Colour enhanced Scanning Electron Microscope image of Anopheles mosquito.Credit: Peter Finch/ Stone/ Getty Images
Joel Odero’s experiences of malaria is wide and deep. Growing up in a village in Kenya, he not only contracted the disease numerous times, but was all too familiar with the relentless daily regimen of spraying insecticides and checking malaria nets were not ripped.
Decades later, as a research scientist with the Ifakara Health Institute in Tanzania, he witnessed firsthand how, for many, that daily grind is still ongoing. As part of the institute’s teams that, between 2018 and 2022, spread out across the country to capture a range of malaria-transmitting mosquitoes for studying, he would collect samples from homes where people had to spray and check their nets every day.
Odero is part of a generation of scientists trying to break the stranglehold of the Anopheles mosquitoes that transmit the disease-causing parasite. Their weapon of choice is genomics.
It’s a challenge taken up by organisations like Target Malaria, a not-for-profit international research consortium featuring teams in Africa, the US and Europe, and funded by, among others, the Bill & Melinda Gates Foundation and Open Philanthropy. There, researchers’ game plan is simple: reduce the population numbers of the mosquitoes, specifically those of three related species responsible for most malaria transmissions in Africa – Anopheles gambiae, Anopheles coluzzii and Anopheles arabiensis.
To do so1, they are looking to capitalise on a naturally occurring phenomenon, gene drive.
Often described as “selfish genetic elements”2, taking the form of bits of DNA code, genes are ‘driven’ when a gene that has a favourable effect becomes more prevalent in successive generations. Typically, with both humans and mosquitoes, offspring inherit two copies of any gene, one from each parent. As a result, there is a 50/50 chance of either of the two copies being passed on to later generations.
Using gene drives, researchers are manipulating the bias that is introduced to that rate of inheritance so that a specific trait is nearly 100% guaranteed to be passed on.
Gene-drive malaria research takes on many forms. Two of the most popular are known as ‘population replacement’ and ‘population suppression’. With population replacement, the aim is to modify the mosquitoes so that they are no longer vectors, aka transmitters, of the malaria parasite. With population suppression – which the work of Target Malaria falls under – the goal is to reduce the mosquito population.
Target Malaria’s strategy is to sterilise and reduce the number of female mosquitoes. The females transmit the malaria-causing parasite known as Plasmodium falciparum to humans, and whose numbers typically determine the size of a mosquito population.
The gene drive approach would be a game changer, says Target Malaria’s Abdoulaye Diabaté, head of medical entomology and parasitology at Burkina Faso’s Research Institute in Health Sciences in Bobo-Dioulasso.
“It’s clear that the tools that we have today are not the ones that can take us to malaria elimination,” says Diabaté.
It is the failure of these ageing tools, or the fear that they might fail, that is driving the gene-based approach to malaria research in Africa and elsewhere.
Africa is embracing the gene
Increasingly, there are concerns that drug and insecticide resistance, sparked by genomic changes in either the vector mosquitoes or the malaria parasite itself, is undercutting the efficacy3 of malaria prevention tools and treatments. This includes artemisinin-based combination therapy (ACT), the go-to treatment for uncomplicated malaria caused by the Plasmodium falciparum parasite.
As a result, many are turning to genomics in pursuing longer-lasting solutions.
In South Africa, for example, researchers at the Wits Research Institute for Malaria (WRIM) at have started field tests using an approach that, too, seeks population suppression, but targets the males rather than the females. To do so they’ve adopted a variation on the Sterile Insect Technique (SIT), in which male mosquitoes are sterilised and, on mating with females, produce few or no offspring. While traditional SIT technologies rely on radiation to sterilise the males, the WRIM scientists use a more-reliable genetic take on SIT known as precision guided Sterile Insect Technique (pgSIT), allowing them to alter the genes linked to fertility.
The work in gene drive modified mosquitoes has been accelerated thanks to advances in gene editing4, specifically CRISPR-Cas9, allowing scientists to remove, add or alter sections of an organism’s DNA. “However, genome editing is currently underexplored in Africa, where it could be transformative in addressing key challenges in major sectors,” write the authors of a Nature Biotechnology correspondence5 on the wider application of the technology in Africa.
Monitoring of the genes involved in resistance is another part of the picture but it, like gene editing and gene drive, is hampered by a lack of access to local research capacity.
In a recent paper6, researchers in Japan and Uganda point out how large-scale and sustainable monitoring of artemisinin-resistance is hampered by the scarcity of even sequencing facilities. The benefits of easy access to such facilities are obvious. “The development of new technologies optimised for resource-limited settings will make drug resistance surveillance easier, faster, and cheaper,” says co-author Naoyuki Fukuda of the Department of Tropical Medicine and Parasitology at Juntendo University.
Africa’s genomic research challenges were highlighted during the COVID-19 pandemic and the global rush to sequence the various strains of the SARS-CoV-2 virus. Up to 71% of next-generation sequencers were concentrated7 in five countries, found the Africa Centres for Disease Control and Prevention (Africa CDC) in 2020 — some 70% of that capacity was found outside of national public health institutes.
Organisations like the Africa CDC and the WHO Regional Office for Africa (WHO AFRO) went a long way to roll technologies and training over the pandemic. But as the focus shifts back to more regional priorities – such as malaria – that momentum may be slowing.
Researchers at Tanzania’s Ifakara Health Institute in Tanzania can speak to that challenge. From their mosquito collection exercise, a number of studies emerged. In a paper published in Parasites & Vectors in May 2024, for example, the authors illustrated how the spread of five known genetic markers associated with insecticide resistance (the kinds used in mosquito nets) varied across the country. In a paper currently under review, the Ifakara researchers also report on their detection of the genetic mutations responsible for what’s known as knock-down resistance (kdr), the first time such mutations have been observed in this Anopheles species.
“On the surface you observe the growing resistance to insecticides across the country, but at the genomic level the pattern is so complex,” says Fredros Okumu, research scientist at Ifakara, and professor of vector biology at the University of Glasgow in the UK. “So there isn’t going to be one simple solution.”
But. in drawing up this new picture, sequencing and analysis was conducted at the University of Glasgow and commercial laboratories in the UK.
“But we shouldn’t be talking about sending mosquitoes from Africa to Europe in 2024,” says Joel Odero, also a research scientist at Ifakara, as well as a doctoral candidate at the University of Glasgow. “We should be doing all these things, sequencing and analysing, locally, especially in the countries where this research is being done.”
But putting that capacity in place is thwarted by several factors, including some related to the building of a skilled workforce. These range from inadequate funding and infrastructure, and the brain drain to other regions. “A number of post-graduate students and post-docs leave African countries for studies, and then don’t return to their countries,” says Lizette Koekemoer, professor at South Africa’s WRIM, who also contributed to the Ifakara studies.
“We can also add the challenges with procurement, water, electricity,” adds Koekemoer. “The list is very long.”
