Can we make mosquitoes resist malaria?
A new gene drive approach is promising but needs further development
Gene drives were in the news again recently, and readers of this blog will know that I’m strongly in favor of using them to end malaria, which kills over 600,000 people per year. Previously, I’ve written about gene drives which cause female-specific sterility in mosquitoes, leading to collapse of mosquito populations.
Now, researchers from Ethan Bier’s lab have demonstrated a different approach. Instead of a gene drive causing sterility, they engineered a drive which makes mosquitos resistant to infection with the malaria parasite. Although this drive currently doesn’t work as well as the ones that cause sterility, in the future it could be a useful approach to combat malaria.
How does this work?
After a mosquito eats blood infected with malaria parasites, the parasites move from the mosquito’s gut to its salivary gland, whence they can then spread to the mosquito’s next victim. However, a variant allele of the mosquito FREP1 gene can prevent the malaria parasite from escaping the mosquito’s gut. The researchers engineered a gene drive to spread the resistant FREP1 allele through a population of Anopheles stephensi mosquitoes.1
The drive consists of a guide RNA expression cassette inserted into an intron of FREP1, close to the variant site of the resistant allele. In order to track the spread of the drive, it also contains a fluorescent protein expression cassette (either GFP or RFP). When supplied with a separate source of Cas9, the guide RNA will cut the wild-type FREP1 allele, and the mosquito will use the gene drive FREP1 allele as a repair template.
The researchers showed that the resistant FREP1 allele doesn’t negatively impact mosquito reproduction, but greatly decreases the number of malaria parasites able to infect the mosquito salivary glands. When fed with infected blood, 80% of wild-type mosquitoes carried malaria, but only 30% of resistant mosquitoes did. Finally, the researchers showed that their gene drive could spread through a population of mosquitoes expressing Cas9 in their germline cells.
How might this be better than other gene drives?
Compared to the other gene drives I’ve written about (which cause female-specific sterility), this gene drive would spread faster through mosquito populations since both males and females could spread it. Furthermore, there would not be any selection pressure for drive resistance among mosquitoes. Finally, in theory it would address the "mosquitoes are important for ecosystems" objection. However, in practice, people who hate GMOs will probably just invent a new objection to this gene drive.
What are the next steps?
This is a promising demonstration, but if I were a peer reviewer for Nature,2 I would have asked them to show a few more things:
As currently designed, the drive needs a separate source of Cas9 in order to spread, so it wouldn’t work in the wild. Can the drive be re-engineered with Cas9 (or a smaller Cas gene) in place of the fluorescent protein marker? Alternatively, can a second, separate gene drive spread Cas9 in a neutral safe-harbor site?
Does the drive work in A. gambiae? This mosquito species is responsible for most malaria deaths worldwide, so it’s a bit puzzling why the researchers chose to use A. stephensi instead. Did they try it in A. gambiae and it didn’t work? Or perhaps because they already had a strain of A. stephensi expressing Cas9 from a previous paper, it was easier to use that.
Is the reduction in malaria parasite load enough to be clinically meaningful in preventing malaria infection? For example, if someone gets bitten by 10 mosquitoes per day,3 does it matter if 8 or 3 of them carry malaria if all it takes is one infected bite?
How easily could malaria parasites evolve resistance?
Overall, I still think the best approach is to eliminate mosquito populations using sterility-inducing gene drives. But if that doesn’t work, then this could be a good backup option.
Thanks to Richard Fuisz and Eryney Marrogi for inspiring me to write about this paper. If you’re interested in gene drives, you should also check out Eryney’s post on them.
A. stephensi is the main species which transmits malaria in Asia. By contrast, A. gambiae, which transmits malaria in Africa, is responsible for most malaria deaths worldwide.
Nature often publishes the reviewers’ comments, but unfortunately not for this paper. I’m curious to see what they said.
This number is a guess, but I’ve certainly had more than 10 bites per day on some bad camping trips. And this drive, unlike drives which sterilize mosquitoes, wouldn’t reduce the frequency of mosquitoes biting people.