Mosquitoes carry some of the world’s deadliest diseases, including malaria, yellow fever and dengue. But challenging geography, conflict, budgets and insecticide resistance are among the issues hampering efforts to fight them.
With global malaria cases continuing to rise and the climate crisis hastening the spread of virus-carrying mosquitoes into more countries, scientists are searching for low-cost, equitable ways to stop them transmitting disease.
Could harnessing gene drive – a process that can rapidly spread a genetic modification – be the answer?
What is gene drive?
“Gene drive is simply a mechanism that enables a gene to spread itself through a population,” says Prof Luke Alphey, chair in genetics at the University of York. “When it becomes important is when we use it to spread a trait that is useful to humans.”
Under normal genetic rules, animals have a 50:50 chance of inheriting a single gene from either parent. But a gene drive is a naturally occurring process where a specific gene is prioritised, meaning its chances of being inherited are up to 99%. Within a few generations, almost all of the species will carry that gene.
Scientists have studied this process for decades but have only recently developed ways to artificially replicate it in the lab. Now they hope to use it to spread genetic modifications through animal populations – such as mosquitoes – to help reduce their numbers or stop them transmitting disease.
In broad terms, genetic modification is where scientists make changes to certain genetic characteristics, such as the ability of mosquitoes to carry the malaria-causing parasite. Whereas in an (artificial) gene drive, scientists alter the way genes are passed between generations to prioritise the spread of a certain gene.
By pairing these processes, scientists can spread desired genetic modifications – potentially throughout an entire species.
Dr Nikolai Windbichler, a geneticist at Imperial College London, describes it as a way of “genetically engineering entire populations”, rather than individuals.
Why does it matter?
Malaria is transmitted through the bites of the female Anopheles mosquito, which is widespread in sub-Saharan Africa. While the Aedes species (the yellow fever mosquito), lives across the Americas, Africa and Asia and spreads other serious viruses, including dengue, yellow fever and Zika – of which there have been outbreaks in the past decade, particularly in South America.
The climate emergency is pushing disease-carrying mosquitoes further afield, with the first mosquito-transmitted Zika case in Europe recorded in 2019, and global malaria cases have risen since the Covid pandemic after two decades of gradual decline. In 2023, there were 263m cases, 11m more than the previous year – and 600,000 deaths, three-quarters of them in children under five. More than 1,200 children a day are dying from malaria.
Dr John Connolly, senior regulatory science officer at research group Target Malaria, says: “The tools we developed 10 to 20 years ago – particularly insecticide-treated bed nets – have been really effective in reducing [malaria] prevalence and deaths but the improvements we have seen have stalled.”
As well as developing insecticide resistance, mosquitoes are also adapting to bite other than at night-time. Anti-malaria campaigns are limited by human willingness to comply with bed nets and vaccinations, and broader problems such as challenging geography, conflict, fluctuating government priorities and funding issues.
“There’s a need to identify innovative tools to integrate into our approach to deal with these factors,” Connolly says.
Rather than replacing existing tools, scientists hope gene drives will add to the toolkit in the fight against mosquito-borne disease. And, unlike most other interventions, its effects would be felt equally because it targets mosquitoes rather than relying on human action.
How are gene drives being used?
Different research teams are exploring unique ways of using gene drives, although they all have the ultimate aim of reducing disease burden.
The Target Malaria project, for example, is focused on population suppression. The partnership between Imperial College London and teams in Italy, US, Burkina Faso, Ghana and Uganda hopes to use a gene drive to spread a genetic modification that makes female Anopheles gambiae mosquitoes infertile.
Lab-based tests on 1,000 mosquitoes in 5-cubic-metre cages found the gene drive effectively spread the modified gene to most of the population within months (the lifecycle of a laboratory mosquito is about three weeks), leading to an increase in the number of sterile females which caused the population to plummet.
Transmission Zero, a separate Imperial project that works with the Ifakara Health Institute (IHI) in Tanzania, is focusing on using a gene drive for population modification. Its aim is to reduce mosquitoes’ ability to transmit malaria without affecting their numbers. First, scientists modify mosquitoes so they cannot transmit the malaria-causing parasite (the “resistance”) and then they use gene drive (the “driver”) to spread this resistance through mosquito populations.
The University of California Malaria Initiative (UCMI) is also exploring population modification in partnership with teams in Portugal and São Tomé and Príncipe, but using a mechanism where the genetic modification and gene drive are combined into one process.
All three projects have received funding from the Bill and Melinda Gates Foundation, which is prioritising the eradication of malaria.
Could it tackle diseases other than malaria?
The Alphey Lab at York University is researching using gene drive to limit the ability of the Aedes aegypti mosquito to spread dengue and other viruses.
The team are working on “local gene drives” which will spread a modification in a small target population, but not throughout an entire species. This is particularly important as Aedes aegypti is much more widespread than its malaria-carrying cousins.
“We don’t always want to modify an entire species – it might be a species is invasive in one area but we want to preserve a native population elsewhere,” Alphey says.
Local gene drives are technically more complex than species-wide examples because they require multiple different genetic components in order to both spread and limit the desired trait as needed, but the team expects to have a prototype ready for testing in the wild within 10 years. The Alphey Lab has also received Gates Foundation funding for gene drive research.
Other research teams around the world are at earlier stages of exploring using gene drive to reduce populations of invasive species, such as the golden mussel, and agricultural pests such as mice.
What are the risks?
As with any groundbreaking genetic engineering technology, gene drives are controversial.
A 2021 paper by Connolly’s team identified 46 potential harms – but he stresses few are likely to be serious or even possible.
Concerns around its use include the unknown potential knock-on effects on the ecosystem of removing mosquitoes, or whether removing or modifying malaria-carrying species could cause other types, carrying other diseases, to thrive.
“It is our responsibility to assess and analyse all the possible risks, using modelling and experiments if necessary, and we could only move towards a field trial once we are satisfied,” says Connolly, while stressing Target Malaria is focusing on just three species of mosquito out of about 3,500 that exist.
Researchers have carried out large engagement programmes with officials and communities to address concerns, including in Burkina Faso, Uganda and Tanzania.
Alphey believes local gene drives could help allay some fears around the unknown consequences as any impact would be short-lived and not spread throughout the species. “We are erring on the side of caution,” he says.
When are we likely to see gene drives used outside the lab?
“The results we have in the lab are very compelling,” says Connolly. “But the real test is what happens to mosquitoes in the field – and then what happens to malaria rates as a result.”
Target Malaria’s Burkina Faso team tested Africa’s first release of genetically modified mosquitoes (sterile males) in 2019. And last year, Transmission Zero’s partner, the Ifakara Health Institute (IHI) in Tanzania, became the first African centre to create a generation of genetically modified mosquitoes.
While neither involved a gene drive, these are essential steps if gene drive mosquitoes are ever to be released into the wild. Scientists hope to start experimental field trials within the next five years – but legal technicalities are impeding progress.
“The results we have in the lab are very compelling,” says Connolly. “But the real test is what happens to mosquitoes in the field – and then what happens to malaria rates as a result.”
As the technology is new, there are no existing processes for approving gene drive experiments. Before any can go ahead, research groups first have to work with each country to establish who will regulate the gene drive and approve its use.
Although existing laws around the use of GM crops could form the basis for gene drive regulation, these typically state there should be no cross-border movement of any modified species without the agreement of the countries affected. “Mosquitoes don’t understand international borders so we need regional-level agreement in sub-Saharan Africa,” says Connolly. The African Union is understood to be considering the issue.
As local gene drives require only local approval, it may prove quicker to roll out – but the technology is taking longer to develop.
But no field tests of any kind will happen until communities and governments approve. “We are just developing a technology – whether countries decide to adopt or use it is beyond us,” says Prof George Christophides, Transmission Zero co-director.
Windbichler adds: “Ultimately the question of when it will happen is not a technical question, it’s a political one.”