Game-Changer in Malaria Prevention: CRISPR-Based Genetic Engineering May Eradicate Malaria Vector Anopheles

Although science has come a long way in combating malaria in recent decades, as per the latest World Malaria Report, still 229 million cases were reported in 2019, accounting for 409,000 deaths worldwide. Therefore, mammoth advancements are warranted against surging cases, which pose an increased threat to global health.

In the landmark study, published in Nature, a team of investigators has reported for the first-time successful suppression of a population of malaria-transmitting mosquitoes, Anopheles gambiae, in a year-long experiment mimicking a natural environment.

The team comprising of researchers from the Imperial College, London, Italy’s Polo Genomics Genetics and Biology, and the Liverpool School of Tropical Medicine, utilized “CRISPR-based gene-drive” technology, a novel form of genetic engineering to render the malaria vector, female mosquitoes A. gambiae, a species responsible for most of the malaria transmission in sub-Saharan Africa infertile.

Gene Drive Technology

This technology is potentially a powerful strategy for sustainable vector control by effectively reducing the total number of malaria-spreading mosquitoes by targeting the gene doublesex in female vectors. doublesex is a crucial sex-determining gene that plays a pivotal role in the physiological development of female mosquitoes.

In principle, CRISPR-based gene drives are essentially certain DNA inserts that can rapidly transmit deleterious mutations across populations, thereby enabling the successful elimination of an entire population of malaria mosquitoes.

This technology was first explored in 2003 as a mechanism of cut and paste-the gene drive in the germline to facilitate their autonomous spread. However, it hit a hurdle when researchers discovered that their suppression drives failed to spread after several generations because of the emergence of de novo mutations and the selection of drive-resistant alleles.

In this study, the investigators identified a crucial sex determination gene, doublesex, that was identical across individual A. gambiae mosquitoes. The gene drive was precisely designed against this ultra-conserved and an essential sequence within the female-specific isoform of the doublesex gene that facilitated gene drives to survive longer. Female Anopheles carrying the gene drive in this gene failed to produce offspring resulting in an entire population crash.

Study Results

In this study, the investigators revealed that the doublesex-targeting gene drive strain Ag(QFS)1 effectively suppressed age structured populations reared in large cages that partially mimicked natural surroundings and induced some mosquito behaviors observed in the field. Notably, complete suppression of A. gambiae populations was observed within one year and without selecting for resistance to the gene drive.

Unlike small cages, large indoor cages facilitated complex feeding, mating, resting, and egg-laying behaviors of female vectors. Additionally, investigators performed Bayesian computation that allowed them to draw a retrospective inference of life-history parameters from the large cages and infer a more accurate prediction of gene-drive behavior under more ecologically relevant settings. It allowed informing go/no-go decisions by reducing uncertainty on the efficiency of gene-drive modified mosquitoes.

In conclusion, the findings from this study outline a promising future to create a powerful tool to fight against malaria, which remains one of the world’s most life-threatening diseases. Although generating data to bridge laboratory and field studies for invasive technologies is challenging, this remarkable study represents a paradigm for the stepwise and rational development of vector control tools based on the precision “gene-drive” technology.

Author

Isha Kapoor