A swarm of mutant mosquitoes is out to eradicate malaria

More than 400,000 people died of malaria in 2015 – many of them children. CRISPR-edited mosquitoes are being released in the hope of reducing deaths
WIRED

Over the next year in the village of Bana, Burkina Faso, a group of scientists will set loose up to 10,000 mosquitoes sprinkled with fluorescent dust. The sterile, male swarm will represent the first ever release of a genetically modified, malaria carrying mosquito species into the wild. It's a milestone not only for science, but also for community engagement and regulatory hurdles in Africa.

Most significantly, however, these mosquitoes will lay the ground for the eventual deployment of a powerful biological tool which researchers hope will one day stop malaria altogether.

The Target Malaria consortium, based at Imperial College London, wants to drastically reduce the world’s population of malaria-transmitting mosquitoes by forcing selective bias in the insects’ inheritance of certain genes – a process known as gene drive.

Led by professor of evolutionary genetics Austin Burt and professor of molecular parasitology Andrea Crisanti, the team aims to bend the rules of genetic inheritance, meaning the chance of a mosquito passing down a given gene is closer to 100 per cent, rather than the 50-50 we would normally expect.

Only female mosquitoes bite and transmit malaria. In December 2015, the research group published a paper in Nature proving in the lab that a gene drive could reduce female fertility in Anopheles gambiae mosquitoes.

Nearly three years on, the Burkina Faso release will be the first major test for their techniques in a real-life setting, and is aimed at observing how long the modified mosquitoes live in the wild, and whether they join the swarms that males naturally form in the wild for mating. “We release males because we don’t want to release females who will go bite people and annoy them, and potentially transmit disease. We want to filter out as many females as possible,” Burt explained.

Few argue with the principle of eradication: more than 400,000 people died of malaria in 2015, according to World Health Organisation (WHO) figures, the majority of them were children under five in sub-Saharan Africa.

Public health efforts to hang mosquito nets in homes and warn communities of how malaria is transmitted have halved deaths since 2000, but progress has since stalled. “Of all the vector borne diseases, malaria is the big one in terms of the morbidity and mortality that it poses,” Burt noted.

Several other diseases are being tackled with genetically modified mosquitoes, which have been released in Brazil to combat the Zika virus, and in Australia to tackle Dengue fever. Meanwhile, scientists at the University of California are using the gene “cutting” tool known as CRISPR-Cas9, also employed by Burt’s team, to manipulate mosquitoes genes into blocking malaria.

So far, no one has yet succeeded in using genetically modified mosquitoes, or a gene drive, to reduce rates of malaria, but Target Malaria believes it is coming closer than anyone else with their projects in Burkina Faso, Mali and Uganda. “For malaria, 90 per cent of the burden is in Africa, so it makes sense to focus on sub-Saharan Africa, and those three countries all have very good entomologists,” Burt says. “It’s important to have that expertise as part of the team.”

Crucially, he adds: “They also have a regulatory system which allows for genetically modified organisms to be considered”.

Burkina Faso’s government approved the import of the genetically modified strain of Anopheles coluzzii mosquitoes more than a year ago, and has just given the green light for them to be released.

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Target Malaria’s mosquitos would ideally overwhelmingly produce males and a few infertile females, thereby reducing the overall population size. This “gene drive” would then spread these tendencies through future generations, decimating targeted species within the Anopheles group responsible for malaria transmission. The results would be visible, the researchers believe, in under a decade.

Not everyone likes the idea of altering mosquitoes’ genes in perpetuity, and Target Malaria’s work also raises ethical questions regarding the communities involved in the experiments. Jeantine Lunshof, a philosopher and bioethicist who advises the Sculpting Evolution Group based at Massachusetts Institute of Technology (MIT), said malaria might be the only case in which the the immense suffering the disease causes could outweigh the inherent risk of propagating genes indefinitely.

“When all these tests and pilots go well, when it would be possible to apply a gene drive that really ends these specific mosquitos… that could be justifiable,” she says. Lunshof works with Kevin Esvelt, an assistant professor who helped pioneer the development of CRISPR and its use in gene drives, but who has warned against any gene drive that could spread globally.

Esvelt is also a strong proponent of “responsive science”, promoting transparency and community feedback for his work with gene-edited mice and Lyme disease on the islands of Martha’s Vineyard and Nantucket in Massachusetts.

Citing this standard within Esvelt’s MIT lab, Lunshof praised Target Malaria’s sustained engagement with local communities via its stakeholder teams, who translate its experiments into local languages and obtain informed consent to unleash the mosquitoes.

It was crucial to avoid the mistakes of the past, Lunshof says, citing the HapMap project of global human genetic variation, where unfulfilled promises of healthcare facilities were made in Nigeria in return for DNA samples.

“We have to introduce the project to them and they have to understand why we are doing this. We have to seek approvals from them, going house to house,” agreed Jonathan Kayondo, who leads Target Malaria’s operations in Uganda.

The main problem raised by local residents and with politicians who began enthusiastically backing the project, Kayondo said, was “the timeline” – the research will take years, if not decades, and people wanted results “tomorrow”.

Even with enthusiastic community consent, another question circles around the ecological effects of potentially removing a species from the food chain within a relatively short period of time. The impact is “likely to be minimal,” Burt said, adding there was “no predator that specialises in this particular species of mosquito”. Target Malaria has also only been gene-editing in one species of mosquito, rather than all the known malaria transmitting types present in Burkina Faso, he added.

Despite these assumptions, time will be needed following the sterile male release to study the effects on the environment, and a gene drive would only go ahead if another batch of mosquitoes, this time of fertile males, was also successful.

Ultimately, nature itself may outfox any future Target Malaria gene drive. The use of CRISPR is not perfect, and sometimes individual cells can add or remove random DNA letters, meaning the modified code does not spread properly.

However, just like in antibiotics, natural resistance will also occur, meaning the team must tweak their models to give their gene drive enough time to work before evolution takes its own course.

This article was originally published by WIRED UK