By Nik Zeps
The ability to manipulate the genomes of organisms has been available for nearly 50 years, ever since the earliest reported uses of genetic recombination technologies (Cohen, Chang et al. 1973) laid the foundations for the emergence of the biotechnology industry that has revolutionised medicine and agriculture. These early discoveries were made in a bacterium called Escherichia coli, more commonly known as the abbreviation E. coli. It is perhaps poetic then that the discovery of repetitive DNA sequences now known as CRISPR was also made in E.coli (Ishino, Shinagawa et al. 1987). The acronym stands for “Clustered regularly interspaced short palindromic repeats” (CRISPRs) and trips off the tongue much more readily than the literal description does (thanks to Mojica and Jansen who proposed it). For an excellent review of the history of CRISPR, one should read the historical review paper (Ishino, Krupovic et al.) by Yoshizumi Ishino who first discovered it.
CRISPR is most often used with the suffix ‘Cas9’, which refers to the enzyme it is most frequently associated with that is used to cut DNA sequences at highly specific places under the direction of a guide RNA molecule. The discovery and development of the CRISPR-Cas9 system into an everyday tool for researchers to manipulate genomes by Emmanuelle Charpentier and Jennifer Doudna led to their award of the Nobel Prize for Chemistry in 2020. It is worth watching Prof. Doudna’s acceptance speech for a masterclass in understanding how science progresses; “if I have seen further it is by standing on the shoulders of Giants” as Newton put it so eloquently. Her co-awardee’s speech should also be watched to appreciate the breathtaking advances we have made in comprehending and manipulating biological processes.
The incredible promise of using CRISPR technologies has expanded far beyond simple gene cutting at highly specific sites but now includes switching genes on and off in living organisms as a form of ‘gene therapy’. However, prior to the pandemic distracting us all, CRISPR technologies received significant adverse press in 2018 due to the reports of its use to edit human embryos that were allegedly implanted and that led to the birth of two children in China harbouring a gene that was related to enhanced resistance to HIV infection. In January 2020, the doctor at the centre of the scandal, He Jiankui, was sentenced to three years in prison for ’illegal medical practice’. His two colleagues were also jailed for lesser terms. His rap sheet was a litany of improper practice; practising medicine without a license, using assisted reproductive technologies in people with HIV and forging ethics documents related to his research. The response to the announcement by He and his colleagues prompted calls for greater regulation of CRISPR technology in human gene editing. An excellent review of the steps taken since 2018 is presented by Owen Schaefer and colleagues (Schaefer, Labude et al. 2021) as well as a consideration of the options in registering and reporting on such activities.
Unfortunately, human genome editing has somewhat fallen off the radar of the public of late and there are scant stories relating to it in the media. This is hardly surprising given the global pandemic due to COVID-19 and its variant strains. Nevertheless, it remains an important subject and in July 2021 the WHO issued three documents; a position paper, recommendations and a framework for governance, containing new recommendations on human genome editing. Peter Mills, the Assistant Director of the Nuffield Council on Bioethics and a member of the WHO expert advisory groups responsible for the reports wrote a blogpost on their release on the 14th July that summarised the key findings and identified important elements about the recommendations. The central issues he identified in his post were:
- The recommendation that the WHO Director General use the WHO’s moral authority to coordinate an international consensus, and
- The statement that “it would be irresponsible at this time for anyone to proceed with clinical applications of human germline [i.e. heritable] genome editing”.
Pete Mills notes that the latter statement implies that the current caution and moratorium could conceivably be lifted in the future. If this is to be the case then the WHO is placing itself in a global leadership position and, based on the recommendations in the reports, setting itself a major piece of work in undertaking an ‘extensive review’ in no more than three years’ time. The scale of work required would, he states “propel the WHO Science Division into becoming a major presence in the international governance of ‘frontier technologies’ (and their distinct and branching temporalities)”.
It is of interest that the preamble of the WHO Framework for governance notes that “Application of heritable human genome editing is likely to be a much more limited activity/endeavour in the coming years”, indicating that, in their view, the scandals have largely resulted in persuading the scientific community towards a self-imposed moratorium on such work.
One area included in the WHO framework is the possibility of applying human genome editing technology to various approaches that are functionally like gene therapy. That is, the use of CRISPR based technologies on somatic as opposed to germ line or embryonic human genome editing. The application of somatic human genome editing has already been undertaken using traditional gene manipulation technologies, including in vivo editing, to address, for example, HIV, muscular dystrophy and sickle-cell disease. Scientists have been able to adapt CRISPR technologies to enable gene editing for somatic applications but also to combine it with adapters that do not change the underlying DNA structure but instead the methylation status of the DNA. Methylation of DNA is one of the ways in which genomes are regulated naturally and is a critical component of normal gene function. However, it can be changed through use of drugs and some of these are already in use to treat certain types of blood cancer.
In a recent paper, we (Zeps et al. 2021; Zeps, Lysaght et al. 2021) explored the ethical issues regarding the use of epigenome editing technologies and asked whether they should be regulated in the same manner as other gene therapies. Overall, our position was that the present evidence in the scientific literature indicated that epigenetic editing did not specifically raise any additional concerns compared to the types of gene editing already available and being researched around the world. Importantly, we noted that the current evidence did not indicate epigenetic editing affected gametes and so was unlikely to affect future generations. We suggested that, since this meant the major concern with uses of human gene editing was with directly manipulating the genome of germ cells or embryos, any framework to regulate the latter should not inadvertently mean less worrying uses of this incredible technology should be caught in a broader moratorium.
It was therefore reassuring that in the recent WHO reports epigenetic editing was considered as being akin to other mechanisms for transcriptional modulation of genes (altering how they are switched on and off without affecting the underlying sequence itself). However, unlike our paper, which had raised significant concerns by reviewers in our speculations around use for ‘enhancement’, the WHO working group actually focused on this and specifically in terms of athletic ability. In Section 3.4 of the Framework for Governance, the WHO identified that epigenetic editing was different to germline gene editing for several important reasons, namely;
- The underlying DNA sequence is unchanged (they assumed this posed little actual risk of damage to the DNA itself)
- Epigenetic changes were unlikely to be heritable (the current science tells us that methylation is reset in germ cell development)
- Notwithstanding the reversibility of this approach making any actual effects difficult to detect other than through their consequential effects. Some of these effects may have longer term or permanent effects on the body even if the initial change is reversed.
- The field is moving very quickly and the development of CRISPoff and CRISPon tools could rapidly change the ease of use and applicability of this technology.
In our paper, we explored several actual uses of epigenetic editing and held them up against relevant ethical principles to examine whether there was anything new. Interestingly some reviewers of our paper used the ‘nothing to see here’ finding as a criticism suggesting this meant the paper was less interesting. The WHO also explored whether there does need to be additional oversight of somatic cell alteration but did not conclude that the technology presented any new challenges other than a greater possibility of achieving success. They did ask “Will epigenetic editing on gametes and embryos be permitted for non-reproductive purposes, for example, to explore gene function?” Curiously they also asked as a follow on “Will any distinction be made between work with public versus private funding?” although they do not provide any explanation of why this matters from an ethical principle perspective.
The Framework devotes most of its considerations to the use of somatic epigenetic editing in the context of athletic enhancement, taking the perspective that its transient nature might alter considerations of its use versus more permanent changes. The authors explore the use as applied to a modified form of eugenics, that is, using the technology to ‘iron-out’ undesirable traits or to apply enhanced traits in people after birth. They ask whether societal perceptions of such enhancement might differ if applied in sport or academic versus for military applications. It is not clear why these ethical issues are specific to epigenetic methods to achieve enhancement versus any other mechanisms such as performance enhancing drugs.
Overall, the WHO documents do not shed any new light on the topic of what to do about research that involves any sort of manipulation of a person and how this may be managed internationally across jurisdictions with differing legislation and levels of societal acceptance of the applications of technology. Instead, it is a timely reminder of the issues that we should maintain in our consciousness for all research activities that directly influence human health and wellbeing. As Pete Mills notes, perhaps its major implication is positioning the WHO to be a significant player in any international oversight framework.
Cohen, S. N., A. C. Chang, H. W. Boyer and R. B. Helling (1973). “Construction of biologically functional bacterial plasmids in vitro.” Proceedings of the National Academy of Sciences of the United States of America 70(11): 3240-3244.
Ishino, Y., M. Krupovic, P. Forterre and W. Margolin “History of CRISPR-Cas from Encounter with a Mysterious Repeated Sequence to Genome Editing Technology.” Journal of Bacteriology 200(7): e00580-00517.
Ishino, Y., H. Shinagawa, K. Makino, M. Amemura and A. Nakata (1987). “Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product.” J Bacteriol 169(12): 5429-5433.
Schaefer, G. O., M. K. Labude, Y. Zhu, R. S.-Y. Foo and V. Xafis (2021). “International Reporting Mechanism for Unethical Germline Gene Editing Experiments Is Needed.” Trends in Biotechnology 39(5): 427-430.
Zeps, N., T. Lysaght, R. Chadwick, A. Erler, R. Foo, S. Giordano, P. San Lai, G. O. Schaefer, V. Xafis, W. L. Chew and J. Sugarman (2021). “Ethics and regulatory considerations for the clinical translation of somatic cell human epigenetic editing.” Stem Cell Reports 16(7): 1652-1655.
This post may be cited as:
Zeps, N. (31 August 2021) Regulation of human epigenetic editing: ensuring international frameworks for governing Human Genome Editing don’t impede vital medical research. Research Ethics Monthly. Retrieved from: https://ahrecs.com/regulation-of-human-epigenetic-editing-ensuring-international-frameworks-for-governing-human-genome-editing-dont-impede-vital-medical-research/