Malaria kills a half-million Africans a year. Gene-edited mosquitoes might stop it

And now there are two: For the second time in less than a month, scientists are reporting that they used a powerful new genetic technique to change the DNA of mosquitoes in a way that could reduce the spread of malaria and, crucially, that they have “driven” the new trait through a population of the insects.

In the new study, scientists in London modified the insects’ genome to make females sterile, which should cause a malaria-carrying population of mosquitoes to crash. Last month, a group at the University of California announced that inserted DNA gave mosquitoes the ability to block the malaria parasite so it would not be transmitted through the insects’ bites.

Both groups are “probably no more than a year away from something that could conceivably be released in the wild and expected to work,” said Kevin Esvelt of Harvard’s Wyss Institute for Biologically Inspired Engineering, a pioneer in the “gene drive” technology used by both groups who has led efforts to insure its safety.

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But because the UC study used a mosquito species that is “a comparatively trivial vector responsible for about 100,000 cases each year” of malaria, and the new one used the species “responsible for about 100 million,” Esvelt said, “this latest study is a much bigger deal.”

In practical terms, because much more lab research as well as field trials are needed before gene-drive mosquitoes could be released into the environment, it “will be at least 10 more years before gene-drive malaria mosquitos could be a working intervention,” said Austin Burt of Imperial College London. In 2003 Burt proposed using gene drive for that purpose and is considered the founding father of the idea.

The latest research, published on Monday in Nature Biotechnology, is another success for the fast-moving science of gene drive. That technology flouts the rules of inheritance, causing a trait to be passed on to all of a parent’s offspring rather than only some. Gene drive, proponents say, could fight insect- or arachnid-borne illnesses such as malaria, dengue, and Lyme disease by quickly spreading a fatal trait through an entire population of carriers rather than waiting for standard inheritance to, say, make ticks immune to Lyme bacteria.

But gene drive also raises fears that it could be used for nefarious purposes by terrorists or have unexpected environmental consequences. At a recent meeting of a National Academy of Sciences panel studying gene drive, for instance, one scientist discussed the possibility of “entomological warfare.”

For the new work, in the lab of Imperial College’s Andrea Crisanti, scientists used the gene-editing system called CRISPR-Cas9 to disrupt three genes of Anopheles gambiae mosquitoes. That species is a major carrier of malaria in sub-Saharan Africa, responsible for 90 percent of malaria deaths — about half a million annually.

One gene affects the front-to-back development of embryos. The other two seem to be involved in egg formation. “Their precise roles are still to be discovered,” said biologist Tony Nolan, who led the study, but somehow when mosquitoes inherit the genes the females either fail to lay eggs or produce eggs that don’t hatch.

With standard inheritance, it would take countless generations for such female sterility to spread through enough of a population to make a dent: Normally, each gene variant has a 50 percent chance of being passed down from parent to offspring, much as a human gene for, say, hair color does.

But with gene drive, scientists use CRISPR-Cas9 not only to edit genes for the desired traits but also to insert a sort of molecular Xerox machine into the mosquitoes’ chromosomes. That causes the edited genes to be copied onto the second of a mosquito’s two chromosomes. As a result, the genes are passed down to nearly all offspring — more than 90 percent, the Imperial College team reported.

At that rate, they said, gene drive for female sterility could sharply reduce or eliminate local populations of the malaria-carrying Anopheles “within a few years.”

If scientists had to painstakingly insert sterility genes into mosquito embryos, and wait for them to mature and mate and spread the sterility trait without gene drive, it would take forever.

It may seem paradoxical that genes for sterility could spread through generations, since by definition sterile individuals have no offspring. But all three genes are recessive, which means two copies are needed to cause infertility, Nolan told STAT. Female mosquitoes with only one copy are therefore fertile but carriers, and so can spread the genes.

“The idea is that females that have only one copy intact are fertile but actually pass on the disrupted copy to nearly all of their offspring, instead of half, because of this gene drive design,” Nolan said. “Males that have the gene drive are also transmitting it to virtually all of their offspring. As the element rapidly spreads through a population and increases in frequency so does the likelihood of more and more females that have both copies disrupted” and therefore are sterile, making the population crash.

Current efforts to control malaria rely on insecticides and bed nets. They have reduced the spread of the disease, but they’re expensive and probably temporary because mosquitoes develop resistance to insecticides. The Bill & Melinda Gates Foundation, which funds those more traditional anti-malaria efforts, also provided financial support to the gene drive experiment.

With two lab successes using gene drive to target malaria, experts have begun to ask which might work best in practice.

“All successful malaria control programs to date have relied on [mosquito] control through population suppression,” said Nolan, but “there is no reason to think the approaches are incompatible. Finding new tools to fight malaria should mean that we look at all possible options.”

Flaminia Catteruccia of the Harvard T.H. Chan School of Public Health and an expert on malaria said “there are pros and cons in both strategies.” Using gene drive to spread female sterility and thus decimate the mosquito population might provide an opening for a new species to start carrying malaria. “If the final goal is malaria elimination, this strategy [of female sterility] may not be good enough,” she said. “If it’s malaria reduction, it may work,” since any new malaria-transmitting insects will probably not be as good at it as Anopheles.

With the alternative strategy — using gene drive to introduce antibodies that block the plasmodium malaria parasite from reaching mosquitoes’  salivary glands — she said, “the issue is whether these will be 100 percent effective. In the lab, no single gene is 100 percent effective at eliminating plasmodium.”

Another issue is unintended consequences of gene drive. In some areas of Africa, Esvelt said, local spiders eat malaria mosquitoes, so their population might collapse if the mosquito’s does. That could make the population of termites, which spiders control, “explode and everyone’s houses to fall down.”

Changing mosquito genes to block the malaria parasite with new antibodies “should have fewer ecological side effects,” Esvelt said. But the parasite might “evolve a way around” the new gene-drive antibodies. He therefore thinks gene drive for sterility “is more likely to lead to successful malaria eradication.”

Other lab successes using gene drive against malaria are expected. Although Esvelt has labored to get scientists to share their plans with the public, he said, “I have as yet failed to convince the mosquito community to be transparent.”

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