Small-scale release of non-gene drive mosquitoes in Burkina Faso: from engagement implementation to assessment, a learning journey.

BACKGROUND: Innovative tools are needed to complement the existing approach for malaria elimination. Gene drive mosquitoes are one potential new technology in the control of malaria vectors. Target Malaria is one of the research projects developing this technology, and in July 2019, the project proceeded to an important step for this evaluation pathway: the small-scale release of non-gene drive sterile male mosquitoes in a village in Burkina Faso. In addition to the entomological and laboratory work to prepare for this important milestone, significant community and stakeholder engagement work was done. The existing guidelines on gene drive mosquito provide an overall framework for such engagement work. However, they do not provide a road map on how to proceed or what benchmarks should be used to assess this work. METHODS: This study provides a review of engagement activities relevant to field trials on non-gene drive genetically-modified mosquitoes as well as an assessment framework-using both qualitative and quantitative studies as well as an audit procedure. The latter was implemented to evaluate whether the release activities could proceed with the appropriate level of agreement from the community. RESULTS: This paper shows the importance of this first phase of work to innovate and learn about engagement processes for responsible research in the field of genetic approaches for malaria vector control. The function of these assessments is crucial for the learning agenda. The assessments demonstrated ways to increase understanding and ensure effective progress with field studies and, therefore, the pathway for responsible research. CONCLUSION: Gene drive technology is increasingly considered as a promising approach to control vector borne diseases, in particular malaria. Stakeholders' involvement in this research process is one of the recurring requirements in international guidance documents. With this paper Target Malaria offers an opportunity to explore the practical achievements and challenges of stakeholder engagement during early phases of a technology evaluation, and in particular how it implemented an assessment framework to learn from its experience.

Embracing Dynamic Models for Gene Drive Management.

Robust methods of predicting how gene drive systems will interact with ecosystems is essential for safe deployment of gene drive technology. We describe how quantitative tools can reduce risk uncertainty, streamline empirical research, guide risk management, and promote cross-sector collaboration throughout the process of gene drive technology development and implementation.

The ethical landscape of gene drive research.

Gene drive technology has immense potential. The ability to bypass the laws of Mendelian inheritance and almost ensure the transmission of specific genetic material to future generations creates boundless possibilities. But alongside these boundless possibilities are major social and ethical issues. This article aims to introduce gene drive technology, some of its potential applications, and some of the social and ethical issues that arise during research into the technology. For example, is investigation into gene drives hubristic? Would applications of gene drives count as technological fixes? Or does research into such a technology sit on a slippery slope or lock us in to its full-scale use? Are there perverse effects of engaging in research, and, most importantly, who ought to be included in the decision-making process regarding research and field trials? Understanding the basic ethical landscape of this technology will prove invaluable to the public, scientists, and policy-makers as research moves forward.

Daisy-chain gene drives for the alteration of local populations.

If they are able to spread in wild populations, CRISPR-based gene-drive elements would provide new ways to address ecological problems by altering the traits of wild organisms, but the potential for uncontrolled spread tremendously complicates ethical development and use. Here, we detail a self-exhausting form of CRISPR-based drive system comprising genetic elements arranged in a daisy chain such that each drives the next. "Daisy-drive" systems can locally duplicate any effect achievable by using an equivalent self-propagating drive system, but their capacity to spread is limited by the successive loss of nondriving elements from one end of the chain. Releasing daisy-drive organisms constituting a small fraction of the local wild population can drive a useful genetic element nearly to local fixation for a wide range of fitness parameters without self-propagating spread. We additionally report numerous highly active guide RNA sequences sharing minimal homology that may enable evolutionarily stable daisy drive as well as self-propagating CRISPR-based gene drive. Especially when combined with threshold dependence, daisy drives could simplify decision-making and promote ethical use by enabling local communities to decide whether, when, and how to alter local ecosystems.

Considerations for the governance of gene drive organisms.

Governance is a broader and more flexible concept than statute-driven regulations as it incorporates components outside the latter's remit. Considerations of governance are critical in the development of emerging biotechnologies such as gene drive organisms. These have been proposed or are being developed to address public and environmental health issues not addressed easily by conventional means. Here, we consider how the concept of governance differs from statute-driven regulation with reference to the role each may play in the development of gene drive organisms. First, we discuss existing statute-based regulatory systems. Second, we consider whether novel risks or different concerns derive from gene drive organisms, concentrating on characteristics that contribute to public health or environmental risk and uncertainties that may affect risk perceptions. Third, we consider public engagement, outlining how existing statute-driven regulatory systems and other governance mechanisms may provide opportunities for constructive interactions. Finally, we provide some observations that may help address science- and values-based concerns in a governance space larger than that of statute-driven regulatory systems.

Pathway to Deployment of Gene Drive Mosquitoes as a Potential Biocontrol Tool for Elimination of Malaria in Sub-Saharan Africa: Recommendations of a Scientific Working Group†.

Gene drive technology offers the promise for a high-impact, cost-effective, and durable method to control malaria transmission that would make a significant contribution to elimination. Gene drive systems, such as those based on clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein, have the potential to spread beneficial traits through interbreeding populations of malaria mosquitoes. However, the characteristics of this technology have raised concerns that necessitate careful consideration of the product development pathway. A multidisciplinary working group considered the implications of low-threshold gene drive systems on the development pathway described in the World Health Organization Guidance Framework for testing genetically modified (GM) mosquitoes, focusing on reduction of malaria transmission by Anopheles gambiae s.l. mosquitoes in Africa as a case study. The group developed recommendations for the safe and ethical testing of gene drive mosquitoes, drawing on prior experience with other vector control tools, GM organisms, and biocontrol agents. These recommendations are organized according to a testing plan that seeks to maximize safety by incrementally increasing the degree of human and environmental exposure to the investigational product. As with biocontrol agents, emphasis is placed on safety evaluation at the end of physically confined laboratory testing as a major decision point for whether to enter field testing. Progression through the testing pathway is based on fulfillment of safety and efficacy criteria, and is subject to regulatory and ethical approvals, as well as social acceptance. The working group identified several resources that were considered important to support responsible field testing of gene drive mosquitoes.

Developing standard operating procedures for gene drive research in disease vector mosquitoes.

Numerous arthropod species represent potential targets for gene-drive-based population suppression or replacement, including those that transmit diseases, damage crops, or act as deleterious invasive species. Containment measures for gene drive research in arthropods have been discussed in the literature, but the importance of developing safe and effective standard operating procedures (SOPs) for these types of experiments has not been adequately addressed. Concisely written SOPs link safe work practices, containment measures, institutional training, and research-specific protocols. Here we discuss information to be considered by principal investigators, biosafety officers, and institutional biosafety committees as they work together to develop SOPs for experiments involving gene drive in arthropods, and describe various courses of action that can be used to maintain the effectiveness of SOPs through evaluation and revision. The information provided herein will be especially useful to investigators and regulatory personnel who may lack extensive experience working with arthropods under containment conditions.