The End of Malaria?

“This breakthrough shows that gene drive can work, providing hope in the fight against a disease that has plagued mankind for centuries.”–A. Crisanti

    Each year malaria causes about a half million deaths worldwide.  In Africa it kills a child every two minutes.  The disease is caused by a microscopic parasite, Plasmodium that infects red blood cells, producing symptoms like fever, chills and anemia that can lead to coma and death.  While several species of mosquitoes in the genus Anopheles can spread malaria, one, A. gambiae is the prime disease vector.  Now a report in the November 2018 issue of Nature Biotechnology has employed a gene drive to eradicate this disease-carrying mosquito.  Gene drives disobey normal inheritance rules, forcing themselves onto all an organism’s progeny and spreading rapidly through a population.

    A research team, led by Andrea Crisanti, Imperial College London, UK, used a powerful new gene editing tool called CRISPR* to mutate a gene to make lab female mosquitoes sterile.  CRISPR contains two molecular components: (1) The Guide RNA has an RNA sequence that can be custom designed to seek out and bind to a specific DNA sequence; (2) Cas9* is an enzyme that cuts out the targeted DNA sequence and allows a different one to replace it.

    Crisanti et al. selectively altered the wild type doublesex (dsx) gene that determines sex in insects by injecting A. gambiae embryos with a CRISPR that targeted the normal dsx gene and replaced it with a mutated version (dsxF-).  Females with two copies of the mutant gene have altered mouth parts that prevent them from biting to get a blood meal.  Thus, they are unable to produce eggs and are sterile.

     A mutation causing sterility would normally be hugely disadvantageous in the wild and quickly wiped out.  So the team changed the odds to favor inheriting dsxF- by attaching CRISPR to the mutated gene to create a gene drive that could spread the mutation among caged wild type mosquitoes. Since mutant mosquitoes are sterile they used non-sterile hybrids carrying one mutant and one wild type gene.

    When wild type (dsx/dsx) and hybrid (dsx/dsxF-) mosquitoes mate the dsxF- gene would normally be inherited by only 50% of each new generation. This is because each progeny receives a chromosome from each parent.   But the new gene drive composed of CRISPR and dsxF- changed the inheritance pattern.   Half the progeny still inherit one chromosome with dsx and the other with dsxF-, but the dsxF--containing chromosome also contains CRISPR.  Now CRISPR can excise dsx on the adjacent chromosome inducing the cell to repair the damage by copying CRISPR and dsxF- onto the chromosome that previously lacked them.  This effectively converts the wild type gene into the mutant (see Figure).

    The scientists expected the new gene drive to spread dsxF- throughout each new generation until all the females were sterile and that is exactly what happened. They set up two laboratory cages containing hundreds of wild type and hybrid mosquitoes and let them mate.  They randomly picked 650 eggs laid by these mosquitoes to start the next generation, and repeated the process for each new generation.  One cage yielded no progeny by the 8th generation and other by the 12th.

    By making a laboratory population of Anopheles mosquitoes go extinct, the scientists have caused some to worry about releasing such genetically modified mosquitoes in the wild.  Suppose the gene drive somehow transfers itself to honeybees?  Others are concerned that the mosquitoes in the wild may develop resistance to the gene drive, blocking its spread.  But while lab mosquitoes developed resistance to other gene drives, that didn’t happen here.  “We have a solution to the functional resistance that arises in gene drives,” says team member Kyros Kyrou.

    Crisanti is also part of the “Target Malaria” project, an international consortium funded by the Bill and Melinda Gates Foundation, which has received permission to release gene drive mosquitoes in three African countries.  In January 2019 they released 10,000 mosquitoes genetically modified to cause male sterility but lacking a gene drive in a Burkina Faso village to study the impact on the wild mosquito population.

    The group plans to release mosquitoes with the dsxF- gene drive in 2024.  Stay tuned.

Saul Scheinbach

*CRISPR = Clusters of Regularly Interspersed Short Palindromic Repeats

*Cas9 = CRISPR associated protein 9

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