Title: Synergizing Two Forms of Vector Control: Insecticides and Gene Drive
Funder: The Academy of Medical Sciences

Abstract: Insecticide-based control of mosquitoes has driven the recent huge gains in malaria control, yet insecticide resistance necessitates both new control approaches and ways to combine approaches that drastically reduce the overall likelihood of resistance. My recent research has demonstrated a new form of genetic control, called gene drive, that can spread a genetic element rapidly in a population and cause its suppression. The gene drive, based on a modified CRISPR element, effectively acts as a very specific form of genomic parasite designed to recognise and disrupt a target sequence in any essential mosquito gene, copying itself in the process. I have shown that gene drives are also subject to resistance, in the form of sequence variation at the target site. Both forms of control show similarities in the dynamics of selection and spread of resistance yet show completely independent modes of action. After initial suppression, insecticide programs can leave a residual resistant population that shows drastically reduced genomic variation (‘selective sweeps’) making it more susceptible to subsequent control by gene drive. Conversely, it should be possible to engineer gene drives in a way that, after causing long term suppression, any residual population is newly susceptible to insecticide. Therefore, this Springboard will show proof of principle and feasibility for the wider approach of synergizing insecticides and gene drive by achieving these objectives: Objective1: Test CRISPR-based gene drives that target conserved genes within insecticide-induced selective sweeps. Objective2: Show feasibility of targeting insecticide-resistant alleles and converting these to susceptible alleles.

Lay abstract: One third of the world’s population is at risk of malaria, a parasitic disease infecting more than 200 million people every year resulting in 400,000 deaths. Human-to-human transmission occurs through the bite of a female mosquito when she takes repeated blood meals needed to develop her eggs. Only a handful of mosquito species are responsible for the bulk of malaria transmission. The best way to control malaria is to control the mosquito populations that transmit it - over the last 15 years malaria deaths have been halved largely through the use of insecticide-treated bednets and insecticide spraying. Due to insecticide resistance, other mosquito control methods are needed to augment and complement insecticide-based approaches. One such method is ‘gene drive’, which I have recently shown can work in the mosquito. The gene drive is a genetic element designed to copy itself every time a mosquito reproduces, meaning that a disproportionate number of offspring receive it every generation. The gene drive is designed as a mosquito-specific genetic parasite, disrupting essential genes and thereby suppressing the population as it spreads. Just as with insecticides, mosquitoes can develop resistance to gene drives. Since the mechanism of action of each control method is different however, resistance to one approach will not provide compromise the other. Moreover, resistant populations that survive insecticides are less genetically diverse, increasing their susceptible to targeting by gene drive. This project investigates combining gene drives and insecticides to increase the effect of each approach and delay the overall emergence of resistance.

Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION