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Driving Mosquitoes out of Town

Credit: nechaevkon/Adobe

Credit: nechaevkon/Adobe

By Jack Scanlan

Existing techniques to control mosquito-borne diseases are coming up short. Can gene drives offer hope to the millions affected?

It might come as a surprise that one of the biggest threats to global health is a seemingly harmless, albeit annoying, insect. The mosquito, the scourge of summer barbecues, causes more human deaths than any other animal – far surpassing sharks, snakes and even human murderers – by passing diseases to its victims while feasting on their blood.

Malaria, caused by the microscopic parasite Plasmodium, is a particularly nasty mosquito-transmitted disease responsible for more than 700,000 deaths every year, as well as hundreds of millions of non-lethal yet debilitating infections. African, Asian and South American countries suffer most of the toll, as Plasmodium’s mosquito hosts, species in the genus Anopheles, thrive in their tropical climates. Many other fatal diseases are also spread from person to person by mosquitoes, including dengue fever, yellow fever and an emerging threat to South America, Zika.

The huge cost of these diseases, both in terms of human life and economic damage in heavily affected regions, have warranted equally huge campaigns to control them. However, treating disease once in the human body is risky, as drugs need to be prescribed before serious effects can occur. Prevention is harder: vaccines don’t exist for most of these diseases and, even when they do, increasing the vaccination rate in affected regions past the point where transmission of the disease drops off (known as herd immunity) is a substantial and expensive challenge.

Targeting the mosquito vectors that spread the diseases is a far more attractive choice. These vectors are typically essential for the spread of disease through human populations;

Plasmodium completes part of its complex life cycle inside a mosquito, and has no realistic way to pass from an infected person to a healthy person without this vector. Since a person infected with malaria poses no infection risk to others if there are no Anopheles mosquitoes around, eliminating the vector would effectively eliminate the disease.

For this reason, controlling mosquito populations has been a major focus of public health campaigns targeting diseases like malaria and dengue fever for many decades. Insecticides are sprayed near villages and cities, even inside houses, while bed nets are distributed to protect people while they sleep. The sterile insect technique is also used, wherein male mosquitoes are blasted with fertility-destroying radiation and released into the wild to compete with healthy males for females, slowing the growth of mosquito populations over time.

These techniques can control diseases like malaria in areas with small mosquito populations and low incidence of the disease, such as Europe, as they fail to spread quickly or intensively. But in tropical regions where mosquitoes thrive and the disease has already spread to a substantial percentage of the human population, temporary control measures cannot effectively contain the problem.

Mosquito vectors are becoming increasingly resistant to insecticides, many of which cause serious ecological problems when sprayed indiscriminately – they will kill any insect, not just mosquitoes, and can be toxic to fish, birds and sometimes even mammals. Bed nets are effective at night, but they do not protect people during the day. And the sterile insect technique can be time-consuming, expensive and ineffective in large regions with huge mosquito populations. Small battles are being won against these diseases, but the war is still raging.

Given all this, it’s no surprise that some experts are looking to gene drives in mosquitoes as a way to get rid of these diseases once and for all. Recent computer modelling suggests the use of a gene drive could eliminate mosquito-borne diseases completely, or even just reduce them enough to raise the effectiveness of existing control strategies.

A similar strategy is already being trialled in many places around the world using a naturally occurring bacterium called Wolbachia, which lives inside the cells of around half of all insect species. Wolbachia causes a variety of weird and wonderful changes to mosquito reproduction, such as feminising males and preventing uninfected males from successfully mating with infected females. As infections are passed from mother to egg, the bacterium usually spreads itself through populations rapidly.

Some strains of Wolbachia even prevent mosquitoes from incubating certain diseases. The best known example is in Aedes aegypti, the vector of dengue fever. Strains of Wolbachia taken from fruit flies stop the dengue virus from replicating inside the mosquitoes. Coupled with the bacterium’s ability to spread through populations, it seems like a fantastic way to remove the vectoring capacity of Aedes mosquitoes without having to suppress Aedes populations. Release programs for Wolbachia-infected Aedes mosquitoes are being trialled or planned in India, Indonesia, Vietnam and northern Australia.

Yet this may not be a silver bullet as subsequent research has found that some of the most promising strains of Wolbachia aren’t well-suited to the high temperatures in tropical regions, and may lose their effectiveness in blocking the transmission of dengue in the wild. Furthermore, disease-blocking Wolbachia strains haven’t been found for many mosquito-borne diseases, so its application may be limited in practice.

Synthetic gene drives are potentially a more universal solution. The high-quality DNA sequence data required to develop gene drives are now available for nearly all of the most important mosquito vectors, and applications of the CRISPR/Cas9 tools that will form the gene drive itself are becoming increasingly sophisticated.

There are two ways a gene drive could be used to target mosquito-borne diseases: to eliminate populations of mosquitoes completely in disease-ridden areas, or to genetically alter mosquitoes so they cannot transmit the disease in the first place. The former could be done by spreading a gene that makes one sex infertile, shrinking the population as the gene drive moves through it, while the latter could borrow tricks from Wolbachia and change how the mosquito interacts with the virus or parasite it carries.

Eliminating a population is, from a technical perspective, a lot easier than removing vectoring capacity. Many of the genes involved in fertility are well-studied in insects; the genes that control how the mosquito’s immune system fights the diseases they carry are not. But such “sterility” gene drives could spread from local populations to every population of a species, killing it off completely. The implications of removing an entire mosquito species from an ecosystem aren’t clear, and discussions about the ethics of such an action are also ongoing in the scientific community.

Removing vectoring capacity from mosquitoes would bypass this problem, as the populations would stay intact. And the lack of a negative impact on the mosquitoes would also mean the gene drive would spread through populations faster. But the interplay between parasites and their insect hosts is not fully understood, so progress on developing such a “blocking” drive would be a lot slower compared to a “sterility” drive. It’s still unclear which type of drive would be better in the long term.

Despite these issues, many research teams around the world are working to develop gene drives in mosquitoes. In 2015, scientists published the first description of a female-sterility gene drive in the malaria vector Anopheles gambiae, and last year another gene drive in the same species was developed that results in only male progeny. Neither has been, as yet, cleared for use outside of a laboratory environment.

Unfortunately, a thorn may be waiting to plant itself in the side of gene drive researchers: evolved resistance. High genetic diversity in mosquito populations could hamper the spread of gene drives, which rely on DNA regions with perfect or near-perfect similarity between individuals. This is similar to how insecticide resistance evolves – over time, entire populations could shrug off the gene drive, rendering it useless. Successful applications of gene drive technology may have to find ways to take this into account, lest the researchers be back to the beginning.

There is still a long way to go until gene drives could be used to stop diseases like malaria and dengue fever once and for all. Even if a useful gene drive is developed, it’s possible that government policy may block them from ever being used at all. The severity of the diseases at hand, however, at least warrants a discussion of all available options. The human toll is far too great to ignore.

Jack Scanlan is a PhD candidate in insect genetics at The University of Melbourne.