Mosquitoes swat back via resistance to CRISPR gene drive

What’s more worrisome, potential disease-carrying mosquitoes or releasing self-perpetuating CRISPR gene drive out into the wide world to combat them?

We know how the mosquitoes would answer that question, right?

And they are fighting back, in a sense, at least in the context of experiments.

Mosquitoes were able to develop resistance to gene drive intended to harm their population in intriguing even if disappointing recent studies as reported in an excellent piece by Ewen Callaway over at Nature.

This area of study has big health implications. Mosquitos don’t just make annoying sounds (see YouTube video above), but also carrying sometimes fatal diseases including the major killer malaria.

It turns out that mosquitoes have ways of resisting gene drive that for instance makes females infertile. These mechanisms include several key resistance pathways:

CRISPR Indels that stop the gene drive in its tracks by making the target sequence no longer targetable.

Natural variation in the mosquito genome, even in supposedly the “same” kind of mosquitoes is a source of resistance too. Apparently mosquitoes have extreme genetic diversity so those target sequences that CRISPR-Cas9 is supposed to cut for the gene drive to work are not present in all the mosquitoes and naturally the ones that have a DNA sequence not recognized by the gene drive will take over relative to their targetable counterparts.

Isolated, untargeted subpopulations of mosquitoes may evolve phenotypically to not breed with other populations that are vulnerable.

Jill George, NIH

Can scientists overcome these issues with next generations of gene drives? Nobody can be sure, but all in all these and other factors have put a wet blanket on the idea of gene drive working efficiently out in the real world to target mosquitoes and other disease-carries.

A team in Italy, Target Malaria, which is spending millions to gear up for studies of gene drives to target mosquitoes is proceeding anyway and are quoted in Callaway’s piece:

“The Target Malaria team has developed a second generation of gene-drive mosquitoes, hoping to slow the development of resistance, says Andrea Crisanti, a molecular parasitologist at Imperial College London. The researchers plan to test them in their new Italian facility later this year to get a sense of how the mosquitoes might fare in the wild. But molecular biologist Tony Nolan, also at Imperial, expects evolution to throw up some surprises. He says that his greatest worry about gene drives is that they simply won’t work.”

I don’t agree with that last statement about risks as gene drives could be harmful to the environment, but in the immediate future simply getting indications that gene drives can work against the evolutionary forces of resistance is the top priority for that and other teams.

3 thoughts on “Mosquitoes swat back via resistance to CRISPR gene drive”

  1. Thanks for this excellent explanation, Paul.

    I was reading yesterday about the advisory referendum in the Florida Keys about Oxitec’s proposed release of GM mosquitoes. The county voted yes (57% in favor), but the residents of the specific release site voted no (65% against).

    What interested me most, however, was this response from Oxitec’s chief science officer to the question of vector competence:

    “Simon Warner, Oxitec’s chief scientific officer in Abingdon, U.K., says there’s no reason to think their lab strain—descendants of mosquitoes collected in Cuba, crossed with a Mexican strain—would be any more dangerous than another strain of A. aegypti. ‘Vector competence is not a question that we’ve been asked by the [FDA] regulators,’ he says. ‘We haven’t studied it, because we don’t think it’s a concern.'”

    (excerpt from Science,

    That last bit blows my mind: “We haven’t studied it, because we don’t think it’s a concern.”

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