Each year, 263 million people get malaria. But from the parasite's perspective, infecting humans is harder than you might think, and requires completing an epic journey within the tiny body of a mosquito.
First, the mosquito must suck the blood of an individual infected with malaria — bringing the Plasmodium parasite into the insect's gut. Then the parasite must travel to the critter's salivary glands, where it's poised to be injected into the mosquito's next victim via a bite.
Now a team of researchers have found a way to interrupt this crucial journey.
By using gene editing to make a tiny tweak to the mosquito's genome — one that changes just a single amino acid — parasites were largely prevented from reaching their final destination. The change effectively rendered laboratory mosquitoes highly resistant to spreading malaria, researchers report Wednesday in Nature.
"The idea that you could change just one amino acid and not have the parasite transmitted is a pretty big deal," says Fred Gould, an entomologist at North Carolina State University who wasn't involved in the study. "It's really exciting."
That tiny tweak could be spread through a whole mosquito population using a gene drive, a genetic technology that breaks the normal 50-50 rules of inheritance. Gene drives are sequences of DNA that can be inserted into the genome of an individual and cause a specific mutation or gene to be passed on to virtually all offspring, instead of just 50%.
Next steps
Eventually, researchers hope to engineer mosquitoes with this approach and release them into the wild.
"These mosquitoes will spread on their own and gradually transform the malaria-transmitting mosquito population to one that cannot transmit malaria," says George Dimopoulos, a biologist at Johns Hopkins University and study co-author.
Dimopoulos isn't claiming this technique will be the final nail in malaria's coffin, and it's far from being ready for release. It'll likely be several years, at least, before field tests, and will require buy-in and approval by local communities and governments. But he argues new genetic tools are needed to quash the disease, since existing ones like bed nets and antimalarial drugs haven't been able to turn malaria — which kills 600,000 a year — into a disease of the past.
What about consequences?
But gene drive technology is controversial.
"Gene drives could have far-reaching, unpredictable negative consequences," says Dana Perls, senior program manager on emerging technologies at Friends of the Earth, an environmental non-profit. Because they distort normal patterns of inheritance, "the genetic changes from a gene drive to a population of mosquitoes are very likely to persist for a long time, possibly permanently."
Critics worry that gene drives designed to spread one tiny change to the genome could end up mutating to affect other parts of the genome. That could result in unanticipated changes spreading fast through a population before researchers would have a chance to stop it, potentially upending the delicate balance of an ecosystem.
Still, researchers are exploring several gene editing strategies. Some aim to suppress mosquito populations by rendering individuals infertile. But there are worries that wiping out mosquitoes could have unintended consequences for ecosystems — for example by removing a food source for birds and bats.
Another strategy is to engineer mosquitoes with new genes that would make proteins that mess with the parasite itself, curbing transmission without harming the bugs.
Dimopoulos and his colleagues wanted to take a different approach, one that messed with the parasite, but without adding an entirely new gene. They settled on a gene called FREP1. It helps mosquitoes feed on blood. But it also appears to be important to the parasites, which use it to complete their crucial journey to the salivary glands in ways researchers don't fully understand.
Some mosquitoes have a small genetic change that seems to disrupt this journey. The researchers used CRISPR, a gene editing technology that can very precisely change the genome, to create two nearly-identical Anopheles stephensi groups, one with the normal FREP1 gene and one with the variant. The variant is very small, changing just one amino acid, the basic building blocks of proteins.
But that small change had big effects.
Mosquitoes with the edited variant have about 5 times fewer infective parasites in the salivary glands, a median of zero compared with thousands in non-edited mosquitoes. There were significantly fewer parasites in the gut, too. Otherwise, the insects appeared perfectly healthy.
It's unclear exactly how much this genetic tweak would impair a mosquito's ability to transmit malaria. But previous research suggests "something on the order of a 90% reduction in malaria transmission would be more or less what you'd expect," says Ethan Bier, a geneticist at the University of California San Diego and study co-author. "I was surprised myself that a single amino acid change could do that."
Next, the researchers showed that they could rapidly spread this beneficial change with a gene drive. It took just 10 generations for the variant to spread to over 90% of their laboratory population.
"It's really excellent work," says Anthony James, a molecular biologist at the University of California Irvine who wasn't involved in the study, but works on introducing new resistance genes to mosquitoes. Since the change is naturally occurring, he says it could be "marginally more acceptable" to people wary of genetic engineering.
"It's good to have more than one approach available," he says. That's especially important if the malaria parasite evolves resistance against these new tools.
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