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

Abstract

Background Population suppression gene drive has been proposed as a strategy for malaria vector control. A CRISPR-Cas9-based transgene homing at the doublesex locus (dsxFCRISPRh) has recently been shown to increase rapidly in frequency in, and suppress, caged laboratory populations of the malaria mosquito vector Anopheles gambiae. Here, problem formulation, an initial step in environmental risk assessment (ERA), was performed for simulated field releases of the dsxFCRISPRh transgene in West Africa. Methods Building on consultative workshops in Africa that previously identified relevant environmental and health protection goals for ERA of gene drive in malaria vector control, 8 potentially harmful effects from these simulated releases were identified. These were stratified into 46 plausible pathways describing the causal chain of events that would be required for potential harms to occur. Risk hypotheses to interrogate critical steps in each pathway, and an analysis plan involving experiments, modelling and literature review to test each of those risk hypotheses, were developed. Results Most potential harms involved increased human (n = 13) or animal (n = 13) disease transmission, emphasizing the importance to subsequent stages of ERA of data on vectorial capacity comparing transgenics to non-transgenics. Although some of the pathways (n = 14) were based on known anatomical alterations in dsxFCRISPRh homozygotes, many could also be applicable to field releases of a range of other transgenic strains of mosquito (n = 18). In addition to population suppression of target organisms being an accepted outcome for existing vector control programmes, these investigations also revealed that the efficacy of population suppression caused by the dsxFCRISPRh transgene should itself directly affect most pathways (n = 35). Conclusions Modelling will play an essential role in subsequent stages of ERA by clarifying the dynamics of this relationship between population suppression and reduction in exposure to specific potential harms. This analysis represents a comprehensive identification of plausible pathways to potential harm using problem formulation for a specific gene drive transgene and organism, and a transparent communication tool that could inform future regulatory studies, guide subsequent stages of ERA, and stimulate further, broader engagement on the use of population suppression gene drive to control malaria vectors in West Africa.

Potential use of gene drive modified insects against disease vectors, agricultural pests and invasive species poses new challenges for risk assessment

“…Some international/ regional entities have suggested that the risk assessment of GDMIs can build on existing risk assessment frameworks for GMIs that do not contain engineered GDs, and be informed by the experience gained releasing insects for genetic and biological disease vector/ pest control. Moreover, the problem formulation approach has been acknowledged to provide a compelling framework to organize existing knowledge and identify relevant new knowledge and uncertainties on engineered GDs to support case-specific risk assessments and decision-making [15,95,98]. It is also recognized that there are specific areas where further guidance may be needed for the risk assessment of GDMIs [15,86].…”

“…The problem formulation, which serves as the starting point for conducting a risk assessment, can be applied in case-by-case evaluations of GDMI releases [3,71,77,90,98]. Precedents suggest that the problem formulation approach provides a compelling framework to organize existing knowledge and identify relevant new knowledge and uncertainties on engineered GDs to support case-specific risk assessments and decisionmaking [3,71,77,98].…”

“…The problem formulation, which serves as the starting point for conducting a risk assessment, can be applied in case-by-case evaluations of GDMI releases [3,71,77,90,98]. Precedents suggest that the problem formulation approach provides a compelling framework to organize existing knowledge and identify relevant new knowledge and uncertainties on engineered GDs to support case-specific risk assessments and decisionmaking [3,71,77,98]. The approach involves (Figure 1), (1) identifying protection goals and making them operational in risk assessment, (2) devising plausible pathways to harm that describe how a release could be harmful, (3) formulating risk hypotheses about the likelihood and severity of such events, (4) identifying the information needed to test risk hypotheses, and (5) developing plans to acquire new data for hypothesis testing if tests with existing information are insufficient for decision-making [15,[81][82][83][84].…”

Modeling the efficacy of CRISPR gene drive for schistosomiasis control

“…Its potential uses include controlling diseases, invasive species, and pests by spreading targeted genes through a population faster than traditional Mendelian inheritance allows [4]. For example, there are currently large efforts to harness genetic technology targeting mosquito species that are vectors of malaria and other vector-borne diseases [5][6][7][8][9]. Similar efforts could be on the horizon for schistosomiasis, a debilitating disease of poverty caused by blood flukes of the genus Schistosoma [10].…”

Population replacement gene drive characteristics for malaria elimination in a range of seasonal transmission settings: a modeling study

“…Because the potential harms and possible ecological risks associated with releasing gene drive mosquitoes into the wild have not yet been well established, it is not currently feasible or ethical to test such releases in the field. Community understanding, support, and buy-in are also needed before gene drive mosquito releases can proceed [28][29][30]. Modeling is therefore a key step needed to quantify both the potential benefits and harmful impacts of gene drive mosquito release.…”