To facilitate a gathering of additional  information, participants are asked to consider the following points in relation to this topic:
1. Review the potential positive and negative impacts of this trend and issue in synthetic biology on each of the three objectives of the Convention.

2. What is the timeframe for release or potential impact of engineered gene drives to control vector-borne diseases and invasive species? Please provide examples of specific applications (e.g., molecular mechanism, target species, intent of application).

3. What are the potential gaps or challenges for risk assessment, risk management and regulation for this topic in synthetic biology? Evaluate the availability of tools to detect, identify and monitor the organisms, components and products of synthetic biology.

4. Review the potential social, economic, cultural, ethical, political, human health and/other relevant impacts of this trend and issue. What are the relevant considerations for IPLCs, women and youth?

5. Is the trend and issue attempting to address specific problems, and if so, what are these problems and their underlying causes? How else could these problems or causes be addressed?

6. What lessons can be learned of similar tools, techniques or applications in other domains? How might those lessons from elsewhere be relevant or shed insight in assessing this topic in the context of the aims of the Convention on Biological Diversity?

7. Where are limits of knowledge with respect to this trend and issue? Are there any other considerations that would be important to raise?

Dear colleagues,

It is my pleasure to welcome you to the Open-ended Online Forum on Synthetic Biology. The forum will be open from 6 to 15 November at 17.00 EST. I will be moderating the discussion and will provide support should the need arise. Please also bear in mind the forum guidelines that you can find on the website.

Thank you in advance for your engagement and I am looking forward to productive discussions!

Kind regards,
Florian Rabitz

My name is Christoph Then and I am a member of ENSSER (The European Network of Scientists for Social and Environmental Responsibility) and representing Testbiotech (http://www.testbiotch.org) in this discussion. In my contribution, I refer to points 2., 3. and 7 of the questions raised by the moderator.

Testbiotech recently made a submission of information relevant to risk assessment of gene drives (Testbiotech, 2023). It discusses recent experiments with the X-shredder application in Anopheles and highlights the need for in-depth risk assessment on a case-by-case basis, including questioning the assumptions made by experts involved in the development of the Synbio Gene Drives organisms.

It is shown that field trials were announced with genetically engineered mosquitoes based on incorrect assumptions regarding the strain, the insertion site of the artificial gene constructs and potential gene flow (Vitale et al., 2022, Pollegioni et al., 2023). If released, this application could have severe consequences for both the target and non-target species.

The backgrounder shows that ‘cut-off’ criteria are essential in the risk assessment of organisms developed to actively spread artificial genetic elements (Then et al., 2020). Such criteria could facilitate decision-making when faced with numerous unknowns. In addition, the regulators are requested to introduce a prospective technology assessment and investigations into systemic risks.

Pollegioni P., Persampieri T., Minuz R.L., Bucci A., Trusso A., Martino S.D., Leo C., Bruttini M., Ciolfi M., Waldvogel A.-M., Tripet F., Simoni A., Crisanti A., Müller R. (2023) Introgression of a synthetic sex ratio distortion transgene into different genetic backgrounds of Anopheles coluzzii.
Insect Mol Biol 32: 56–68. https://doi.org/10.1111/imb.12813

Testbiotech (2023) Submission of information and supporting documentation relevant to risk assessment of gene drives, TESTBIOTECH Background 15 - 3 – 2023, https://www.testbiotech.org/node/3037

Then, C., Kawall, K., Valenzuela, N. (2020) Spatio-temporal controllability and environmental risk assessment of genetically engineered gene drive organisms from the perspective of EU GMO Regulation. Integr Environ Assess Manag, 16(5), 555-568. https://doi.org/10.1002/ieam.4278

Vitale M., Leo C., Courty T., Kranjc N., Connolly J. B., Morselli G., Bamikole C., Haghighat-Khah R.E., Bernardini F., Fuchs, S. (2022) Comprehensive characterization of a transgene insertion in a highly repetitive, centromeric region of Anopheles mosquitoes. Path Glob Health. https://doi.org/10.1080/20477724.2022.2100192

Dear colleagues,

My name is Dr. Swantje Schroll and I work at the German Federal Office of Consumer Protection and Food Safety as a scientific officer in the office of the German Central Committee for Biological Safety (ZKBS, https://www.zkbs-online.de/ZKBS/EN/Home/home_node.html), where I have been responsible for risk assessment of Synthetic Biology for the last ten years (see also post #3105).
The development of engineered gene drives (EGD) to control vector-borne diseases and invasive species is, similar to self-limiting insects, not a new trend in biotechnology. The development of EGDs has been going on for several years and the CBD has been working on EGDs for some years already. As stated in post #3099, gaps and challenges for risk assessment of EGDs are already being addressed under the CBD by the Ad Hoc Technical Expert Group on Risk Assessment that is working on voluntary guidance materials on risk assessment of living modified organisms containing engineered gene drives. Additionally, EGD organisms are considered LMOs.

Best regards,
Swantje

I´m Carolina Torres from the NGO Island Conservation. Our mission is to prevent extinctions on islands by the removal of IAS. I just want to highlight and support comment #3098, made by Dan Tompkins. It is crucial to use all the tools available on a safety way if we want to meet the GBF goals. Regarding IAS removal, it is of high importance to identify and research for innovative solutions to tackle one of the main biodiversity drivers of extinction. At the same time, I support the comment #3099, #3113.

Thank you.

Carolina.

Dear CBD Secretariat, dear colleagues,

Many thanks to the Secretariat for moderating this valuable exchange. My name is Margret Engelhard, and I work at the German Federal Agency for Nature Conservation, where I head the Division Assessment Synthetic Biology and Enforcement Genetic Engineering Act. I’m a member of the current mAHTEG and have also in the previous Synthetic Biology AHTEGs.

Thank you very much for compiling issues brought up within the mAHTEG in the Issue Brief. Please bear with me for this message being rather long, as I have considered all of the points brought up in the facilitation and try in parts to refer directly to Issue Brief contents.

1. Impacts on the objectives of the Convention
a. Controlling invasive species & potential invasiveness of engineered gene drives:  It remains unclear for the specific application scenarios whether, and if so in what period, the anticipated phenotypic and/or ecosystem impacts of the release of gene drive LMOs would be attained, and which additional (potentially undesired) impacts might occur. Doubts have thus been raised as to the feasibility, effectiveness and adequateness of engineered gene drives for managing invasive species (Dolezel et al. 2019; Champer et al. 2021). At the same time, gene drive LMOs are themselves potentially invasive in wild populations (Noble et al. 2018) and experience with insects released for biological pest control has shown that they can become invasive particularly in non-native environments (Louda et al. 2003).
b. Normative classification of gene flow from LMO: Gene flow between an LMO and a wild or weedy relative has so far been considered an unintended consequence of LMO release which may result in adverse environmental effects (EFSA 2010; Ellstrand et al. 2013). In contrast, with gene drive LMOs, highly accelerated and possibly total and infinite spread of edited genes or novel traits within populations typically is a key feature of the application.
c. Elimination or suppression of non-target organisms due to gene flow: Suppression drives can have the potential to eradicate non-target species. If interspecific gene flow and hybridisation of gene drive LMOs with related species is possible, then effects on species other than the target species generally need to be considered (particularly if the gene drive target site or a similar sequence is present). For example, interspecific gene flow and hybridisation between different mosquito species within the genus Anopheles and the potential for adaptive gene flow within this genus across the African continent have been highlighted (Miles et al. 2016).
d. Elimination of an endogenous species: Elimination of (populations of) endogenous species is discussed for instance with regard to invasive non-native rodents on islands. Just as the rodents once got there, gene drive rodents could also inadvertently get off the islands, spread into the rodents’ original natural habitat and decimate a population there.
e. Off-target impacts within the host organism & reduction of genetic diversity: Evolutionary consequences for the targeted population can comprise decreased fitness, population declines and risk of extinction for a (meta)population or the whole species. Other effects may include depletion of genetic or phenotypic diversity, changes in the mating system of a species and changes in ecological interactions (David et al. 2013; Bull 2016).
f. Disruption of ecosystems (e.g., food webs) due to removal or suppression of a species from the environment: Suppression drive LMOs could impact food chains and whole ecosystems and their biodiversity, e.g. by the loss of prey and important food sources for higher trophic levels. Depending on the specific role of the species targeted by gene drives in a particular ecosystem, predators, prey species, competitors or even complex ecological functions may be negatively affected.

2. Timeframes: The timeline to environmental release that is set out in the Issue Brief relates to the technological development. On the societal level, the timeline is longer. Reasons include that (i) risk assessment, risk management and regulation are not yet in place; (ii) significant cultural and conceptual issues have not been addressed; and (iii) it is unclear how FPIC could be ensured.

3. Gaps or challenges for risk assessment, risk management and regulation
a. Potential emergence of unintended consequences: Arising from ecosystem complexity, there are fundamental constraints on possible predictions of the ecological impact of releasing LMOs (Tiedje et al. 1989; Snow et al. 2005). On the molecular level, unintended modifications can be analysed in the laboratory, but not where genetic modifications take place outside laboratories, as would be the case with synthetic gene drives (inheritance of functional elements, i. e. “labs in the field” (Simon et al. 2018)). Additional sources of unintended consequences are (i) regulatory mechanisms at genome level, (ii) the (often poorly understood) genetic diversity of wild organisms, (iii) physiological interactions and environmental influences at higher biological organisational levels (cell, tissue, organism, population, community of species), and (iv) interactions between the biota and the environment.
b. Need for effective risk assessment and monitoring: At present, recognised methods and strategies for risk assessment and monitoring of environmental impacts of wild LMO are generally missing, as they differ widely from those developed for crops (Otto et al. 2020). For gene drive LMOs in particular, it would be difficult to collect the requisite data, trial releases cannot be carried out safely, and retrievability cannot be expected. Data on the behaviour of gene drive constructs in nature are therefore based on theoretical modelling approaches. However, the use of models in risk assessment is challenging and associated with many uncertainties. Where biologically sound models of gene drives have been established, the results have in some cases been the opposite of what was expected (e.g. Champer et al. 2021). The European Food Safety Authority (EFSA) Panel on GMO holds that EFSA's guidelines would be adequate, but insufficient for the molecular characterisation, environmental risk assessment and post-market environmental monitoring of gene drive LMOs and identifies specific areas where further guidance is needed (EFSA GMO Panel 2020).
c. Lack of available risk management and containment measures & irreversibility of release: Implementing an experimental release – which is generally considered an important step towards assessing the potential environmental repercussions of LMOs – is much more difficult with wild LMOs than with crops, and especially so with  gene drive LMOs. Available risk mitigation measures are a necessary requirement before first field releases can be conducted (Oye et al 2014). However, experience with managing invasive species and with imported species for biological pest control shows that they cannot be expected to be retrievable. Initial experiences with releasing LMOs into wild populations confirm this: For Aedes aegypti mosquitos, genetic modifications became established in local populations contrary to the expectations and goals of the project (Evans et al. 2019; this is also discussed under Topic 2). For gene drive LMOs, there are theoretical considerations as to how they could be removed from a population, but it is completely unclear whether this would be realistic. Since it is questionable whether a geographical and time limit on trial releases with gene drive LMOs would be feasible, any experimental release would at present be tantamount to an unrestricted release.
d. Spatio-temporal scale of release & unintended persistence in the environment: Currently, it cannot be reliably estimated for concrete application scenarios of gene drives how long it would take until the gene drive would spread throughout the entire population. This makes it unclear for gene drive LMOs intended to eradicate a population how long they would remain in the population. However, the longer a gene drive remains in nature, the more likely it also becomes that unintended events and evolutionary changes will take place. Depending on the mode of action, so called pulse chase dynamics were observed in modelling gene drive applications. If such a mechanism is triggered by e.g. a suppression drive, timeframes of releases can be very long (theoretically infinite) (Champer et al. 2021).
e. Transboundary movements and the need for international cooperation: It is open how gene drive LMOs could be prevented from spreading over national borders (CBD/AHTEG 2019, Annex 1, 48). Art. 17 of the CPB only provides for notification and information obligations in the event of unintentional transboundary movements of LMOs. In order to ensure an adequate level of protection (cf. Art. 1 CPB), there would, however, be a need to create participation opportunities in the run-up to such a release where this involves the long-term, uncontrolled spread of LMOs (as particularly intended with gene drive LMOs), as well as to establish effective protective measures in order to prevent them impacting foreign territories.
f. Precautionary principle: As gene drive LMOs bear the potential for significant and irreversible environmental harm, and risk assessment and management of gene drive LMOs continue to be highly problematic, strict precautionary conditions are needed as recognised in COP 14 decision (14/19). The Norwegian Biotechnology Advisory Board recommended a moratorium on the use of gene drives until international regulations for handling and risk assessment are in place (Norwegian Biotechnology Advisory Board 2017, 17). The European Parliament has called for a moratorium on gene drives at CBD level (European Parliament 2020, item 13), and has repeatedly confirmed that it should not be permissible to release genetically modified gene drives (European Parliament 2021a, item 148; European Parliament 2021b, item 32).

4. Potential social, economic, cultural, ethical, political, human health and/other relevant impacts of this trend and issue.
a. Ethics related to human intervention in nature:
i. Not only (i) potential consequences, but also (ii) underlying goals of interventions and (iii) characteristics of the technologies employed are subject to normative evaluation.
ii. A practice of higher-risk release of LMOs would place supraordinate goals and principles of nature conservation in question (including the precautionary principle) (Sandler 2019).
iii. Gene drive LMOs are deep interventions in nature’s unique character and in future dynamic development of natural processes, and thereby in conflict with the value of biodiversity in its own right. This value emerges from organisms’ intrinsic value, in their networks with the ecological systems and is stressed in Recital 1 of the Preamble of the CBD, and also, for example in the German Federal Nature Conservation Act. The intrinsic value adds to the prudential arguments of protecting nature’s intrinsic dynamic processes in humanity’s own interest.
iv. Although there may not be any completely pristine nature, there is are still pristine aspects of nature worthy of protection. Also, an extensive loss of pristine nature does not mean that the best strategy is to intervene even more profoundly (cf. Sandler 2017), this would be an “Anthropocene fallacy” (Toepfer 2020).
b. Justice: Gene drive LMOs could impact many people who have not chosen to deploy them. “The full context of gene drive development and deployment will need to be scrutinized for justice-based concerns [...]. This includes considerations such as: who has the power to shape the technological development; who decides about its deployment; whose stories are being heard in decision-making processes; whose history is being taken into account; which generations and species count in the assessments; who profits from any potential successes; and who bears the burdens of any failure.” (Preston and Wickson in CSS et al. 2019: 224).
c. Public outreach, engagement, inclusion and FPIC; potential changes to traditional methods and communities managing biological resources:
i. The far-reaching ecological and conceptual challenges associated with gene drive LMOs warrant particular attention to exchange of knowledge and evaluation across cultures, based on participatory approaches, in order to promote transparency and legitimacy with regard to framing (e. g., validity of assumptions about biodiversity in the view of local communities), the choice of topics, as well as procedures of organisation, facilitation and communication of assessment processes.
ii. An ongoing project commissioned by BfN and conducted by ETC Group (see CBD/SYNBIO/AHTEG/2023/1/INF/2, item 82) has specifically sought exchange on gene drive applications with grassroots communities. One result is that because technological interventions have in the past shown a potential to interfere negatively with local food production systems, suggestions for biotechnological interventions did not elicit positive interest and would not be supported uncritically. With regard to guidelines for participation, the project demonstrated the need for ongoing and iterative communication processes.
iii. FPIC is a requirement under the Helsinki Declaration in the case of medical research applications, e. g., in the case of LMOs to reduce disease transmission (Macer 2005, Resnik 2012).
iv. FPIC for gene drive LMOs has been discussed in scientific and CBD contexts (cf. George et al. 2019). In establishing guidelines for FPIC and for the exchange of knowledge and evaluation across cultures more generally, care must be taken to ensure that power imbalances do not invalidate the processes, and that procedures of organisation, facilitation and communication are valid.
v. “Genuine empowerment of all affected parties [...] must not be conducted with the premise that the technology will be accepted and that it only needs some small modification and technical changes to achieve that goal” (Lebrecht et al. in CSS et al. 2019: 200).
d. Transparency in research, development and decision-making:
i. The importance of transparency is widely acknowledged, but the implementation is more problematic, which leads to unresolved matters both in risk assessment and for the societal discourse (Boete 2018, see also #3080 by Guy Reeves).
ii. Guiding principles for sponsors of research (e. g., Emerson et al. 2017) are helpful and need to be complemented by mechanisms of accountability (cf. CSS et al. 2019: 161 ff.).
iii. An international register would help ensure transparency.

5. Problems addressed / alternatives:
a. Framing of problems: The way problems are framed and tackled is a subject of democratic discourse. Perspectives of technological development need to be contrasted with other societal perspectives.
b. Consideration of alternative interventions: Gene drive applications are developed to address a range of important problems, all of which have underlying causes at societal levels. Exaggerating effectiveness of technological solutions can lead to opportunity costs when alternative solutions are neglected, and it can close down public debate about the best ways of developing salient knowledge collectively in order to tackle societal problems (CSS et al. 2019: 200). A dynamic that puts off tackling the causes whilst hoping for technical solutions is problematic for nature conservation and climate change mitigation (cf. McLaren and Markusson 2020).

6. Lessons to be learned:
a. Lessons for the management of gene drive LMOs could be learned from other domains in which there is poor retrievability, for example nanotechnology, but also the control of invasive alien species, as some types of gene drive LMOs are likely to become invasive if released (Noble et al. 2018). The recently published Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services report on Invasive Alien Species (IPBES 2023) was recognised at the SBSTTA 25 and provides a point of reference in this regard.
b. The use of other technologies has repeatedly demonstrated that it is not easy to apply technical solutions in the complex system that is nature, and that such solutions may have unexpected detrimental effects (European Environment Agency 2001, 2013).

7. Limits of knowledge, other considerations:
a. Complexity of ecological systems & predictability of impacts: It is not currently possible to estimate the scale of the ultimate risk that would be run were gene drive LMOs to be used in any specific manner. Uncertainties and knowledge gaps of basic biological parameters may result in highly speculative risk estimations. Our knowledge on the biology, ecology, genome-environment interactions, ecosystem role and function of wild species in natural environments is incomplete, as it is for general ecosystem functioning and community dynamics. For example, in the case of gene drive applications targeting weed species, polygenic resistance mechanisms are not yet fully understood (Neve 2018). The long-distance dispersal ability of mosquitoes high above ground was discovered late (Lehmann et al. 2018). Experience with pest eradication programs such as the New World screwworm fly has shown that knowledge on the ecological impact of pest species as well as of their eradication is limited and more ecological knowledge is required before and after population suppression programs (Scott et al. 2018). On a more general note, the use of technology in increasingly complex systems magnifies the effects of missing data and insufficient knowledge about possible impacts (Gleich 2013). Releasing functional elements of a genetic modification, as would be the case with gene drive LMOs, would exacerbate this effect further and make it virtually impossible to reliably model and predict impacts, both desired and undesired.
b. Existing and ongoing multidisciplinary and assessments as resources: As detailed in my response to Points 1, 3 and 4 above, it has been widely acknowledged that gene drive LMOs, if released in the wild, would pose very significant risks to the environment and also raise a number of cultural, conceptual and legal issues. A range of institutions and research groups have recognised that an assessment needs to be multidisciplinary and have analysed the issues deeply (e. g., NASEM 2016; AAS 2017; CSS et al. 2019; Gleich and Schröder 2020; the Office of Technology Assessment at the German Bundestag TAB is in the process of finalising a comprehensive study (https://www.tab-beim-bundestag.de/english/projects_gene-drives-technologies-for-propagating-genetic-modifications-throughout-populations.php)). When a topic – although still new – has already elicited intensive multidisciplinary analysis in institutions specialised in the assessment of emerging technologies, these existing assessments can be valuable resources for assessment at CBD level.

Dear Colleagues and CBD Secretariat,
My name is Ronit Justo-Hanani, and I am assistant professor at the Steinhardt Museum of Natural History and the Department of Public Policy at Tel Aviv university. I am an expert in risk regulation and policies on environmental, health and safety risks. My background include law, biology, politics and public policy. I am a member in the mAHTEG.
I would like to draw your attention to the regulation of invasive species in the European Union (Regulation (EU) 1143/2014), many parts of which can be used as a model for the case of gene drive LMOs. This regulation provides for a cross-border ‘three-stage hierarchy’ of risk management: prevention, early detection, and long-term control, in line with Article 8(h) of the CBD.
In the context of potential invasiveness of engineered gene drives, it is especially important to develop the following three regulatory issues:
1. Dedicated legal instrument for regional/international cooperation;
2. Early detection and rapid response: the development of a framework for risk assessment and regional/international-wide information and early warning system are fundamental to effective action before invasions take hold, consistent with the precautionary principle.
3. A list of species of regional concern, based on coordinated risk assessment framework. The decision to include a gene drive LMO in this list is based on the assessment of potential adverse effect across relevant countries and/or regions. 
For the purpose of understanding the regulatory model for invasive species and comparison with our case of engineered gene-drives, see:
R. Justo-Hanani, and T. Dayan. 2021. Risk regulation and precaution in Europe and the United States: The case of bioinvasion. Policy Sciences 54 (1): 3-20
R. Justo-Hanani, and T. Dayan. 2020. Environmental policy expansion in the EU: The intriguing case of bioinvasion regulation. Journal of Environmental Policy & Planning 22 (3): 315-327

Regarding the use of Evans et al. 2019 as reference for the establishment of genetic modifications as results of the use of LMOs, it should noted that the title of that publication is completely misleading and cannot be used as scientific reference for this.
While there is nothing wrong with the data presented in this publication, the title is misleading and the interpretations and speculations are farfetched and not supported by the data.

In this study they analyzed the local population at a time there was still release going on and they actively disregarded transgenitically marked individuals, as they could have been released ones.
Therefore, the study only shows that you get introgression of parts of the released genome into the genome of the local population at least during the time of release, which is an obvious thing, when the released individuals are not 100% sterile. This however has nothing to do with the released individuals being trangenic or not. This does also happen in any classical SIT approach without transgenes in them. Therefore the actual data of that manuscript show a scientific triviality and putting the word "transgenic" into the title is maybe catchy but completely misleading, as it has nothing to do with the released insects being transgenic or not.

What would actually have been interesting, is a similar study but about two years after the stop of the release and then really analyze whether the transgenes stayed in the population or what of the introduced genomic parts were kept, or whether all this would be elimited over time and the population would mostly go back to its original composition. In case introduced genomic parts would stay, it would be interesting to see what are the genes that are kept and then potentially identify the reasons for that.

This would be an insightful story. The data published in Evans et al. 2019 are a scientific triviality with a misleading title and farfetched speculations. This is the reason why actually an official co-author of the paper is vehemently pointing out the shortcomings and misleading character of this paper!

Best regards,
Ernst Wimmer
Professor for Developmental Biology at the Georg-August-University Göttingen, Germany.
My research includes applied approaches in insect biotechnology to establish modern genetic pest management methods.
For the Open-ended Online Forum , I was nominated by the German Federal Ministry of Education and Research.

The dark side of Development of engineered gene drives to control vector-borne diseases and invasive species
The development of engineered gene drives for the control of vector-borne diseases and invasive species is a field that holds great promise but also raises significant ethical, ecological, and social concerns. While the potential benefits are substantial, it's crucial to acknowledge and address the dark side of this technology.
Ecological Risks: Engineered gene drives have the power to spread genetic modifications rapidly through populations, which could result in unintended consequences for ecosystems. Targeting a specific species might inadvertently affect other non-target organisms, disrupting ecological balance and biodiversity.
Unintended Consequences: The complexity of ecosystems makes predicting the long-term effects of gene drives challenging. Genetic modifications intended to control a particular species may lead to unexpected outcomes, such as the emergence of resistant populations or the evolution of new, potentially more harmful traits.
Ethical Concerns: The deliberate alteration of entire populations raises ethical questions about playing with the fundamental building blocks of life. Questions of consent, especially in the case of organisms that interact with human habitats, are crucial. The potential for unintended harm to non-target species and ecosystems also raises ethical issues.
Social and Cultural Implications: The deployment of gene drives can have profound social and cultural implications. Local communities, especially those in regions targeted for gene drive interventions, may have diverse perspectives on the acceptability and desirability of such technology. Informed and inclusive decision-making processes are essential to address these concerns.
Potential for Misuse: The powerful nature of gene drives raises the specter of intentional misuse. In the wrong hands, this technology could be used for bioterrorism or to create ecological imbalances for strategic or economic purposes. Establishing robust regulatory frameworks to prevent misuse is crucial.
Lack of International Governance: Given the global nature of ecosystems and the potential for gene drives to cross borders, there is a lack of comprehensive international governance and regulatory frameworks. Coordinated efforts are necessary to ensure responsible research, development, and deployment of gene drives on a global scale.
Erosion of Genetic Diversity: The widespread use of gene drives could lead to a reduction in genetic diversity within target populations. This reduction may decrease the resilience of these populations to environmental changes and increase their vulnerability to diseases and other threats.
Unknown Long-Term Effects: The long-term effects of releasing engineered gene drives into the environment are largely unknown. Once released, it may be challenging to recall or reverse these genetic modifications if unforeseen issues arise, emphasizing the need for caution and thorough risk assessment.
In conclusion, while the development of engineered gene drives holds great potential for addressing pressing issues such as vector-borne diseases and invasive species, it is essential to approach this technology with careful consideration of its potential risks and ethical implications. Robust regulatory frameworks, transparency in research, and inclusive public engagement are crucial for ensuring the responsible development and deployment of gene drives.

Dear Colleagues

My name is Dan Tompkins, and I am the Science Director for Predator Free 2050 Limited, helping to drive New Zealand’s mission to eradicate invasive species impacting biodiversity from the country.

My apologies for joining this discussion late – as already noted elsewhere, reminders would have been useful!

I would like to raise the longstanding problem of the conflation of the issues at hand with multiple other broad considerations, some of which are already well resolved while others already have their own far more fit-for-purpose processes in place. This ongoing conflation continues to bloat the considerations in question out to an unresolvable scale, effectively preventing progress on them.

For example, the concern that invasive species removal may have negative ecological or ecosystem consequences has nothing to do with the approach employed but is part of the management consideration to carry out the removal (irrespective of the approach used). And that boat – the decision to remove invasive species for large proven net conservation benefits – has long sailed.

Those of us who are working to address global conservation issues urgently need progression of this topic through an objective and focused assessment of the technology at hand – we need to know how the specific potential (both benefits and risks) of synthetic biology weighs up against other tools to inform our research and operational decision making for already justified conservation management actions.

Thank you for your consideration.

Dear Colleagues,
My name is Brinda Dass and I am a Senior Policy Expert at The Foundation for the National Institutes of Health in USA. I have been a member of the AHTEG on Risk Assessment in 2020 and 2023 and have been following the interest in engineered gene drive containing organisms in the synthetic biology space. Thank you for the opportunity to comment. My responses are as follows-

1. Review the potential positive and negative impacts of this trend and issue in synthetic biology on each of the three objectives of the Convention.
Managing invasive or non-native species at a population level has the potential to return balance to ecosystems. This is more critical for rewilding programs that could be positively impacted via the use of engineered gene drive organisms (EGDOs) especially in the case of rodents. The proposed EGDO methods would also reduce the reliance on rodenticides and current chemical methods for removing rodents. The drive aspect could be a positive in terms of decreasing human interference and footprint on fragile island ecosystems. Engineered gene drive mosquitoes if developed for management of Avian malaria burden would provide a major boost to songbird conservation in Hawaii. This would also have implications for climate change induced impacts on those ecosystems. The strongest use case made so far has been to propose engineered gene drive mosquitoes for malaria control. Other positive impacts from this have been enumerated in the policy brief provided to the Online Forum.
In terms of benefit sharing, LM and EGD mosquito projects to date has been using various models of co-development and information gathering/sharing that are housed within the local communities (Malar J. 2021 April; 20: 204. doi: 10.1186/s12936-021-03736-9). Local communities have knowledge and insight of mosquito breeding sites, changes in their behavior, seasonal impacts on mosquito breeding and behavior and are key partners in monitoring changes in mosquito populations and disease burden. Capacity building initiatives related to vector control are being tailored for local communities as well as women (e.g., https://pamca.org/en/projects/view/2/enhancing-women%E2%80%99s-role-in-the-control-of-vector-borne-diseases )

2. What is the timeframe for release or potential impact of engineered gene drives to control vector-borne diseases and invasive species? Please provide examples of specific applications (e.g., molecular mechanism, target species, intent of application).
5-10 years would be an optimistic timeframe given that some target species are less tractable to engineering (e.g., t-haplotype in rodents) and contained studies require larger laboratory or field cage footprint to allow sufficient numbers of organisms to be studied. EGD rodents would be intended for population suppression possibly by skewing the sex ratio. Safety and efficacy data would be needed from contained use, baseline environmental data would be required at the proposed use sites, risk assessments and applicable national legal requirements such as ESHIA would need to be completed at minimum.

3. What are the potential gaps or challenges for risk assessment, risk management and regulation for this topic in synthetic biology? Evaluate the availability of tools to detect, identify and monitor the organisms, components and products of synthetic biology.
To avoid unnecessary duplication of efforts this forum may wish to take note that gaps and challenges for risk assessment of EGDOs are being discussed and addressed by the CBD currently with an Ad Hoc Technical Expert Group working to provide guidelines for risk assessment of engineered gene drive organisms more specifically mosquitoes (https://www.cbd.int/meetings/CP-RA-AHTEG-2023-01) and this will include information on identifying and monitoring the released mosquitoes and their progeny in the release area. Additionally, there is information from the African Union Development Agency tailored to risk assessment of EGD mosquitos at https://www.nepad.org/publication/guidelines-risk-analysis-testing-and-deployment-of-genetically-modified and monitoring of the same at https://www.nepad.org/node/17165 . AUDA is also working with West African countries to build a regional platform that would streamline testing of EGD mosquitoes and potentially address data sharing and transboundary issues.
This forum may also want to note that Biosafety Technical Series 05: Training Manual on the Detection and Identification of Living Modified Organisms in the Context of the Cartagena Protocol on Biosafety (https://bch.cbd.int/api/v2013/documents/09E586CA-105F-65C5-4C8E-0D019A06E17A/attachments/611877/CBD-BioSafetyTechSeries05-TrainingManual-f-web.pdf ) is available via the Biosafety Clearing House. Online discussions related to the Network of Laboratories for the Detection and Identification of LMOs from 17-24 November 2023 will cover topics related to detection and identification of LMOs, new techniques, experience and capacity building all of which could be relevant to the discussions of the synbio mAHTEG as well.

4. Review the potential social, economic, cultural, ethical, political, human health and/other relevant impacts of this trend and issue. What are the relevant considerations for IPLCs, women and youth?
Improving human and animal health by decreasing vector borne disease will have long term impacts on women and children especially in the case of malaria which is a leading cause of death for infants 5 years or younger in Sub-Saharan Africa. There are a few programs that specifically focus on training women in vector control such as the Pan African Mosquito Control’s Women In Vector Control Program (https://www.pamca.org/en/projects/view/2/enhancing-women%E2%80%99s-role-in-the-control-of-vector-borne-diseases ). These efforts could have far reaching impacts on several Sustainable Development Goals including 1,3,5, and 10

5. Is the trend and issue attempting to address specific problems, and if so, what are these problems and their underlying causes? How else could these problems or causes be addressed?
EGD mosquitoes for vector control to impact human and animal health (malaria, Dengue, Avian malaria etc.) are all trying to address disease burden as well as spread of invasive species due to climate change impact on vector species range. Malaria continues to be a major cause of death and a stressor of public health systems especially in Sub Saharan Africa which accounts for ~95% of all cases and ~96% of deaths in 2021. The World Health Organizing is stressing the use of existing tools for prevention, diagnosis and treatment including vaccine, insecticides, lures, treated bed nets, source management, and antimalarial drugs. However, there is also a push to innovate with many new products in research and development including new targeted baits, eave tubes, and genetically modified mosquitoes including those with engineered gene drives (https://www.who.int/news/item/25-04-2023-who-urges-increased-implementation-of-recommended-tools-to-combat-malaria ). The COVID pandemic has impacted the distribution of existing tools causing malaria cases to rise in the last 2 years reversing previous gains in disease reduction. Insecticide resistance in mosquitoes and ecosystem impact of widespread use of insecticides and larvicides are some other considerations for the use and effectiveness of current methods and tools. Continued use of existing vector management tools and introduction of safe and effective new tools would allow for greater impact on driving down vector borne diseases.

6. What lessons can be learned of similar tools, techniques or applications in other domains? How might those lessons from elsewhere be relevant or shed insight in assessing this topic in the context of the aims of the Convention on Biological Diversity?
In the context of biodiversity, risk assessment and release of organisms into the environment one could look at classical biocontrol (Kaufman LV, Wright MG. Assessing Probabilistic Risk Assessment Approaches for Insect Biological Control Introductions. Insects. 2017 Jul 7;8(3):67. doi: 10.3390/insects8030067; Risk Analysis Frameworks Used in Biological Control and Introduction of a Novel Bayesian Network Tool Nicolas Meurisse, Bruce G. Marcot, Owen Woodberry, Barbara I. P. Barratt, Jacqui H. Todd Risk Analysis. August 2021 https://doi.org/10.1111/risa.13812 ), sterile insect technique (Oliva CF, Benedict MQ, Collins CM, Baldet T, Bellini R, Bossin H, Bouyer J, Corbel V, Facchinelli L, Fouque F, Geier M, Michaelakis A, Roiz D, Simard F, Tur C, Gouagna LC. Sterile Insect Technique (SIT) against Aedes Species Mosquitoes: A Roadmap and Good Practice Framework for Designing, Implementing and Evaluating Pilot Field Trials. Insects. 2021 Feb 24;12(3):191. doi: 10.3390/insects12030191 ; https://www.who.int/news/item/16-05-2023-scientists-in-tahiti-prepare-to-release-sterilized-mosquitoes-to-control-dengue; https://www.iaea.org/topics/sterile-insect-technique ) as well as existing LM mosquito testing in the US (Notice of availability of Draft Environmental Assessment and Preliminary Finding of No Significant Impact Concerning Investigational Use of Oxitec OX513A Mosquitoes Mar 2016. https://www.regulations.gov/document/FDA-2014-N-2235-0001, US Environmental Protection Agency, Approves Experimental Use Permit. May 1, 2020. https://www.epa.gov/pesticides/epa-approves-experimental-use-permit-test-innovative-biopesticide-tool-better-protect , US Environmental Protection Agency, EUP Letter of Issuance https://www.regulations.gov/document/EPA-HQ-OPP-2019-0274-0353 ) and Brazil and commercial availability in Brazil for Oxitec’s “Friendly Aedes” (https://www.aedesdobem.com.br/)

Hello everyone. I am Reynante L. Ordonio. I am a career scientist from the Philippine Rice Research Institute (PhilRice) working on GMOs (e.g., Golden Rice, High Iron and Zinc Rice) deregulation and deployment and I also helped in crafting the Philippines’ policy on New Plant Breeding Techniques (e.g., gene editing). Apologies for entering the discussion late. I would just like to give my opinion about the possible use of gene drive mosquitoes in the Philippines, and this may ring true for other countries as well. The Philippines still has the problem on malaria especially in the beautiful island of Palawan. So for me, it seems very attractive to use gene drive mosquitoes for obvious health-related benefits. However, the island of Palawan is also known for its vast biodiversity that can potentially be affected by the loss of the mosquito population. This, and the fact that one of the objectives of the CBD is conservation of biodiversity, leads me to think that the Wolbachia-carrying mosquitoes of the World Mosquito Program is better aligned with the said objective of the CBD. Also, in the Philippines also there is active opposition against GMO crops and I believe that there will be even more opposition on gene drive mosquitoes being planned for environmental release.
Thank you for this opportunity to share my opinion.

Dear colleagues, I’m Luke Alphey, Professor of Genetics at the University of York, UK. I have >20 years experience developing synbio insects.

Reynante Ordonio (#3100) raises an important distinction. This is between (i) population suppression – aiming to reduce the numerical size of the target population, perhaps to zero and (ii) population modification – aiming to change one or more traits of individuals in the target population without substantial change to the numerical size. The argument presented in #3100 is that population modification may be more appropriate in a particular instance in the Philippines. Indeed, for species that simultaneously (i) cause harm, e.g. pathogen transmission and (ii) some benefit, e.g. native species forming key elements of a complex ecosystem, this may well be the case. In other cases, perhaps a recently arrived invasive population, suppression may be preferred. Engineered gene drives can potentially be designed to provide either outcome – compare, for example, the population-suppression approaches of Target Malaria (https://targetmalaria.org/) with the population-modification approach of the University of California Malaria Initiative (https://stopmalaria.org/). One might hope that in the future each of these approaches, and more, will be available to communities to choose which is most appropriate for their particular problem.

Dear colleagues, I’m Kathleen Lehmann, policy officer at the European Commission, Directorate-General of Health and Food Safety, biotech unit. I’m a biochemist by training. In the Commission I’m taking care of questions in synthetic biology and genetically modified (GM) microorganisms primarily in industrial biotech and pharmaceutical uses. I’ve several years experience with the risk assessment of GM microorganisms in contained use and the environmental risk assessment for the market authorisation of GM medicines. I’m a member of the mAHTEG.

I've a bit of a longer reply trying to go through most of the questions raised.

On question 1:
An overview of potential effects of the environmental release of gene drive modified insects can be found in Devos et al. 2022 doi:10.1080/07388551.2021.1933891

• In comparison to broad-scale alternative applications like use of pesticides or poisoned bait, any gene drive with a high target specificity would have a positive impact on the conservation of biodiversity. On the other hand, if horizontal gene transfer/spill-over of the gene drive into non-target species occurs, biodiversity may be negatively affected.

• vector control applications:
As relates to the objectives of the Convention potential negative impacts could arise in relation to biodiversity if an insect population collapses or is significantly diminished in response to the use of a suppression gene drive. In this case also other species could be negatively affected through ecosystem interactions, for example changes in the food web. Additionally, other species might fill the vacant ecological niche, which might also impact ecosystems. Such effects need to be addressed in an appropriate environmental risk assessment.
Potential positive impacts do not relate to the objectives of the Convention and are addressed under question 4.

• applications controlling invasive species:
These applications may have both potential positive and potential negative impacts on biodiversity. As their intended goal such gene drives aim to uphold the natural biodiversity in threatened ecosystems by eradicating an exotic species, for example certain rodent species in island ecosystems, thereby reducing pressure on endemic, endangered species and protecting the local ecosystem. On the other hand, the unintended spread of the gene drive organism to areas where the targeted species is endemic may negatively impact the biodiversity in these areas. The extent of this effect would depend on the frequency of the spill-over (i.e. how many individuals carrying the functional gene drive would move from the target area to an outside area per given time period) and the molecular design of the gene drive.

On question 3:
The topic of risk assessment of gene drive modified insects is currently addressed in another AHTEG. In the context of the associated open-ended online forum my colleague Yann Devos from the European Food Safety Authority (EFSA) posted the following (shortened). Similar considerations will be applicable to non-insect species modified with gene drives.

“International/regional entities (such as NASEM, 2016; AHTEG 2020; EFSA GMO Panel, 2020; WHO, 2021, 2022) concluded that: (1) the risk assessment of gene drive modified insects (GDMIs) can build on existing risk assessment frameworks for genetically modified insects that do not contain an engineered gene drive; and (2) can be informed by experience releasing insects for biological and genetic disease vector/pest control. It is, however, recognised that there are specific areas where further guidance may be needed for the risk assessment of environmental releases of some GDMIs to ensure appropriate levels of safety. These include cross-cutting considerations pertaining to receiving environments, comparators, experimental design and statistics, long-term effects and modelling, and specific areas of risk such as persistence and invasiveness, vertical gene flow, pathogens, infections and diseases, interactions with target organisms, post-market environmental monitoring, and some molecular characterisation related aspects.
Several publications (such as Roberts et al., 2017; Teem et al., 2019; Devos et al., 2020, 2021; EFSA GMO Panel, 2020; Romeis et al., 2020; Connolly et al., 2021) have demonstrated that problem formulation (the initial risk assessment step) offers a fit-for-purpose and scientifically robust framework for case-specific risk assessment of GDMI environmental releases. The stepwise approach followed in the problem formulation facilitates the systematic identification of potential harms and associated uncertainty, as well as their routes of exposure, while being transparent about the assumptions made during the process. Overall, the problem formulation approach provides a compelling framework to organise existing knowledge and identify relevant new knowledge and uncertainties on GDMIs to support case-specific risk assessments and decision-making.
While problem formulation is conceptually straightforward, its implementation is often hindered by an absence of clear policy goals and regulatory decision-making criteria on what constitutes harm (e.g. setting of specific/operational protection goals, limits or thresholds of concern, trigger values for action or acceptance of risk, judgments on sufficiency of scientific knowledge and agreement on the extent any uncertainty should be reduced for regulatory decision-making) that are needed to guide interpretation of scientific information in risk assessment. Even in jurisdictions with well-developed regulatory systems, such criteria are often general, requiring refinement for operational use. If what constitutes harm is not clearly defined, risk assessors have no effective way to decide whether particular potential effects of an environmental release of a GDMI are relevant to risk assessment. While causal pathways to harm have a scientific rationale, the definition of harm is subjective and rooted in societal values. Perhaps additional voluntary guidance materials could explore such aspects and give recommendations on how to best address them.
Furthermore, risk assessment for environmental releases of some GDMIs is expected to require greater reliance on (pre-release) modelling and (post-release) monitoring to address uncertainty, compared with genetically modified insects that do not contain an engineered gene drive or other self-limiting genetic control approaches. Improving the integration of modelling and monitoring through a more dynamic, iterative interplay between risk assessment and risk management would reduce risk uncertainty associated with the environmental release of some GDMIs. However, for this approach to be more or fully effective, both modelling and monitoring capabilities would need to be enhanced further.”

On question 4:
• Gene drives may give rise to particular concerns on social justice and legitimacy. Among those questions could be who decides which community would have access to a gene drive application, what would be a legitimate purpose, whose social/ethical values should determine the use or not use of gene drives, who decides what are acceptable risks in view of uncertain benefits, etc. These and similar aspects have been raised by the European Group on Ethics in Science and New Technologies
• For all gene drive applications that have at least the theoretical potential to spread beyond the initial release site it will be difficult to define whose consent for a release will be necessary.

• For vector control applications:
- In case of successful limitation or elimination of the spread of a pathogen,
    a) reduction in cases of and deaths caused by vector-borne diseases (particularly in disproportionately affected children);
    b) decreased health care costs and costs for other mitigation measures;
    c) decreased loss of economic output due to illness and death;
    d) increased economic security in affected communities;
    e) area wide effect ensures protection independent of individuals’ characteristics such as wealth or education
- The decision to use or not use the application may or may not be based on a democratic process but will always affect all individuals of a community; an opt-out of individual members of the community will not be possible; this may challenge the concept of individual consent in health-related questions. However, this is also true for other vector control methods like use of insecticides.
  - Changes in the behaviour, density or distribution of the vector or interacting species may result in increased disease burden if new vectors are established or the properties or behaviour of pathogens change.

• For applications controlling invasive species:
  - In case of successful eradication,
    a) protection of culturally important environments;
    b) protection of environment-based economic sectors like agriculture, tourism
  - It may be difficult to justify using or not using gene drive applications in certain environments and to define who should be involved in the decision.

On question 5:
• For vector control applications:
Intends to reduce or disrupt transmission of pathogens with relevance for human health;
Direct alternatives are the use of bed nets, insecticides, sterile insect technology, Wolbachia-mediated techniques.
Indirect alternatives to mitigate the impact are the development and use of drugs and vaccines.

• For applications controlling invasive species:
Intends to protect endemic species from extinction;
Alternatives are the use of traps, toxic baits, hunting/fishing, transmissible pathogens. A gene drive can be expected to be more targeted than most of the alternatives.

Best,
Kathleen

Dear Colleagues,
My name is Silke Fuchs and I am a Regulatory Scientist for Target Malaria at Imperial College London, working on genetic technologies in mosquitoes (including gene drives) to reduce malaria transmission.
I have been following the comments with great interest. I would like to address some of the issues that were raised in the discussion and are part of the issue brief.

1. Potential positive and negative impacts on each of the three objectives of the Convention 
There are many different types of gene drive constructs being considered or currently under development to control pests, including invasive rodents and insect pests in global health, conservation, and agriculture (Redford et al., 2019). Given the potential different uses and contexts of gene drives (e.g. suppression, replacement, low threshold, high threshold drive), impacts may differ and risks and benefits associated with each gene drive approach will primarily depend on the objective targeted, the type of modification made, the species it is applied to, and the ecosystem and geography where the organism with the drive system will be used, rather than on the gene drive mechanism itself. 

The gene drive risk assessments must be therefore grounded in science and evidence-based and consistent with the principle of case-by-case assessment, in keeping with the Cartagena protocol on biosafety to the CBD, which in its preamble reaffirms the precautionary principle (Principle 15) of the Rio Declaration on Environment and Development (A/CONF.151/26/Vol.I: Rio Declaration on Environment and Development (un.org)).

The International Union for Conservation of Nature (IUCN) provides a comprehensive list of the risks and benefits associated with gene drives based on eight case studies that represent a diversity of applications (Redford et al., 2019). They present a) issues directly related to conservation goals  (e.g. eradicating invasive rodents from islands, controlling invasive mosquitoes to prevent bird extinctions in Hawaii, transgenic American chestnut for potential forest restoration) and b) issues not directed at achieving conservation goals but are designed for other objectives but which might have secondary impacts on conservation (e.g. agriculture, human health such as Gene drive approach for malaria control in Africa, product replacement such as Horseshoe crab replacement for Limulus Amebocyte Lysate test).

Potential positive and negative impacts of some of the gene drive approaches on the 3 objectives of the CBD are listed below:

Objective 1: Conservation of biological diversity
Pos. impact: 
Gene drives have the potential to contribute to biodiversity by for example reducing the use in the environment of pesticides and rodenticides, which can be problematic to conservation goals given (1) emergence and spread of resistance to chemical insecticides in many parts of the world (2) extensive use of synthetic pesticides could pose health risks to humans and animals; in addition to acute toxicity concerns, such as chemical residue accumulations in the food web leading to impacts on non-target organisms (3) difficulty of targeting some pest species that have cryptic behaviours and habitats or protective coating over their bodies, or wide host range, making it difficult to target and control effectively (4) the high cost of pesticides and the limited use of personal protective equipment (PPE) in LMICs. 
Gene drives can also be used to control invasive species that are damaging to endemic and beneficial species and ecosystem services and I fully support the post made by Dan Tompkins  (#3098). 
They also provide a useful complement to other approaches to important public goals because of their anticipated lower cost (for example, because of inherent potential spread and persistence of low threshold gene drive without the need for human intervention or changes in behaviour). In that sense, they share many similarities with classical biocontrol agents (also mentioned by Dr Brinda Dass in #3099), which have been used extensively and successfully in the field in many countries around the world, but only after rigorous pre-release ERA has been conducted. Gene drive constructs can be designed to be species-specific or even population-specific (e.g. using private alleles) in their direct effect compared with the impact of broad-spectrum chemical use in the environment. 

Neg. impact:
Gene drives can make changes to the natural environment and may impact ecosystem dynamics. Those impacts depend on the nature of the application (e.g. replacement vs. suppression), the role of the target organism in the ecosystem and the spatial spread and temporal persistence of the specific driving genetic element though. 

However, impacts on ecosystems are not limited to Gene Drives. There are many activities that make changes to the natural environment (such as conventional removal of invasive species or biocontrol organisms, establishing a nature reserve, road constructions, building a hydroelectric dam etc). I would also like to reiterate Ben Durhams point (#3072) that biodiversity is continually evolving and changing. Further, the definition of conservation entities in the context of genomics is evolving too at subspecific and species complex levels rather than the anthropomorphic construct of “species” as a definitive conservation unit (Connolly et al., 2023; Coates et al. 2018, Cook et al., 2023). 
Ecosystems are complex and dynamic, and the consequences of interventions are difficult to measure and evaluate.  Uncertainty is a common challenge in decision-making, and there are frameworks to account for this (e.g. Santos et al., 2020; NASEM 2016). Moreover, as stated in Annex III paragraph 4 of the Cartagena Protocol on Biosafety to the Convention on Biological Diversity, "lack of scientific knowledge or scientific consensus should not necessarily be interpreted as indicating a particular level of risk, an absence of risk, or an acceptable risk" and paragraph 8(f) "Where there is uncertainty regarding the level of risk, it may be addressed by requesting further information on specific issues of concern or by implementing appropriate risk management strategies and/or monitoring the living modified organism in the receiving environment.”
Risk assessments allow us to systematically identify potential harms and characterize their likelihood (quantitative/qualitative) as well as routes of exposure which form the basis for plausible risk hypotheses and subsequent analysis plans. There are already examples of systematic identification of plausible pathways of harms for population suppression gene drives against agricultural pest Drosophila suzukii (Romeis et al., 2020) and malaria vector Anopheles gambiae (David et al., 2013, Teem et al., 2019, Connolly et al., 2021) that have been published. 

Experiences with other pest control measures can also be helpful for risk assessment, such as other LMOs or non LMO insects released as part of biocontrol initiatives. Examples include the release of genetically modified Aedes aegypti by Oxitec in Florida and Brazil as well as the release of Wolbachia-infected Aedes aegypti mosquitoes (a primary dengue vector) in Australia and Indonesia. The results of the risks analysis conducted to evaluate the hazards associated with the releases are published (EPA, 2020, Buchori et al., 2022; Murray et al., 2016). Additonal examples have also been mentioned in the previous post by Dr Brinda Dass (#3099).

Objective 2: Sustainable use of its components
Pos. impact:
Due to their potential to spread and persist, gene drives may provide a long- term wide-spread use against agricultural pests, invasive species and disease vectors. Further, as mentioned in Objective 1 under positive impacts, they can contribute to reducing the use in the environment of pesticides and rodenticides.

Neg. impact:
The potential spatial spread and temporal persistence of some gene drive approaches create also a challenge in terms of stakeholder engagement and decision-making beyond country boundaries. However, those challenges are common to other decisions about the shared environment, and thus there are precedents (e.g. dam construction).

Also Article 14 of the Cartagena Protocol allows parties to enter into bilateral, regional and multilateral agreements and arrangements regarding transboundary movements. Dr Brinda Dass (#3099) already mentioned that in case of malaria control, “AUDA is also working with West African countries to build a regional platform that would streamline testing of EGD mosquitoes and potentially address data sharing and transboundary issues.”

Objective 3: Fair and equitable sharing of the benefits arising out of the utilization of genetic resources
Pos. impact:
Gene drive approaches may promote equity because their benefits apply to the areas in which they are used, rather than to individuals, and thus do not depend on individual resources such as wealth and time (Santos, 2020). Most gene drives also do not require changes in human behaviour from individuals and can benefit everybody in the community.
Developers have publicly committed to sharing the technology at minimal cost and in case of gene drive for malaria control all include partners in African countries.  

Neg. Impact:
Everybody in the community is impacted by the effect, therefore there are no options for opting out by specific individuals. However, again this is not limited to gene drives, and can also be applied to some conventional biocontrols, nearby crop spraying or mining operations in the locality. Governments regularly make decisions for communities. There are some elements of research, such as social science research, clinical assessment or access to private property, may still require individual consent (Kolopack and Lavary, 2017; Santos 2020).  
Which communities will be affected, and when, will depend on properties of the gene drive approach and natural environment. Therefore, there might not be one process that can be applied to all gene drives.

2. Timeframe for release or potential impact of engineered gene drives
Currently there no plans for commercialization of gene drive for malaria control. First small-scale field studies are probably >5 years away and will depend on risk assessments and regulatory approvals.

3. Challenges for risk assessment, risk management and regulation for this topic in synthetic biology?
Additional voluntary guidelines for RA of engineered gene drives are currently being considered by the Cartagena Protocol RA AHTEG as mentioned in the post by Brinda Dass (#3099).  This could be a useful resource also for countries that are not party to Cartagena.

4. Other impacts
ESHIA/ESIA and SEA can be used to cover socio-economic, health impacts in an integrated way with public engagement as an integral part of the process of field release application.  
As with ERAs, ESHIAs would be conducted on a case-by-case basis ahead of any proposed field trials.
There are also ethical impacts and consultation with stakeholders and agreement from participating communities during the research process is an important element of the evaluation of gene drive approaches. Gene drive developers have been engaging with the public for many years, including local communities (Roberts and Thizy, 2022; Bartumeus et al., 2019; Wanyama et al., 2021).  There has been consideration of the role and engagement of IPLC in decision making around gene drive and FPIC in accordance with national circumstances and legislation (decision 14/19 on synthetic biology made at COP14). I also support Dr Brinda Dass’s assertion (#3099) regarding the impact on women and children with regards to vector control including training opportunities for women.

5. Is the trend and issue attempting to address specific problems, and if so, what are these problems and their underlying causes? How else could these problems or causes be addressed?
In addition to supporting the 3 objectives of the CBD (see point 1 above), gene drives can help to contribute to global targets of the Kunming-Montreal Global Biodiversity Framework, such as Target 6 - controlling invasive alien species, Target 7 - reducing pollution by 50% including pesticides, and Target 20 – technology transfer and increasing capacity for North-South collaboration and technology development in the global South and complement existing tools that face for example challenges in terms of accessibility or resistance by the vector/ pest species. 

In case of malaria control for example Gene drive mosquitoes are recognised as a potential valuable addition to the vector control tool box. See also WHO Global technical strategy for malaria 2016-2030 https://iris.who.int/handle/10665/176712 and AUDA NEPAD Gene Drives for Malaria Control and Elimination in Africa https://www.nepad.org/publication/gene-drives-malaria-control-and-elimination-africa.

Thank you very much,
Silke

Some further relevant publications are below:
Redford KH et al. (eds.) (2019). Genetic frontiers for conservation: An assessment of synthetic biology and biodiversity conservation. Technical assessment. Gland, Switzerland: IUCN. xiv + 166pp.Genetic frontiers for conservation...technical assessment - resource | IUCN

Santos MR (2020). Evaluating Gene Drive Approaches for Public Benefit. In: Chaurasia, A., Hawksworth, D.L., Pessoa de Miranda, M. (eds) GMOs. Topics in Biodiversity and Conservation, vol 19. Springer, Cham. https://doi.org/10.1007/978-3-030-53183-6_19.

National Academies of Sciences, Engineering, and Medicine (2016). Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values. Washington, DC: The National Academies Press. https://doi.org/10.17226/23405.

Romeis J et al. (2020). The value of existing regulatory frameworks for the environmental risk assessment of agricultural pest control using gene drives. Environ Sci Policy.108:19–36. doi: 10.1016/j.envsci.2020.02.016.

David AS et al. (2013). Release of genetically engineered insects: a framework to identify potential ecological effects. Ecol Evol.;3:4000–15. doi: 10.1002/ece3.737.

Teem JL et al. (2019). Problem formulation for gene drive mosquitoes designed to reduce malaria transmission in Africa: results from four regional consultations 2016–2018. Malar J.;18:347. doi: 10.1186/s12936-019-2978-5.

Connolly JB et al. (2021). Systematic identification of plausible pathways to potential harm via problem formulation for investigational releases of a population suppression gene drive to control the human malaria vector Anopheles gambiae in West Africa. Malaria journal, 20(1), 170. https://doi.org/10.1186/s12936-021-03674-6

Connolly JB et al. (2023). Gene drive in species complexes: defining target organisms. Trends in biotechnology, 41(2), 154–164. https://doi.org/10.1016/j.tibtech.2022.06.013

EPA (2020). Human Health and Environmental Risk Assessment for the New Product OX5034 Containing the Tetracycline-Repressible Transactivator Protein Variant (tTAV-OX5034;New Active Ingredient) Protein, a DsRed2 Protein Variant (DsRed2-OX5034; New Inert Ingredient), and the Genetic Material (Vector pOX5034) Necessary for Their Production in OX5034 Aedes aegypti.Regulations.gov

Buchori D et al. (2022). Risk Assessment on the Release of Wolbachia-Infected Aedes aegypti in Yogyakarta, Indonesia. Insects. 13(10):924. doi: 10.3390/insects13100924. PMID: 36292872; PMCID: PMC9604481.

Murray JV et al. (2016). Risk Associated with the Release of Wolbachia-Infected Aedes aegypti Mosquitoes into the Environment in an Effort to Control Dengue. Front Public Health. Mar 22;4:43. doi: 10.3389/fpubh.2016.00043. PMID: 27047911; PMCID: PMC4802996.

Coates DJ et al. (2018). Genetic diversity and conservation units: dealing with the species-population continuum in the age of genomics. Front Ecol Evol 6: 165. Frontiers.

Cook CN et al. (2023). Species conservation in the era of genomic science, BioScience, biad098, https://doi.org/10.1093/biosci/biad098

Kolopack PA and Lavery JV. (2017). Informed consent in field trials of gene-drive mosquitoes. Gates Open Res. 1:14. doi: 10.12688/gatesopenres.12771.1. PMID: 29355214; PMCID: PMC5757819

Roberts, AJ and Thizy D. (2022). Articulating ethical principles guiding Target Malaria's engagement strategy. Malar J 21(1), 35. https://doi.org/10.1186/s12936-022-04062-4

Bartumeus F et al. (2019). Sustainable innovation in vector control requires strong partnerships with communities. PLoS Negl Trop Dis. 13(4):e0007204. doi: 10.1371/journal.pntd.0007204. PMID: 31022178; PMCID: PMC6483154.

Wanyama CE et al. (2021). Co‐developing a common glossary with stakeholders for engagement on new genetic approaches for malaria control in a local African setting. Malar J 20, 53. https://doi.org/10.1186/s12936-020-03577-y

Dear colleagues,

I am Barbara Couto Pilz, representing the civil society organisation Save our Seeds. Please see below my comments on each of the guiding questions.

1. Review the potential positive and negative impacts of this trend and issue in synthetic biology on each of the three objectives of the Convention.

Existing scientific knowledge falls short in accurately forecasting the diverse negative impacts gene drives could have on the complex layers of biodiversity. These impacts span across various ecosystems and timelines.

The use of gene drives essentially introduces large-scale genetic manipulation of wild species, conflicting with the objectives of the Convention.

Conservation -
Uncontrollability and irreversibility: Once released into the wild, a gene drive organism actively propagates in free-living populations and can rapidly spread over large distances. The unmanageable diversity of the natural habitats and ecosystems affected will make it massively more difficult to predict and control possible risks.

A gene drive causes a permanent genetic modification of the genetic material, which is passed on to all subsequent generations. Once released into the environment, gene drive organisms cannot be recalled nor controlled thus preempting and overriding the ability of nations, Indigenous Peoples, local communities and future generations to take their own decisions.

Unpredictable effects on ecosystems and overstepping planetary boundaries: The extermination or even manipulation of a species will have consequences for the entire ecosystem. By forcing human-chosen genes into wild populations through gene drives, we actively limit the ability of species to increase their genetic diversity adapt to changing environments.

Outcrossing across species, resistance and unpredictability of CRISPR/Cas9:
Gene drives are tailored to the genome of a single species, but in many cases outcrossing across species boundaries would likely be impossible to prevent. Resistance can arise when CRISPR/Cas9 itself generates mutations that destroy the target sequence. CRISPR/Cas9 can change the activity of the target gene in unpredictable ways, increase the mutation rate in the genome, lead to unexpected mutations or be disrupted in its function by emerging resistance.

Agricultural concerns: Since most proposals for applications of gene drives are intended for use in agricultural settings to eliminate ‘pests’ or ‘weeds’, there is a high likelihood that altering or eliminating these species will lead to declines in biological diversity and ecosystem stability.

Sustainable Use -
Potential negative effects include risk of monocultures and wide socioeconomic impacts.

By driving specific genetic traits through a population, gene drives can reduce genetic diversity within the target species and lead to homogenization. Reduced genetic diversity can make populations more vulnerable to diseases, environmental changes, and other stresses, thereby impacting their sustainability. Furthermore, the widespread use of gene drives could have economic repercussions for communities that rely on traditional methods of managing biological resources.

Fair and Equitable Sharing -
Potential negative impacts include loss of traditional knowledge and inequality in distribution of impacts.

Indigenous Peoples and Local Communities (IPLCs) hold unique insights into local biodiversity. Introducing gene drives risks disrupting these ecosystems, potentially rendering their traditional knowledge less effective or irrelevant. This scenario could amount to a loss of their intellectual property. Additionally, all impacts of gene drives would not be evenly distributed, potentially intensifying existing social and economic inequalities. The development of gene drives is currently dominated by entities and corporations in wealthier countries in the Global North, who would most likely hold monopoly over this technology, generating dependency dynamics.

Current levels of scientific understanding are not sufficient to predict the potential impacts on biodiversity at the many different layers of all the complex ecosystems in time and space that gene drive organisms would interfere with. Gene drives open the door to wide-scale genetic engineering of wild species, which is at odds with the objectives of the Convention and raises fundamental ethical questions regarding the role of humanity in natural evolution.

References
Courtier-Orgogozo, V., Danchin, A., Gouyon, P. H., & Boëte, C. (2020). Evaluating the probability of CRISPR-based gene drive contaminating another species. Evolutionary Applications, 13(8), 1888–1905. https://doi.org/10.1111/EVA.12939

ETC Group, & Heinrich Böll Stiftung. (2018). Forcing the Farm: How Gene Drive Organisms Could Entrench Industrial Agriculture and Threaten Food Sovereignty. https://www.etcgroup.org/content/forcing-farm

Hammond, A. M., Kyrou, K., Bruttini, M., North, A., Galizi, R., Karlsson, X., Kranjc, N., Carpi, F. M., D’Aurizio, R., Crisanti, A., & Nolan, T. (2017). The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito. PLOS Genetics, 13(10), e1007039. https://doi.org/10.1371/JOURNAL.PGEN.1007039

Imken, M., & Haerlin, B. (2020). Gene Drives: Die neue Gentechnik zum Umbau der Evolution.

Loening, H. (2022). Can gene drives spread between mosquito species? https://www.stop-genedrives.eu/en/can-gene-drives-spread-between-mosquito-species/

Reed, F. A. (2017). CRISPR/Cas9 Gene Drive: Growing Pains for a New Technology. Genetics, 205(3), 1037–1039. https://doi.org/10.1534/GENETICS.116.198887

Unckless, R. L., Clark, A. G., & Messer, P. W. (2017). Evolution of resistance against CRISPR/Cas9 gene drive. Genetics, 205(2), 827–841. https://doi.org/10.1534/GENETICS.116.197285


2. What is the timeframe for release or potential impact of engineered gene drives to control vector-borne diseases and invasive species? Please provide examples of specific applications (e.g., molecular mechanism, target species, intent of application).

For gene drive mosquitos the time frame for release could be within the next 3-5 years. The Target Malaria consortium is in the testing phase for developing gene drives using CRISPR-Cas9 technology in Anopheles gambiae sensu stricto.

For invasive species, the most well-known proposal relates to using a CRISPR gene drive in mice to facilitate a bias of subsequent rodent generations to all be a single sex. According to GBIRD a feasible release could be a decade away given all issues of feasibility of, and assessing the social, ethical, and biological risks of, gene-drive modified organisms.
While the public focus of gene drive technology has been on vector-borne diseases, there's a significant attention towards applications in agriculture and other areas. Most patent application for gene drives are for agricultural uses.

In addition to that, there is a broad range of potential non-insect targets for gene drives, totalling around 43 as of end 2022. The primary intent, in most cases, is to suppress or eradicate the target species. These targets span diverse taxonomic groups, including mammals, fish, snails, arachnids, fungi, and plants. This diversity suggests that the scope of gene drive applications is wide and not just limited to insect vectors or invasive species. This expansion opens doors to a wider array of applications and escalates the potential risks and uncertainties involved.

The timeframe for the release of gene drives could be imminent in some cases (like mosquitoes), while it might be more prolonged for non-insect species due to technological challenges. The potential ecological impacts, ethical considerations, and unforeseeable consequences call for a critical assessment of the technology and its development. It would be negligent to support any release of gene drives until there is a comprehensive understanding of their long-term impacts and robust regulatory frameworks are in place.

This stance aligns with the need for precaution, emphasising that while the technology might be proposed as a tool for addressing pressing environmental and health challenges, its development must be carefully controlled to prevent unintended and irreversible harm to ecosystems and biodiversity.

The timeframe for the release and impact of GDOs for insect vector and invasive species remains a contentious and critical topic, necessitating a cautious and scrutinised approach.

References
Bendana, C. (2023). Anti -GM activists target Malaria Eradication Program in Uganda. https://sciencenowmag.com/2023/10/30/anti-gm-activists-target-malaria-eradication-program-in-uganda/

Dolezel, M., Simon, S., Otto, M., Engelhard, M., & Züghart, W. (2020). Gene Drive Organisms: Implications for the environment and nature conservation. https://www.umweltbundesamt.at/fileadmin/site/publikationen/rep0705.pdf

Dressel, H. (Ed.). (2019). Gene Drives. A report on their science, applications, social aspects, ethics and regulations. Critical Scientists Switzerland, European Network of Scientists for Social and Environmental Responsibility, Vereinigung Deutscher Wissenschaftler. https://ensser.org/publications/2019-publications/gene-drives-a-report-on-their-science-applications-social-aspects-ethics-and-regulations/

ETC Group, & Heinrich Böll Stiftung. (2018). Forcing the Farm: How Gene Drive Organisms Could Entrench Industrial Agriculture and Threaten Food Sovereignty. https://www.etcgroup.org/content/forcing-farm

Stop Gene Drives. (2021). Gene drive applications. Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values; National Academies Press. https://doi.org/10.17226/23405

Wells, M., & Steinbrecher, R. A. (2023). Gene Drive Development: Current and proposed non-insect targets, including vertebrates, snails, fungi and plants. https://www.econexus.info/publication/gene-drive-development-current-and-proposed-non-insect-targets-including-vertebrates

3. What are the potential gaps or challenges for risk assessment, risk management and regulation for this topic in synthetic biology? Evaluate the availability of tools to detect, identify and monitor the organisms, components and products of synthetic biology.

Risk assessment and risk management -
Current risk assessment models may not adequately account for the complex interactions between gene drives and natural systems and the higher levels of scientific uncertainty associated with it. The unpredictability of how gene drives will interact with other organisms and ecosystems necessitates broader, more comprehensive assessments that consider not just environmental impacts, but also socioeconomic, cultural, and ethical dimensions.

Predictive modelling, which is a tool commonly proposed by gene drive developers and researchers to predict impacts, is very limited. It struggles due to uncertain ecological interactions, lack of historical comparators and data, and the inability to foresee long-term complex genetic and environmental interactions and consequences. This casts further doubt on the ability to, based on current levels of scientific knowledge, fully anticipate and control their far-reaching and potentially irreversible impacts on ecosystems and biodiversity.

For risk management, the inability to contain or recall gene drives once released means that there is no feasible emergency response to halt or reverse their effects. This could lead to the need for another technological tool to counteract the original, potentially leading to a cycle of interventions without clear solutions and its own set of new risks.

The long-term nature of managing effects, as exemplified by the 20-year expected timescale for mice population control, requires significant commitment and resources.

Another example of a critical challenge is the evolution of parasites in relation to vectors. With climate change influencing mosquito migration pathways and adaptation to new vectors, a risk that new niches may be created, potentially to be filled by yet unknown species. This uncertainty makes it challenging to predict and manage the ecological consequences of gene drives.

Furthermore, many Parties may lack the capacity to conduct thorough risk assessments and manage risks in line with the precautionary principle. This gap is particularly concerning given the potential for long-term and transboundary impacts of gene drives applications.

Regulation -
The absence of robust regulation leads to accountability and liability issues. This is particularly concerning for transboundary movements of GDOs. Without clear regulatory frameworks, the responsibility for managing and mitigating risks becomes ambiguous, enabling negligence and uncoordinated responses.

The mobility of organisms like mosquitoes complicates consent and regulatory frameworks. This raises questions about jurisdiction and responsibility for managing transboundary impacts.

The current gaps in risk assessment, management, and regulation present significant hurdles. These challenges underscore the need for a more holistic, adaptive, and precautionary approach to developing and deploying gene drives. Developers and stakeholders in this field must critically evaluate the long-term and wide-ranging implications of their work as well as be thoroughly scrutinised by the international community.

References
Boëte, C. (2018). Technoscience and Biodiversity Conservation. Asian Bioethics Review, 10(4), 245–259. https://doi.org/10.1007/S41649-018-0071-Y/METRICS

Frieß, J. L., Lalyer, C. R., Giese, B., Simon, S., & Otto, M. (2023). Review of gene drive modelling and implications for risk assessment of gene drive organisms. Ecological Modelling, 478, 110285. https://doi.org/10.1016/J.ECOLMODEL.2023.110285

Gierus, L., Birand, A., Bunting, M. D., Godahewa, G. I., Piltz, S. G., Oh, K. P., Piaggio, A. J., Threadgill, D. W., Godwin, J., Edwards, O., Cassey, P., Ross, J. V., Prowse, T. A. A., & Thomas, P. Q. (2022). Leveraging a natural murine meiotic drive to suppress invasive populations. Proceedings of the National Academy of Sciences of the United States of America, 119(46), e2213308119. https://doi.org/10.1073/PNAS.2213308119/SUPPL_FILE/PNAS.2213308119.SM03.MOV

Li Ching, L. (2017). Synthetic Biology and Relevant International Law. TWN Biotechnology & Biosafety Series. https://www.twn.my/title2/biosafety/pdf/bio18.pdf

Lim Li, C., & Lim Li, L. (2019). Gene Drives: Legal and Regulatory Issues. https://www.twn.my/title2/books/Gene-drives.htm

Molina-Cruz, A., & Barillas-Mury, C. (2014). The remarkable journey of adaptation of the Plasmodium falciparum malaria parasite to New World anopheline mosquitoes. Memórias Do Instituto Oswaldo Cruz, 109(5), 662. https://doi.org/10.1590/0074-0276130553

Vella, M. R., Gunning, C. E., Lloyd, A. L., & Gould, F. (2017). Evaluating strategies for reversing CRISPR-Cas9 gene drives. Scientific Reports, 7(1), 1–8. https://doi.org/10.1038/s41598-017-10633-2

Xiang-Ru Shannon Xu, A., Bulger, E. A., Gantz, V. M., Akbari, O. S., Marshall, J. M., & Bier Correspondence, E. (2020). Active Genetic Neutralizing Elements for Halting or Deleting Gene Drives. Molecular Cell, 80, 246-262.e4. https://doi.org/10.1016/j.molcel.2020.09.003

4. Review the potential social, economic, cultural, ethical, political, human health and/other relevant impacts of this trend and issue. What are the relevant considerations for IPLCs, women and youth?

The socioeconomic implications of gene drives are as crucial as environmental impacts. The development of this technology in the Global North, with testing mostly carried out in the Global South and without proper Free Prior and Informed Consent, raises concerns about equity and the distribution of impacts. This imbalance exacerbates existing inequalities and imposes unintended socioeconomic burdens on affected communities.

In addition to that, the ethical dilemma of who gets to decide to eliminate a species is profound. This decision-making process is often dominated by a small group of scientists and policymakers, frequently detached from the communities most affected by these decisions.

The need for transparency in research and acknowledgment of potential conflicts of interest is critical. The involvement of private interests in the development of gene drives raises concerns about profit motives overriding public good and ecological safety.

While gene drives aim to eliminate disease vectors, this could inadvertently create ecological niches for other vectors. This approach also diverts attention and resources from addressing the social determinants of diseases like malaria. The reliance on technological solutions may necessitate further technological interventions, perpetuating a cycle of dependency on 'techno-fixes'.

For IPLCs, issues of Free, Prior, and Informed Consent (FPIC) are paramount. Gene drives can affect cultural practices, livelihoods, and deeply held beliefs about nature. The use of a tool not developed or controlled by these communities, and which can only be altered by further external interventions, represents a significant imposition on their autonomy and relationship with their environment.

The long-term effects of gene drives are largely unknown, meaning future generations are faced with decisions made today that cannot be reversed. This lack of reversibility raises serious ethical questions about the intergenerational impacts of gene drives.

References
Antia, M., & Stop Gene Drives. (2023). Gene Drives: exploiting the lack of awareness. https://www.youtube.com/watch?v=MFk9ng2G3tA&list=PLwAtMBHW6BhjRMQ2XQT1cvH6KHgfS9Rxn&index=9&ab_channel=SaveourSeeds

Harry, D., & Stop Gene Drives. (2023). Gene Drives: extending the patterns of colonisation. https://www.youtube.com/watch?v=iOsDfhX3770&list=PLwAtMBHW6BhjRMQ2XQT1cvH6KHgfS9Rxn&ab_channel=SaveourSeeds
Synbiowatch. (2017). Gene Drive Files. https://genedrivefiles.synbiowatch.org/

Taitingfong, R., & Stop Gene Drives. (2023). Gene Drives: the missing perspectives. https://www.youtube.com/watch?v=66BsBFgAY-E&list=PLwAtMBHW6BhjRMQ2XQT1cvH6KHgfS9Rxn&index=4&ab_channel=SaveourSeeds

5. Is the trend and issue attempting to address specific problems, and if so, what are these problems and their underlying causes? How else could these problems or causes be addressed?

Malaria  -
The persistence of malaria is closely linked to social determinants like poverty, lack of education, inadequate healthcare infrastructure, and poor housing conditions that facilitate mosquito breeding.

Factors such as stagnant water bodies contribute to mosquito breeding, making environmental management a key aspect of malaria control.
Countries that have successfully eradicated malaria have employed sustained funding, improved healthcare infrastructure, and comprehensive strategies tailored to local contexts. These include rapid diagnosis and treatment, effective larval control, and widespread educational campaigns about prevention.

Tackling the root causes of malaria, such as poverty and lack of education, can be more sustainable in the long run. Improving living conditions, ensuring access to healthcare, and educating the public about prevention can significantly reduce malaria transmission. Continued research into malaria vaccines is crucial as the development and deployment of an effective vaccine could significantly reduce the incidence of malaria.
The development and testing of gene drives are primarily driven by interests in the Global North, often with testing in the Global South. This raises issues of consent, equity, and the imposition of risks on communities that are not being adequately consulted or involved in the decision-making process.

Addressing problems like malaria requires integrated approaches that combine public health initiatives with social and environmental interventions. Focusing on technological fixes like gene drives overlooks the complexity of these issues and the need for holistic solutions.

Invasive species -
Invasive species are usually characterised by being non-native organisms that disrupt local ecosystems, outcompete native species, and harm agricultural productivity. Gene drives are being proposed mainly to reduce the fertility of an invasive species, leading to a gradual decline in their numbers. Although the most popular proposition relates to mice, there are also multiple proposals to use it in agriculture. Similarly, suppression gene drives are proposed to reduce or eliminate specific weed or insect populations considered ‘pests’. This might be done by modifying organisms so to render them less competitive, or more sensitive to herbicide/pesticide.

The increased movement of goods and people across the globe has inadvertently led to the spread of species to new environments where they have no natural predators. In addition to that, changing climate conditions can make environments more hospitable to certain invasive species, allowing them to thrive. Mitigating climate change and managing habitats to be resilient to climate impacts can help control the spread of invasive species. Moreover, human activities such as agriculture, urbanisation, and deforestation can create conditions that favour invasive species over native ones.

Effective policy and regulatory frameworks to prevent the introduction and spread of invasive species, and to manage infestations, are crucial. Ongoing research to understand invasive species and their impacts, along with monitoring programs to detect new invasions early, are essential for effective management.

In sum, instead of applying genetic engineering fixes, focus should be on improving ecosystem health, biodiversity, and sustainable farming practices. These methods emphasise working with nature rather than trying to engineer it, offering a pathway to sustainable wildlife management/coexistence and agriculture, and ecological balance.

References
ACBIO. (2022). The financialisation of malaria in Africa. https://acbio.org.za/corporate-expansion/financialisation-of-malaria-in-africa

Barat, L. M. (2006). Four malaria success stories: how malaria burden was successfully reduced in Brazil, Eritrea, India and Vietnam. Am. J. Trop. Med. Hyg., 74(1), 12–16. https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=ac2735b24db8934cc408770abc9909098d5c6ffb

Castro, M. C. (2017). Malaria Transmission and Prospects for Malaria Eradication: The Role of the Environment. Cold Spring Harbor Perspectives in Medicine, 7(10). https://doi.org/10.1101/CSHPERSPECT.A025601

Courtier‐Orgogozo, V., Morizot, B., & Boëte, C. (2017). Agricultural pest control with CRISPR‐based gene drive: time for public debate: Should we use gene drive for pest control? EMBO Reports, 18(6), 878. https://doi.org/10.15252/EMBR.201744205

Olivera, M. J., Peña, C., Yasnot, M. F., & Padilla, J. (2022). Socioeconomic determinants for malaria transmission risk in Colombia: An ecological study. Microbes, Infection and Chemotherapy, 2. https://doi.org/10.54034/mic.e1339

Quagliata, M., Papini, A. M., & Rovero, P. (2023). Malaria vaccines. Expert Opinion on Therapeutic Patents. https://doi.org/10.1080/13543776.2023.2190884

6. What lessons can be learned of similar tools, techniques or applications in other domains? How might those lessons from elsewhere be relevant or shed insight in assessing this topic in the context of the aims of the Convention on Biological Diversity?

The Oxitec mosquito experience can provide important lessons. It involves the field testing of genetically modified (GM) Aedes aegypti mosquitoes, developed by the biotechnology company Oxitec. These mosquitoes were engineered with the aim to control the spread of diseases such as dengue, zika, and chikungunya by reducing the populations of Aedes aegypti. The release of such mosquitos in Brazil and other locations provides a lesson on the extent of risks associated with releasing genetically modified mosquitos into the environment without proper assessment, FPIC, and knowledge about potential impacts.

Some of the ecological concerns related to this release where linked to, among others: failure to follow the Cartagena Protocol’s procedure for exporting of LMOs; mistake in class risk placement; release in communities without their consent; precarious conditions of release; no previous evaluation related to native populations with regards to resistance, permanence and viral transmission; no understanding of the profile of hybrid mosquitos after contamination; and developers’ failure in disclosing conflicts of interest.

As pointed out by a report led by The African Centre for Biodiversity (ACB), “Oxitec failed to acknowledge the extent of the ignorance and uncertainty surrounding the complexity of ecosystem responses to its releases of GM insects and instead made unsubstantiated and unrealistic claims about what its GM mosquitoes could deliver” – a parallel that can be directly made to the plans of the Target Malaria consortium regarding their work on GM and gene drive mosquitos.

As highlighted by ACB in the same report, “there is a lack of fully informed consent to the planned experiments; poor compliance with regulatory requirements and a lack of public consultation; unjustified hype about what the experiments can deliver; a lack of transparency and public consultation; and a lack of debate about alternatives”.

From these lessons, it's evident that the development of gene drives must be approached with caution, robust technology and risk assessment, consideration of long-term impacts, and civil society vigilance. These lessons reinforce the CBD's principles of precaution, ecosystem conservation, sustainability, and the importance of considering ethical, socioeconomic, and cultural dimensions in biodiversity-related technologies.

References
Bendana, C. (2023). Anti -GM activists target Malaria Eradication Program in Uganda. https://sciencenowmag.com/2023/10/30/anti-gm-activists-target-malaria-eradication-program-in-uganda/

Evans, B. R., Kotsakiozi, P., Costa-da-Silva, A. L., Ioshino, R. S., Garziera, L., Pedrosa, M. C., Malavasi, A., Virginio, J. F., Capurro, M. L., & Powell, J. R. (2019). Transgenic Aedes aegypti Mosquitoes Transfer Genes into a Natural Population. Scientific Reports 2019 9:1, 9(1), 1–6. https://doi.org/10.1038/s41598-019-49660-6

Gusman Ferraz, J. M., & Stop Gene Drives. (2023). José Maria Gusman Ferraz - Q1. Circumstances of the Release of Oxitec’s GMO Mosquitos in Brazil. https://www.youtube.com/watch?v=4iTJlvo87DU&list=PLwAtMBHW6BhgkzekFdAE3p8BTU0vVcsh_&ab_channel=SaveourSeeds

Gusman Ferraz, J. M., & Stop Gene Drives. (2023, I). José Maria Gusman Ferraz - Q10. Oxitec’s GM Mosquitos Persistence in the Environment. https://www.youtube.com/watch?v=sqGpY2i9Cpw&list=PLwAtMBHW6BhgkzekFdAE3p8BTU0vVcsh_&index=11&ab_channel=SaveourSeeds

Wallace, H., Jackson, A., Ching, L. L., Dr Sirinathsinghji, E., & Mayet, M. (2019). Oxitec’s failed GM mosquito releases worldwide: Forewarnings for Africa and the Target Malaria project.

7. Where are limits of knowledge with respect to this trend and issue? Are there any other considerations that would be important to raise?

Current scientific levels of understanding of gene drives are limited from multiple perspectives. These include long-term ecological impacts of gene drives, genetic unpredictability and off-target effects, lack of reversibility (developers themselves caution to release gene drives on the basis of counting with the potential to reverse gene drives), transboundary movements, as well as potential for dual and misuse. An especially critical area of uncertainty is the potential for widespread application of gene drives in agricultural systems.

These are all underpinned by the dangerous assumption that it would be possible to permanently control and manipulate complex natural systems without unforeseen consequences.

In this context, the use of predictive modelling for gene drives has significant limitations, making it an incomplete tool for informed decision-making. A fundamental issue is the lack of appropriate comparators (unprecedent technology without historical parallels, making it highly speculative and lacking empirical evidence). Models also fail to accurately simulate the intricate and dynamic interactions within ecosystems and with other species, rarely account for altered mating behavior, are based on controlled conditions lacking field-generated data and are not efficiently able to predict long-term ecological consequences and potential off-target effects.

These limitations are compounded by the inability of models to incorporate the socioeconomic, ethical, and cultural dimensions integral to the development of gene drives. Finally, knowledge on how to monitor, detect and manage gene drives once released is severely limited.

References
Federal Agency for Nature Conservation. (2022). Genetic engineering, nature conservation and biological diversity: Boundaries of design. https://www.bfn.de/en/publications/position-paper/genetic-engineering-nature-conservation-and-biological-diversity

Frieß, J. L., Lalyer, C. R., Giese, B., Simon, S., & Otto, M. (2023). Review of gene drive modelling and implications for risk assessment of gene drive organisms. Ecological Modelling, 478, 110285. https://doi.org/10.1016/J.ECOLMODEL.2023.110285

Xiang-Ru Shannon Xu, A., Bulger, E. A., Gantz, V. M., Akbari, O. S., Marshall, J. M., & Bier Correspondence, E. (2020). Active Genetic Neutralizing Elements for Halting or Deleting Gene Drives. Molecular Cell, 80, 246-262.e4. https://doi.org/10.1016/j.molcel.2020.09.003

Dear colleagues, I’m Luke Alphey, Professor of Genetics at the University of York, UK. I have >20 years experience developing synbio insects.

I sat down to try to write a comprehensive response to the moderator’s questions, but realised that almost everything I would wish to say had been covered – perhaps better than I would have done - by Brinda Dass (#3039), Silke Fuchs (#3104) and Kathleen Lehmann (#3039). So I will not take up everyone’s time repeating, merely commend those responses.

My name is Silvia Ribeiro and I am the Latin America Director for ETC group (Action Group on Erosion, Technology and Concentration).

This comment is related to question 4, 5 and 6; also related to the technologies under discussion under Topic 1: “Trends and issues in synthetic biology identified for more detailed assessment” as well as others mentioned but not included in the detailed assessment exercise of mAHTEG.

Most technologies under discussion at mAHTEG have the ability to spread into the environment, either intentionally or unintentionally, with potential serious impacts. Several of them, such as gene drives, are specifically intended to do so. Therefore the consequences and potential impacts could be also spread over large areas and unknown fields, and may trigger cascade effects and unpredictable eco-systemic interactions.

The social, economic, cultural, ethical, political and human health impacts could also be unpredictable, difficult to assess or poorly estimated , as can be concluded from several prior inputs into this and March Online Forum which point to the many uncertainties and risks of gene drives and other synthetic biology applications. (E.g., Then [#3087], Engelhard [#3090], Sirinathsinghji, [#3109], Couto Pilz, [#3108])

Therefore, the assessment of these technologies ­must recognize these inherent limitations and therefore adhere to a strict implementation of the precautionary principle, which includes to not endorse the development and release of these technologies into the environment, or into a context where the release could accidentally happen.

Because of the broad and complex possible impacts, the assessment of these technologies can not be limited to just technical assessment and biosafety risk assessment, nor should it only involve  scientists and technical experts. It should also observe a clear principle requiring that participants are free from conflict of interest, to ensure that those with vested interests and commercial investments  in a technology are not the ones shaping the assessment of a technology.

The recognition of other knowledge systems and ways of understanding the environment and biodiversity must be fully integrated into the assessment as well as the right to the Free Priori and Informed Consent of Indigenous Peoples (FPIC) and of local communities, rural communities and other rural populations. It is also important for technology assessments to recognize how a technology and its applications can affect women and youth in particular.

Because of the presence of novel characters in synthetic biology organisms and the fact that in many cases, it is impossible to limit the technology to a specific area or to only one use/application, gene drives and other synthetic biology technologies under consideration of the mAHTEG, pose new challenges for a meaningful consultation process and for the realization of the right to FPIC.

If these challenges are not met and resolved, assessments may contribute to understanding certain technical aspects but they can not be considered as complete and therefore should not be used as reference to endorse the development or deployment of a technology.

In this context, ETC group has been working with Indigenous and peasant communities in Mexico and Chile, in the framework of the project “Intercultural Assessment of Synthetic Biology Applications” commissioned by the German Federal Agency for Nature Conservation. The project aims to offer draft guidelines for the participatory and intercultural assessment of new biotechnologies. It is based on the exchange of knowledge and evaluation across cultures, with participatory technology evaluation approaches, in order to promote transparency and legitimacy with regard to the way the issues are framed, the choice of topics, as well as procedures of organization, facilitation and communication of the assessment process.

Two 3-day forums and workshops with grassroots Indigenous and peasant communities and organizations were conducted in 2022 and 2023, to discuss how participatory assessment could and should be conducted, using the example of the applications of gene drives and genome editing technologies.  Among other conclusions that will be presented in a coming report, one clear demand from communities was the need to allocate proper and culturally adequate time for the assessment, with prior information and sufficient context (e.g. background, interactions and potential indirect and medium/long term impacts of the technologies, not just technical information).

Participants in both forums, coming from several countries and communities in Latin America, reached consensus that much more information about the potential effects of gene editing technologies in general and gene drive organisms in particular is required, as well as more time for communities to discuss them, if there was to be an effective process of intercultural assessment and genuine and meaningful FPIC.

Based on their life experiences, participants in the workshops and forums were also highly aware of the dangers in allowing technologies to be dumped on their communities by those who do not have to live with the potentially adverse consequences, and therefore the need to be especially thorough in the evaluation.

Other conclusions included the need to have clear and solid information independent of the promoters of a particular technology, to have adequate prior information and discussions in Indigenous and local languages, to not only use technical and written language, but also other means of communication, such as graphics and pictures. They also pointed out the need to not accept that a consultation with one or a few communities or some organizations, often mediated by paid projects to the participants, could be taken as representative for all the potentially affected communities and peoples.

There is no off-the-shelf formula that can be simply applied to intercultural assessment of technologies. Just as it is too simplistic to think of a single technology solving complex social, health or environmental problems, so processes of assessment have to address the complexity that underpins communities, ecosystems and issues of justice and cultural diversity.

Dear Colleagues,

I would like to fully support the previous inputs from Chrstoph Then, Barbara Pilz, Silvia Ribeiro, Margret Engelhard and Prof Shinwari on the issues of RA challenges, limitations in knowledge, GDO characteristics of uncontrollability and irreversibility, lack of mitigation strategies, transboundary movement potential, and the subsequent need for a precautionary approach and wide public participation as a means to address these risks and uncertainties. I would also like to refer to my comments on self limited insects with regard to issues around consent and alternative approaches that are also relevant to gene drive mosquito projects.

I will thus not repeat those aspects but pick up on a couple of other points regarding potential efficacy challenges.

Q4,5,6

Efficacy issues tie into to wider SE, ethical considerations with regard to costs, and potential neglect of alternative solutions beyond the narrow biomedical/technological paradigm, and the ability to successfully achieve the important aims of addressing disease or invasive species.

With resistance development expected, developers envisioning additional product releases over the course of a decade. Moreover, as acknowledged by developers, gene drives targeting one vector species such as A. gambiae and coluzzii and arabiensis would not be sufficient, with James et al., (2020 https://doi.org/10.1089/vbz.2019.2606) stating: “Although An. gambiae s.s. and sibling species An. coluzzi and An. arabiensis are major malaria vectors in sub-Saharan Africa, the working group recognized that other Anopheles species (notably Anopheles funestus) also transmit malaria, and may, in certain situations, contribute a significant proportion of the residual transmission. Products directed at these mosquitoes also will be required for malaria elimination”.  A funestus mosquitoes are becoming an increasingly important malaria vector (e.g. Msugupakulya et al., 2023 https://doi.org/10.1186/s13071-023-06019-1). However, LM or LMO GDO development is lagging due to technical issues with the species. This raises important questions with regard to reducing disease burden, as even if GDOs were successful at reducing the numbers of one vector population (for suppression drives), impact on disease could still be negligible.
One gene drive developer institution has launched a biotech spin-off company that is planning to licence the double-sex genetic platform as a ‘self-limited’ gene drive technology, to be deployed in agricultural pests and other vector-borne disease (Biocentis, n.d.). The use of intellectual property rights and patents also raises socioeconomic considerations over potential monetisation of a product that has been thus far promoted as a technology for ‘public good’.

Considering the above issues, there are concerns with regard to promoting dependence and technological lock-ins, as I have raised in the other topic regarding self-limited insect systems.

Thanks very much,
Eva

My name is Joel Andres Rojas Gonzalez and I represent the Global Youth Biodiversity Network. In order to not repeat several of the key points highlighted in this forum by some of my colleagues, I would love to show my support to the insights shared by Chrstoph Then, Barbara Pilz, Silvia Ribeiro, Margret Engelhard, and Eva Sirinathsinghji on these matters of importance. Vector-borne diseases are a key problem in developing countries, where resource mobilization and distribution of treatments are challenges we face every day, especially the youth, women, IPLCs, and other vulnerable populations. Nevertheless, the use of gene drives to control these dangers has been suggested but, at the current level of knowledge we currently have, including the lack of coverage of the potential risks and detriments to our biodiversity, it could pose a problem for biodiversity, health (covering the One Health vision) and other sectors that see this as an alternative. We also have to think in regard to the rights of the people and how this process could affect not only traditional knowledge and practices but also traditional species that interact with IPLCs.

Let's have these considerations in mind for future conversations. Thanks to everyone for their comments and views.

With regards,
Joel

Dear Participants of the Open-ended Online Forum on Synthetic Biology,

Thank you for your interventions and active engagement.
The forum is now closed for comments.

Thank you,
The Secretariat