An International Commission on the Clinical Use of Human Germline Genome Editing was assembled by the Royal Society, the US National Academy of Sciences and the US National Academy of Medicine. Members of the commission included academies of sciences and medicine from around the world, and was formed to review applications of heritable human genome editing (HHGE) to establish guidelines for its clinical use in humans (see BioNews 1062).
The report opens with a strong justification for the commission stating that '[t]he commission was specifically tasked with defining a responsible pathway for clinical use of HHGE, should a decision be made by any nation to permit its use'.
The report sought to determine whether the safety and efficacy of genome editing methodologies and associated assisted reproductive technologies are, or could be, sufficiently well developed to permit responsible clinical use of HHGE; 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. By a translational pathway for HHGE, the commission means the steps that would be needed to enable a proposed clinical use to proceed from preclinical research to application in humans.
The aims of the report have been achieved through the commission's diligent use of transparent meetings and information gathering activities.
The commission hosted public meetings and webinars, welcomed public comments, called for evidence to assist their deliberations, and, as was expected, consulted with experts in the field. Collectively, these activities and methodologies enabled the commission to make 11 justified recommendations which the main body of the report starts with, reiterates throughout, and then concludes with.
In this respect, the commission's recommendations are relatively sound. However, while the report is very clear and engaging, and the recommendations made within it are well argued on a scientific basis, some of the recommendations invite further, critical, discussion. This is conceivably because societal considerations lay beyond the commission's charge and therefore their recommendations do not benefit from as rigorous engagement with such considerations.
Here, I critically discuss some of the arguments underlying the commission's conclusion to highlight potential areas of societal interest and concern that could benefit from further deliberation.
The commission concluded that a responsible translational pathway for initial uses of HHGE would need to meet all of the following four criteria:
The use of HHGE is limited to serious monogenic diseases; the commission defines a serious monogenic disease as one that causes severe morbidity or premature death.
The use of HHGE is limited 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.
No embryos without the disease-causing genotype will be subjected to the process of genome editing and transfer, to ensure that no individuals resulting from edited embryos were exposed to risks of HHGE without any potential benefit.
The use of HHGE is limited to situations in which prospective parents: (i) have no option for having a genetically related child that does not have the serious monogenic disease, because none of their embryos would be genetically unaffected in the absence of genome editing, or (ii) have extremely poor options, because the expected proportion of unaffected embryos would be unusually low, which the commission defines as 25 percent or less, and have attempted at least one cycle of preimplantation genetic testing (PGT) without success.
In relation to the first criterion, limiting the initial uses of HHGE to serious monogenic conditions could balance the potential risks and benefits of using the technology for such purposes more equitably. Once a level of reassurance exists, this limitation could be eased. The second criterion is quite pragmatic; other research shows that there are relatively high levels of support for using HHGE technologies to prevent disease, but far less support for other applications. The third and fourth criteria are more controversial.
Perhaps, like vaccinations, HHGE could be considered a preventative intervention. Some embryos may have never had the disease-causing genotype, but the technology could be designed to not make any changes if the pathogenic variant is not identified, thereby not exposing these embryos to unnecessary risk. This could mean that the technology benefits far more people.
The fourth criterion is two-fold. The first part is relatively self-explanatory; however, the second part is less so. PGT is an expensive and tolling intervention that in itself can expose women to many risks due to its reliance on in vitro fertilisation (IVF) techniques. Stipulating that prospective parents must have undergone at least one cycle of PGT is seemingly remiss to this fact, and should be reconsidered more sensitively. These are minor but important points that each nation considering developing transitional pathways for applications of HHGE should be mindful of. But, overall, the commission's efforts and report are commendable in pulling together these foundational guidelines in such a timely manner, especially due to the unprecedented events that unfolded with the COVID-19 pandemic while reviewing and finalising the report.