For as long as humans have shared the planet with mosquitoes, the goal has been to get rid of the winged pests, or at least keep them at bay. Drain the swamp. Spray the landscape. Put up screens and netting. And if all else fails — thwack!
Biologist Michael Povelones has a far more sophisticated, if subtle, approach in mind:
Boosting the insects' immune systems.
Povelones' goal is not to eradicate mosquitoes, but to stop them from spreading disease. Each week, he breeds thousands of the insects in his custom-designed, escape-proof lab at the University of Pennsylvania's School of Veterinary Medicine, studying the intricate biology of how they become infected with malaria, Zika virus, and other threats to human health. If he can ramp up the insects' ability to fight off these disease-causing agents, they are less likely to be passed on.
Already, Povelones has identified a type of protein in the mosquito immune system that seems to act like a brake, impairing its ability to fight off the parasite that causes malaria. Working with colleagues at Imperial College London and the American University of Beirut, Povelones used a type of genetic manipulation that caused the insect to make less of the protein, resulting in the production of fewer parasite-laden cysts in infected mosquitoes.
"We're kind of removing the brakes," he said. "If we can push the infection levels lower, then we'd have really resistant mosquitoes."
Cocooned in an environment of screens, air conditioning, and robust government pest-eradication efforts, Americans of recent memory view the insects primarily as a backyard annoyance.
But for much of the world, the insects are killers, transmitting such maladies as malaria, yellow fever, and dengue — "breakbone" fever. Povelones likes to show people an illustration that the Gates Foundation produces each year, listing the deadliest animals in order. Sharks, those much-maligned creatures of horror movies and beachgoer phobias, are always near the bottom of the list, killing fewer than a dozen people a year. Tigers are a bit higher, blamed for 50 deaths in 2015.
The two biggest killers of people around the globe, each accounting for hundreds of thousands of deaths each year, are other people – generally in second place – and then at the top: the object of study in the Povelones lab.
The toll from mosquitoes has been at least 500,000 for years, hitting 830,000 in 2015, the foundation estimates.
"I respect mosquitoes," Povelones said. "But I hate mosquitoes."
That kind of thinking gained a lot more public attention here in 2016 with the spread of Zika virus, blamed for causing brain damage and abnormally small heads in thousands of babies.
Transmission of the virus by mosquito is not yet widespread in the United States, and is not thought to pose a threat in Philadelphia, because the primary type of Zika-carrying mosquito does not live here. But it can be transmitted between people who have sexual contact, prompting a billboard campaign this summer by the Philadelphia Department of Public Health.
"Mosquitoes aren't the only ones that spread Zika" reads one such sign. "Love your partner. Use condoms."
Povelones, who came to Penn's vet school in 2014, is tackling the problem through science.
A key tool in his lab is a gene-silencing technique called RNA interference, allowing him to temporarily "turn off" individual genes in mosquitoes to test how that might affect their ability to ward off the malaria parasite or viruses.
First, he knocks out a cupful of mosquitoes by administering a stream of carbon dioxide.
"They're going to sleep now," he said, demonstrating the process recently. "They're out cold."
Then, while looking through a microscope, he administers a dose of gene-silencing fluid to one mosquito at a time, using a slender pipette. The precision instrument, made by Drummond Scientific in Broomall, can be used to inject mere nanoliters of fluid — billionths of a liter — at a time.
A few days after the treatment, Povelones can then "challenge" mosquitoes by exposing them to a parasite or virus. In the case of malaria, he and his colleagues would later pull out the stomach of an infected mosquito and count how many cysts had formed.
There are many layers of protection to prevent any risk to the outside world. The lab, which Povelones calls the insectary, is laid out in a warren of climate-controlled little rooms with sealed vents and air "curtains" — jets of air rippling across the doorways. Each successive space has lower and lower air pressure, gently sucking errant insects away from the exit on the rare occasion that one gets loose within the insectary. None has gotten outside of the lab, and even if it did, Povelones works with only two species, and they do not thrive in Pennsylvania's climate.
An extra level of caution is exercised with mosquitoes that are exposed to disease-causing agents. Glove-wearing lab members handle them only inside a plexiglass containment box fitted with multiple fail-safe measures, including a carbon dioxide port to gas the insects, if necessary. Povelones has never needed to use it.
Each infected mosquito is carefully logged to ensure that all are accounted for.
"The books are always balanced," he said. "We're like mosquito accountants."
If he and colleagues identify some sort of promising immune-system pathway that influences the insects' ability to ward off viruses and parasites, the idea is that someday mosquitoes could be permanently modified to improve this ability and then be released into the wild.
Or scientists could go the other direction, said Sara Cherry, a professor of microbiology at Penn's Perelman School of Medicine who has collaborated with Povelones.
"There are two different ways of thinking about it," she said. "One is to boost the immune system of the mosquitoes so they don't get infected. Another is to destroy the immune system of mosquitoes so they get so infected that they die."
Other cutting-edge approaches already are being tested in the real world. In Brazil and other warmer climes, officials have released mosquitoes that have been genetically modified so their offspring will die. In Florida and California, mosquito-control specialists have released insects that are infected with a bacterium called Wolbachia that renders them less able to become infected by Zika.
The term "genetic modification" provokes concern in some quarters. If humans were to use such techniques to disrupt or eradicate the mosquito population, would that somehow be bad for the ecosystem? The general thinking in the scientific community, for now, is no. For example, birds and bats eats mosquitoes, but the insects make up such a small part of their diets that they are unlikely to be missed.
Cherry and Povelones also are exploring another intriguing possibility: the insect's microbiome. When a mosquito bites a human being, it ingests twice its body weight in blood. That is fuel for the insect, and also for the bacteria that live within it, causing them to multiply by the hundreds and even thousands — though some types of bacteria thrive on blood more than others.
Research has shown that these altered bacterial populations can directly impact the mosquito's ability to fight off malaria. And Cherry's lab discovered that certain components of the mosquito microbiome could boost the insect's immunity to viruses.
All of these potential strategies hinge on a basic element of the insect's behavior: the bite. In order for a mosquito to transmit a virus or the malaria parasite, it must first bite someone with the disease, become infected, and then bite someone else. Interfering with that middle step is what excites Povelones.
"The mosquito is sort of the choke point," he said.
In a similar vein, he is investigating why certain types of mosquitoes transmit heartworm, a serious health threat for dogs, while other species of the insect do not. Pet owners can treat their animals for heartworm, but even if all of them did so, the parasite still can persist in feral dogs and wolves. What if Povelones could modify more mosquitoes so they could not transmit heartworm from animal to animal?
He and Cherry are well-aware that their object of study wins no popularity contests, yet they also feel moved to come to its defense, to a degree.
"It's not like the mosquitoes particularly want to transmit these pathogens," Cherry said. "It's not like they have some insidious plan."
It is just biology. Over millions of years, mosquitoes evolved an efficient mechanism for feeding on blood. The parasites and viruses simply take advantage of that phenomenon to spread human disease.
Unless, someday, science can help mosquitoes fight off these diseases at the choke point.