In our December edition, we provided a high-level summary of responses to the startling inclusion of HHGE – as a “matter-of-fact” topic area – in the 2024 South Africa Ethics in Health Research Guidelines. We include below selected text from the Guidelines and from the important editorial by Ramsey et al. arguing that the “…current wording for HHGE for research purposes in the guidelines should be deleted in its entirety.” We are not aware of any new action by the South Africa NDoH but assess that this issue deserves close monitoring and further engagement by the global community.

:::::::::::::

South African Ethics in Health Research Guidelines: Principles, Processes and Structures
2024 Third Edition
4.3.2 Heritable human genome editing
Research on heritable human genome editing (HHGE) holds significant potential for addressing genetic diseases and improving human health. It also presents ethical challenges that require careful consideration and deliberation. A framework for analysing the protocol emphasises responsible and cautious practices.
a) Scientific and medical justification
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.
b) Transparency and informed consent
Researchers must maintain transparency throughout the research process, ensuring that participants and stakeholders are well-informed about the goals, methods, and potential implications of HHGE. Informed consent must be obtained from all parties involved, including prospective parents and individuals whose genetic material is used in the research.
c) Stringent ethical oversight
HHGE research should be subject to rigorous ethical review by health research ethics committees to evaluate its ethical implications. Ethical oversight should especially be illuminated by the right to freedom of scientific research, the right to access to healthcare, the best interests of prospective children, and the dignity of all individuals involved.
d) Ongoing ethical evaluation and adaptation
Ethical scrutiny of HHGE research projects should be a continuous process that adapts to evolving circumstances. This entails regular re-evaluation as new information emerges and as the technology progresses.
e) Safety and efficacy
Researchers must prioritize safety in all HHGE experiments, with thorough assessments of potential risks and strategies for mitigating them. The research should demonstrate a high level of scientific rigor and provide evidence of the technique’s efficacy.
f) Long-term Monitoring
Researchers should commit to ongoing monitoring of individuals born as a result of HHGE interventions to assess their health, wellbeing, and potential unforeseen consequences.
g) Legal compliance
Researchers must adhere to all relevant laws governing HHGE research. In particular, researchers must adhere to the fourteen-day rule, and must obtain the necessary ministerial permission to conduct research on embryos.

:::::::::::::

In the context of a number of other commentaries and analyses, we note again the editorial titled Heritable human genome editing in South Africa – time for a reality check [South Africa Medical Journal, Early Online -2024-11-29] by Michele Ramsay, Michael Pepper, Jantina de Vries, Safia Mahomed and Eleni Flack-Davison.

The editorial is well structured and provides discussion of the “origins of the current controversy” and its consequences. One contextual clarification in the piece is around public consultation processes leading to the inclusion of the HHGE language in SA guideline referenced above:

“…A draft of the guidelines released for public comment in 2023 did not include text on HHGE. A subsequent draft released early in 2024 included the section on HHGE with a brief window for comment. It is unclear why the National Health Research Ethics Council (NHREC) chose not to consult widely with topic experts to ensure that the text of the guidelines was appropriate, considering the national legal context, ethical concerns and international recommendations and guidelines for HHGE. It is unfortunate that this situation has arisen. The misguided wording in the current guidelines may serve to precipitate a troubling change in opinions in favour of permitting or promoting HHGE in SA…”

More important is the editorial’s clear-thinking conclusion:

…What should happen next?
Revision of the NHREC guidelines
The NHREC must clarify its view on HHGE. We note the recent press release that was circulated to ethics committees around the country by the chair of the NHREC on 8 November 2024. But this does not sufficiently address nor resolve the controversy, and the press release has no legal standing. The current wording for HHGE for research purposes in the guidelines should be deleted in its entirety. The underlying premise of section 4.3.2 of the guidelines appears to rest on the fact that there will be prospective parents, prospective children and individuals born because of HHGE research interventions specifically, which is problematic and inconsistent with the law. In addition, this current ambiguity in wording blurs the line between HHGE research and clinical application.

In summary, we assess this to be an extremely important, troubling and unresolved matter with global implications. We will continue to monitor for any further analysis, and, hopefully, action!

Heritable Human Genome Editing [HHGE] – South Africa Law/Regulation/Ethics Guidance
We explore below the startling inclusion of HHGE as a “matter-of-fact” topic area in the 2024 South Africa Ethics in Health Research Guidelines. We certainly paused when we encountered reference to “the best interest of prospective children” [presumably resulting from HHGE] in 4.3.2 [c]: “…Ethical oversight should especially be illuminated by the right to freedom of scientific research, the right to access to healthcare, the best interests of prospective children, and the dignity of all individuals involved…”

:::::::::::::

South African Ethics in Health Research Guidelines: Principles, Processes and Structures
2024 Third Edition
4.3.2 Heritable human genome editing
Research on heritable human genome editing (HHGE) holds significant potential for addressing genetic diseases and improving human health. It also presents ethical challenges that require careful consideration and deliberation. A framework for analysing the protocol emphasises responsible and cautious practices.
a) Scientific and medical justification
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.
b) Transparency and informed consent
Researchers must maintain transparency throughout the research process, ensuring that participants and stakeholders are well-informed about the goals, methods, and potential implications of HHGE. Informed consent must be obtained from all parties involved, including prospective parents and individuals whose genetic material is used in the research.
c) Stringent ethical oversight
HHGE research should be subject to rigorous ethical review by health research ethics committees to evaluate its ethical implications. Ethical oversight should especially be illuminated by the right to freedom of scientific research, the right to access to healthcare, the best interests of prospective children, and the dignity of all individuals involved.
d) Ongoing ethical evaluation and adaptation
Ethical scrutiny of HHGE research projects should be a continuous process that adapts to evolving circumstances. This entails regular re-evaluation as new information emerges and as the technology progresses.
e) Safety and efficacy
Researchers must prioritize safety in all HHGE experiments, with thorough assessments of potential risks and strategies for mitigating them. The research should demonstrate a high level of scientific rigor and provide evidence of the technique’s efficacy.
f) Long-term Monitoring
Researchers should commit to ongoing monitoring of individuals born as a result of HHGE interventions to assess their health, wellbeing, and potential unforeseen consequences.
g) Legal compliance
Researchers must adhere to all relevant laws governing HHGE research. In particular, researchers must adhere to the fourteen-day rule, and must obtain the necessary ministerial permission to conduct research on embryos.

::::::::::::

Credit to our colleagues Françoise Baylis and Katie Hanson for bringing attention to the underlying issues and raising questions about the current legal status of such research in their article in The Conservation [24 October 2024]. A number of commentaries and articles ensued including Sarah Wild’s piece in Nature [07 Nov 2024]: Will South Africa become first country to accept controversial form of human genome editing?

ARM’s Executive Director Tim Hunt weighed in as well on LinkedIn [at least] noting:
…This misguided type of ‘research’ must not overshadow the tremendous progress being made every day by leading biotechnology companies and academic pioneers in the field of somatic cell gene editing and gene therapy. There must be a bright line between that kind of important, well-regulated, and ethical R&D that is in service to patients living with life-threatening rare disorders vs. the highly speculative and troubling world of HHGE. This development highlights the need for continued convening – with leading biotechnology companies, scientists, medical experts, patients/patient groups, bioethicists, religious leaders, regulators, and legal scholars – around the topic of HHGE.

The latest on all this appears to be a round-up article by Pete Shanks in Biopolitical Times: South Africa Does Not Allow Heritable Human Genome Editing [11.24.2024] as carried on the Center for Generic and Society website.

A number of commentaries have referenced a statement on November 8, 2024 by Professor Penelope Engel-Hills, Chairperson of the National Health Research Ethics Council , responding to The Conversation piece by Baylis and Hanson referenced above. Here is an excerpt [our text bolding]:

::::::::::::

…Firstly, the National Health Research Ethics Council of South Africa (NHREC) wishes to clarify that neither the National Health Act, nor the 2024 National Guidelines on Ethics in Health Research, legalise HHGE for use in therapy in any way. The prohibition in the National Health Act makes this position very clear. The “reproductive cloning of a human being” is prohibited in section 57(1) of the National Health Act, punishable as a criminal office by a fine and up to 5 years’ imprisonment. Furthermore, the same section states that the Minister may permit research on stem cells and human fertilised eggs that are less than 14 days old. We believe that “reading in” a permissive approach concerning HHGE to the guidelines is unconvincing but, nevertheless, we will address this potential confusion by clarifying the wording in the 2024 ethical guidelines.

The NHREC concedes that the wording in the guidelines may have caused some confusion and unnecessary alarm. However, it is important to note that the 2024 research ethics guidelines are grounded in a set of key principles that ensure the integrity and ethical conduct of research involving human participants. As a principle-based document, the context of the entire set of guidelines is relevant and we caution against any interpretation that fails to consider the key principles expressed in the guidelines. These ethical guidelines provide a framework for ethical reasoning and decision-making rather than a set of legal rules.

As the prohibition of HHGE is stated in the National Health Act, the 2024 research ethics guidelines stipulate with regard to HHGE that South African researchers “must adhere to all relevant laws governing HHGE research” (par 4.3.2(g)). Section 73 of the National Health Act requires every organisation that conducts “health research” to have a health research ethics committee (registered with the NHREC) or have access to a registered health research ethics committee that must review research proposals and protocols, and grant approval where research proposals and protocols meet the prescribed ethical standards; and have oversight on the approved study. The definition of “health research” is broad, meaning that HHGE research would fall within the scope of health research, making ethics approval a legal requirement…

::::::::::::

At this writing, [14 December 2024] we find no posted statements or comment on the relevant SA Department of Health website pages around this, so we are left, for the moment, with the not-entirely-satisfying construction in Professor Engel-Hills’ statement text above.

Two additional analyses have been published over the last week.

One is titled South Africa’s new research guidelines are not a green light for heritable human genome editing [The Conversation, December 4, 2024] by Bonginkosi Shozi. This piece explores the relevant South Africa statutory provision Section 57(1) of the South African National Health Act, the role of the national ethics guidance at issue above, and the independent role that ethics review bodies presumably enjoy in reviewing protocols that involve HHGE, utilizing that national ethics guidance. This analysis does not seem to move things forward.

The other is an editorial titled Heritable human genome editing in South Africa – time for a reality check [South Africa Medical Journal, Early Online -2024-11-29] by Michele Ramsay, Michael Pepper, Jantina de Vries, Safia Mahomed and Eleni Flack-Davison. The editorial is well structured and provides discussion of the “origins of the current controversy” and its consequences. One contextual clarification in the piece is around public consultation processes leading to the inclusion of the HHGE language in SA guideline referenced above:

“…A draft of the guidelines released for public comment in 2023 did not include text on HHGE. A subsequent draft released early in 2024 included the section on HHGE with a brief window for comment. It is unclear why the National Health Research Ethics Council (NHREC) chose not to consult widely with topic experts to ensure that the text of the guidelines was appropriate, considering the national legal context, ethical concerns and international recommendations and guidelines for HHGE. It is unfortunate that this situation has arisen. The misguided wording in the current guidelines may serve to precipitate a troubling change in opinions in favour of permitting or promoting HHGE in SA…”

More important is the editorial’s clear-thinking conclusion:

…What should happen next?
Revision of the NHREC guidelines
The NHREC must clarify its view on HHGE. We note the recent press release that was circulated to ethics committees around the country by the chair of the NHREC on 8 November 2024. But this does not sufficiently address nor resolve the controversy, and the press release has no legal standing. The current wording for HHGE for research purposes in the guidelines should be deleted in its entirety. The underlying premise of section 4.3.2 of the guidelines appears to rest on the fact that there will be prospective parents, prospective children and individuals born because of HHGE research interventions specifically, which is problematic and inconsistent with the law. In addition, this current ambiguity in wording blurs the line between HHGE research and clinical application

So…all this suggests an extremely important, troubling and still unresolved matter with global implications. We will continue to monitor for any further analysis, and, hopefully, action!

DSI and Benefits Sharing: Public Consultations
A key outcome from COP16 held at Cali, Columbia was around benefits sharing and digital sequence information [DSI]. COP16 made progress in the areas of synthetic biology and other matters, and we urge readers to review the full media release: Biodiversity COP 16: Important Agreement Reached Towards Goal of “Making Peace with Nature”, November 2, 2024. In our view, establishing “the Cali Fund” [excerpt from media release below] was a milestone that will have ripple effects in the decades ahead. We also include below the IFPMA response.

Biodiversity COP 16: Important Agreement Reached Towards Goal of “Making Peace with Nature”
November 2, 2024, CBD Secretariat.
[Excerpt]
…Call Fund is Launched: Sharing the Benefits of Digital Genetic Information
Having agreed at COP 15 to establish a multilateral mechanism, including a global fund, to share the benefits from uses of digital sequence information on genetic resources (DSI) more fairly and equitably, delegates at COP 16 advanced its operationalization – a historic decision of global importance.

This complex decision addresses how pharmaceutical, biotechnology, animal and plant breeding and other industries benefiting from DSI should share those benefits with developing countries and Indigenous Peoples and local communities.

Under the agreed guidelines, large companies and other major entities benefiting commercially from DSI uses should contribute to “the Cali Fund,” based on a percentage of their profits or revenues. The model targets larger companies most reliant on DSI and exempts academic, public research institutions and other entities using DSI but not directly benefiting.

Developing world countries will benefit from a large part of this fund, with allocations to support implementation of the KMGBF, according to the priorities of those governments.

At least half of the funding is expected to support the self-identified needs of Indigenous peoples and local communities, including women and youth within those communities, through government or by direct payments through institutions identified by Indigenous peoples and local communities. Some funds may support capacity building and technology transfer.

Strong monitoring and reporting will ensure industries see the impact of their contributions in a transparent and open way, and regular reviews will build the mechanism’s efficiency and efficacy over time.
This agreement marks a precedent for benefit-sharing in biodiversity conservation with a fund designed to return some of the proceeds from the use of biodiversity to protect and restore nature where help is needed most….

:::::::::::

Conclusion of COP16 Negotiations on Multilateral Mechanism for Benefit-Sharing of DSI
IFPMA Statement 02 Nov 2024
On the conclusion of the COP16 negotiations on proposals to include digital sequence information (DSI) within the scope of the Convention of Biodiversity (CBD), IFPMA delivered a Statement:

“The pharmaceutical industry has long supported the Convention on Biological Diversity’s objective to protect our natural world and will continue to engage in discussions on mechanisms that safeguard biodiversity while fostering scientific research and innovation”.
“The decision adopted today does not get the balance right between the intended benefits of such a mechanism and the significant costs to society and science that it has the potential to create”.

“The ability to rapidly use scientific data known as “digital sequence information” (DSI) is essential for developing new medicines and vaccines. Any new system should not introduce further conditions on how scientists access such data and add to a complex web of regulation, taxation and other obligations for the whole R&D ecosystem – including on academia and biotech companies. New technologies that use DSI can contribute to conservation and sustainable use of biodiversity and should be encouraged”.

“Ahead of COP17, it is critical that governments work to ensure the implementation of any new mechanism on digital sequence information does not stifle the medical research and innovation that can bring the next wave of medical progress to people around the world.”

WHO – Normative Guidance
WHO continues development of guidelines and normative guidance overall, including the important, recently released Guidance for best practices for clinical trials – September 2024, intended to “strengthen the global clinical trial ecosystem and to review existing guidance and develop new guidance as needed on best practices for clinical trials.” The new WHO normative guidance below articulates eight “principles” for ethical human genome data collection and sharing.

WHO releases new principles for ethical human genomic data collection and sharing
20 November 2024
The World Health Organization (WHO) has issued a set of principles for the ethical collection, access, use and sharing of human genomic data. Created with guidance from the WHO Technical Advisory Group on Genomics (TAG-G) and other international experts, these principles establish a global approach to help protect individual rights, promote equity and foster responsible collaboration in genomic research…

“The potential of genomics to revolutionize health and disease understanding can only be realized if human genomic data are collected, accessed and shared responsibly,” says Dr John Reeder, Director of WHO’s Research for Health Department. “This document outlines globally applicable principles designed to guide ethical, legal and equitable use of human genome data, fostering public trust and protecting the rights of individuals and communities. It serves as a call to action, urging all stakeholders to adhere to these principles and ensure the benefits of genomic advancements are accessible to everyone.”

The principles emphasize several core themes:
:: Informed consent and privacy are foundational, with clear guidelines to ensure that individuals understand and agree to how their genomic data will be used. WHO underscores the importance of transparency, requiring that data collection processes are openly communicated and safeguarded against misuse.
:: Another core focus is equity. The principles call for targeted efforts to address disparities in genomic research, especially in low- and middle-income countries (LMICs), and for ensuring that genomic research benefits populations in all their diversity. By prioritizing the inclusion of underrepresented groups, the guidelines aim to promote broader and fairer representation in genomic research and its applications.
:: Recognizing the importance of international collaboration through partnerships across borders and sectors, WHO encourages collaborative efforts between governments, academia and the private sector to maximize the positive impact of genomic research. Responsible data sharing, supported by robust governance structures, is essential for advancing global health while respecting privacy.
:: WHO’s principles also address capacity building in regions with limited genomic infrastructure. By encouraging investment in local expertise and resources, the organization aims to close global disparities in research capacity, making genomic data practices more inclusive and sustainable.

The release of these principles represents a significant step forward in WHO’s mission to promote ethical genomics practices. As the field continues to evolve, these guidelines offer a trusted framework to support genomic research that is equitable, transparent and respectful of individual rights.

::::::::::::::

Guidance for human genome data collection, access, use and sharing
WHO – Guidance [normative]
20 November 2024 :: 22 pages
Overview
The ethical, legal, and equitable sharing of human genomic data is critical to advancing global health research and ensuring fair access to the benefits of genomics. The WHO’s new document outlines a comprehensive set of globally applicable principles designed to guide stakeholders in the responsible collection, use, and sharing of human genome data. This document serves as a key resource to navigate complex issues surrounding data governance, with the aim of fostering transparency, promoting equity, and safeguarding individual and collective rights. These principles are intended to support the implementation of best practices across diverse settings, thereby enhancing the global capacity for genomic research and its translation into health benefits for all.

::::::::::::::

Table of Contents [excerpt]

3. Principles for human genome collection, access, use and sharing
   3.1 To affirm and value the rights of individuals and communities to make decisions
   3.2 Social justice
   3.3 Solidarity
   3.4. Equitable access to and benefit from human genome data
   3.5 Collaboration, cooperation and partnership
   3.6. Stewardship of human genome data
   3.7. Transparency
   3.8. Accountability

Glossary [excerpts]
Benefit-sharing refers to profit-sharing agreements, equitable access to diagnostics, therapeutics and technology transfer, as well as capacity-building and -strengthening initiatives. What constitutes a benefit (and the nature of that benefit) is both subjective and context dependent

Human genome data include but is not limited to:

• DNA sequence(s) from the nuclear and mitochondrial genomes.
• Transcriptome (complete set of RNA transcripts).
• Proteome (complete set of proteins produced by an organism, from which the corresponding
• genetic sequences can be inferred)
• Methylome and other epigenetic modifications.

.

Genomic Analysis – Cholera
Through our Center for Vaccine Ethics and Policy, we closely track infectious diseases and vaccines/immunization response in our weekly digest. The current upsurge in cholera in a number of sites – often linked to conflict/post-conflict settings – is troubling as is the contuing severe shortage of OCV [oral cholera vaccine] severely limiting outbreak response. We highlight this article as a powerful application of genomic analysis on the “front-end: projecting and analyzing cholera spread.

medRxiv
2024.11.15.24317392; doi: https://doi.org/10.1101/2024.11.15.24317392
Analysis
Multicountry genomic analysis underscores regional cholera spread in Africa [Pre-Print]
Gerald Mboowa, Nathaniel Lucero Matteson, Collins Kipngetich Tanui, Mpanga Kasonde, Guyguy Kusanzangana Kamwiziku, Olusola Anuoluwapo Akanbi, Jucunu Johane Elias Chitio, Mathews Kagoli, Rene Ghislain Essomba, Alisen Ayitewala, Isaac Ssewanyana, Valentina Josiane Ngo Bitoungui, Adrienne Aziza Amuri, Andrew S Azman, Olajumoke Atinuke Babatunde, Blaise Mboringong Akenji, Anais Broban, Espoir Bwenge Malembaka, Francis Ongole, Chimaobi Emmanuel Chukwu, Nalia Ismael, Otridah Kapona, Osvaldo Laurindo, Placide Kingebeni Mbala, Georges Alain Etoundi Mballa, Imelda Carlos Zulfa Miambo, Alex Ansaye Mwanyongo, Grace Najjuka, Joseph Mutale, Kunda Musonda, Allan Muruta Niyonzima, Mirriam Ethel Nyenje, Michael Popoola, Doreen Mainza Shempela, Christiane Medi Sike, Sofiao Manjor Sitoe, Dorcas Waruguru Wanjohi, Placide Okitayemba Welo, Mtisunge Yelewa, Sebastian Yennan, Lucius Ziba, CholGEN Consortium, Joseph Ephram Bitilinyu-Bangoh, Roma Chilengi, Hamsatou Hadja, Jide Idris, Jose Paulo Mauricio Langa, Daniel Mukadi-Bamuleka, Susan Nabadda, Amanda K Debes, David A Sack, Jean Kaseya, Yenew Kebede Tebeje, Shirlee Wohl, Sofonias Kifle Tessema
Abstract
Cholera remains a significant public health burden in many countries in sub-Saharan Africa, though the exact mechanisms of bacterial emergence and spread remain largely undefined. We generated genomic data from 728 Vibrio cholerae O1 isolates predominantly collected between 2019-2024 to create the largest dataset of V. cholerae genomes sequenced locally in Africa. This dataset enabled us to interrogate recent patterns of spread, including the rapid circulation of the AFR15 lineage associated with unusually large outbreaks in Southern Africa.
We provide evidence for the movement of the AFR15 lineage into new African Member States and confirm previously observed differences in V. cholerae transmission dynamics in West versus East Africa, though cross-border transmission is prevalent on both sides of the continent. Despite observed differences, evolutionary processes are similar across lineages and we find no evidence for significant changes in antimicrobial resistance genotypes.
Overall, our findings emphasize the importance of regionally coordinated cross-border surveillance and interventions, while also demonstrating the critical role of locally generated genomic data in understanding the spread of cholera in Africa.

Molecular Informatics
Unprecedented advances in omics and informatics are helping drive a revolution in disease prevention, detection, and management. The editorial below provides a useful overview on a set of key articles in Frontiers in Medicine around molecular informatics in precision medicine.

Frontiers in Medicine
https://www.frontiersin.org/journals/medicine/volumes?volume-id=1237
Editorial
Molecular Informatics in Precision Medicine
Abdul Azeez Sayed, Hari S Sharma, PhD, DSc, FIABS, J. Francis Borgio
Accepted on 22 Nov 2024
Introduction
The emerging concept in medicine shifts towards precision medicine personalised to an individual’s unique genetic makeup and environmental factors. By integrating advanced molecular technologies such as genomics, transcriptomics, proteomics, metabolomics and microbiomics we can unlock the potential to revolutionize healthcare.

Molecular informatics plays a crucial role in this transformation. By analysing vast amounts of biological data, researchers can identify genetic markers, predict disease risk and develop personalized treatment strategies. This research topic deals the latest advancements in molecular informatics, exploring how these technologies can be connected to improve patient outcomes.

Key areas of focus include:
(i) next-generation sequencing, a leveraging cutting-edge sequencing technologies to unravel complex genetic variations,
(ii) computer-aided drug discovery for utilizing computational tools to accelerate drug discovery and development,
(iii) molecular modeling and simulation for simulating biological processes at the molecular level to gain insights into disease mechanisms and
(iv) bioinformatics specially applying computational methods to analyze and interpret biological data.

Through a comprehensive exploration of these topics, this collection of articles aims to provide a valuable resource for researchers, clinicians and industry professionals working at the forefront of precision medicine. By understanding the power of molecular informatics, we can move closer to a future where healthcare is truly personalized.