Love in the Time of Zika In the Middle of the World's Zika Crisis, These Researchers Are Studying What It Means When Mosquitoes Are Able to Learn

Levi Hastings

In a third-floor University of Washington laboratory hidden behind a fragrant row of cedar trees, Clément Vinauger and Chloé Lahondère are interrogating mosquitoes. Because the mosquitoes can answer them only in a handful of ways—pricking their antennae, beating their wings—the researchers talk to the insects through a $2,000 machine called the Arena.

Vinauger, a soft-spoken, 31-year-old French entomologist, lifts the lid off a plastic case to show me 18 wriggling Aedes aegypti mosquitoes glued to what look like long needles by the back of their thoraxes. These are the same mosquitoes scientists believe are spreading the Zika virus throughout the Americas. The species, along with the fear, panic, and disease it carries throughout the hemisphere, is not native to Washington State. Vinauger and Lahondère's lab is just one of two places in Seattle you can encounter them—the other is the Center for Infectious Disease Research in South Lake Union.

"This one seems happy," Vinauger says, using a pair of tweezers to pick up a particularly twitchy animal. Lahondère, another quiet 32-year-old entomologist with a small piercing below her lower lip, watches for several seconds as the mosquito's antennae probe the air.

Vinauger and Lahondère are married. They've known each other since their graduate-school days, when both had developed a fascination with insects that are potent vectors for the spread of disease and Lahondère began studying mosquitoes. Aedes aegypti, which also carries dengue, yellow fever, and chikungunya, was a natural choice for the pair to study.

But the Aedes aegypti mosquito can do something special, the scientists tell me. It can do something that biologists for a long time could not prove.

This mosquito can learn.

A lot of research has been conducted on mosquitoes over the last century, but what researchers at the University of Washington are doing is breaking new ground. If mosquitoes are capable of learning—just like Pavlov's drooling canines learned to associate feedings with the ringing of a bell—they're actually much more sophisticated, individually complex, and formidable than anyone imagined.

Vinauger fixes the glued mosquito to a position at the center of the Arena, a machine that resembles a green, blinking amphitheater. It's a mosquito flight simulator, he explains. The Arena's sensors pick up the mosquito's movements and feed that information to a computer. The computer then arranges green and black patterns on the inside of the Arena to match the mosquito's movements. Vinauger and Lahondère believe that the mosquito, seeing these changing patterns, senses it is flying.

"You can see now that the mosquito is actually controlling its visual environment," Vinauger says. Holy shit, I think.

Vinauger and Lahondère have a lot of questions for the mosquito. How do you find and track humans? What makes you attracted to some humans but not others? How do you even know what a human is?

In 2016, these questions are more important than ever. Four thousand miles southeast of Lahondère and Vinauger's lab, women are giving birth to babies with small heads and underdeveloped brains. The newborns can cry more often than babies without microcephaly, and sometimes they develop convulsions. The Zika virus, which can be carried by the Aedes aegypti mosquito, has been labeled a cause of the birth defects by a consensus of international health officials, and nine countries have discovered evidence that the virus has spread further by human-to-human (likely sexual) contact. More than a dozen countries are reporting an uptick in Guillain-Barré syndrome, another rare condition caused by Zika in which the body attacks its own peripheral nervous system.

Brazilian president Dilma Rousseff is facing a corruption scandal, possible impeachment, the international attention of the Summer Olympics in Rio de Janeiro—and nearly 5,000 microcephaly cases that could be linked to Zika, according to the Brazilian Health Ministry. In January, Rousseff declared "war" on Aedes aegypti through her Twitter account. A month later, she marched through Rio de Janeiro in a T-shirt printed with the hashtag #ZikaZero as 220,000 troops visited homes across the country to instruct people on how to eradicate Aedes aegypti breeding grounds. A slogan on Rousseff's shirt read: "A mosquito is not stronger than an entire country."

But mosquitoes aren't just threatening one country. The virus has spread to 69 countries and territories—44 countries since 2015 alone, including the United States. Dr. Anthony Fauci, head of the United States National Institute of Allergy and Infectious Diseases, has called Zika "a pandemic in progress." In early May, Zika was detected in a King County man who had recently traveled to Colombia. Experts believe it's only a matter of time until Zika takes root in the Southeastern United States.

Nevertheless, many Americans remain blissfully unaware of the virus. A recent Associated Press and University of Chicago survey estimated that 4 out of 10 Americans had never even heard of Zika, or if they had heard of it, they knew very little about it at all. The president of the United States has asked Congress for $1.9 billion to speed up Zika research, the development of vaccines, mosquito control, and international aid, but congressional Republicans are stonewalling the effort. In the meantime, health officials in Latin American countries that restrict women's access to reproductive health care are telling their female citizens not to get pregnant.

Mosquitoes continue to hunt humans—and they're constantly evolving to hunt us more efficiently. They've become specialists in exploiting human ignorance and cruelty toward our own species.

"The relationship between the mosquito and the human host is central," Lahondère tells me during a later Skype call. She rubs her temples. "How can we break this thing, this relationship between the host and the mosquito? How can we find a way to do that?"

Back in the safety of the UW lab, where the Aedes aegypti lives but poses no threat, a mosquito squirms and beats its wings inside the Arena. Its surroundings shift from green, to black, to green again.

This isn't the first war humans have waged on mosquitoes.

In the early 1900s, health officials in Rio de Janeiro set out to kill as many Aedes aegypti mosquitoes as they possibly could. Scientists had recently discovered Aedes aegypti as the source of devastating yellow-fever outbreaks, and health officials went into battle well-armed. They used mineral oil and insect-eating fish to kill young mosquitoes that hatched in water, sealed cracks where mosquitoes might decide to breed, and fumigated to kill flying adult mosquitoes. In people's backyards, "everything that could collect water was removed, buried, or destroyed," according to a 1955 report by Brazil's former chief of the National Yellow Fever Service, Octavio Pinto Severo. Thousands of men inspected houses.

But health officials didn't know much about mosquitoes, and these early efforts were haphazard. Still, by 1908, yellow-fever outbreaks subsided, and with most people thinking the virus had gone for good, the fight against mosquitoes lapsed for 20 years.

A 1928 outbreak of yellow fever in Rio de Janeiro woke everyone up. Health officials made a second attempt at wiping out mosquitoes "with a certain amount of disorganization and near panic," according to Severo. Officials spent millions of dollars on fumigation, but the outbreak raged on for two years. In 1932, Brazil enlisted the help of the Rockefeller Foundation to try to eliminate the Aedes aegypti mosquito from the country altogether.

Then a discovery made during the Second World War would change the war on mosquitoes forever: DDT—a chemical insecticide used to kill lice living in soldiers' clothing—was found to work particularly well on mosquitoes.

After the war, American officials wielded DDT as an instrument of international diplomacy. Presidents Eisenhower and Kennedy endorsed a global fight against mosquitoes, and countries all over the world subscribed to USAID and World Health Organization–supported spraying campaigns. At Brazil's request, the Pan American Sanitary Bureau authorized an international Aedes aegypti eradication program that included DDT spraying campaigns throughout the Americas. In 1958, Brazil was proclaimed mosquito-free. (Widespread use of DDT also had unintended consequences. In 1962, Rachel Carson published Silent Spring, a book that publicized DDT's severe damage to bird populations and other animals that feed on mosquitoes. The United States banned DDT in 1972.)

Curiously, the United States, which both acknowledged that the majority of its Southern states were susceptible to yellow fever carried by mosquitoes and produced DDT, didn't attempt to get rid of the Aedes aegypti until years after Brazil had already concluded its mosquito control program. And by that point it was too late; the countries that did get rid of the mosquito weren't rid of it for long.

Aedes aegypti came back with a vengeance in the early 1960s, reinfesting countries that had previously sprayed the mosquitoes into oblivion—and now the Aedes aegypti had developed a resistance to DDT. Throughout the 1970s and '80s, new dengue outbreaks cropped up throughout the Americas, extending as far north as Texas. Dengue reached an epidemic level in Cuba by 1981, killing 158 people, most of them children. People in countries that had never dealt with dengue before were also getting sick—partly a consequence of international trade and unprecedented quantities of trash that made for excellent mosquito breeding territory. In the first decade of the new millennium, dengue cases throughout the Americas spiked. A 2002 Pan-American outbreak of dengue killed 255 people and made more than a million ill in Brazil, Honduras, Trinidad and Tobago, Costa Rica, El Salvador, Colombia, Venezuela, the Caribbean, Cuba, and the Dominican Republic. A 2010 outbreak in the same countries and Puerto Rico sickened 1.7 million people and killed 1,185.

Halting the spread of mosquito-borne disease takes effort on many fronts, or what public health experts call "vector control." This includes everything from draining mosquito breeding areas to improving water supply and sanitation systems. "The only control measure currently available is vector control, but this method has proven difficult to maintain over time," authors of a paper on the history of dengue outbreaks wrote in the American Journal of Tropical Medicine and Hygiene in 2012.

Many of the problems that allow mosquitoes to proliferate come down to issues of basic human rights and public health: a right to live in decent housing without standing water, a right to basic sanitary services like garbage collection, governments investing in draining mosquito breeding areas. But governments and corporations have often ignored pandemics' socioeconomic factors in favor of technological and biomedical interventions, says Sonia Shah, author of the 2016 book Pandemic.

"I think since the development of antibiotics and the rise of evidence-based medicine, there's been this sense of 'Oh, we don't have to worry about the drivers of pandemics,'" she says. That line of thinking continues: "We are the masters and we don't have to think about how pathogens function, or ecology or biology, because if they start bugging us, we'll start zapping them with some fancy drug or chemical."

And there's a reason that human attempts at mosquito extinction have failed or backfired, or both. "These are not creatures that we can easily squelch, and I think that's a really important thing to understand," Shah says. "We live on a planet with microbes, with insects. We can't just eliminate them all."

Lahondère and Vinauger's Arena, the mosquito flight simulator, isn't the only way to ask mosquitoes what they're capable of learning and how that might impact disease transmission. The couple has also built a number of contraptions to use in mosquito experiments.

One of the devices they use is a mosquito craniotomy machine. It looks like a microscope, mostly, with metal arms and wires sprouting from the sides. While a mosquito is still alive, Lahondère or Vinauger place its body beneath a metal plate with a tiny hole bored through the middle, allowing space for the mosquito's head. The researchers can then remove part of the mosquito's head to reveal two grape-shaped lumps behind the mosquito's compound eyes. Those are antennal lobes, which are used for processing signals for smell and heat. The researchers can then hook up tiny electrical wires to pick up signals from the mosquito's antennal lobes and the neurons connected to it.

"And then if you follow the pathways of the neurons, they connect to higher centers of integration, where activities such as learning take place," Vinauger says. "That's where mosquitoes are making decisions."

But it's one thing to be a mosquito making decisions after two humans have pried open your head, and another to be a mosquito making decisions in the wild. That's why Lahondère and Vinauger keep a wind tunnel in the basement of the University of Washington's biology building. The wind tunnel, a contraption about the size of a child's coffin, is supposed to create conditions that more closely replicate a mosquito's natural environment. There, the researchers can feed mosquitoes heat, smells, and changing visual patterns—and then film their responses.

Still, one of the potential pitfalls of performing experiments the way Lahondère and Vinauger do is to assume mosquitoes in the lab behave similarly in complex human environments. A mosquito's environment can be just as complex and dynamic as whatever's happening inside a mosquito's head, Nick Ruktanonchai, an infectious disease epidemiologist at the University of Southampton, tells me.

"You have these studies looking at what mosquitoes are doing in response to certain stimuli," Ruktanonchai explains. "What happens when we translate that into this really complicated real-world setting of villages, rice paddies, seasonal rainfall, spraying campaigns, and all that? That's the critical link I think is really fascinating and really exciting."

But the Zika virus could still be transmitted in places without the Aedes aegypti mosquito—or any mosquitoes at all. Another real-world complication of Zika is sex. In late April, Canada registered its first sexually transmitted case.

Chloé Lahondère and Clément Vinauger at the University of Washington study how mosquitoes make decisions. Lahondère wants to break the relationship between a mosquito and its human host—a relationship that’s central to the spread of viruses like Zika. Kiley Riffell Photography

The Aedes aegypti mosquitoes that Lahondère and Vinauger study in their University of Washington lab likely first came to the United States from Africa five centuries ago.

They didn't always feed on humans. The oldest mosquito fossil in the world goes back at least 90 million years, long before the 200,000-year-old Homo sapiens came along. Before they began drinking human blood, Aedes aegypti mosquitoes fed on other animals. They bred in tree holes or any other warm, wet, and dark cavity found in the natural world.

When human populations started booming and settling permanently in places that had previously been known only to wildlife, mosquitoes began to evolve side by side with humans. Two more developments in human history benefited mosquitoes significantly: the creation of trash and the transatlantic slave trade.

When slave ships from West Africa carried millions of shackled and suffocating humans to the Americas, they also carried wooden casks for water. After those casks were emptied, a small amount of water would remain at the bottom—a perfect mosquito breeding ground. The ships also provided ideal blood meals for insect travelers in the form of free whites and enslaved blacks.

Mosquitoes carrying parasites from across the ocean unleashed havoc on Native Americans and white colonizers. Yellow-fever epidemics flared along the Atlantic Coast, killing thousands. When Napoleon sent an army to try to suppress the Haitian slave rebellion led by Toussaint L'Ouverture in 1802, yellow fever ravaged his forces. The Aedes aegypti mosquito fought on the side of the Haitians: Fewer than 3,000 of the 20,000 French troops originally sent to Haiti survived. Two years after French soldiers arrived, the French would evacuate Haiti and the country would declare its independence.

Throughout the 18th and 19th centuries, populations set upon by sudden and devastating yellow-fever epidemics had no idea the disease was related to mosquitoes. Protestants thought that yellow fever was brought on by sin. Other theories—supported by the wrongheaded medical science of the time—reinforced preexisting racist ideas.

Well into the late 19th century, Henry Rose Carter, the grandly mustachioed chief medical officer of the state of Mississippi, insisted that yellow fever was spread by black people. In their book Mosquito: The Story of Man's Deadliest Foe, scientist Andrew Spielman and journalist Michael D'Antonio write that this kind of "shaky science" was used "to justify mob vengeance."

"The KKK set up roadblocks and quarantines to prevent the movement of blacks and immigrants," Spielman and D'Antonio write. "In one of the few lynchings that was actually reported in local newspapers, five immigrant Italians in Louisiana, who were blamed for spreading yellow fever after socializing with blacks, were hunted down and then hanged by a mob."

In 1855, Philadelphia physician René LaRoche nonchalantly speculated that black people's "susceptibility" to yellow fever was "inferior" to that of whites. He then quoted a colleague by the name of Dr. Ferguson: "The negro may also be said to be fever-proof; and the marshy savannas, which lie low and scattered and unventilated, prove to him the most healthful abode."

In the 19th century, public-health officials even advocated for racial segregation as a way to combat mosquito-borne illnesses. Eventually, after germ theory was established in the 1880s, scientists started linking mosquitoes and mosquito-borne illnesses together. Still, some doctors and health officials continued to support segregationist public-health policies. Ronald Ross, the British Nobel Prize winner who discovered that the Anopheles mosquito carried malaria, recommended such tactics in colonial India. As late as 1908, Carter, the Mississippi medical chief, supported segregating white laborers on the Panama Canal from "the natives and colored laborers—a source of infection to the insects."

In the age of Zika, right-wing publications in the United States are now reliving racist history. At the National Review, conservative pundit Michelle Malkin pointed at immigrants—not mosquitoes or travelers or people having sex with other people—as the reason to fear Zika in the United States. Breitbart.com further noted that the 2013 appearance of the Aedes aegypti mosquito in California coincided with a year that saw a lot of undocumented border crossings—as if mosquitoes could be stopped by border control checkpoints.

Three years ago, when Vinauger, Lahondère, and their University of Washington colleague Jeff Riffell started asking Aedes aegypti mosquitoes if they could learn, the researchers weren't concerned with Zika in particular. No one had heard of Zika-caused birth defects or neurological problems. The researchers did know, however, that Aedes aegypti mosquitoes spread illnesses like dengue and chikungunya. In the wild, mosquitoes have been observed with life spans as long as two years. If mosquitoes could learn, two years is plenty of time to acquire formative experiences with humans. The more researchers understood the mechanisms underlying mosquito behavior, the more that knowledge could be applied to fighting diseases.

First, the researchers wanted to see if learning might affect mosquitoes' natural aversion to DEET, perhaps the most popular and effective mosquito repellent on the planet. According to the US Environmental Protection Agency, about a third of US citizens use products with DEET in them every year to guard themselves against mosquito bites and the diseases that can tag along. More than 100 insect repellents use DEET as their active ingredient.

In order to teach the mosquitoes to ignore DEET, the researchers fed the insects cow's blood and fanned them with DEET and a compound produced by humans—lactic acid. Then the researchers placed the mosquitoes in a Y-shaped maze. In one arm of the maze, they wafted the scents of DEET and lactic acid toward the mosquitoes. In the other, they wafted clean air. The mosquitoes that hadn't received the DEET training preferred flying into the arm with clean air.

But the mosquitoes that had received the DEET training earlier did something strange. They didn't care about getting a whiff of DEET in the direction of food. The mosquitoes with DEET training were just as happy to fly into the arm with the DEET scent as they were to fly into the arm of the maze without it. In other words, DEET had stopped working as a repellent—and after controlling for a number other explanations of the mosquitoes' behavior, researchers concluded that the mosquitoes learned DEET was irrelevant.

The study on mosquito learning was a breakthrough. This showed that they could learn, and subsequent experiments are now showing how they make decisions.

"This is the first trial of getting deep into the brain of the mosquito as related to associative learning," Jeff Tomberlin, the program director for forensic and investigative sciences at Texas A&M University, tells me. Tomberlin wasn't involved with the University of Washington research, but he's conducted experiments showing how mosquitoes act after being reared in repellent water. The notion that mosquitoes can learn changes the way humans have viewed them for hundreds of years. "I think it's an understudied area of mosquito behavior that more emphasis should be placed on," Tomberlin says.

Claudio Lazzari, a leader in experimental biology and a former instructor of the UW researchers, puts it another way: "The better you know your enemy, the closer you are to fighting it." Once scientists fully understand mosquito learning, they'll better understand how it affects the transmission of disease.

And maybe they'll better understand how to fight disease through outsmarting mosquitoes. One way to fight a learning mosquito is to build clever traps that deceive them, or to implement behaviors that teach mosquitoes to prefer biting nonhumans.

In South America, people do this with kissing bugs that transmit Chagas' disease, an illness that can sometimes kill people or leave them with heart, digestive system, and nervous system problems for life. Kissing bugs' ability to learn has been studied, too. Placing a rabbit in a cage in the middle of your house, for example, creates something of a kissing-bug decoy. Rabbits, which are naturally pretty docile, and additionally restrained because of the cage, make an easy meal for kissing bugs. In this way, kissing bugs—which can also learn—learn to prefer feeding on the rabbit instead of humans.

Another more controversial way of dealing with mosquitoes could be to one day genetically modify mosquitoes so that they're incapable of learning—and maybe, just maybe, make them less of a threat toward humans in the process. "A lot of people are thinking about having mosquitoes that are sense-deprived so that they can't smell," Lahondère says. Entomologists have also speculated about using gene editing to make the female insects—the only sex that sucks blood—more rare in mosquito populations. Male mosquitoes eat nectar and don't pose a threat to humans.

But even if we do eventually figure out what mosquito learning means for human pandemics, that doesn't change the fact that we're in the middle of one. Nor does it change the fact that mosquitoes have evolved, specifically, to prey on humans. "This is a formidable organism: sophisticated and highly refined, highly specialized," Phillip McCall, an entomologist who has studied the Anopheles mosquito, says. "It's not just a crazed, blood-sucking machine that's out to get us."

The Arena is a mosquito flight simulator. Lahondère and Vinauger believe that the Aedes aegypti mosquito senses it’s flying while attached at the center of the blinking green insect amphitheater. On the right, they’re gluing the mosquito by its thorax so it can go inside the Arena. The Stranger

But are we actually the ones out to get us?

All the ways humans have preyed on one another—through slavery, colonialism, economic inequality—have provided new opportunities for mosquitoes to prey on us. It is another cruel irony that Zika now disproportionately impacts people of color, even within the global south. Brazil has one of the highest measures of economic inequality in the world, and Afro-Brazilians are disproportionately represented among Brazil's urban poor, often forced to live in cramped conditions and shoddy housing that allows for buildup of stagnant water.

Globalized trade has also played a role in opening up the mosquito's world.

Once they evolved to hunt humans, mosquitoes began to flourish in places that resembled tree holes but weren't: human-made containers, trash, and tires. The Aedes albopictus, another suitable carrier of the Zika virus, came to the United States at the same time that the country started importing used tires from Japan and Taiwan. Between 1978 and 1985, the United States imported 7.6 million used tires from countries native to the Aedes albopictus, and exported some 6.3 million. Houston, one of the centers of the tire importing and refurbishing business, experienced the first public Aedes albopictus infestation in the United States. Not long after, the mosquito conquered much of the southern portion of the United States.

Burning fossil fuels—and packing the atmosphere with carbon—will also expand mosquitoes' reach.

Neither the Aedes albopictus nor the Aedes aegypti currently live in Washington State—at least not outside of a lab. But that might not stay true forever. Human-caused climate change threatens to shift the natural limits on where mosquitoes thrive. Some scientists predict that changing temperatures will affect the way mosquitoes migrate, pushing them—and the diseases they carry—further north. And once Zika erupts in the United States, some experts predict the virus would stay, erupting in periodic epidemics. A vaccine, meanwhile, is at least several years away.

Until a vaccine is developed, preventing human contact with mosquitoes is the only option we have—and that hasn't worked very well. In the United States, the National Institutes of Health anticipates that 200 million Americans, more than 60 percent of the population, could eventually be at risk of contracting Zika because they live in areas where mosquitoes bite in the summer. Nearly 23 million Americans live in places where mosquitoes bite all year long. The World Bank has estimated that the short-term costs of Zika in Latin America and the Caribbean will cost $3.5 billion, largely because of the tourism impacts—but it's still unknown what the long-term costs will be, particularly when it comes to taking care of more children born with microcephaly. A vaccine could take a while to develop and implement, and Shah, the science journalist, predicts that human populations on earth could take a hit—not through deaths, but through prevented births.

In the basement of the University of Washington's biology building, Vinauger and Lahondère seem to exist in a world far away from a city preparing for the Summer Olympics while panicked health officials wage social-media wars on insects. Their focus isn't Zika, even though their work has newfound relevance for the transmission of the virus. "It's not the first disease," Lahondère says. "Every day, people are dying. It's just one more disease that's coming. It's one more disease that means it's urgent to know mosquitoes better in order to fight them efficiently."

When I ask Lahondère and Vinauger which insects they were studying when they fell in love, Lahondère doesn't miss a beat: "Tsetse fly," she says. Vinauger's answer: "Kissing bug." I gently correct them. I wasn't asking what insects they were studying when they fell in love with entomology, but which bugs they were studying when they fell in love with each other. They both laugh. You can't help but fall in love with the insects you're studying, they say.

Their laughter unsettles me. I don't know if Lahondère and Vinauger ever get overwhelmed by the bigness of the world, by the complexity of something as tiny as the mosquito learning. I don't know how they keep so calm when everything seems to be going to shit. I don't know if their "love" for a living thing that everyone else hates can help save us from ourselves, from the man-made suffering that mosquitoes have capitalized on over the last several centuries, but I hope it can.

I think about this on my way over to the University of Washington lab to hand Lahondère and Vinauger my socks. I've spent all day walking around with tiny glass beads in my shoes that are intended to soak up my foot sweat. In order to study why mosquitoes like to bite only certain humans, Lahondère and Vinauger are collecting samples of sweat that they can then use to stimulate their mosquitoes.

Back in the lab, I empty my socks into a makeshift tinfoil container; Vinauger then transfers the tiny glass beads into a jar. Eventually, my sweat will be mixed with a solvent and analyzed by a gas chromatography machine. One day, these results could help scientists understand how mosquitoes identify which humans to bite—assuming scientists continue to receive the funding to do such a thing.

Later, Lahondère admits that sometimes she does get overwhelmed. "Like every day," she tells me.

But it's not anxiety that's overwhelming her. It's wonder.

"It's amazing how a thing that small could be able to not be killed by a predator, not be killed by a host, be able to take food, be able to lay eggs," she says.

Lahondère's eyes go wide, but she doesn't smile: "Every day, I'm like, 'Wow. Those guys are amazing.'"