Genetically modified mosquitoes to fight malaria

Getting rid of a biting issue...
31 May 2024

Interview with 

Grey Frandsen, Oxitec

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Oxitec mosquito lab

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Genetically engineered mosquitoes are taking to the air in an experiment to attempt to curtail malaria in Djibouti. The tiny African nation all but eliminated malaria just over a decade ago. But rising population and urbanisation has seen disease cases skyrocketing again, making it an ideal venue to test the technology, which uses a genetic trick to kill off selectively female mosquitoes; this leaves the males - which don’t bite humans - unharmed to breed and pass on the trait to other members of the species. Oxitec’s CEO is Grey Frandsen…

Grey - We are the pioneers in using genetics to engineer good mosquitoes. And these are non biting male mosquitoes. When released, they seek out and mate with wild type female mosquitoes and all female progeny, all the female babies of that mating will die. And over a successive number of releases of our good mosquitoes into the environment, we will see a dramatic suppression of those malaria transmitting mosquitoes. And we're now bringing that technology, that approach, to the fight against malaria precisely because all of the tools that we have used to date have begun to lose effectiveness. Mosquitoes have engineered themselves around all of our existing tools or weapons to fight these mosquitoes. And thus we are in a race against time to save lives.

Chris - I think they call this a gene drive, don't they? It's one of the ways it's referred to. How do you make that happen?

Grey - So in this case, in Africa, there's a spreading malaria transmitting mosquito called Anopheles stevensi. This particular mosquito is spreading very rapidly in urban settings, in cities where millions of people live. Most malaria cases to date have been transmitted in rural areas, rural Africa for example. We introduce two genes into the genome. One is a fluorescent marker just so we can see under a certain microscope where our mosquitoes are. But the magical gene is one that in essence allows us to release only males, and that kills all female progeny, therefore rapidly reducing the population. It's targeted, it's specific, and has no impact on any other part of the environment or the ecosystem.

Chris - How does it kill the females selectively?

Grey - The team we have, just outside of the Oxford area, have pioneered the ability to create, in essence, an on and off switch inside the genome of a particular targeted mosquito. What that on and off switch allows us to do, in essence, is manufacture mosquitoes at scale, which requires us to keep females alive so we can create lots of male mosquitoes. And then when we release those mosquitoes outside of our factory or outside of the lab, and in the absence of a certain antidote, the kill switch in essence turns on and the kill switch only turns on and interrupts cell production machinery in female mosquitoes.

Chris - And why have you gone for Djibouti to test this? Apart from the fact that levels of this disease are rife there again and they're going up so it makes it a good target from that point of view. But why specifically Djibouti? There are lots of places where malaria is active.

Grey - Indeed. So Djibouti is at the perfect and troubling intersection of climate change, of rapid urbanisation, of increased transportation between countries. And when you add all of those things together, it creates a perfect environment for this malaria mosquito that is spreading very rapidly in these urban environments. So Anopheles stephensi has, in essence, invaded Djibouti and has had a deadly impact. They went from near elimination in 2012, 13 to now tens and tens and tens of thousands of malaria cases spread by this particular mosquito. Now, in 2018, Djibouti's public health leadership reached out to our team and asked if we would develop a new mosquito, a new Anopheles stephensi Oxitec friendly mosquito to help them. And that is a request we could not deny. We had to lean into this and help them solve this problem. And frankly, it's not just a Djiboutian problem. This invasive mosquito now has spread across the African continent and continues to enter into densely populated urban environments.

Chris - Presumably you've modelled how you expect this to play out as the mosquitoes spread and they carry this kill switch into the females and slowly suppress the population. You must have a sort of trajectory in mind as to what you're expecting to see. So how will you monitor that?

Grey - Great question. So the trajectory we hope to see does start in Djibouti. We're basically comparing where we released ours to an area where we didn't release ours, and we will see significant suppression in the area we've treated. Beyond that, we begin scaling up, we demonstrate the effectiveness of the mosquito solution in successively larger environments, and then we begin preparing to scale it for interventions where an Oxitec mosquito plays a direct role in a government's efforts to control this particular vector. Then we begin spreading across the African continent to treat those cities where governments wish to see us deployed.

Chris - What's the end point for this? Because there must be a law of vanishing returns applying here where you end up, to drive it really down, you have to release so many of these mosquitoes to get to the last vestiges of the mosquitoes that are still breeding. And as soon as you take your foot back off that accelerator, does the whole thing not change direction and come roaring back?

Grey - Frankly, for this particular malaria transmitting mosquito, we see this as the primary method by which we will secure control over this mosquito. Now to your particular question, yes. Over time we will have been successful in knocking down maybe 90% of the population. That last 10% of the population requires fewer and fewer releases of Oxitec mosquitoes because we have fewer and fewer mosquitoes to target. And ultimately we would hope to create a significant suppression such that we drop that remaining wild type presence below a disease transmission threshold where it becomes either completely unimportant or not a threat to the civilian population.

Chris - What about the possibility given that the mosquitoes have just in our generation adapted and continue to do so? That will drive the evolution of wild type mosquitoes through doing this and will evolve a new generation of Anopheline mosquitoes that don't die when they get this genetic switch. And that means we'll end up with a really tooled up mosquito that <laugh> is gonna bypass your blockade.

Grey - It's a very good question and one that we are asked often, but the manner in which our technology works, it's a mating based, species specific, female focused solution. We will not see resistance to our particular gene technology. And that's good news. Unlike chemical pesticides or insecticidal properties or a bed net, for example. Those are blanket active ingredients or chemicals that are spread time after time, after time, giving mosquitoes a chance to generate resistance by way of mutations and normal selection processes. For ours, we are introducing male mosquitoes that will target only the targeted species. And again, all females die and thus there is no chance for selection on those grounds.

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