First published in our Biotech Review of the year – issue 8.

Ever since Crick and Watson discovered the double helix in 1953, many researchers, not to mention the public at large, have been captivated by the idea of altering genomes to avoid genetic disease. Ultimately, however, Heritable Human Genome Editing (HHGE)[1] is not just a question of scientific capability, but rather one of society and ethics, too.

The issue was brought into sharp relief in 2018 when researcher He Jiankui announced that, by editing the DNA of healthy embryos, he had helped bring about the birth in China of two ‘CRISPR babies’[2]. The scientific establishment erupted, but conceded the absence of international consensus. In response, the International Commission, convened by the US National Academies of Medicine and Sciences and the UK Royal Society, was established ‘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’, and to define ‘a responsible pathway for the clinical use of HHGE, should a decision be made by any nation to permit its use.’

The subsequent report, published in September 2020, could have significant implications for the continued development of genome editing in the months and years ahead.

Gene editing explained

‘Gene editing’ (GE) is the use of molecular tools to make precise alterations to DNA in order to correct, replace or add genes. GE is not new, but the appearance, nearly a decade ago, of CRISPR/Cas9 as a precision editing tool revolutionised biology[3] , not least because of its simplicity, speed and cost. Obvious applications include correcting genetic pathologies at source to avoid or cure disease, or to improve the body’s ability to fight it (as He had attempted, in disabling the CCR5 gene in efforts to immunise the infants from HIV), but distinguishing disease avoidance from à la carte trait selection may not be easy. For example, HIV avoidance may be a more legitimate goal in China than in, say, France. GE may lead to off-target edits and, in embryos, ‘mosaics’ of edited and non-edited cells. CRISPR/Cas9 has given rise to ever more accurate versions, but quality control remains a paramount concern.

There are two forms of human GE: somatic and germline. Somatic GE involves alteration of genetic information in targeted cells in a person’s body, that will not be inherited. Examples of somatic cell editing include therapies for cystic fibrosis and sickle cell disease, which involve localised edits to restore target tissues or cell types to ‘normal’ function. The European Medicine Agency addressed editing quality standards in a 2018 draft guideline[4], and therapies are showing considerable promise[5].

The other form of gene editing is germline editing. Here, edits are not only made prior to any person existing, but before embryological development. As cells multiply, genetic modifications are copied into all cells of the growing embryo and, should it be implanted (ie not used solely for research), into those of any eventual person. As this includes such a person’s reproductive cells, edits may be passed down to children and enter the wider human genome. When editing may have transgenerational impacts, it falls under the term Heritable Human Genome Editing (HHGE). As the entire organism is affected, this form of GE is true ‘genome editing’. How should humanity govern it?

The International Commission concluded its HHGE investigation with a list of 11 Recommendations setting out what it considers necessary for a responsible translational pathway to HHGE.

A pathway to clinical use

Recommendation 1 endorses the prevailing view in the scientific community that the possibility of making precise edits in human embryos efficiently, reliably and without undesired effects has yet to be established. The Commissioners did not recommend restricting research (using CRISPR in human embryo research is permissible in the UK subject to standard rules under the HFE Act 1990. It is not HHGE as edited genomes are not inherited.), but did consider that CRISPR germline editing should not be used clinically (ie HHGE) until certain criteria are met, offering detailed guidance on how the Commission thought HHGE trials should proceed. Some regret that the Commission did not recommend a moratorium, but others think it a sensible approach: if society accepts certain uses, HHGE may be made lawful subject to quality standards, even if currently unattainable.

A moratorium would probably have more totemic than practical value: if HHGE technology exists, parents wishing to have genetically-related children who are free of hereditable disease could probably circumvent any prohibition without being discovered.

The Commission identified six broad categories of potential clinical applications of HHGE, only two of which it said should be considered at this time:

1. cases of serious monogenic diseases (defined by the Commission as diseases caused by a mutation in a single gene, which causes severe morbidity or premature death) in which all of a couple’s children would inherit the disease genotype or;
2. serious monogenic diseases in which some, but not all, of a couple’s children would inherit the disease genotype.

Recommendation 4 then set out criteria that the Commission believed should be met by any initial use of HHGE:

1. it should be limited to serious monogenic diseases;
2. it should be 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 is known not to be disease-causing (sometimes referred to as a ‘wild type’ edit);
3. only embryos in which the disease-causing genes have been edited should be implanted, to ensure that no resulting individuals are exposed without significant benefit to potential HHGE risks; and
4. the use of HHGE should be limited to situations in which prospective parents:

1. 1. have no option for having a geneticallyrelated child that is free of serious monogenic disease, because without GE all their embryos would carry the disease variant or;
   2. have attempted at least one cycle of preimplantation genetic testing without success, and only 25% or less of embryos would, without GE, be unaffected.

Some view these recommendations as endorsing a move to clinical HHGE, subject only to quality and ethical acceptance, that many clinicians consider unnecessary, arguing that preimplantation genetic diagnosis is more effective and less ethically problematic than HHGE, so that the number of parents who might benefit from HHGE may be vanishingly small. The Commission had anticipated this in point 4(ii) above. As PGD options are merely for or against implantation, a short supply of eggs may not qualify it as an ethical alternative to HHGE.

While some express concerns that already unequal access to reproductive healthcare may become more extreme in the case of GE, others speculate wryly that normal development may be threatened more by quality assessment requirements, such as the biopsy and monitoring of early GE embryos, than by the original editing process. Indeed, the Commission recognised that the need for such tests would be obviated if gamete progenitors were edited and tested for quality prior to fertilisation.

Notably, the Report encourages research on developing methods to produce functional human gametes from edited progenitors, highlighting an approach that, though far from ready, might provide prospective parents with a safer option for avoiding the inheritance of disease-causing genotypes than embryo editing: avoiding the hazards of embryo biopsy by preimplantation screening of gametes derived from a culture of edited progenitors.

Beyond the science

Although the Commissioners emphasised that HHGE invokes issues of ethics and society as well as of biomedicine and technology, some complained that their reluctance to pronounce upon ethics was an abnegation of responsibility. It’s doubtful, however, that the Commission, which endorsed the view of the UK’s Nuffield Council on Bioethics that engagement with publics should form an integral part of policy development, had a mandate to impose global ethical standards.

Recommendations 9-11 propose an international scientific advisory panel to monitor development of editing technologies and to assess their safety and efficacy. Though a whistle-blower mechanism may help to uncover unethical practice, the deterrent effectiveness of the recommendations seems questionable. Proposing that HHGE should not occur in places without appropriate expertise or regulation appears futile.

These are exactly the places where HHGE appears most likely, while its deterrent effect in places where HHGE is already prohibited, such as the UK and (debatably[6]) He Jiankui’s China, seems improbable. Equally vague is how the proposed panel would operate between existing international entities, such as WHO or UNESCO, and national laws, although a separate WHO inquiry has produced a draft governance framework[7] .

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[1] National Academy of Medicine, National Academy of Sciences, and the Royal Society. Heritable Human Genome Editing. Washington, DC: The National Academies Press. 2020. DOI: 10.17226/25665. https://royalsociety.org/news/2020/09/heritablegenome-editing-report/
[2] Not mentioning that the clinicians who implanted the GE embryos into a healthy mother were not informed.
[3] The discovery secured Emmanuelle Charpentier and Jennifer Doudna a Nobel Prize in 2020. https://www.nobelprize.org/prizes/chemistry/2020/press-release/
[4] https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guidelinequality-non-clinical-clinical-aspects-medicinal-products-containing-genetically_en.pdf
[5] https://www.globenewswire.com/news-release/2020/12/05/2140152/0/en/CRISPRTherapeutics-and-Vertex-Present-New-Data-for-Investigational-CRISPR-Cas9-GeneEditing-Therapy-CTX001-at-American-Society-of-Hematology-Annual-Meeting-andExposition-Together.htm
[6]  https://www.bristows.com/viewpoint/articles/beware-of-cheap-imitations-justiceand-he-jiankui/
[7] https://www.who.int/docs/default-source/ethics/governance-framework-forhuman-genome-editing-2ndonlineconsult.pdf?ua=1