Humans have been locked in a struggle with disease-carrying mosquitoes for most of recorded history. With just two bites—one to pick up a pathogen and another to transmit it—the bugs have fueled countless outbreaks. Malaria exploded across Africa as humans first gathered for agricultural development. Yellow fever nearly wiped out Memphis, Tenn., in the 1870s as urbanization and river transport brought infected people and mosquitoes together. Some archaeologists suspect that mosquito-borne disease even hastened the fall of the Roman Empire.

The Bill & Melinda Gates Foundation, where I head up vector control, now puts the death toll from mosquitoes at around 725,000 people a year. By comparison, 475,000 humans die at the hands of other humans annually. In parts of the world where people are exposed to the bugs during much of the year, including sub-Saharan Africa and swathes of South America and Asia, mosquitoes cripple economic growth. All told, the bugs are responsible for killing more people than all the wars in history combined.

It once seemed like we would defeat mosquitoes. In 1939 Paul Hermann Müller discovered that a colorless, tasteless synthetic substance called dichlorodiphenyltrichloroethane, better known as DDT, was an excellent bug killer. The powerful chemical was applied to many homes, farms and military bases, accomplishing the miracle of eliminating malaria in some of the areas hardest hit by the disease. Müller was awarded a Nobel Prize in 1948 for his lifesaving work. But this insecticide came with unknown consequences for human health and a steep cost to the environment. The chemical accumulated in fish, plants and the fatty tissue of mammals, wreaking havoc throughout the food chain. When certain birds, including bald eagles, ospreys and falcons, ate DDT-contaminated fish, the exposure weakened their eggs, and as a result their populations fell to alarming levels. By the early 1970s DDT use was severely restricted, and mosquitoes—and malaria—soon flourished once again.

In recent decades climate change and globalization have combined to exacerbate the mosquito threat, making mosquito-borne disease an increasingly common problem in myriad settings, including the U.S. Last year about 2,000 people contracted West Nile virus in the U.S. In the past five years chikungunya virus—which causes severe joint pain—spread to 45 countries, causing more than two million reported cases, including multiple large outbreaks in the U.S. territories. And although only 21 cases of Zika have occurred in the U.S. in 2018 at the time this article went to press—all among travelers returning from Zika-affected areas—the virus is still a problem in many parts of the world. In all, more than 47,000 cases of human illness caused by mosquito bites were reported throughout the U.S. and its territories in 2016; a decade earlier there were fewer than 7,000.

Illustration by Immy Smith; Research by Amanda Hobbs

The best mosquito-control strategies home in on specific mosquito species that carry diseases and kill enough of them to disrupt transmission. Yet increasingly it has become clear that our existing weapons are failing: mosquitoes have developed resistance to many of the insecticides that we place on bed nets to ward off malaria, and as the spread of Zika in recent years has shown, it is incredibly difficult to effectively kill off certain species of mosquitoes, such as Aedes aegypti, that live in our homes and can breed in tiny pools of stagnant water.

To counter this trend, scientists in dozens of countries have been working to develop new tools for mosquito control: improved insecticides, better traps, and even schemes to use radiation or gene manipulation to render mosquitoes sterile. The ideas underpinning some of these tools are sometimes decades old. Yet technical advances, investments by many groups, including ours, and widespread acceptance that mosquito control is an inherent part of disease control are finally putting this approach back on the map.

A Better Trap

Of the diseases spread by mosquitoes, malaria has proved particularly intransigent and deadly. In 2016, 216 million people were sickened by malaria worldwide, 445,000 of whom died. Certain species of Anopheles mosquitoes are carriers for the malaria-causing Plasmodium parasite. When female mosquitoes bite humans—seeking the nutrients they need for their eggs—the bugs may unwittingly pick up these parasites. (Male mosquitoes do not bite.) Plasmodium then reproduce in the mosquito's gut before they travel to the bug's salivary glands. About a week later, when the mosquito feeds again, the parasite hitches a ride in the bug's spit to a new human host, ultimately infiltrating that person's liver and bloodstream and causing sickness or death.

The disease's wide reach and alarming death toll have netted it the biggest and best-funded mosquito-control efforts. In 2016, $2.7 billion was spent on malaria research and elimination. Yet the greatest obstacle is often pinning down where the control should be applied—finding ways to wipe out the bugs in their environment while minimizing harm to nearby humans and wildlife. Enter eave tubes. The small gap between the roof and the top of the exterior wall in most tropical houses is called an eave. Mosquitoes find human prey in many ways, including following a person's carbon dioxide output through the eaves in their house. In the past few years researchers have started to roll out eave tubes that simultaneously close off those openings and help to reduce malarial transmission. An eave tube is a simple, safe device consisting of a plastic tube and an electrostatic screen dusted with insecticide powder. The tubes transform entire homes into mosquito traps with humans as the bait. When mosquitoes try to enter the home through the tube, they land on the insecticide-coated screen and die.

Researchers have been testing eave tubes in the field for close to a decade. Preliminary unpublished results from a 2016–2017 field trial in Ivory Coast, conducted by Pennsylvania State University in cooperation with European and African partners, indicate that in homes where eave tubes were installed malaria transmission in children may have been cut by as much as 40 percent. The hope is that eave tubes will eventually replace indoor residual spraying—a technique that works well but is more difficult to apply and requires more insecticide. Eave tubes are also safer for kids; the poison is located too high up for them to reach. Moreover, the approach can help minimize the growth of insecticide resistance. As the bugs try to wriggle through these small openings, the powder coats the whole body with a much larger dose than when the bugs briefly land on a surface treated with insecticides, making it more likely the tubes will kill their target.

Not all mosquitoes feed indoors, however, and not every house is suitable for eave tubes. To fight those bugs, Israeli scientists have been developing insecticide-laced sugar baits that attract both male and female mosquitoes. The baits deliver massive doses of poison compared with other traps designed to kill adult mosquitoes because mosquitoes think the poison is sugar they need to survive; a mosquito will imbibe about 20 percent of its body weight in the sweet bait. The bugs consistently fly up to the trial product (which is about the size of a standard sheet of printer paper) and bite through a sheath that contains small chambers of poison-laden bait. Field experiments in Mali have shown that the sheath membrane's tiny openings allow mosquitoes and other insects adapted for blood feeding to access the poison while keeping it out of reach for pollinators such as bees.

Researchers reported at a recent tropical medicine conference that when they hung two traps on the outside of each home in a Malian village, almost half of the malaria-carrying mosquitoes in that immediate area consumed the poison. (To count mosquitoes, researchers caught a sampling of the bugs and examined their guts for signs of the colored dyes that the poison bait had been laced with—a sign that would confirm the mosquitoes had visited the traps and consumed the poison.) As a result of their intervention, about 90 percent of female mosquitoes in that area—the only sex that bites humans—died shortly after their poison meals, before they were able to transmit malaria via their bites.

Mosquito Birth Control

Rather than killing mosquitoes, what if we could prevent them from ever being born? One plan, spearheaded by the United Nations' International Atomic Energy Agency, is to release male mosquitoes sterilized by exposure to ionizing radiation, which harms cellular growth and development in the testes. The idea is that these laboratory-grown sterile insects will mate with wild females, producing eggs that will never hatch. Because most females mate only once in their life, this method could substantially decrease mosquito populations.

In a separate U.N.-supported project run by the Tropical Medicine Research Institute in Sudan, lab workers are mass-producing sterile Anopheles arabiensis mosquitoes—the most prevalent malaria vector in the country—in a special rearing facility for future release. The project is still at the testing stage, but there is reason to be optimistic. In the early 1950s American entomologist Edward Knipling set out to use the same approach—known simply as the sterile insect technique—with the New World screwworm fly, a pest that lays eggs on wounds in livestock and humans that later hatch into flesh-eating maggots. It took decades, but by 2006 the screwworm fly had been eliminated from North and Central America, saving the livestock industry billions of dollars a year.

Similarly, sterilization offers the possibility of a nearly permanent area-wide solution to the mosquito problem with minimal ongoing maintenance work. Yet it requires a lot of organization and infrastructure without much possibility of financial profit; therefore, it has mostly been explored by governments rather than by private enterprise.

Private companies, energized by new interest in mosquito control following the Zika crisis, are hoping that a different type of sterilization effort will prove to be a faster, easier and more thorough way to take out mosquitoes. In these schemes, scientists manipulate the genetics of the bugs themselves. For example, to help Brazil get rid of the mosquitoes that transmit dengue and Zika, a private company called Oxitec has been releasing genetically engineered mosquitoes into the wild—mosquitoes that have been bred in the lab to pass on a gene that kills female offspring. The genetically altered mosquitoes go on to mate with wild mosquitoes, rapidly spreading the trait in a population. During an experimental release of these lab-grown mosquitoes in a suburb of the city of Juazeiro in northeastern Brazil, the number of A. aegypti mosquitoes there fell by 95 percent within nine months. Two other Brazilian cities have also reported successes with the mosquitoes. But this work remains controversial, and critics say there are lingering questions about unintended environmental consequences.

In Mali, workers from the University of Bamako's Malaria Research and Training Center check on a sugar-bait mosquito trap. Credit: Gunter Muller University of Bamako

Genetically driven sterilization efforts could take years to work on any significant scale, but there is another option. Researchers at Imperial College London contend that we should employ “gene drive” tools to quickly push specific genetic changes through the mosquito population. The best way to control malaria, they explain, is to use gene-editing tools such as CRISPR to introduce a specific gene into individual bugs and then “drive” that change throughout an entire population. The CRISPR-editing system is encoded into an embryonic insect's DNA, ensuring that the trait is preferentially passed on to its offspring. Theoretically, after many generations, the entire population will have that gene—overriding the natural rules of inheritance in which sexually producing organisms have a 50–50 chance of inheriting a gene from each of their parents because scientists make the desired change on both chromosomes.

For malaria control, that altered genetic information could either change the mosquitoes so they could not transmit malaria, disrupt the sex ratio in the next generation or simply kill the next generation of bugs. There are clear similarities to the radiation- and gene-based sterile insect techniques, but gene drive would potentially work with far fewer mosquito releases because the modified genes would spread throughout the population within several generations of its introduction.

Yet gene drive, too, is also controversial because of concerns about unforeseen consequences. As a result, thus far no community field trials have gotten the green light. Some scientists who work in the field have also said that wild mosquito populations will develop resistance to gene drives over time—something that has already occurred in lab experiments—and could ultimately render this approach ineffective. Such resistance could arise in a number of ways. In one, natural genetic variation could alter the short genetic sequences that gene-drive systems would otherwise target. Alternatively, cellular repair processes may alter target DNA sequences so that a gene-drive system can no longer recognize them.

The Danger of Reintroduction

Eliminating all mosquitoes is a fantasy. In the U.S., the most effective abatement districts spend from about $1 to $10 per person per year to spray insecticides, remove standing water and clear mosquito-friendly vegetation—yet even that does not completely get rid of them. Killing all mosquitoes could also disrupt food chains and plant pollination in ways we do not even suspect. Besides, only a couple of hundred of the 3,500 mosquito species scientists have identified bite humans and carry diseases, so it would also be overzealous to obliterate them all. The best we could hope for, and probably the only option that would be environmentally safe, would be to eliminate some of the key species from specific areas.

I believe we could achieve that. In Haiti, for example, perhaps we could kill off the main malaria-transmitting species with the sterile male technique while protecting people against other disease-carrying mosquito species with effective eave tubes and sugar-bait traps. We would also need to preemptively monitor human patients and the local mosquito population for signs of emerging threats and tamp down any small outbreaks that may arise. With such comprehensive strategies, it is not unimaginable that within five years the parasites that cause malaria would be gone from the entire island.

Even then, however, there would still be a danger of reintroduction. History demonstrates that if a ship of infected people arrives in a previously disease-free area—or worse, a mosquito species capable of carrying the disease from Africa or Southeast Asia—maladies such as malaria can resurface. Although the worldwide trend has been to free countries from malaria, there are at least 68 documented examples of resurgence of the disease in communities following a reduction in mosquito control. The A. aegypti mosquito managed to make a comeback in Brazil in the 1980s after DDT spraying ceased there, for example. As a result, dengue and yellow fever reappeared in the nation, and chikungunya and Zika viruses cropped up, too. When DDT spraying stopped in India, because of shortages of the chemical and other factors, malaria returned there as well.

We have never had so much innovation or funding in the area of mosquito control. Private foundations such as ours, government agencies and the World Health Organization are collectively spending about $570 million annually on dedicated malaria research, whereas in 2002 the annual spending levels were closer to $100 million. But even with the aid of new tools, mosquito control requires constant vigilance. Mosquito problems are seldom solved permanently and must be attended to constantly—just like any other public health hazard.

Editors’ note: The Bill & Melinda Gates Foundation financially supports several of the discussed projects, including aspects of eave tubes, sugar baits and gene drive.