NEW YORK – Heritable human genome editing (HHGE) isn't yet safe or effective enough to be used in human embryos, and if or when any nation does allow its use, it should be limited to the prevention of serious monogenic diseases, the International Commission on the Clinical Use of Human Germline Genome Editing said in a report released on Thursday.
The commission — which is made up of representatives from the US National Academy of Medicine (NAM), the US National Academy of Sciences (NAS), and the Royal Society of the UK — convened in May 2019 in the wake of the controversy over the work of He Jiankui, the Chinese scientist who shocked the world in November 2018 when he announced that he had edited the germlines of twin embryos. He was widely condemned by the global scientific community for violating scientific principles and ethical norms.
The commission was charged with identifying the scientific, medical, and ethical requirements that should be considered before genome editing research can be applied to the clinic, if society concludes that HHGE applications are acceptable. At the panel's first meeting in August 2019, NAM President Victor Dzau said that although germline genome editing is a technological breakthrough with transformative potential for medicine, it's controversial because the use of gene editing in embryos would produce permanent alterations that would be passed down to further generations.
He also noted at the time that the scientific and ethical issues surrounding germline editing are linked, and that several problems would have to be solved before the technology could be considered usable in the clinic — for example, identifying appropriate protocols for assessing on- and off-target effects and long-term side effects; assessing mosaicism; assessing potential benefits and harms to a potential child; designing appropriate protocols to obtain consent from patients; and creating mechanisms for long-term monitoring of children who are edited.
In its new report, the commission noted that it didn't seek to make judgements about whetherclinical uses of a safe and effective HHGE methodology should be permitted at some point. Rather, the commissioners sought to determine whether the safety and efficacy of genome editing methodologies are or could be sufficiently well developed to permit responsible clinical use of HHGE. They also aimed to identify initial potential applications of HHGE for which a responsible clinical translational pathway can currently be defined, and to delineate the necessary elements of such a translational pathway.
They also outlined what they believe to be necessary national and international mechanisms for appropriate scientific governance of HHGE that would allow for whistleblowing on rogue scientists or countries seeking to perform germline genome editing in unsafe or unethical ways.
In a press conference to discuss the report, commission Cochair and University of Oxford Professor of Genetics Kay Davies said that the commission considered the technical, scientific, medical, and regulatory requirements, "as well as the societal and ethical issues that are inextricably linked to these requirements," but was not charged "with addressing broader societal ethical issues of HHGE." She noted that these issues, among others, are expected to be part of a broader report on genome editing issues being written by a World Health Organization panel.
"The key messages from the report are, first, no clinical use of HHGE should be considered until it has been clearly established that it is possible to efficiently and reliably make precise genomic changes without undesired changes. And we clearly recommend that there are a lot of gaps in our knowledge and further research is necessary," Davies said. "Secondly, before any country decides to approve the use of HHGE, there should be national and international mechanisms to ensure that the preclinical requirements have been met for initial responsible use, and any clinical use of HHGE should proceed cautiously with initial use restricted to a limited set of circumstances."
Eleven recommendations
The report specifically outlined 11 recommendations. First, the commission said, "No attempt to establish a pregnancy with a human embryo that has undergone genome editing should proceed unless and until it has been clearly established that it is possible to efficiently and reliably make precise genomic changes without undesired changes in human embryos. These criteria have not yet been met and further research and review would be necessary to meet them."
Second, the commission said that societies around the world need to engage in extensive dialogue not only about the scientific and medical considerations of HHGE, but also about the ethical and social issues that will arise if use of the technology becomes more widespread. In its introduction to the report, the commission acknowledged the deep societal inequities laid starkly bare by the COVID-19 pandemic, as well as the recent civil uprisings calling for social justice, and warned against the use of HHGE in ways that would widen the gaps of bias and discrimination.
For its third recommendation, the commission said that HHGE should proceed "incrementally," and that there should always be a clear threshold for permitted uses based on whether a responsible translational pathway can be and has been clearly defined for evaluating the safety and efficacy of the proposed use.
The fourth recommendation laid out four criteria for initial uses of HHGE, should a country decide to permit them: to limit it to the correction of serious monogenic diseases; to limit it to changing a pathogenic genetic variant known to be responsible for the serious monogenic disease to a sequence that is common in the relevant population and that is known not to be disease-causing; that no embryos without the disease-causing genotype will be subjected to genome editing; and to limit HHGE to situations in which prospective parents have no or poor options for having a genetically related child that doesn't have the serious monogenic disease.
Specifically, the commission broke down diseases into categories ranging from A to F. Diseases in category A are cases in which all of the prospective parents' children would inherit the disease-causing genotype for a serious monogenic disease. In category B, some but not all of the prospective children would inherit the pathogenic genotype for a serious monogenic disease. Category C encompasses cases involving other monogenic conditions with less serious impact, category D encompasses polygenic diseases, and category E encompasses cases involving other applications of HHGE, including changes that would enhance or introduce new traits or attempt to eliminate certain diseases from the human population. Finally, they classified cases in category F as special circumstances of monogenic conditions that cause infertility.
Commissioner Michele Ramsay, director and research chair of the Sydney Brenner Institute for
Molecular Bioscience, said that this recommendation was based on the question of where the science is in understanding the relationship between a genetic variant and disease, and asking what the other options are for correcting the disease.
"The initial uses would have similar criteria to what is used for other new medical procedures," she said. "For example, organ transplants were first made [available] for patients who were the most severely affected, who then had the most to gain and the least to lose, because if they didn't have the transplant, their deaths would be inevitable."
She said the recommendations basically boiled down to restricting initial uses of HHGE to category A cases as well as a subset of category B in which prospective children would have a 25 percent or less chance of being unaffected by the disease, and if the parents had gone through at least once unsuccessful cycle of IVF and genetic testing.
These are people most likely to be found in founder populations, such as the Afrikaners of South Africa, or in populations where consanguineous marriage is common. Because of these requirements, there would be very few cases worldwide that would fit the criteria for initial use, Ramsay said, and international cooperation would be needed to get the affected couples to labs or hospitals in countries with the necessary technology to administer treatment, if they wanted it.
In Group A, there may be fewer than 20 families worldwide that would be affected, and they may not all want HHGE. Even with the expansion to the subcategory of group B, that still only includes a few thousand people across the world, the commissioners estimated.
Importantly, added commission Cochair and Rockefeller University President Richard Lifton, "One of our concerns is medical hubris." The commission wanted to emphasize that the initial use of HHGE should be reserved for applications in which all the consequences are known. With a well-studied monogenic disease, the chances of causing unintended consequences through genome editing are significantly reduced compared to changes intended to affect a polygenic disorder or to increase muscle mass to improve athletic performance, for example.
Further, Lifton said, there are certain diseases in which a patient will almost certainly have the disease if they have the associated gene, but other alleles at the same loci can modify the severity of the disease. In other illnesses, the disease gene requires a second gene or environmental cofactor for the disease to manifest. In comparison, there is a long list of monogenic diseases where penetrance is sufficiently high and editing would be beneficial to the prospective child, he added — all of these points were taken into account when the panel was considering its recommendations.
Davies also noted that while more than 4,000 single-gene disorders have been recorded in the literature, the problem is the variation in expression, which is why it's so important to limit HHGE to instances in which we know exactly how a monogenic disease will express itself in a certain family.
Ensuring safety and precision
Fifth, the commission said, before any attempt to establish a pregnancy with an embryo that has undergone genome editing, preclinical evidence must demonstrate that HHGE can be performed with sufficiently high efficiency and precision to be clinically useful. For initial uses of the technology, preclinical evidence of safety and efficacy should be based on the study of a significant cohort of edited human embryos and should demonstrate that the process has the ability to generate suitable numbers of embryos that have the intended edits with no off-target effects and no mosaicism, are of suitable clinical grade to establish a pregnancy, and have aneuploidy rates no higher than expected based on standard assisted reproductive technology procedures.
The commission also recommended that any proposal for the initial clinical use of HHGE should meet the criteria for preclinical evidence set forth in the previous recommendation, and should include plans for evaluating embryos prior to transfer to check for off-target effects. If regulatory approval for embryo transfer is granted after such analysis, "monitoring during a resulting pregnancy and long-term follow up of resulting children and adults is vital," the report added.
According to commissioner and Chinese Academy of Sciences Professor Haoyi Wang, a large part of the reason why the criteria for safe and efficient HHGE have not yet been met is because the current technology for assessing both on-target and off-target effects isn't sufficiently accurate to warrant use on human embryos. Research teams need to show that HHGE methods can reach high specificity and sensitivity without mosaicism, which means establishing robust clinical evaluation techniques to evaluate the possibility of unintended consequences in one or a few cells in edited human embryos.
He also noted the need for improved genotyping technology that can be used to sequence embryos at the single-cell level, without which it wouldn't be possible to reliably evaluate the effects of any genome editing technology.
Wang emphasized that although CRISPR was being used by the commission as an example of genome editing technology, the recommendations laid out in the report apply to all genome editing methodologies, including zinc finger nucleases, TALENs, or any possible enzyme constructs that might be invented in the future. He added that base editing and prime editing have been shown in research studies to be very promising avenues for efficient embryonic editing as well, but that without robust genotyping technology to go along with safe and efficacious HHGE technology, it wouldn't be possible to use HHGE in the clinic.
According to the report, research should also continue into the development of methods to produce functional human gametes from cultured stem cells. Generating large numbers of stem cell-derived gametes would provide a further option for prospective parents to avoid the inheritance of disease. However, the report also noted that such technology would raise medical, scientific, and ethical considerations of its own that must be considered.
Regulatory oversight
Eighth, the commission said that any country in which the clinical use of HHGE is being considered should have mechanisms and competent regulatory bodies to ensure that individuals conducting HHGE-related activities adhere to established principles of human rights, bioethics, and global governance; that the clinical pathway for HHGE incorporates best practices from related technologies such as mitochondrial replacement techniques, preimplantation genetic testing, and somatic genome editing; that decision-making is informed by findings from independent international assessments of progress in scientific research and the safety and efficacy of HHGE; that the norms of responsible scientific conduct by individual investigators and laboratories are enforced; and that reports of deviations from established guidelines are received and reviewed, and sanctions are imposed where appropriate. The commission also emphasized the need for transparency at all times.
The report further said an International Scientific Advisory Panel (ISAP) should be established with clear roles and responsibilities before any clinical use of HHGE is undertaken, with a diverse, multidisciplinary membership of independent experts who can assess scientific evidence of safety and efficacy of both genome editing and associated assisted reproductive technologies. The ISAP could provide regular updates on advances in HHGE technologies, assess whether preclinical requirements have been met for clinical use, review data on clinical outcomes, and provide input and advice on any responsible translational pathways.
Beyond the ISAP, the commission said, an international body with appropriate standing and diverse expertise and experience should then be formed in order to evaluate and make recommendations concerning any proposed new uses for HHGE. This international body would clearly define each proposed new class of use and its limitations, convene ongoing discussions on the societal issues surrounding new uses, and provide responsible translational pathways for new uses of HHGE.
And finally, the commission recommended that the establishment of an international mechanism through which concerned parties could blow the whistle on research or conduct of HHGE that deviate from established guidelines or recommended standards to relevant national authorities or the public.
Lifton suggested the World Anti-Doping Agency as one possible model for this international body that could be used to keep rogue scientists and countries in check.