Controlling Malaria Mosquitoes With Genetics

A chemical-free eradication method for the human malaria mosquito, Anopheles gambiae, that is self-sustaining and requires no additional inputs beyond ‘pushing the button’ to get it started, sounds fantastic.

For geneticists it has not been terribly difficult to think of ways this could be accomplished but putting theory to practice has been a different matter altogether.

Galizi and collaborators (2014) report laboratory results that show significant progress has been made in assembling the right genetic bits and pieces, and getting all of them to behave as planned in Anopheles gambiae. Using insect genetic modification technologies they ‘made’ a strain of Anopheles gambiae which, when released into caged populations in the laboratory, cause those populations to go extinct in less than 10 generations.


Genetically Modified Anopheles gambiae

Here is how they did it.

Galizi et al. have been working with an enzyme (I-PpoI) found in a common slime mold, Physarum polycephalum. This enzyme is called a homing endonuclease or a meganuclease and while the biology of these enzymes and the genes that encode them are interesting in their own right, Galizi et al. were only interested in the fact that this enzyme could cut DNA at specific sequences that are very rare in most genomes.

These investigators found quite by chance that some essential genes (ribosomal RNA genes) on the X chromosome of Anopheles gambiae contained  cleavage sites for I-PpoI.

Galizi et al. did two things at this point.

First, they did some clever protein engineering to make a version of I-PpoI that was very unstable and quickly lost activity soon after it was made. This was actually a key piece of the puzzle.

Second, they inserted the gene encoding this unstable I-PpoI into the genome of Anopheles gambiae using fairly routine methods (transposon vectors) such that the gene would only be expressed in developing sperm. Technically, they accomplished this by using the promoter from the gene beta-Tubulin, which is expressed only during sperm development, to regulate the expression of I-PpoI. So, I-PpoI was only made in developing sperm.


Sex Ratio Distortion Scheme

The system works like this. In Anopheles gambiae, females are XX and males are XY. In males with the sperm-specifically-expressed I-PpoI the X chromosomes are cut and destroyed by the enzyme, resulting in sperm that only carry Y-chromosomes. Normal females found in nature (XX) mated to these males will only produce males (XY) since none of the sperm contain X-chromosomes. Because the I-PpoI used in this experiment was highly unstable it quickly became inactive and consequently had no affect on the X chromosomes in the male embryos of the next generation until they too began to make sperm.

The upshot of this is that every time a male expressing I-PpoI mates to a female, only males expressing I-PpoI will be produced. They will mate with females and only produce males and eventually the population “crashes” because there are no more females – at least this is how it is suppose to work and Galizi et al’s results in the laboratory showed that this was pretty much how it did worked.

An attractive feature of this insect control strategy is its self-sustainability. A small introduction of these “special” males could initiate a chain reaction that spreads through the pest population resulting in its extinction.

There is more to be done to investigate this system in the laboratory but Galize et al. have created a pest control system that had been theorized many years ago. This is a nice example of the use of insect genetic technologies and their application to a problem of great significance.

A synthetic sex ratio distortion system for the control of the human malaria mosquito
Roberto Galizi, Lindsey A. Doyle, Miriam Menichelli, Federica Bernardini, Anne Deredec, Austin Burt, Barry L. Stoddard, Nikolai Windbichler & Andrea Crisanti
Nature Communications 5, Article number: 3977 doi:10.1038/ncomms4977

This is an open access publication.



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