CORRESPONDENCE

 

In defence of South Africa's National Health Research Ethics Council guidelines on heritable human genome editing

 

 

To the Editor: Ramsay et al.^[1] critique South Africa (SA)'s National Health Research Ethics Council (NHREC) guidelines^[2] on heritable human genome editing (HHGE) and our defence of these guidelines.^[3] They claim first that the NHREC guidelines 'permit' live births resulting from HHGE, which they suggest is premature and ethically unsound; and second, that there is no legal certainty surrounding HHGE in SA, particularly in relation to section 57(1) of the National Health Act 61 of 2003 (NHA). Additionally, they question the methodology and relevance of our public engagement study on HHGE policy, which explored SA perspectives.^[4]

We address these critiques in three parts.

The NHREC guidelines as a future-ready framework

Ramsay et al.'s^[1] assertion that the NHREC guidelines 'permit' live births resulting from HHGE requires careful clarification. While we agree that HHGE is not yet at a stage where its safety and efficacy would justify clinical trials, the guidelines do not impose an explicit and rigid ban. Instead, the guidelines adopt a flexible framework of ethical considerations that emphasise safety, efficacy and rigorous ethical oversight. For instance, the guidelines require that the potential benefits of HHGE to individuals and society must outweigh the associated risks and uncertainties, while safeguarding the best interests of any child born because of HHGE. This is not an unconditional approval of live births, but a structured framework of stringent requirements that must be satisfied before such applications could be contemplated. Under the current state of scientific knowledge, the NHREC guidelines therefore would not permit live births resulting from HHGE.

Although HHGE is not at a stage where live births would be permissible, the central ethical question remains whether, if certain breakthroughs were achieved - such as preclinical trials demonstrating the safety and efficacy of HHGE to prevent serious illnesses - it would then be ethical to proceed with clinical trials, including live births. Provided that rigorous ethical oversight is maintained, we suggest that in such a scenario, it would be ethical to proceed. The NHREC guidelines anticipate this possibility, providing a pathway for responsible scientific progress.

If the authors agree with this ethical stance, then our disagreement lies not in principle but in whether the NHREC guidelines should explicitly anticipate the possibility of such advancements. We argue that a proactive, future-ready approach is necessary and appropriate.

Future-ready guidelines, as established by the NHREC, are critical in advancing responsible governance by ensuring that ethical oversight mechanisms are in place and adaptable as technology progresses, thereby preventing governance delays. They foster public trust by demonstrating transparency and foresight and provide scientists with a clear framework for pursuing clinical applications, encouraging responsible innovation rather than fostering uncertainty or stagnation. These factors underscore the prudence and necessity of a forward-looking regulatory approach.

Section 57(1) of the NHA

Section 57(1) of the NHA seems to have become the focus of attention regarding the question of whether HHGE is lawful. It reads as follows - note the formatting:

'57. (1) A person may not -

(a) manipulate any genetic material, including genetic material of human gametes, zygotes or embryos; or

(b) engage in any activity, including nuclear transfer or embryo splitting,

for the purpose of the reproductive cloning of a human being.'

The qualifying phrase at the end, 'for the purpose of the reproductive cloning of a human being', is separated from subsection (b) by a line break and aligned with the main body of section 57(1), rather than being indented like subsections (a) and (b). This formatting is significant, as it indicates that the qualifying phrase applies to both subsections (a) and (b). Accordingly, the manipulation of any genetic material, as described in subsection (a), is prohibited only when it is performed 'for the purpose of the reproductive cloning of a human being'. Manipulation of genetic material for other purposes is not prohibited.

The term 'manipulate' is not defined in the NHA and must therefore be interpreted according to its ordinary meaning, which includes 'to manage or utilize skillfully',^[5] or 'to use something, often with a lot of skill'.^[6] As such, 'manipulate any genetic material' refers to the skilful handling, control or utilisation of genetic material. Common research practices in SA, such as isolating DNA from cells and genetic sequencing, involve the manipulation of genetic material. However, the qualifying phrase at the end of section 57(1) ensures that these practices are lawful, as they are not conducted 'for the purpose of the reproductive cloning of a human being'.

A related question arises: does the prohibition on manipulating genetic material in subsection (a) extend only to the types of genetic material explicitly listed - namely, human gametes, zygotes and embryos? This is unlikely, as the Constitutional Court has held that the term 'including' is not a term of exhaustive definition.^[7] Rather, human gametes, zygotes and embryos are illustrative examples of 'any genetic material', not an exhaustive list. For instance, common practices in fertility healthcare, such as in vitro fertilisation and pre-implantation genetic testing, involve the manipulation of gametes and embryos. Yet their lawfulness is undisputed because they are not performed 'for the purpose of the reproductive cloning of a human being'. This reasoning would also apply to HHGE.

Ramsay et al.^[1] fail to acknowledge the importance of statutory formatting in interpreting section 57(1) by omitting the line break and the alignment of the qualifying phrase with the main body of the section. This omission creates the misleading impression that the qualifying phrase applies only to subsection (b) and not to subsection (a). It is akin to selectively reporting results in genetic analysis that exclude critical variables, leading to erroneous conclusions. Such a misrepresentation fundamentally alters the scope and application of section 57(1).

Ethics and societal views

Ramsay et al.^[1] argue that if the NHA does not explicitly address HHGE, this 'void' should be filled by considerations of ethics, morality and societal views. Regarding ethics, the NHREC guidelines provide an ethical framework for evaluating HHGE, in the present and in the context of future advancements. Regarding societal views, our deliberative public engagement study conducted among South Africans is the first and only reflection of societal views of South Africans on HHGE.^[8,9] The main findings were as follows. Assuming that HHGE is safe and effective, an overwhelming majority of participants supported its use to prevent genetic health conditions and to confer immunity against tuberculosis (TB) and HIV/AIDS, while significant majorities opposed its use for enhancement purposes. Throughout the deliberations, the prevailing theme was the need to balance potential health benefits with the risks of unforeseen consequences, which is encapsulated by the following provision in the NHREC guidelines:

'HHGE research must have a clear and compelling scientific and medical rationale, focusing on the prevention of serious genetic disorders and immunity against serious diseases. The potential benefits to individuals and society should outweigh the risks and uncertainties associated with HHGE.'

The role of international standards

Ramsay et al.^[1] place significant emphasis on international standards, noting their involvement in drafting World Health Organization (WHO) guidelines on HHGE.^[10] While international standards can provide useful guidance, there is no single global consensus on HHGE. Positions vary widely across declarations and organisations. Moreover, the WHO guidelines appear to be less directly applicable to the SA context, as they may not fully account for its unique realities and constitutional imperatives.^[11,12] Even if a general consensus holds that clinical applications of HHGE are premature, this reflects the current state of technology, not a fixed or universal principle. The NHREC guidelines appropriately anticipate future advancements in safety and efficacy, ensuring that SA remains prepared to evaluate HHGE's potential responsibly.

In SA, the Constitution - not any international standard - is the supreme authority. Unlike other constitutions, it uniquely includes rights such as access to healthcare and the freedom of scientific research, having profound implications for HHGE governance. The government is constitutionally obligated to address public health crises, such as the TB epidemic, using all available resources. If HHGE offers a future solution to confer immunity against TB, it must be seriously considered.^[13,14] The right to access to healthcare is complemented by the right to freedom of scientific research.^[15] This is a substantive right.^[16] SA scientists have the freedom to pursue HHGE research, subject only to reasonable and justifiable limitations. The rights of persons born because of HHGE clinical trials would certainly be such a limitation^[15] - hence the emphasis placed on safety in the NHREC guidelines. We suggest that the NHREC guidelines align with SA's constitutional values, ensuring that HHGE research is not left unregulated, or banned, but is conducted responsibly while safeguarding public health and scientific freedom.

Addressing specific critiques

Regarding our research group's work on the legal and ethical aspects of HHGE, Ramsay et al.^[1] state that they 'take no issue' with our view. However, they allege that we are using the NHREC guidelines to create the impression of legal certainty where there is none. Admittedly, legal certainty in the strict sense of case law that interprets section 57(1) does not exist. However, the formatting and language of section 57(1) are clear: it prohibits genetic manipulation for the purpose of reproductive cloning, but does not extend this prohibition to other purposes, such as isolating DNA, genetic sequencing, or HHGE. Suggesting otherwise would have profound implications for genetic research.

The authors comment on our deliberative public engagement study on HHGE, where we invited participants to consider a future scenario where HHGE is safe and effective, and then posed a series of policy questions to them.'⁴¹ First, the authors argue that because HHGE is not yet safe and effective, the findings of our study cannot be used to drive legislative reform. We beg to differ. For the reasons mentioned above, we favour a proactive, future-ready approach to policy-making that anticipates possible scientific advancements. We do not confuse the present with the future; because HHGE is not yet safe and effective, the NHREC guidelines do not currently permit live births from HHGE. Second, the authors express concern that our participants might not have understood what HHGE is. Our methodology included the following mechanisms to ensure that all participants had a reasonable comprehension of HHGE:^[4,8] (i) persons interested in participating in our study were provided with vetted resource materials, including online videos explaining the basics of genetics and gene editing; (ii) they were required to complete an online assessment, achieving 100% accuracy before being considered for participation; and (iii) a geneticist was present during deliberations to answer technical questions. While our participants were not all-knowing, these measures ensured that they had sufficient understanding to deliberate in an informed way and make informed policy choices.

Conclusion

Our defence of the NHREC guidelines regarding HHGE should not be interpreted as an endorsement of the NHREC guidelines in general, some aspects of which are problematic, as was the consultation process. However, in relation to HHGE, they reflect a proactive and balanced approach that responsibly anticipates future scientific developments while safeguarding public health and constitutional values.

By proactively addressing the potential of HHGE, the NHREC guidelines position SA to lead in responsibly advancing genomic science while upholding constitutional imperatives such as access to healthcare, freedom of scientific research, and the best interests of the child. They strike a balance, ensuring that HHGE research is neither unregulated nor unnecessarily hindered, thereby safeguarding the public interest while fostering innovation and addressing pressing public health challenges.

Acknowledgments. ChatGPT-4 was used to improve the language and readability of this manuscript.

Author contributions. All authors contributed to the conceptualisation and writing of this response. DT authored the first draft; the other authors critically assessed and revised the content. All authors approved the final version prior to publication.

Donrich Thaldar

School of Law, University of KwaZulu-Natal, Durban, South Africa thaldard@ukzn.ac.za

Sheetal Soni

School of Law, University of KwaZulu-Natal, Durban, South Africa

Larisse Prinsen

Faculty of Law, University of the Free State, Bloemfontein, South Africa

Ntokozo Mnyandu

School of Law, University of the Witwatersrand, Johannesburg, South Africa

Marietjie Botes

Centre for Research on Evaluation, Science and Technology, Stellenbosch University, South Africa

Julian Kinderlerer

Faculty of Law, University of Cape Town, South Africa

 

References

1. Ramsay M, Pepper M, De Vries J, Mahomed S, Flack-Davison E. Heritable human genome editing in South Africa - time for a reality check. S Afr Med J 2025;115(1):e2872. https://doi.org/10.7196/SAMJ.2025.v115i1.2872.         [ Links ]

2. National Health Research Ethics Council. South African Ethics in Health Research Guidelines - Principles, Processes and Structures. 3rd ed. Pretoria: National Department of Health, 2024. https://www.health.gov.za/nhrec-guidelines/ (accessed 7 December 2024).         [ Links ]

3. Thaldar D, Soni S, Botes M, Prinsen L, Mnyandu N, Kinderlerer J. Comment on: Baylis F, Hasson K. South Africa amended its research guidelines to allow for heritable human genome editing. The Conversation, 25 October 2024. https://theconversation.com/south-africa-amended-its-research-guidelines-to-allow-for-heritable-human-genome-editing-241136 (accessed 7 December 2024).         [ Links ]

4. Thaldar D, Townsend B, Botes M, Shozi B, Pillay S. A virtual deliberative public engagement study on heritable genome editing among South Africans: Study protocol. PLoS ONE 2021;16(8):e0256097. https://doi.org/10.1371/journal.pone.0256097        [ Links ]

5. Manipulate. Merriam-Webster.com Dictionary (Internet). Merriam-Webster. https://www.merriam-webster.com/dictionary/manipulate (accessed 7 December 2024).         [ Links ]

6. Manipulate. Cambridge Academic Content Dictionary (Internet). Cambridge University Press and Assessment. https://dictionary.cambridge.org/dictionary/english/manipulate (accessed 7 December 2024).         [ Links ]

7. Minister of Health v New Clicks South Africa (Pty) Ltd 2006 (2) SA 311 (CC).         [ Links ]

8. Thaldar D, Shozi B, Steytler M, et al. A deliberative public engagement study on heritable human genome editing among South Africans: Study results. PLoS ONE 2022;17(11):e0275372. https://doi.org/10.1371/journal.pone.0275372        [ Links ]

9. Shozi B, Thaldar D. Promoting equality in the governance of heritable human genome editing through Ubuntu: Reflecting on a South African public engagement study. Am J Bioethics 2023;23(2):1-7. https://doi.org/10.1080/15265161.2023.2207524        [ Links ]

10. World Health Organization. Human Genome Editing. Geneva: WHO, 2024. https://www.who.int/health-topics/human-genome-editing/#tab=tab_1 (accessed 7 December 2024).         [ Links ]

11. Shozi B, Kamwendo T, Kinderlerer J. Thaldar DW, Townsend B, Botes M. Future of global regulation of human genome editing: A South African perspective on the WHO Draft Governance Framework on Human Genome Editing. J Med Ethics 2022;48(3):165-168. https://doi.org/10.1136/medethics-2020-106863        [ Links ]

12. Thaldar D, Shozi, B. An unbalanced approach to governance? An analysis of the WHO's position on human genome editing. Bioethics 2023;37(7):656-661. https://doi.org/10.1111/bioe.13193        [ Links ]

13. Kamwendo T. Access to healthcare in the age of CRISPR: An analysis of the right to heritable human genome editing in the context of the tuberculosis epidemic in South Africa. PhD thesis. Durban: University of KwaZulu-Natal 2022. https://researchspace.ukzn.ac.za/handle/10413/21540 (accessed 7 December 2024).         [ Links ]

14. Thaldar D, Shozi B, Kamwendo T. Culture and context: Why the global discourse on heritable genome editing should be broadened from the South African perspective. BioLaw J 2021(4):409-416. https://doi.org/10.15168/2284-4503-2052        [ Links ]

15. Thaldar D, Botes M, Shozi B, Townsend B, Kinderlerer J. Human germline editing: Legal-ethical guidelines for South Africa. S Afr J Sci 2020;116(9/10). https://doi.org/10.17159/sajs.2020/6760        [ Links ]

16. Thaldar D, Steytler M. Time for Cinderella to go to the ball: Reflections on the right to freedom of scientific research. S Afr Law J 2021;138(2):260-288. https://doi.org/10.47348/SALJ/v138/i2a2        [ Links ]

17. Thaldar D, Shozi B. Procreative non-maleficence: A South African human rights perspective on heritable human genome editing. CRISPR J 2020;3(1):32-36. https://doi.org/10.1089/crispr.2019.0036        [ Links ]