Next month, in a laboratory an hour outside of London, scientists will begin stitching bits of DNA together and inserting them into hundreds of tiny, cucumber-shaped insect eggs. It's the first step toward engineering a new kind of mosquito—the kind that could help eradicate malaria on this side of the Prime Meridian.
The mosquito is a species called Anopheles albimanus, the primary transmitter of the deadly disease in Central America and the Caribbean. The scientists work for Oxitec, the UK-based subsidiary of global GMO giant Intrexon, whose portfolio also sports transgenic salmon and non-browning apples. Oxitec has made a name for itself in the pest-prevention business by making mosquitoes and other insects that can't produce offspring.
Now, with a new $4.1 million investment from the Gates Foundation, Oxitec is putting its patented Friendly™ tech inside malaria's main host in the Western Hemisphere. The company intends to have "self-limiting" skeeters ready for field trials by 2020.
The timing isn't coincidental. Five years ago, health ministers from ten countries in Central America and the Caribbean got together in the capital of Costa Rica and committed to eliminating malaria in the region by 2020. It seemed reasonable at the time; cases of the deadly disease had been declining steeply since 2005. But starting in 2015, as the Zika crisis began to unfold, those numbers began to tick back up. The World Health Organization's 2017 malaria report warned that progress in fighting the disease had stalled and was in danger of reversing.
So in January of this year, the Bill & Melinda Gates Foundation—which has become one of the leaders in the recent explosion of malaria funding—joined the fight. Along with the Inter-American Development Bank, they announced a $180 million initiative to help Central America meet its malaria elimination goals. The financing is meant to help those countries continue to invest in anti-malarial drugs, insecticide-laced bed nets, and better clinical diagnostics, even as Zika and Dengue have become the bigger public health bogeyman. But the Gates Foundation, true to its tech founder's roots, is betting that won't be enough.
"We're not going to bed net our way out of malaria," a foundation spokesperson said in an interview with WIRED. "Investments like the one with Oxitec will help bring other tools online, that in combination with existing ones will really get transmission down to zero."
In recent years, the Gates Foundation has become one of the most prolific proponents of harnessing genetic eco-technologies to combat public health threats. It has supported experiments releasing Aedes aegypti mosquitoes infected with the Wolbachia bacterium to prevent them from spreading diseases like Zika and dengue in Brazil. And in Africa it's bankrolling an even more ambitious project called Target Malaria, which intends to use a Crispr-based gene drive to exterminate local populations of mosquitoes.
But neither of those approaches is expected to work very well on malaria in the Americas. Wolbachia doesn't confer sterility in Anopheles albimanus. Gene drives—with all their attendant uncertainties—would be a hard risk to sell, especially when the more urban geography of the region makes more controlled technologies like Oxitec's operationally feasible.
Oxitec has previously worked with local governments in Brazil, Panama, and the Cayman Islands to release its first generation Aedes aegypti mosquito, developed back in 2002. But that technology—which involved inserting a gene to make the mosquitoes die unless fed a steady diet of the antibiotic tetracycline—is already old news. It required egg facility workers to painstaking sort larvae by sex so they could release only the non-biting males into the wild, where they would mate and then die, along with all their offspring. Even with mechanical sorting machines, it was still an overly burdensome process.
So Oxitec has since developed second generation insect sterility tech. Now it does all the sex-sorting with genetics. It starts with the same basic parts: a gene that vastly overproduces a protein that turns deadly in the absence of tetracycline and a fluorescent marker to allow field scientists to keep track of them in the wild. But then Oxitec scientists put those parts somewhere interesting.
Unlike humans, mosquitoes don't have X and Y chromosomes. Instead, they have identical regions of DNA that get translated into different proteins—a regulated process called differential splicing—and those proteins determine whether the mosquito grows up to be a male or a female. Oxitec scientists piggybacked off this natural mechanism by sticking their antibiotic-or-death construct onto that region, where it also got spliced into two different forms: one that worked like it should, in females, and one that was broken, in males. Which means that only the males survive.
It also means Oxitec can release a lot fewer mosquitoes, because those male offspring go on and mate themselves, further reducing the pest population. Unlike a gene drive though, the modification is still inherited in Mendelian fashion, so it eventually disappears from the environment, about 10 generations after the last release. In May, the company launched its first open field trial of this second generation Aedes aegypti mosquito in Indaiatuba, Brazil.
That's the tech that Oxitec plans on developing for the malaria-carrying Anopheles albimanus. But it's not a simple interspecies plug and play. Their scientists don't really know where the American insect keeps its sex determination machinery. Or how best to turn it to their own advantage. "The mosquito family never ceases to surprise me," says Oxitec's chief scientific officer, Simon Warner. "They're very ancient animals and their diversity is huge. So we're relying on nature to actually tell us the answer."
Warner's team of about 15 will start by randomly inserting their self-limiting gene construct into Anopheles albimanus embryos raised on tetracycline. Then they'll take them off the antibiotic diet and select for the lines where only the females die. They'll do that a few hundred times until they find ones that work. Then they'll sequence their DNA to see where the gene inserted and run tests for multiple generations to see how the trait gets passed down. In two and a half years they hope to have a line ready to be released into the open. Then it will be up to the countries in Central America and the Caribbean to decide if they want them.