My research focuses on the development of synthetic systems in mosquitoes that reduces their ability to cause disease, with great potential for field application.
Female mosquitoes transmit pathogens that cause parasitic diseases such as malaria or filariasis, and viral diseases such as dengue fever, chikungunya, Japanese encephalitis and yellow fever. Where available, drugs and vaccines have been widely used to eliminate the pathogen and reduce the host’s susceptibility, or to reduce symptoms. These are often too expensive for the medical systems of resource-poor countries, whilst pathogen resistance to anti-pathogenic drugs has evolved in areas of extensive use. The mosquito is an attractive target to which control methods can be directed. Identifying a sufficient proportion of the disease-transmitting mosquitoes to effectively apply insecticides for other control methods is often an impossible task. There is, however, one thing that is intrinsically good at seeking out female mosquitoes, and that is the male mosquito.
This naturally evolved mate-seeking behaviour can be exploited to introduce novel traits into a target population. If the released male carries a genetic trait that renders his progeny unable to transmit disease, then the wild mosquito population can be changed to be refractory to disease, known as the population replacement strategy. If he instead passes on a gene that causes his progeny to die, the population can be reduced over time, also breaking the cycle of disease, known as the population suppression strategy. These types of efforts together are termed genetic control.
My focus is on synthetic biology and the manipulation of the mosquito genome to develop mechanisms to spread, or at least to maintain, the desirable traits in the target population despite selective pressure. These so called ‘gene drive’ systems are designed to spread or ‘drive’ tightly linked genes (‘cargo’) through the target population at greater-than Mendelian (‘super Mendelian’) rates; they overcome any fitness costs
During my PhD I developed and characterised an improved genome engineering method in the dengue fever mosquito, Aedes aegypti (PLoS One. 2015 Apr 1;10(4):e0121097). This method allows for the integration of genes of interest into specific pre-inserted target sites in the mosquito genome. I also investigated a panel of genetic regulatory elements and effector genes. This was to develop a novel gene drive system to spread anti-pathogen genes in wild mosquito populations based on an engineered underdominance-like system; this system relies on engineering a selective advantage for mosquitoes carrying synthetic constructs via lethal and rescue systems. This project had mixed success and members of my previous group are building up on my preliminary experiments to optimise the system.
Currently I am working on a project that is developing a pioneering genetic control method that distorts the sex ratio of the malaria-transmitting mosquito, Anopheles gambiae. My colleagues at Crisanti Lab recently developed a fully fertile strain carrying molecular machinery that produces 95% male offspring (Nat Commun. 2014 Jun 10;5:3977). The molecular machinery includes a DNA cutting endonuclease I-PpoI that targets and cuts a repeated sequence on the X chromosome specifically during sperm production. As a result, males carrying this ‘male-biased sex-distorter’ machinery will only produce Y-bearing sperm resulting in male offspring. I am engineering a synthetic gene drive system to ensure that a copy of this sex-distorter gene is inherited by all surviving male offspring. This would lead to spread of the element in a self-sustaining manner. Males will produce mainly sons who will do the same, resulting in the effective spread of the desired trait and eventually causing the population of the malaria-transmitting mosquito to crash.
Ultimately, the goal is to eliminate the roughly 1% of the mosquito population responsible for the spread of malaria. This would help people currently living in endemic areas to avoid deadly illness so that they can improve their lives and that of their children.
et al., 2020, Cellular mechanisms regulating synthetic sex ratio distortion in the Anopheles gambiae germline., Pathog Glob Health, Vol:114, Pages:370-378
et al., 2019, The potential for a released autosomal X-shredder becoming a driving-Y chromosome and invasively suppressing wild populations of malaria mosquitoes
et al., 2019, Engineered action at a distance: Blood-meal-inducible paralysis in Aedes aegypti, Plos Neglected Tropical Diseases, Vol:13, ISSN:1935-2735
et al., 2018, Molecular tools and genetic markers for the generation of transgenic sexing strains in Anopheline mosquitoes, Parasites & Vectors, Vol:11, ISSN:1756-3305
et al., 2015, Site-specific cassette exchange systems in the Aedes aegypti Mosquito and the Plutella xylostella Moth, Plos One, Vol:10, ISSN:1932-6203, Pages:1-16