “How to enhance humans.” The “X” social media feed from He Jiankui is flooded with unrepentant pronouncements that suggest the disgraced scientist is back in the lab, itching to try his hand at editing human embryos once again. Indeed, a new Wall Street Journal profile confirms as much.
In 2024, authorities in South Africa rewrote research guidelines that open a pathway for HHGE to take place, putting the country on an “ethical precipice,” according to Canadian bioethicist Francoise Baylis, PhD. And a recent article in Nature proposed that advances in heritable polygenic editing could yield reductions in disease susceptibility.
In part for those reasons, officials at three professional organizations—the Alliance for Regenerative Medicine (ARM), the American Society of Gene and Cell Therapy (ASGCT), and the International Society of Cell and Gene Therapy (ISCT)—recently convened a small group of scientists, policy experts, religious leaders, and patient advocates, in Washington, DC, to review the current state of HHGE guidelines and policies, with particular emphasis on the risks, benefits, and potential guard rails.
The top-billed speaker, Congressman Robert Aderholt (R-Ala), made the short trip from Capitol Hill to offer some brief remarks. In June 2015, the bipartisan Aderholt Amendment was passed in the House of Representatives to preclude the FDA from reviewing any investigational new drug application related to intentional germline editing. It was signed into law by President Obama in December 2015.
“We must maintain essential legal guardrails to protect human dignity, ethical science, and future generations,” Congressman Aderholt said. He said it was important to stand firm against the dangers of heritable genome manipulation. “Once we cross that line, there’s no turning back.”
Tim Hunt, the CEO of ARM, said he believed the Aderholt Amendment had “prevented some very poorly drafted legislation [in 2018–19 after the CRISPR babies] that could have set the field of gene editing back quite a bit.” A report from Baylis and colleagues published in GEN’s sister journal, The CRISPR Journal, in 2020 found that about 70 countries have some form of genome editing prohibition.
By contrast to HHGE, several speakers spoke about the progress in somatic genome editing trials. Devyn Smith, PhD, CEO of Arbor Technologies, expects to see a dozen somatic gene editing clinical trials with readouts in 2025. The translation of results in nonhuman primate (NHP) models into humans was “very exciting.” But investors want to know: “How commercially viable are these therapies going to be?” When it comes to vetting genome editing therapies, the FDA cares about four issues, Smith said: 1) On-target editing; 2) On-target editing in non-target tissues; 3) Off-target editing; and 4) the risks of germline transmission.
Kiran Musunuru, MD, PhD, professor of medicine at the University of Pennsylvania, discussed unpublished data on in utero editing, in particular work in collaboration with surgeon William Peranteau, MD, at Children’s Hospital of Philadelphia, on tyrosinemia type 1. Damage begins before birth.
The Philadelphia group has used base editing in utero to inactivate the hpd gene in monkeys by injecting the tool into the umbilical vein, providing entry into fetal circulation. The results show effective clearance of toxic protein from the liver. “This is a very dramatic outcome by intervening during the fetal stage,” Musunuru said. “We don’t need to go back to the single-cell embryo.”
Gene editing efficiency is significantly greater in utero than when performed in juvenile monkeys, with marked differences in the ability to deliver gene edits into muscles. In the next ten years, Musunuru believes that in utero editing has the potential to treat muscle diseases, including potentially Duchenne muscular dystrophy or congenital heart disease. “I think we’ll be in the clinic for sure,” he said.
Baylis offered an interesting comparison of the various policy statements issued by the organizers of the three major international summits on HHGE since 2015, as well as a National Academies report published in 2017. Highlights of those reports were as follows:
Curiously, organizers’ views evolved and shifted, ending up more or less in line with the first such report in 2015. Sandwiched in between was a commentary in Nature co-authored by Baylis with Eric Lander, Feng Zhang, and others, calling for a five-year moratorium. Nobel laureates Jennifer Doudna, PhD, and David Baltimore, PhD, were notable absentees from that publication. “Banning CRISPR babies won’t work,” Baltimore said in April 2019.
Baylis offered several recent touchpoints on the HHGE debate. She quoted an email from Denis Rebrikov, MD, the Russian scientist who stated publicly in 2019 that he wanted to use CRISPR to help deaf couples edit embryos to become hearing-enabled. Rebrikov now says he is no longer pursuing HHGE for deafness because “deaf couples don’t want hearing children.”
A clinic in Ukraine formerly offering gene editing for hair color, skin, and breast size still exists, but no longer references this service on its website. “Metaphorically, the human genome belongs to all of us,” Baylis said. But it was sobering to realize that today, less than half the world’s population lives in a democracy, which does not bode well for responsible international governance.
Ben Hurlbut, PhD, associate professor at Arizona State University, said it would be difficult to know when we arrive at a societal consensus on HHGE. He Jiankui was widely condemned for performing experiments that most experts deemed medically unnecessary. But that perspective was not shared by the family in question. “We cannot ignore the ‘sense of need’ from patients and families,” Hurlbut insisted. In a letter they wrote to the Chinese court that sentenced the scientist, they said:
“Our participation [in the CRISPR babies trial] was indeed forced, but we weren’t coerced by any person in particular. We were coerced by society.”
Gene editing pioneer Keith Joung, MD, of Arena BioWorks, emphasized the technical difficulties of conducting safe and effective CRISPR gene editing in human embryos. The CRISPR machinery might produce a uniformly edited embryo (one or both alleles). But a more likely outcome was the production of a mosaic embryo. If the editing is not 100% efficient and if the CRISPR machinery persists in daughter cells, then further edits could occur in daughter cells. “There is no good way to ensure the machinery shuts off after [editing] a single cell,” Joung said.
Further complicating this “combinatorial mosaicism” is off-target editing. Moreover, gene edits will be transmitted to subsequent descendants. But it is hard to predict the functional impact of edits in future individuals, Joung said.
Asked about a trio of studies published a few years ago from leading experts in human embryogenesis—the labs of Dieter Egli, PhD, Shoukrat Mitalipov, PhD, and Kathy Niakan, PhD—Joung said that larger deletions, inversions, translocations were “worrisome” and had been largely overlooked by the field.
“Less differentiated cells may be more open and more susceptible to [Cas] nuclease activity,” Joung said. “We need to think about cell context,” Joung said, which is very different in undifferentiated embryos than the somatic cell environment.
Paula Cannon, PhD, a Distinguished Professor of Microbiology at USC, and the current president of ASGCT, pointed out that base and prime editors might not have as many unwanted effects with respect to large-scale genome rearrangements. But the conundrum is that investigators “want high editing efficiency to avoid mosaicism.”
Cannon added that she would like to see gene editing safety studies in NHPs carried into the progeny of the edited animals, but that requirement would require a dozen years at least. “Rogue actors won’t wait” that long, she said.
Performing HHGE safely remained a very difficult task. “You can’t look at all cells in an embryo in a non-destructive way,” Musunuru said. “We’re far away from having a non-destructive process to scan the genome of a cell.” Until that problem is solved, “it would be utterly irresponsible to do anything in a single cell in a zygote. That I can say with 100% certainty.”
Hunt led the closing session with a discussion of potential guardrails for HHGE. The actors likely to perform HHGE would emerge from one of three sectors: fame seekers, fortune seekers, or government-sponsored labs. Hunt offered a series of potential “fence slats” that, in combination, could help deter future rogue efforts at HHGE (see figure).
Reinforcing guardrails to guide if and/or how HHGE should emerge. [ARM/ASGCT/ISCT)]
These fence slats fall into three broad categories: legal, reputation, and means. In the legal category, in addition to statutes like the Aderholt Amendment and the Oviedo Convention, Hunt recalled how the Broad Institute imposed blanket restrictions on its licensed intellectual property for human germline editing.
In the “reputational category,” there was discussion around penalizing HHGE scientists by banning publication or withholding funding or promotions. Joung spoke in favor of asking scientific journals to agree to withhold review and publication of studies detailing future HHGE experiments. But while that might hold sway for many responsible top-tier journal publishers, enforcing that for the long tail of scholarly journals could prove difficult. Hurlbut said the idea was potentially important, but “are the journals the right gatekeeping mechanism? What is the right gate to keep and why?”
Baylis pointed out that there was no lack of initial journal interest in He Jiankui’s 2018 manuscript. Nature originally sent his manuscript out for peer review, as later on did the chief editor of the Journal of the American Medical Association. She also questioned whether seeking a high-impact paper was all that important. Nationalism was increasingly prevalent in biomedical research. Science “is a country sport” now, she said.
Under the “means” category, Baylis noted that the original call for a five-year moratorium published in 2019 had now expired. There was no time to discuss other potentially interesting ideas, including some sort of global watchdog or a rapid response team.
“There aren’t any legitimate uses [for HHGE], only rogue uses,” Cannon concluded. But whether he is considered a “rogue” scientist or not, He Jiankui’s recent social media posts and interviews suggest that his prison term has in no way diminished his eagerness to jump back into the genome editing ring. Recent posts on “X” include:
The next major discussion on HHGE will take place under the auspices of the Global Observatory for Genome Editing, which was formed by Hurlbut and colleagues in 2020. A conference is planned in Cambridge, MA, in late May 2025. Hurlbut said the meeting would be akin to an unauthorized fourth edition of the major international conference series on human genome editing (Washington, DC, 2015; Hong Kong, 2018; London, 2023).
The post Experts Discuss Guardrails for Heritable Human Genome Editing appeared first on GEN - Genetic Engineering and Biotechnology News.
Even as groups of leading scientists called for a temporary moratorium, several distinguished scientific organizations, including the World Health Organization and the National Academies of Sciences, issued detailed reports from blue-ribbon committees proposing guidelines for the future clinical practice and governance of HHGE. Then in 2020, the COVID-19 pandemic hit, and the topic largely disappeared from the headlines. (The health of the CRISPR babies, three in all, remains unknown.)
Five years later, there are signs that the lull is over. A recent article in the Economist is headlined: “How to enhance humans.” The “X” social media feed from He Jiankui is flooded with unrepentant pronouncements that suggest the disgraced scientist is back in the lab, itching to try his hand at editing human embryos once again. Indeed, a new Wall Street Journal profile confirms as much.
In 2024, authorities in South Africa rewrote research guidelines that open a pathway for HHGE to take place, putting the country on an “ethical precipice,” according to Canadian bioethicist Francoise Baylis, PhD. And a recent article in Nature proposed that advances in heritable polygenic editing could yield reductions in disease susceptibility.
In part for those reasons, officials at three professional organizations—the Alliance for Regenerative Medicine (ARM), the American Society of Gene and Cell Therapy (ASGCT), and the International Society of Cell and Gene Therapy (ISCT)—recently convened a small group of scientists, policy experts, religious leaders, and patient advocates, in Washington, DC, to review the current state of HHGE guidelines and policies, with particular emphasis on the risks, benefits, and potential guard rails.
The Aderholt Amendment
The top-billed speaker, Congressman Robert Aderholt (R-Ala), made the short trip from Capitol Hill to offer some brief remarks. In June 2015, the bipartisan Aderholt Amendment was passed in the House of Representatives to preclude the FDA from reviewing any investigational new drug application related to intentional germline editing. It was signed into law by President Obama in December 2015.
“We must maintain essential legal guardrails to protect human dignity, ethical science, and future generations,” Congressman Aderholt said. He said it was important to stand firm against the dangers of heritable genome manipulation. “Once we cross that line, there’s no turning back.”
Tim Hunt, the CEO of ARM, said he believed the Aderholt Amendment had “prevented some very poorly drafted legislation [in 2018–19 after the CRISPR babies] that could have set the field of gene editing back quite a bit.” A report from Baylis and colleagues published in GEN’s sister journal, The CRISPR Journal, in 2020 found that about 70 countries have some form of genome editing prohibition.
By contrast to HHGE, several speakers spoke about the progress in somatic genome editing trials. Devyn Smith, PhD, CEO of Arbor Technologies, expects to see a dozen somatic gene editing clinical trials with readouts in 2025. The translation of results in nonhuman primate (NHP) models into humans was “very exciting.” But investors want to know: “How commercially viable are these therapies going to be?” When it comes to vetting genome editing therapies, the FDA cares about four issues, Smith said: 1) On-target editing; 2) On-target editing in non-target tissues; 3) Off-target editing; and 4) the risks of germline transmission.
Kiran Musunuru, MD, PhD, professor of medicine at the University of Pennsylvania, discussed unpublished data on in utero editing, in particular work in collaboration with surgeon William Peranteau, MD, at Children’s Hospital of Philadelphia, on tyrosinemia type 1. Damage begins before birth.
The Philadelphia group has used base editing in utero to inactivate the hpd gene in monkeys by injecting the tool into the umbilical vein, providing entry into fetal circulation. The results show effective clearance of toxic protein from the liver. “This is a very dramatic outcome by intervening during the fetal stage,” Musunuru said. “We don’t need to go back to the single-cell embryo.”
Gene editing efficiency is significantly greater in utero than when performed in juvenile monkeys, with marked differences in the ability to deliver gene edits into muscles. In the next ten years, Musunuru believes that in utero editing has the potential to treat muscle diseases, including potentially Duchenne muscular dystrophy or congenital heart disease. “I think we’ll be in the clinic for sure,” he said.
Touchpoints
Baylis offered an interesting comparison of the various policy statements issued by the organizers of the three major international summits on HHGE since 2015, as well as a National Academies report published in 2017. Highlights of those reports were as follows:
- 2015 (DC)—Irresponsible to proceed with clinical use of germline editing (until safety/efficacy/societal consensus)
- 2017—Should be permitted with caveats (compelling reasons, strict oversight)
- 2018 (Hong Kong)—Need for a rigorous, responsible translational pathway toward HHGE trials
- 2023 (London)—Remains unacceptable at this time, needs safety/efficacy + societal discussion (not necessarily consensus)
Curiously, organizers’ views evolved and shifted, ending up more or less in line with the first such report in 2015. Sandwiched in between was a commentary in Nature co-authored by Baylis with Eric Lander, Feng Zhang, and others, calling for a five-year moratorium. Nobel laureates Jennifer Doudna, PhD, and David Baltimore, PhD, were notable absentees from that publication. “Banning CRISPR babies won’t work,” Baltimore said in April 2019.
Baylis offered several recent touchpoints on the HHGE debate. She quoted an email from Denis Rebrikov, MD, the Russian scientist who stated publicly in 2019 that he wanted to use CRISPR to help deaf couples edit embryos to become hearing-enabled. Rebrikov now says he is no longer pursuing HHGE for deafness because “deaf couples don’t want hearing children.”
A clinic in Ukraine formerly offering gene editing for hair color, skin, and breast size still exists, but no longer references this service on its website. “Metaphorically, the human genome belongs to all of us,” Baylis said. But it was sobering to realize that today, less than half the world’s population lives in a democracy, which does not bode well for responsible international governance.
Ben Hurlbut, PhD, associate professor at Arizona State University, said it would be difficult to know when we arrive at a societal consensus on HHGE. He Jiankui was widely condemned for performing experiments that most experts deemed medically unnecessary. But that perspective was not shared by the family in question. “We cannot ignore the ‘sense of need’ from patients and families,” Hurlbut insisted. In a letter they wrote to the Chinese court that sentenced the scientist, they said:
“Our participation [in the CRISPR babies trial] was indeed forced, but we weren’t coerced by any person in particular. We were coerced by society.”
Safety first
Gene editing pioneer Keith Joung, MD, of Arena BioWorks, emphasized the technical difficulties of conducting safe and effective CRISPR gene editing in human embryos. The CRISPR machinery might produce a uniformly edited embryo (one or both alleles). But a more likely outcome was the production of a mosaic embryo. If the editing is not 100% efficient and if the CRISPR machinery persists in daughter cells, then further edits could occur in daughter cells. “There is no good way to ensure the machinery shuts off after [editing] a single cell,” Joung said.
Further complicating this “combinatorial mosaicism” is off-target editing. Moreover, gene edits will be transmitted to subsequent descendants. But it is hard to predict the functional impact of edits in future individuals, Joung said.
Asked about a trio of studies published a few years ago from leading experts in human embryogenesis—the labs of Dieter Egli, PhD, Shoukrat Mitalipov, PhD, and Kathy Niakan, PhD—Joung said that larger deletions, inversions, translocations were “worrisome” and had been largely overlooked by the field.
“Less differentiated cells may be more open and more susceptible to [Cas] nuclease activity,” Joung said. “We need to think about cell context,” Joung said, which is very different in undifferentiated embryos than the somatic cell environment.
Paula Cannon, PhD, a Distinguished Professor of Microbiology at USC, and the current president of ASGCT, pointed out that base and prime editors might not have as many unwanted effects with respect to large-scale genome rearrangements. But the conundrum is that investigators “want high editing efficiency to avoid mosaicism.”
Cannon added that she would like to see gene editing safety studies in NHPs carried into the progeny of the edited animals, but that requirement would require a dozen years at least. “Rogue actors won’t wait” that long, she said.
Performing HHGE safely remained a very difficult task. “You can’t look at all cells in an embryo in a non-destructive way,” Musunuru said. “We’re far away from having a non-destructive process to scan the genome of a cell.” Until that problem is solved, “it would be utterly irresponsible to do anything in a single cell in a zygote. That I can say with 100% certainty.”
Guard rails and fence slats
Hunt led the closing session with a discussion of potential guardrails for HHGE. The actors likely to perform HHGE would emerge from one of three sectors: fame seekers, fortune seekers, or government-sponsored labs. Hunt offered a series of potential “fence slats” that, in combination, could help deter future rogue efforts at HHGE (see figure).
Reinforcing guardrails to guide if and/or how HHGE should emerge. [ARM/ASGCT/ISCT)]
These fence slats fall into three broad categories: legal, reputation, and means. In the legal category, in addition to statutes like the Aderholt Amendment and the Oviedo Convention, Hunt recalled how the Broad Institute imposed blanket restrictions on its licensed intellectual property for human germline editing.
In the “reputational category,” there was discussion around penalizing HHGE scientists by banning publication or withholding funding or promotions. Joung spoke in favor of asking scientific journals to agree to withhold review and publication of studies detailing future HHGE experiments. But while that might hold sway for many responsible top-tier journal publishers, enforcing that for the long tail of scholarly journals could prove difficult. Hurlbut said the idea was potentially important, but “are the journals the right gatekeeping mechanism? What is the right gate to keep and why?”
Baylis pointed out that there was no lack of initial journal interest in He Jiankui’s 2018 manuscript. Nature originally sent his manuscript out for peer review, as later on did the chief editor of the Journal of the American Medical Association. She also questioned whether seeking a high-impact paper was all that important. Nationalism was increasingly prevalent in biomedical research. Science “is a country sport” now, she said.
Under the “means” category, Baylis noted that the original call for a five-year moratorium published in 2019 had now expired. There was no time to discuss other potentially interesting ideas, including some sort of global watchdog or a rapid response team.
X Factor
“There aren’t any legitimate uses [for HHGE], only rogue uses,” Cannon concluded. But whether he is considered a “rogue” scientist or not, He Jiankui’s recent social media posts and interviews suggest that his prison term has in no way diminished his eagerness to jump back into the genome editing ring. Recent posts on “X” include:
- Every pioneer or prophet must suffer.
- I hope people remember me as “Chinese Darwin” in 50 years.
- I will not do life extension or immortality research secretly for billionaires.
- I will start to eradicate Alzheimer’s disease in two years.
- Ethics is holding back scientific innovation and progress.
- 13 years and $10B wasted, George Church, Jennifer Doudna, and Feng Zhang promised to change the world with CRISPR, but delivered nothing to help patients.
The next major discussion on HHGE will take place under the auspices of the Global Observatory for Genome Editing, which was formed by Hurlbut and colleagues in 2020. A conference is planned in Cambridge, MA, in late May 2025. Hurlbut said the meeting would be akin to an unauthorized fourth edition of the major international conference series on human genome editing (Washington, DC, 2015; Hong Kong, 2018; London, 2023).
The post Experts Discuss Guardrails for Heritable Human Genome Editing appeared first on GEN - Genetic Engineering and Biotechnology News.