Bitten

There’s no ignoring it. Some of the students enrolled in this medical entomology class are far more attractive than others. They know it, their classmates know it, and so does Susan Paskewitz, professor and chair of the Department of Entomology.

Paskewitz describes herself as “relatively unattractive,” and she proceeds to prove it using the same test her students have just performed. She fills a small vial with warm water, rubs it between her palms to coat it with volatile compounds from her skin, then places the vial on top of a thin membrane stretched over the top of a plastic container akin to an economy-sized ice cream tub. She invites a visitor to do the same.

Waiting on the other side of that membrane are 20 blood-starved specimens of Aedes aegypti, commonly known as the yellow fever mosquito. Hungry as they are, the insects don’t show a lot of interest in Paskewitz’s vial. They hover near where it touches the membrane, but only two or three land. The visitor’s vial, on the other hand, is a busy spot. At least a dozen have landed and are testing the surface with their needle-like proboscises.

“Wow,” says Paskewitz. “You’re really attractive!”

In another context, those three words could make your day. But not here. Nobody wants this kind of animal magnetism. Nobody wants to be the person who’s cursing and slapping and reaching for the DEET while others are calmly eating their brats and potato salad.

If you’re that person, take heart. Paskewitz can tell you a little bit about why you might have more than your share of interspecies charisma and offer some suggestions on how to scale it back. But first, let’s talk about why this matters.

An average American adult outweighs an average-size mosquito by about 30 million to one. Ounce for ounce, that’s like the USS Nimitz vis-a-vis a good-size duck. But while it’s a safe bet that a 100,000-ton aircraft carrier won’t change course to avoid a six-pound mallard, it’s almost certain that, on a regular basis, you change your behavior to avoid being bitten by a 2.5-milligram mosquito.

Mosquitoes cause us to do things we’d rather not, like dosing ourselves with a repellent that’s sticky and smelly and comes with a sobering warning label (you can apply it to your kids’ skin, but keep the bottle out of their reach), or pulling on long pants, long sleeves, a hat and maybe a head net on a sweltering midsummer day.

Mosquitoes keep us inside when we’d much prefer to go out. In the summer of 2009, Paskewitz and environmental economist Katherine Dickinson, of the Colorado-based National Center for Atmospheric Research, asked a sample of Madison residents how they coped when mosquitoes got fierce.

The second-most-common answer (right after applying repellent) was to stay indoors. About two-thirds of the respondents said they had curtailed outdoor household activities—gardening, yard work, sitting on the deck—in the past month because of mosquitoes, especially in the evening hours, which, for working people, may be the only time available to get a little fresh air. About a third said they had avoided outings, and a similar share said they had avoided outdoor exercise.

Nobody wants to be outside more than John Bates, of Manitowish. An author of seven books about Wisconsin’s north woods and a naturalist by trade, Bates leads interpretive hikes year-round—except in June: “We just kind of throw the month out. The mosquitoes cause too much discomfort for people to listen to interpretation. All we can do is keep walking. People hire me because they want to learn more about the place than they knew before they came. If they can’t stop to listen, what’s the point?”

If we do venture out when mosquitoes are massing, we may not get the experience we were hoping for. Andrew Teichmiller, an outfitter of bikes and paddling gear in Minoqua, recalls mountain biking in 2014, arguably the area’s worst mosquito year ever. “You had to ride the complete trail without stopping, all the way back to the parking lot, and jump in the car, quick, because if you stopped there were 15 or 20 mosquitoes on you immediately.” As for camping: “It’s a different type of experience when you can’t sit by the fire at night and tell stories. You’re forced to run for your tent. It definitely affects the feel of the trip.”

But let’s be clear: A ruined camping trip is far from the worst possible consequence of a mosquito bite.

Mosquitoes transmit diseases that kill nearly a million people every year and sicken hundreds of millions. Tropical and subtropical areas bear the brunt of this, but no place is immune, including Wisconsin. Malaria plagued the immigrants who settled in Wisconsin in the 1800s, and various types of encephalitis are diagnosed on a regular basis.

But today the biggest concern is West Nile virus (WNV). Wisconsin has been relatively lucky since the first case arrived here in 2002, with a total of 230 cases reported through 2014. But all four adjacent states have had bigger outbreaks—notably Illinois, with 2,093 cases total and 884 in its worst year, most of them just across the border in the Chicago area. Wisconsin’s worst year brought 57 cases.

Most cases of WNV bring no symptoms, according to the Centers for Disease Control, but about one in five can involve a fever, headache, body aches, vomiting and a fatigue that can last for weeks or months. Fewer than 1 percent of WNV victims display severe neurologic symptoms, including disorientation, coma, tremors, seizures or paralysis, and of those, about 1 percent die.

Nevertheless, Wisconsin residents are bothered much more by the nuisance of biting mosquitoes than they are worried about West Nile virus. The Madison residents responding to Katherine Dickinson’s 2009 survey said they’d be willing to pay an average of $149 for a hypothetical program to control nuisance mosquitoes, but wouldn’t pay anything for one targeted at mosquitoes carrying WNV when risks were as low as they were at the time (about one case per year in Madison with a population of 250,000).

It’s not surprising to find that attitude in Wisconsin, where mosquito-borne disease is relatively rare, but Dickinson says that people tend to think the same way in places where mosquito bites are often fatal. She observes that in Tanzania, biting mosquitoes were a major factor motivating people to use bed nets. “It was a similar situation to ours,” she says. “Some mosquitoes are more noticeable and more of a nuisance, but those that transmit malaria are kind of sneaky; people don’t feel them biting as much. In areas where mosquitoes were more of a nuisance, people used the bed nets more.”

Biting-wise, there’s an important distinction between nuisance mosquitoes and the ones that transmit WNV. The former come at us aggressively, in such staggering numbers that they’re impossible to ignore. They remind us to protect ourselves. Culex pipiens, the WNV vectors, are more subtle and harder to notice.

Nuisance mosquitoes and the WNV carriers also show up at different times. The most annoying biters—Aedes vexans in particular—are floodwater species that breed after a stretch of wet weather. Culex breed in water that stagnates during a dry spell.

“When it’s been really dry, the water just sits in the stormwater catch basins that are the biggest sources of the WNV vectors,” says Paskewitz. “There’s not enough rain to flush them. Things get more fetid, stinkier. That’s the year when we see a ton of Culex.”

The take-home message: If you only grab the DEET when the biting is so bad that you can’t stand to be without it, you’re not protecting yourself against West Nile virus.
“You need to protect yourself against bites even if you’re not getting a lot of them,” says John Hausbeck, director of environmental health services for Dane County and the City of Madison. “We’ll see summers where it’s really dry and the floodwater mosquitoes are very limited, but we still have plenty of small pools that the Culex can breed in.”

That “biting pressure” is something that Hausbeck needs to stay on top of, and Paskewitz helps with that. She and former grad student Patrick Irwin PhD’10 were able to characterize the types of sites where Culex are most likely to breed and identified alternatives for treating them—for example, introducing fathead minnows to feed on Culex larvae. She and her students analyze the mosquitoes trapped in the area to see how many are Culex and whether they’re carrying WNV. Their data tell Hausbeck whether he needs to issue a public alert.

It’s important to remain vigilant. “When West Nile first came into the country, people doubted it would make it through the first winter,” Paskewitz says. “Well, it did persist, and in a very short period of time it whipped across the whole country. We’ve had a lot of cases in new places. First it was really bad in North and South Dakota. Then Colorado and Arizona. Then Texas, Illinois. It’s really hard to predict. And given the vagaries of climate, we just don’t know whether the next year it might be Wisconsin.”

Maybe WNV hasn’t changed Wisconsin residents’ ideas about why to guard against mosquito bites, but it certainly has spurred a lot of questions about how. There is a seemingly endless list of products and strategies, that, according to somebody, will eliminate mosquitoes or repel them—and since WNV arrived, Paskewitz has been getting questions about pretty much all of them.

“They call me to ask, ‘Would this work or wouldn’t it?’ There is a lot of misinformation out there and not many good sources of information, so I realized I needed to get a better idea of what the science was behind these things,” Paskewitz says.

As she comes up with answers, she posts summaries online. Her website, http://go.wisc.edu/mosquitoes, gets plenty of visits (55,000 last year) and triggers a lot of calls from media from across the nation.

A few of her findings:

• Repellents can be very effective, but comparing them is tricky. There are lots of products with varying active ingredients offered in different concentrations and combinations. Generally speaking, DEET, Picaridin, IR3535, and oil of lemon eucalyptus have good track records. There are also a number of other plant-based compounds—garlic, catnip oil, vanilla and oil of cloves, for example—for which there’s less research and conflicting results. The website sums all this up and gives links to more information.
Yard traps get a thumbs-down. “We tested those and didn’t get any positive outcome,” Paskewitz says. Yard traps lure mosquitoes by releasing C02, light or octenol, a compound contained in our breath and sweat. Sure, they can catch mosquitoes by the hundreds, Paskewitz says. But does this significantly reduce the numbers that bite you? Properly controlled studies say “no.”

• “Sonic” devices—wristbands, smartphone apps, etc.—do better at extracting your money than keeping mosquitoes off your deck. “You can test them yourself,” Paskewitz says. “Sit at the picnic table and count how many mosquitoes land on you, then turn on the device and count again. Or you can trust the research and save your money.”

• Bats are busted. The idea that a colony of bats can consume millions of mosquitoes per night came from a study in which someone put a bat in a room full of mosquitoes and estimated how many it ate. The question is, given the choice, is that what bats eat in the wild? Researchers who examined the stomach contents and fecal pellets of bats have found bigger insects, like butterflies, moths and beetles, but very few mosquitoes. “Bat houses are great for conserving bats,” Paskewitz says, “but not for mosquito control.”

• Avoiding bananas—When she first heard the idea that eating bananas makes you more attractive to mosquitoes, Paskewitz raised her eyebrows. “I thought, okay, we’ll debunk that,” she says. She was teaching medical entomology at the time with 24 students—enough for a robust sample—so she made it a class project. For several weeks, each student ate a banana and then performed an attractiveness assay at prescribed intervals. “We were really intrigued. It did look like we were getting an increase a couple hours after eating the bananas.”

Paskewitz repeated the trial the next two times the course was offered, with a few tweaks to the methodology: Half the students ate bananas, the other half grapes. “The third trial was the best of all—the strongest statistical evidence and the most repeatable,” Paskewitz says. “We did it three times and saw a strong difference between the groups. Grapes didn’t matter, bananas did. At that point I was convinced. I think it’s real,” she says. Does that mean you if you leave bananas out of your picnic fruit salad, you can skip the bug spray? Probably not, Paskewitz says.

Because “less attractive” is not the same as mosquito-proof, Paskewitz gets plenty of mosquito bites, probably more than her share, because she spends a lot of time around mosquitoes—in the woods doing field research, in her garden, and in her lab. When you’re a mosquito researcher, getting bitten comes with the job.

What Makes You Attractive?

It sounds like the topic of an article in Seventeen magazine—and, interestingly, some of the same general categories apply whether you’re talking about your appeal to a mosquito or to a certain someone of your own species.

Your breath. If you breathe, you’re mosquito bait. Every breath adds to a plume of carbon dioxide (CO2 levels in your breath are 100 times that of the atmosphere) emanating from where you stand. “That’s the big signal,” says entomology professor Susan Paskewitz. “Insects are very sensitive to chemical cues. They’ll zigzag to pick up the chemical as it gets stronger and stronger, circling to narrow in on you.”

Your aroma. Once they find you, mosquitoes use chemical cues to decide whether to land and dig in. They have a lot to sort through: You emit roughly 400 different compounds from your skin and 200 in your breath. Many mosquito species won’t land on humans, even if they’re starved for blood. Others will bite us in a pinch but prefer other hosts, Paskewitz says.

Your genes. Perhaps you were born to be bitten. A pilot study at the London School of Hygiene & Tropical Medicine found that identical twin sisters were significantly more alike in their attractiveness to mosquitoes than were non-identical twins. Since identical twins are closely matched genetically, this suggests that some of your Culicidae charisma is inherited. Some volatile compounds on our skin are produced by skin cells (others are produced by bacteria), which would be gene-regulated, the study’s authors note.

Your jeans. What color you wear matters. This is based on a series of studies in which researchers draped different colors of cloth on human volunteers or on robots heated to simulate human body temperatures, then counted mosquito landings. For the most part, darker colors were more attractive. White was least attractive, followed by yellow, blue, red and black.

Your smelly feet. “The malaria mosquito is really attracted to the smell of funky feet,” Paskewitz says. “It’s a classic story in medical entomology. The compound that makes feet smell funky and attractive to mosquitoes is the same one that causes Limburger cheese to smell the way it does.” That compound is produced by bacteria that can accumulate in the moist spots between your toes, and are kin to those used to culture Limburger.

Your drinking habits. A number of researchers speculate that drinking alcohol makes you more attractive to mosquitoes. A team in Japan put this to the test. They asked some volunteers to drink 350 ml of beer while a control subject did not. The percentage of mosquito landings after alcohol consumption increased substantially. Why this happens is unresolved, although some have speculated that people who have been drinking are easier targets because they move more slowly.

Getting Under Your Skin

Maybe you don’t get more mosquito bites than other people. Maybe your body just makes a bigger deal of it. The swelling, redness and itching are signs of your immune system kicking into gear, explains Apple Bodemer, an assistant professor of dermatology at the UW–Madison School of Medicine and Public Health. And some people’s immune systems kick harder than others.

A mosquito bite involves give and take. Before drawing out up to .001 milliliters of your blood, the mosquito injects a bit of its saliva, which contains anticoagulants to prevent clotting. You can spare the blood, but the saliva is a problem. That’s how disease gets transmitted. And the saliva contains foreign proteins, or antigens, that spur your immune system to create antibodies, Bodemer explains. “When antibodies bind to the antigens, it initiates an inflammatory response, which includes the release of histamine, which causes the blood vessels to dilate, which brings the swelling and redness and the inflammatory mediators that are responsible for the itching.”

This doesn’t happen the first time you’re bitten. It’s the second time, when your body has built up the antibodies, that your immune system engages. If you get bitten enough times by the same strain of mosquito, you may become desensitized and have either a very mild reaction or no reaction at all to the bites. “People often have more vigorous immune responses early in the season and then, as the summer goes on, they don’t have as much swelling and redness and itching,” Bodemer says. “But when you go a winter without any exposure, you often become resensitized.”

For the same reason, younger kids tend to have more aggressive reactions. Once they’ve had several years of mosquito exposure, their response tends to die down, Bodemer says.
As for scratching? Doctor’s orders: Don’t! “Scratching really promotes the full inflammatory reaction. It causes more irritation, causing the blood vessels to be more dilated and further dispersing the inflammatory mediators. It initiates a cycle of swelling, redness and itching. If you can avoid scratching, a lot of times the bumps will disappear.”

Antihistamines can ease the itching, she says, or you can try a home remedy: “I paint a little clear nail polish on the mosquito bite. That will stop the itching to some degree and allow the inflammation to clear up more quickly,” Bodemer says. “Some people cover the bite with Scotch tape for two to four hours. The tape stops you from scratching and when you peel it off, it removes some of the mosquito saliva.”

Wisconsin’s Pestilent Past

Wisconsin’s 19th-century settlers knew that mosquitoes were biting them, and they knew that something was making them sick—but they didn’t put the two together.

Their doctors blamed the ailment on “malarial vapors” emitted by decaying vegetation in the swamps, according to Peter T. Harstad, a UW–Madison educated historian who authored several articles on the health of Midwestern settlers. Harstad used reports by military and civilian doctors as well as immigrants’ diaries and letters to chronicle the devastation caused by what was sometimes called “intermittent fever” because the symptoms—chills, aches and a general fatigue—often recurred over a period of months or years.

“I became sick as soon as I came here and have been sick for eighteen months with malarial fever, which is very severe and painful and sometimes fatal,” reads one letter excerpted by Harstad, written in 1941 by a resident of Muskego. “My wife and I are now somewhat better, but far from being well. This year seventy or eighty Norwegians died here … Many became widows and fatherless this year.” About 13 percent of Muskego’s population died that year, Harstad estimates. The town was hard hit because of an abundance of marshes, a relatively warm climate, and the fact that Norwegian immigrants had no resistance to the disease.

Soldiers also suffered. Harstad cites army reports of malaria outbreaks as far north as Ft. Snelling, near present-day St. Paul. Hardest hit was Ft. Crawford, located amid miles of Mississippi River wetlands at Prairie du Chien. In the fall of 1930, there were about 150 cases reported among the 190 soldiers stationed there. To treat the disease, army surgeons were directed to “extract from twelve to twenty ounces of blood, an operation which it is sometimes required to repeat once or twice.” Wisconsin was mostly malaria-free by the end of the 19th century, as farmers drained wetlands and better housing shut out mosquitoes.

The Exterminator

The thing Que Lan remembers best about the summer of 1973 is the uncontrollable shaking. A stifling blanket of humid air had settled on top of Wuhan, the capital of Hubei province in central China, and it sat on the near 100-degree days like a deflated cloud. It was the time of year when a city collectively dreams of a sudden rain shower or a cool breeze—and yet 13-year-old Lan lay shivering underneath three blankets as her disease dragged her from profuse sweating into debilitating chills.

The diagnosis had surprised Lan. Malaria seemed like a far-off threat, the scourge of rural areas dotted with rice paddies and infested with mosquitoes. But even in the metropolitan climes of central China’s biggest city, where government trucks rolled down the avenues dousing neighborhoods with DDT, the threat of the disease was never too distant. As everywhere in the tropical and subtropical regions of Earth—where nearly 50 percent of the world’s population now lives—malaria lurks just one fateful bite away.

Lan’s illness was one of roughly one-half billion cases of malaria around the world in 1973. Because her family had easy access to medications, she avoided a far more somber statistic: More than a million people die from malaria every year, most of them children. Instead, Lan endured two weeks of shivering, fevers and aches and then recovered, well enough to return to school. Malaria was finished with her.

But Que Lan was not finished with malaria.

Now, nearly four decades after the bell first rung in her bout with the disease, Lan is halfway across the world, preparing to land her first solid blow. Malaria has not gone away and is as menacing as ever. While the disease has been pushed out of more temperate (and more prosperous) areas like Europe and the United States, malaria is still present in 108 of the world’s 195 countries. In most years, more than 250 million people will get sick with malaria and one million—most of them children—will die. Those statistics have led groups such as the Bill and Melinda Gates Foundation to declare all-out war on malaria, making eradication of the disease its number one medical goal. The World Health Organization and National Institutes of Health are equally engaged in the fight. But while these scientists and public-health officials struggle to control the disease and its devastating effects, Lan, a CALS associate professor of entomology, is attacking the source—the six-legged pest that malaria uses to get around. .

Entomology has come a long way from the days of peering through magnifying glasses at anthills. Today, entomologists like Lan peer at bugs from the inside out, scouring their genes for the drivers of their behavior. In her office on the 8th floor of Russell Labs, Lan hunches over her office computer and motions for a colleague to take a look at the bright bands of color on the screen. The bands are genetic code and, from that code, Lan has teased out a single gene essential to mosquito survival. A weakness. A genetic chink in the armor. In a multi-year study funded partly by the U.S. Department of Defense—which hopes to find better mosquito-control methods to protect troops in tropical regions—she’s also found a way to prevent that gene from doing its job. This is the target her lab is aiming for in a promising new approach in the fight against malaria.A target that, Lan hopes, can  debug the bug.

Humans have been swatting at mosquitoes for millennia. And mosquitoes have returned the favor, injecting us with all sorts of diseases, from dengue fever to lymphatic filariasis to West Nile virus. But malaria is king of them all, a harbinger of death and disease throughout the ages. Descriptions of malaria symptoms can be found in ancient Chinese medical writings dating back to 2700 B.C. and are scattered throughout Greek and Roman texts. The disease has claimed millions upon millions of lives, including those of several popes, the Italian poet, Dante, and, some scholars believe, Alexander the Great. Outbreaks of malaria have sent famous explorers far off course and swung the outcomes of wars by incapacitating entire armies.

As is to be expected with such a devastating disease, we’ve spent centuries battling back. In ancient China, a remedy for malaria’s intense fevers was made from dried wormwood leaves. In the 17th century, it was bark from the Cinchona calisaya tree that grew high in the Peruvian Andes. The active ingredients from both remedies are still used today in some malaria drugs. Other anti-malarial drugs were developed during both World War II and the Vietnam War as prosperous nations searched for ways to minimize the effects of malaria on their forces. Today, travelers to malaria-afflicted regions can take any of a half-dozen drugs to prevent infection and treat symptoms. But the development of new drugs has slowed dramatically, and the old ones are growing less effective as the disease gains resistance to them.

When a mosquito infects a person with malaria, they are actually injecting the plasmodium parasite into the bloodstream. Plasmodium heads for the liver where it begins to reproduce. It eventually builds an army of parasites that swarm into the bloodstream where they kill red blood cells and, sometimes, their host. During this stage of the disease, a single person can have millions upon millions of plasmodium parasites reproducing in their body. Multiply that single infection with hundreds of millions of people also carrying hundreds of millions of plasmodium parasites, and resistance to commonly used drugs is an inescapable result. To stay ahead of malaria means keeping it on its toes. Researchers know that the war will not be won with World War II-era weapons. It will take a modern, multifaceted arsenal to keep pace.

This is a lesson that the World Health Organization learned the hard way. In 1955, the WHO announced its Global Malaria Eradication Programme, aiming to rid the world of the disease with the help of newly developed weapons—including anti-malarial drugs developed during World War II and the insecticide DDT—and some it hoped were on the way. Medical science believed a vaccine to ward off malarial infection was close at hand, and buoyed by that optimism, the WHO boldly predicted the tropics could be soon free from the grip of the disease. But while the campaign did push malaria out of temperate regions of the United States and Europe, the disease proved intractable in other areas. A vaccine did not emerge, and the parasite quickly evolved resistance to many of the new drugs. But the WHO’s biggest shortcoming was underestimating the complexity of eradicating such a disease. That kind of bold aim necessitates more than good medicine.

“With malaria, we have pretty good drugs,” says Bruce Christensen, a parasitologist in the UW School of Veterinary Medicine.. “The problem is you don’t have very good infrastructure for health facilities (in developing nations). So it’s really hard for people to even get medical care. So even if you have good drugs, you probably don’t have them in the areas where you need them.”

At every turn, the WHO’s efforts were thwarted by the realities of human nature. People didn’t use the bed nets that were handed out in villages to prevent mosquito bites because the nets were stifling to sleep under and were handy as fishing nets. A campaign to spray the walls of houses with DDT met with a similarly unexpected failure. “One of the big problems they had with their workers was they would leave one wall unsprayed,” says Christensen. “And the reason they did that is because if they sprayed all the walls and killed all the mosquitoes, then they were out of a job and this was the best job they’d ever had.”

DDT presented other problems, as well. The insecticide had been the go-to weapon for mosquito control since 1948, when Paul Mueller won a Nobel Prize for demonstrating its lethal power over insects. By the 1960s, however, the pesticide once hailed as a miracle was looking more like an environmental monster, laying waste to birds, frogs and other animals. Facing mounting criticism from conservationists, the U.S. Environmental Protection Agency banned its use in 1972. With no U.S. market to serve, many companies stopped manufacturing DDT, making it scarcer and more expensive for widespread applications in the tropics. Plus, after three decades of near-exclusive use, it, too, was losing its potency.

In 1973—the same year that Que Lan was shivering under her blankets and unknowingly preparing for a career doing battle with malaria—the WHO threw in the towel. Malaria, the organization admitted, was hopelessly entrenched in certain parts of the globe.

The failure of eradication triggered a shift in thinking about malaria control. Many scientists and public-health officials realized that malaria and mosquitoes went hand in hand. You could never kill the disease, without also going after its carrier. In his 2010 letter to Gates Foundation supporters, Bill Gates even acknowledges that modern medicine isn’t ready to eliminate malaria. A vaccine, he says, is at least ten years away. We have to get better at killing mosquitoes.

The approach, called vector control, sounds hopeless at first. Places where malaria is endemic are home to multiple millions of mosquitoes that thrive year-round.No method of insect control could possibly eliminate that kind of population.Papua New Guinea is a perfect example, says Bruce Christensen. Mosquitoes there often lay their eggs in puddles of rainwater that collect in cattle hoof prints. Multiply a hundred eggs by a million hoofprints and the numbers quickly become incomprehensible. “What do you do?” Christensen asks. “Do you try to put [pesticide] everywhere? Because there are breeding sites everywhere.” The best that can be hoped for is to knock mosquito populations back, especially around areas more densely populated with people.

The authors of a new report on malaria control say such modest efforts may actually produce major results. . Published in the August issue of PLoS Medicine, the article points out that in parts of sub-Saharan Africa, a person can receive up to one thousand infectious bites from a malaria-carrying mosquito each year. Those mosquitoes aren’t just injecting that person with the disease, they are often also picking up a new batch of the parasite to carry to someone else. That means that, even if a massive campaign of drug delivery pushed the malaria to the brink of regional extinction, a single infected person moving in to the area could give rise to thousands of new infections and quickly re-establish the disease.

Controlling mosquitoes, on the other hand, makes it more difficult for the disease to rebound from successful anti-malaria campaigns. Reduce the number of mosquitoes in a malaria-infected environment by just half, and the instances of multiple infections and transmissions can drop by entire orders of magnitude. You simply can’t overestimate the role mosquitoes play the authors conclude. And that means that, to wage a truly effective campaign against malaria you need more than a doctor. You need an exterminator.

After her bout with malaria, Que Lan went on to study the sciences. She studied  microbiology at Wuhan University in China and earning a master’s degree at Brock College in St. Catharine’s, Ontario. But it took one intriguing offer—an invitation to complete her doctoral work at the University of Minnesota in noted entomologist Ann Fallon’s mosquito lab – for Lan to realize that the mosquito that bit her in 1973 was still buzzing around in the back of her head. It seemed like a crazy idea, the bravado of young ambition, but Que Lan wanted to bite back “I thought maybe someday I can do something about this,” says Lan, laughing at the audacity of her younger self. “It was just this kind of remote idea (that) maybe someday I can do something (to help).”

Under Fallon’s tutelage, Lan learned molecular biology, which she says “was really nothing to do with killing mosquitoes,” Her research had more to do with what makes them thrive. But after joining the UW-Madison faculty in 2000, she set out to turn that knowledge into better weapons for mosquito control.

“The key,” she says, “is to really understand the biology of your target insect and develop specific components that just target that.”

Lan knew from her Ph.D. work that mosquitoes, like all arthropods, don’t make their own steroids or cholesterols. Both substances are essential for survival, and insects must get them from their food sources. So when Lan discovered that a gene called sterol carrier protein-2 was activated in proteins in the gut during feeding, she knew she had found an essential link in a mosquito’s ability to live. “That’s the Achilles’ heel,” she says. “(I thought) if I can destroy this pathway, they may not survive.”

Her lab turned their focus exclusively on the gene. They mapped its proteins to decipher the chemical transactions that took place around the gene and studied when and where it was switched on. They studied the function of the gene during the mosquito’s various development stages, which led to a critical discovery: If the gene was not allowed to activate inside a mosquito egg, the developing larva would not get the cholesterol it needed and the egg would not hatch. In other words, silence the gene and you silence the bug.

The finding was a career-defining achievement in itself. Researchers often only get this far—learning something new that hasn’t been known before. But Lan wanted more. She knew the finding represented an exploitable weakness, one that could be developed into a method of control. Imagine, for example, dropping a pellet into a pool of standing water, where mosquitoes lay their eggs, that would deliver a knock-out blow to the eggs’ cholesterol-uptake capacity. Although her focus had been on mosquitoes of the species aedes egypti, which carry yellow fever, Lan was confident it would work for malaria- and West Nile-transmitting mosquitoes, as well. The idea of those little pellets preventing a disease-carrying swarm from hatching, Lan says, “is really satisfying.”

But what would flip the switch? Lan needed a chemical that could knock the gene out of order. And that chemical needed to pose as little threat to humans, animals or the environment as possible. The last thing she wanted was to create another DDT. To avoid this, she took a trip to see a few robots on the west side of campus.

Housed in the Paul P. Carbone Comprehensive Cancer Center at the UW-Madison School of Medicine and Public Health, the Small-Molecule Screening Facility allows researchers to conduct thousands of experiments simultaneously. The facility boasts three robots that store tens of thousands of chemicals. Introduce those robots to a cell line or protein, and they’ll introduce it to a few molecules of every chemical at their disposal. Advanced and sensitive instruments monitor each experiment and alert researchers when there’s a “hit,” or, rather, when one chemical has achieved its desired results. And that’s what happened when Lan’s lab took sterol carrier protein-2 for run through the robot gauntlet: Out of tens of thousands of chemicals, they found a dozen that worked. And they all worked in much the same way. Like a game of molecular musical chairs, these synthetic chemicals competed with cholesterol for a seat on sterol carrier protein-2. For every molecule of the chemical that bound to the protein, a cholesterol molecule was out of luck. Lan left the facility with a plan—introduce enough molecules of the chemical to the game, and developing mosquitoes don’t get enough cholesterol to ever hatch from their eggs.

The trouble with synthetic chemicals, though, is that they hang around in the ecosystem long after they’ve been applied. If Lan’s chemical tool were going to see wide use, a better alternative would be to employ a natural chemical to muck with the bug’s genes. So Lan again turned to the library to find a natural chemical that mimicked the activity of the synthetics.

The source was unexpected—an Asian fruit called mangosteen, which contains a chemical that turns out to be a dead ringer for the best-performing of the synthetic chemicals Lan tested. Touted for the rejuvenating power of its juice, mangosteen is called “queen of the fruit” in parts of Southeast Asia, and Lan finds the fact that a malaria-infested country could harbor a promising new natural agent against the disease a delicious irony.

“We’re pretty sure this quality is one of (mangosteen’s) main evolutionary traits. It’s a naturally occurring defense compound,” she says. “We would never have imagined to use (mangosteen extract) on insects. Not in a million years if we didn’t get it from our library screening.”

Susan Paskewitz, a CALS entomology professor who also works on mosquito-borne disease, thinks there’s great promise in this new way of methodically developing insecticides. “In the old days we might have started with something that from lab experiments was known to kill agricultural pests and then tested it on mosquitoes,” she says. The power of genetics is to look at species-specific approaches, which could mean fewer unintended consequences.

And that seems true for Lan’s genetic attack strategy. Since the chemical approach employs a different mode of action than traditional pesticides, it promises to be effective against species that have grown resistant to those applications. There’s also little danger of the chemical affecting humans or other animals since chemicals bind differently in our DNA. And even if some of the chemicals bound and prevented uptake of cholesterol, it wouldn’t matter much since vertebrates make their own cholesterol.

Lan has taken this particular avenue of research as far as she can as a researcher. Her naturally derived cholesterol inhibitor has been submitted for a patent, and she’s now waiting to hear if industry will license the technology and develop a commercial product from it. She knows her find is not the “answer” to the malaria question. But she is convinced it will be a welcome addition to the fight.

“The toolbox is almost empty,” she says. “We’re just putting more tools into the toolbox.”

Of course, Lan knows her new tool won’t last forever. Someday the compound will grow obsolete as mosquitoes slowly evolve resistance. But she is confident science will uncover new weaknesses in mosquitoes’ makeup and reveal new routes of attack.

“You’re never going to win,” she says. “(Mosquitoes) have been around for millions of years, and they’re going to be around for another million years. We just try to avoid their contact (with humans) in high-density populations. That’s all we can do.” But, mosquitoes, beware. Just because she knows she can’t win, doesn’t mean Lan isn’t going to fight. As long as little girls  shiver under heavy blankets in the sweltering heat, she won’t give up. What that mosquito started back in 1973, Lan will never finish.