Regulation and Policy

Risk assessments, regulation of gene drive, and thought leadership on gene drive policy

Infravec2 guidelines for the design and operation of containment level 2 and 3 insectaries in Europe

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E. Pondeville, A.-B. Failloux, F. Simard, P. Volf, A. Crisanti, R. E. Haghighat-Khah, N. Busquets, F. X. Abad, A. J. Wilson, R. Bellini, S. Marsh Arnaud, A. Kohl and E. Veronesi,  Pathogens and Global Health,  2022-08-22 07:08:22.
With the current expansion of vector-based research and an increasing number of facilities rearing arthropod vectors and infecting them with pathogens, common measures for containment of arthropods as well as manipulation of pathogens are becoming essential for the design and running of such research facilities to ensure safe work and reproducibility, without compromising experimental feasibility. These guidelines and comments were written by experts of the Infravec2 consortium, a Horizon 2020-funded consortium integrating the most sophisticated European infrastructures for research on arthropod vectors of human and animal diseases. They reflect current good practice across European laboratories with experience of safely handling different mosquito species and the pathogens they transmit. As such, they provide experience-based advice to assess and manage the risks to work safely with mosquitoes and the pathogens they transmit. This document can also form the basis for research with other arthropods, for example, midges, ticks or sandflies, with some modification to reflect specific requirements.

Natural selfish genetic elements should not be defined as gene drives

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M. A. Wells and R. A. Steinbrecher,  Proceedings of the National Academy of Sciences,  119:e2201142119. 2022-08-16 07:53:39.
Gene drives are increasingly discussed in the political realm,and how the term is defined therefore has important impli-cations. The opinion piece from Alphey et al. (1) identifies alack of consensus on the definition and makes explicitchanges in how the terminology is being used by someresearchers. As such it is a timely invitation for debate.The definition of the term“gene drive”Alphey et al. (1)propose would include naturally occurring selfish geneticelements (SGEs) and natural processes causing biasedinheritance. We disagree with this aspect of the proposal,which does not reflect the original use of the term, whichrelated to engineered system

What do we mean by “Target Organism” in Target Malaria’s gene drive research?

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J. B. Connolly,  Target Malaria,  2022-07-27 08:46:32.
In the wild and in laboratory settings, sibling mosquito species can successfully mate to produce viable offspring, regardless of whether they are vectors or not. Importantly, females, but not males, of these offspring can be fertile. Nonetheless, the likelihood of finding such hybrid mosquitoes in field samples varies greatly between different combinations of species. According to some field studies, typically, only about 0.1% of mosquito collected in the wild could be An. gambiae s.s./An. coluzzii hybrids. In addition, some species that do not overlap geographically, and therefore would not come into direct contact, cannot produce hybrids in the field. This includes An. melas, which is found along the coast of West Africa, and An. bwambae, which is restricted to hot springs in the Toro District of Uganda. This means that the gene drive could eventually transfer to all sibling species of the complex, both by direct hybridisation between geographically-overlapping species and, indirectly, by transferring from one species to another overlapping ones like stepping-stones until the gene drive was transferred to all species of the complex, including to the likes of An. melas and An. bwambae

Operationalizing stakeholder engagement for gene drive research in malaria elimination in Africa-translating guidance into practice

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L. Pare Toe, B. Dicko, R. Linga, N. Barry, M. Drabo, N. Sykes and D. Thizy,  Malaria Journal,  21:225. 2022-07-23 10:16:04.
Gene drive mosquitoes are increasingly considered a potential transformational tool for vector control of malaria mosquitoes. As part of efforts to promote responsible research in this field, a number of guidance documents have been published by the World Health Organization, National Academies and expert groups. While virtually all recent guidance documents on gene drive research stress the importance of stakeholder engagement activities, no specific guidelines on implementing them have been established. Target Malaria, a not-for-profit research consortium developing a vector-control gene drive approach to eliminate malaria, has reflected on how its stakeholder engagement strategy translates engagement guidance documents into practice. The project analysed and addressed the tension between the context specificities and the international recommendations. The engagement strategy combines published recommendations for responsible gene drive research, information collected from the local context where the project operates and a set of principles guiding the choices made. This strategy was first developed during the early phases of the project's research, years ahead of any activities with gene drive mosquitoes in those countries of operations. These earlier activities, and their related engagement, allow the project to develop and adapt an engagement strategy appropriate for potential gene drive research in its field site countries. This paper offers a description of a stakeholder engagement strategy operationalization based on (1) adaptation to stakeholder preferences, (2) inclusiveness and (3) empowerment and accountability. The authors hope to offer concrete examples to support other projects with the development and implementation of their engagement strategies with particular attention to the co-development principle.

Gene Drive in Species Complexes: Defining Target Organisms

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J. B. Connolly, J. Romeis, Y. Devos, D. C. M. Glandorf, G. Turner and M. B. Coulibaly,  Trends in Biotechnology,  2022-07-12 06:21:17.
Engineered gene drives, which bias their own inheritance to increase in frequency in target populations, are being developed to control mosquito malaria vectors. Such mosquitoes can belong to complexes of both vector and non-vector species that can produce fertile interspecific hybrids, making vertical gene drive transfer (VGDT) to sibling species biologically plausible. While VGDT to other vectors could positively impact human health protection goals, VGDT to non-vectors might challenge biodiversity ones. Therefore, environmental risk assessment of gene drive use in species complexes invites more nuanced considerations of 'Target Organisms' and ‘Non-Target Organisms' than for transgenes not intended to increase in frequency in target populations. Incorporating the concept of ‘Target Species Complexes’ offers more flexibility when assessing potential impacts from VGDT.

Larval mosquito management and risk to aquatic ecosystems: A comparative approach including current tactics and gene-drive Anopheles techniques

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R. K. D. Peterson and M. G. Rolston,  Transgenic Research,  2022-07-07 09:39:09.
Genetic engineering of mosquitoes represents a promising tactic for reducing human suffering from malaria. Gene-drive techniques being developed that suppress or modify populations of Anopheles gambiae have the potential to be used with, or even possibly obviate, microbial and synthetic insecticides. However, these techniques are new and therefore there is attendant concern and uncertainty from regulators, policymakers, and the public about their environmental risks. Therefore, there is a need to assist decision-makers and public health stewards by assessing the risks associated with these newer mosquito management tactics so the risks can be compared as a basis for informed decision making. Previously, the effect of gene-drive mosquitoes on water quality in Africa was identified as a concern by stakeholders. Here, we use a comparative risk assessment approach for the effect of gene-drive mosquitoes on water quality in Africa. We compare the use of existing larvicides and the proposed genetic techniques in aquatic environments. Based on our analysis, we conclude that the tactic of gene-drive Anopheles for malaria management is unlikely to result in risks to aquatic environments that exceed current tactics for larval mosquitoes. As such, these new techniques would likely comply with currently recommended safety standards.

Public perspectives towards using gene drive for invasive species management in Australia

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A. Mankad, E. V. Hobman and L. Carter,  CSIRO,  2022-06-30 07:55:31.
Many pest animal species live and reproduce in high numbers across Australia. This includes animal species, such as cane toads, feral cats, foxes, rodents, wild pigs, wild rabbits. These species significantly damage Australia’s agricultural industries, natural landscapes, and biodiversity. For example, feral cats kill an estimated 1.8 billion Australian animals every year. Feral animals can also carry livestock diseases and cause significant damage to land and native vegetation. This results in agricultural production losses of more than $800 million per year. Sites of cultural significance to Indigenous peoples are also at risk to pest incursions. Adding further complexity, current methods of pest control being used to manage local landscape, such as baiting, trapping and shooting, are labour-intensive and expensive. They also have animal welfare implications and are considered ineffective at scale. Genetic technologies that are developed using synthetic biology have the potential to reduce or in some cases eliminate populations of invasive pests in parts of Australia. But there are multiple social, cultural and institutional considerations to understand before genetic technologies could feasibly be integrated with current pest management practices.

Public deliberation and the regulation of gene drive in the USA

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W. F. West, L. W. Buchman and R. F. Medina,  Science and Public Policy,  scac032. 2022-06-27 10:41:33.
Gene drive is a new form of biotechnology designed to bias the inheritance of selected traits in animal or plant species that reproduce sexually and have relatively short reproductive cycles. Unlike traditional breeding techniques and other forms of biotechnology, gene drive is designed to spread in wild populations. As such, the prospect of its application raises ecological and socioeconomic concerns that the current system of biotechnology regulation in the USA is ill-equipped to address. Foremost among the proposals for reform is the need for deliberative participation in decision-making by stakeholders representing a broader range of interests and analytical perspectives. As appealing as they are in the abstract, these recommendations overlook both practical and political challenges to democratic governance in administration that have received little attention.

Genetic Approaches for Controlling CRISPR-based Autonomous Homing Gene Drives

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P. R. Chennuri, Z. N. Adelman and K. M. Myles,  Frontiers in Bioengineering and Biotechnology,  10:897231. 2022-06-15 08:41:17.
CRISPR-based autonomous homing gene drives are a potentially transformative technology with the power to reduce the prevalence of, or even eliminate, vector-borne diseases, agricultural pests, and invasive species. However, there are a number of regulatory, ethical, environmental, and sociopolitical concerns surrounding the potential use of gene drives, particularly regarding the possibility for any unintended outcomes that might result from such a powerful technology. Therefore, there is an imminent need for countermeasures or technologies capable of exerting precise spatiotemporal control of gene drives, if their transformative potential is ever to be fully realized. This review summarizes the current state of the art in the development of technologies to prevent the uncontrolled spread of CRISPR-based autonomous homing gene drives.

Genetically Modified Mosquitoes to Fight Malaria in Nigeria, Burkina Faso, Mali and Uganda: What Legal Response?

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O. J. L. Tung,  Potchefstroom Electronic Law Journal,  25:1-42. 2022-06-07 10:05:47.
Advanced applied research on genetically modified (hereafter GM) insects is being undertaken to control insect vectors of human diseases such as mosquitoes. GM insect technologies are being developed in countries where there is a legal framework for genetically modified mosquitoes (hereafter GMM), but the beneficiaries of such insect technologies to control insect-borne diseases are most likely to be in malaria-endemic countries where the regulation of GM insect technologies is inadequate. Although no commercial release of GMM has been conducted in Africa yet, there may be prospects for the use of GMM to control malaria in malaria-endemic countries such as Nigeria, Burkina Faso, Mali and Uganda. Nigeria has the highest rate of deaths related to malaria in Africa and will potentially be targeted by companies seeking to introduce GMM as a public health tool in African countries. Research is being carried out on GMM in Burkina Faso, Mali and Uganda in collaboration with foreign companies. Whereas the control of diseases is certainly needed and there are potential public health benefits for GM insect technologies to address mosquito control, there are environmental and health concerns, and there is also the potential of the misuse of such technologies. Consequently, the use of GMM requires prior robust domestic, regional and international regulation. While the Cartagena Protocol on Transboundary Movements of Living Modified Organisms (LMOs) to the Convention on Biological Diversity (hereafter the Cartagena Protocol)and voluntary guidelines on the testing of GM mosquitoes are applicable with respect to GM insect technologies, there is a lack of international and regional guidance on the regulation of such technologies. Domestic legislation tends to focus on GM crops and is inadequate for regulating GMM. This paper discusses the legal response for the above Africancountries which may perhaps use GMM as a public health tool and makes recommendations for the necessary regulatory response

Beware the Unknown: Views on Genetic Technology in Conservation

H. G. W. Dixson, J. Balanovic, F. Medvecky, E. D. Edwards and E. A. MacDonald,  Narrative Inquiry in Bioethics,  12. 2022-06-06 08:59:56.
Artificial Gene Drive (GD) may offer a number of transformative impacts on society. Despite potential usage in the area of conservation, GD remains largely unfamiliar to the public and little is known about their views. In our study, participants from New Zealand were placed in groups based upon one of four worldviews. They had a brief free word association session before considering a concise, technical definition of GD and were asked to discuss their views. Overall, discussions made use of narrative devices that expressed caution and concern around large-scale technological intervention with the natural world. However, specific worldviews presented unique themes. While fears of human overstep causing uncontrollable feedback across wild species and environments were universally present, this differed according to the group's worldview. We conclude that conversations on such technologies, especially those relating to gene modification, provide insight into deep-rooted social, cultural and even metaphysical concerns that transcend the technology's stated purpose.

Recommendations for environmental risk assessment of gene drive applications for malaria vector control

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J. B. Connolly, J. D. Mumford, D. C. M. Glandorf, S. Hartley, O. T. Lewis, S. W. Evans, G. Turner, C. Beech, N. Sykes, M. B. Coulibaly, J. Romeis, J. L. Teem, W. Tonui, B. Lovett, A. Mankad, A. Mnzava, S. Fuchs, T. D. Hackett, W. G. Landis, J. M. Marshall,  Malar J,  21:152. 2022-05-25 09:36:02.
Building on an exercise that identified potential harms from simulated investigational releases of a population suppression gene drive for malaria vector control, a series of online workshops identified nine recommendations to advance future environmental risk assessment of gene drive applications.

Bayesian network-based risk assessment of synthetic biology: Simulating CRISPR-Cas9 gene drive dynamics in invasive rodent management

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E. A. Brown, S. R. Eikenbary and W. G. Landis,  Risk Analysis,  2022-05-14 07:22:34.
Gene drive technology has been proposed to control invasive rodent populations as an alternative to rodenticides. However, this approach has not undergone risk assessment that meets criteria established by Gene Drives on the Horizon, a 2016 report by the National Academies of Sciences, Engineering, and Medicine. To conduct a risk assessment of gene drives, we employed the Bayesian network-relative risk model to calculate the risk of mouse eradication on Southeast Farallon Island using a CRISPR-Cas9 homing gene drive construct. We modified and implemented the R-based model "MGDrivE" to simulate and compare 60 management strategies for gene drive rodent management. These scenarios spanned four gene drive mouse release schemes, three gene drive homing rates, three levels of supplemental rodenticide dose, and two timings of rodenticide application relative to gene drive release. Simulation results showed that applying a supplemental rodenticide simultaneously with gene drive mouse deployment resulted in faster eradication of the island mouse population. Gene drive homing rate had the highest influence on the overall probability of successful eradication, as increased gene drive accuracy reduces the likelihood of mice developing resistance to the CRISPR-Cas9 homing mechanism.

Governing Gene Drive Technologies: A Qualitative Interview Study

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N. de Graeff, K. R. Jongsma, J. E. Lunshof and A. L. Bredenoord,  AJOB Empirical Bioethics,  13:107-124. 2022-04-04 12:10:12.
Gene drive technologies (GDTs) bias the inheritance of a genetic element within a population of non-human organisms, promoting its progressive spread across this population. If successful, GDTs may be used to counter intractable problems such as vector-borne diseases. A key issue in the debate on GDTs relates to what governance is appropriate for these technologies. While governance mechanisms for GDTs are to a significant extent proposed and shaped by professional experts, the perspectives of these experts have not been explored in depth.Methods A total of 33 GDT experts from different professional disciplines were interviewed to identify, better understand, and juxtapose their perspectives on GDT governance. The pseudonymized transcripts were analyzed thematically.Results Three main themes were identified: (1) engagement of communities, stakeholders, and publics; (2) power dynamics, and (3) decision-making. There was broad consensus amongst respondents that it is important to engage communities, stakeholders, and publics. Nonetheless, respondents had diverging views on the reasons for doing so and the timing and design of engagement. Respondents also outlined complexities and challenges related to engagement. Moreover, they brought up the power dynamics that are present in GDT research. Respondents stressed the importance of preventing the recurrence of historical injustices and reflected on dilemmas regarding whether and to what extent (foreign) researchers can legitimately make demands regarding local governance. Finally, respondents had diverging views on whether decisions about GDTs should be made in the same way as decisions about other environmental interventions, and on the decision-making model that should be used to decide about GDT deployment.Conclusions The insights obtained in this interview study give rise to recommendations for the design and evaluation of GDT governance. Moreover, these insights point to unresolved normative questions that need to be addressed to move from general commitments to concrete obligations.

Prescribing engagement in environmental risk assessment for gene drive technology

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S. Hartley, A. Kokotovich and C. McCalman,  Regulation and Governance,  2022-03-29 08:17:38.
Abstract Gene drive technology is a nascent biotechnology with the potential to purposefully alter or eliminate a species. There have been broad calls for engagement to inform gene drive governance. Over the past seven years, the gene drive community has been developing risk assessment guidelines to determine what form future gene drive risk assessments take, including whether and how they involve engagement. To explore who is developing these guidelines and how engagement in risk assessment is being prescribed, we conduct a document analysis of gene drive risk assessment guideline documents from 2014 to 2020. We found that a narrow set of organizations have developed 10 key guideline documents and that with only one exception the documents prescribe a narrow, vague, or completely absent role for engagement in gene drive risk assessment. Without substantively prescribed engagement in guidelines, the relevance, rigor, and trustworthiness of gene drive risk assessment and governance will suffer.

Opening up, closing down, or leaving ajar? How applications are used in engaging with publics about gene drive

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A. W. Russell, A. Stelmach, S. Hartley, L. Carter and S. Raman,  Journal of Responsible Innovation,  2022-03-22 12:32:50.
Public engagement and responsible innovation are strongly emphasised in gene drive research, together with the goal of addressing societal challenges, notably, malaria and environmental conservation. We aim to explore whether public engagement is used to ‘open up' or ‘close down' opportunities to shape gene drive research. Drawing on interviews with gene drive developers and stakeholders, we investigate how the public communication of gene drive is conceived. We find that traditional closing-down tendencies remain, but that there are new and encouraging opening-up approaches. Consistent with responsible innovation thinking, these frame gene drive as multifaceted, context-dependent and requiring deeper deliberation. We also identify a third ‘leaving ajar’ approach that seeks to engage with and respond to local communities and modify technological applications to be more acceptable. Innovation system constraints may well temper current aspirations to open up; framing public conversations around understandings of public good could offer a way forward.

Could species-focused suppression of Aedes aegypti, the yellow fever mosquito, and Aedes albopictus, the tiger mosquito, affect interacting predators? An evidence synthesis from the literature

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J. A. S. Bonds, C. M. Collins and L.-C. Gouagna,  Pest Management Science,  2022-03-16 07:20:33.
The risks of Aedes aegypti and Aedes albopictus nuisance and vector-borne diseases are rising and the adverse effects of broad-spectrum insecticide application has promoted species-specific techniques, such as sterile insect technique (SIT) and other genetic strategies, as contenders in their control operations. When specific vector suppression is proposed, potential effects on predators and wider ecosystem are some of the first stakeholder questions. These are not the only Aedes vectors of human diseases, but are those for which SIT and genetic strategies are of most interest. They vary ecologically and in habitat origin, but both have behaviourally human-adapted forms with expanding ranges. The aquatic life stages are where predation is strongest due to greater resource predictability and limited escape opportunity. These vectors' anthropic forms usually use ephemeral water bodies and man-made containers as larval habitats; predators that occur in these are mobile, opportunistic and generalist. No literature indicates that any predator depends on larvae of either species. As adults, foraging theory predicts these mosquitoes are of low profitability to predators. Energy expended hunting and consuming will mostly outweigh their energetic benefit. Moreover, as adult biomass is mobile and largely disaggregated, any predator is likely to be a generalist and opportunist. This work, which summarises much of the literature currently available on the predators of Ae. aegypti and Ae. albopictus, indicates it is highly unlikely that any predator species depends on them. Species-specific vector control to reduce nuisance and disease is thus likely to be of negligible or limited impact on non-target predators

Regulation of genetically engineered (GE) mosquitoes as a public health tool: a public health ethics analysis

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Z. Meghani,  Globalization and Health,  18:21. 2022-02-21 08:33:18.
In recent years, genetically engineered (GE) mosquitoes have been proposed as a public health measure against the high incidence of mosquito-borne diseases among the poor in regions of the global South. While uncertainties as well as risks for humans and ecosystems are entailed by the open-release of GE mosquitoes, a powerful global health governance non-state organization is funding the development of and advocating the use of those bio-technologies as public health tools.

An Ethical Overview of the CRISPR-Based Elimination of Anopheles gambiae to Combat Malaria

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I. J. Wise and P. Borry,  Journal of Bioethical Inquiry,  2022-02-17 09:30:10.
Approximately a quarter of a billion people around the world suffer from malaria each year. Most cases are located in sub-Saharan Africa where Anopheles gambiae mosquitoes are the principal vectors of this public health problem. With the use of CRISPR-based gene drives, the population of mosquitoes can be modified, eventually causing their extinction. First, we discuss the moral status of the organism and argue that using genetically modified mosquitoes to combat malaria should not be abandoned based on some moral value of A. gambiae. Secondly, we argue that environmental impact studies should be performed to obtain an accurate account of the possible effects of a potential eradication of the organism. However, the risks from the purposeful extinction of A. gambiae should not overtake the benefits of eradicating malaria and risk assessments should be used to determine acceptable risks. Thirdly, we argue that the eventual release of the genetically modified mosquitoes will depend on transparency, community involvement, and cooperation between different nations.

A Closing Window of Opportunity for Gene Drive Governance in the United States

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K. L. Warmbrod, M. Montague and G. K. Gronvall,  Health Security,  20:3-5. 2022-02-15 09:35:05.
The COVID-19 pandemic has brought forth a number of biotechnological advances to enhance the public's health: new diagnostic tests, mRNA vaccines, and new antiviral medications. Biotechnology is also being used to address global challenges like climate change, food insecurity, and building the bioeconomy, which directly or indirectly improve public health. Gene drives are one such biotechnology. They are genetically engineered systems that can alter the inheritance patterns in a host species, such as a mosquito, so that a greater percentage of its progeny inherit a specific desired trait. Research and investments in biotechnology have been used to reduce arthropod-borne infectious diseases, such as malaria and Zika, and to manage or eliminate invasive species.2 Funding thus far has been adequate. For example, Target Malaria, a global consortium of researchers developing a gene drive to decrease the burden of malaria, has an average of US$11.5 million per year in funding.3 Although no gene drive has been released into the environment yet, technologies with similar attributes have been released in field trials, notably by Oxitec in Florida

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