Reducing numbers of malaria-transmitting mosquitoes using gene drive technology: a modelling approach

Malaria-transmitting mosquitoes pose a serious threat to human health, and numerous approaches to reduce these disease-vectors are currently in use or development – including release of genetically modified mosquitoes. Here, Dr Ace North describes his recent paper in BMC Biology, showing how mathematical modelling can be used to plan and predict the effects of such approaches for maximal effect.

A simulation of the model (the black outline demarks Burkina Faso). There are annual oscillations in mosquito numbers because the dry season occurs at the same time of year across the study area, though its duration and severity varies by location. This simulation supposes 10 driving-Y modified male mosquitoes are released at one in every hundred settlements each year.
GIF provided by author. Ace North

In much of sub-Saharan Africa, malaria is a huge public health burden. Burkina Faso is one of the worst afflicted countries with an estimated 7.9 million clinical cases of malaria in 2017, causing in the region of 28,000 deaths mainly in children under five. Worryingly, despite major investment in malaria control in this country (circa 50 million USD per year), progress has stalled (WHO World Malaria Report 2018). It is particularly concerning that current measures (the most important of which is the use of insecticide treated bed-nets) are losing potency as mosquitoes are evolving resistance.

There is a compelling need to develop new tools to complement existing control programs. These might include gene-drive technologies to modify mosquito populations, either to reduce their fitness and cause a drop in population size or to make the mosquitoes unable to transmit disease. Gene drives are genetic constructs that positively bias their own inheritance and thus can spread rapidly through populations, even if they reduce individual survival or fecundity.

Figure 1: Top: Wooden model of a mosquito (from the author). Bottom – An Anopheles gambiae spermathecae, crushed to allow the sperm to come out and be screened for fluorescence to determine which genotype of male the female had mated: courtesy of Rosemary Lees, LSTM

In our recent study in BMC Biology, we modelled the potential of modifying mosquitoes with a type of gene-drive called a “driving-Y chromosome” to reduce mosquito populations. A driving-Y chromosome has been genetically modified so that the male mosquitoes that carry it produce predominantly male offspring (which also carry the modification). Since only female mosquitoes bite, the spread of this Y-chromosome will result in fewer females to transmit the disease, and fewer mosquitoes overall.

The technology, which is still under development, proposes targeting the most important species of malaria mosquitoes of sub-Saharan Africa. Before modified mosquitoes can be considered for release in the wild, we need to know the likely impact – how much reduction of overall populations might we reasonably expect – which is affected by numerous factors like the timing/extent of release, and the geography of the environment. For example, releasing driving-Y mosquitoes in a region far from human vectors or just prior to the dry season may be less than ideally effective.

The study area centered on Burkina Faso (yellow).
Figure from article.

We modelled a one million square km area including all of Burkina Faso. The model represents the biology of two mosquito species, Anopheles gambiae and the closely related Anopheles coluzzii. These are probably the two most efficient malaria vectors in the world, largely because they evolved with us humans and have a particular preference for our blood. The model couples biological dynamics with external data on rainfall, hydrology, and human settlements.

Population elimination is more likely in regions with mild dry seasons, while reduction is more likely in regions with strong seasonality.

The model predicted elimination of the species in some areas and population reduction in others. We found seasonality to be the most critical predictor of the local impact of the gene-drive. Population elimination is more likely in regions with mild dry seasons, while reduction is more likely in regions with strong seasonality. However, even in the most challenging environments, populations were reduced. Overall, we found that repeated introductions of genetically modified mosquitoes into a small fraction of human settlements per year may be sufficient to substantially reduce the overall number of malaria transmitting mosquitoes across the entire study area.

The genetic modification of a mosquito vector is a novel approach to disease control, and must be subject to rigorous and independent scrutiny to ensure it is safe for humans and for the environment. A crucial component of this process is understanding mosquito population dynamics after the release of a construct. Our model suggests that a driving-Y chromosome could have a major impact in reducing malaria.

Ace North

Ace North is a Post-Doctoral Research Associate in the Department of Zoology at the University of Oxford. He creates mathematical models of mosquito populations to investigate methods for the control of malaria, and wooden models of mosquitoes for his amusement.
Ace North

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