Box 2 Problem formulation of the specific use of a population suppression gene drive for malaria vector control in West Africa

A CRISPR-Cas9 transgene homing at the doublesex locus (dsxF^CRISPRh) causes homozygous transgenic females to be both sterile and non-biting [31]. When introduced into both small and large cages of laboratory populations of the malaria mosquito vector Anopheles gambiae, the transgene increases rapidly in frequency, ultimately causing those populations to collapse [31, 74]. Drawing on protection goals identified from a series of consultative workshops in Africa [38], problem formulation as a first stage in an ERA (see Box 1) was used for simulated investigational releases of the dsxF^CRISPRh transgene carrying mosquito in West Africa [21, 48], where the transgene would be expected to act as a non-localized, self-sustaining gene drive. Plausible pathways to potential harm were developed that described the cause-effect chain of events that could lead to 46 discrete potential harms, such as increased disease transmission in humans or reduced ecosystem services [21]. For each pathway, risk hypotheses were developed that would allow future investigation of key individual steps, drawing on data and evidence gathered from an analysis plan to test each of those individual risk hypotheses, in subsequent stages of ERA