T HE M OSQUITO G ENOME: A NOPHELES GAMBIAE

1 NEWS 2 Sexual predator 3 What Mosquitoes Want: Deinocerites cancer 4 (Crabhole ) 5 6 The struggle for Secrets of Host Attraction sex gets extreme. 7 Adult males 8 Why do mosquitoes feast on some people and leave others alone? emerge first and 9 Researchers are trying to find out, hoping it will help them design the per- grab female pupae credit: University of Florida/FMEL 10 fect mosquito trap with their forelegs while keeping other males at 11 bay. Copulation, which lasts up to 30 minutes, 12 Life isn’t fair. Whereas some people never But the ultimate goal is a far cry from takes place as the female emerges from her 13 seem to get bitten by mosquitoes—and often such pricey gadgets, says Willem Takken skin—a phenomenon dubbed “pupal rape.” 14 don’t even seem to notice the critters— of Wageningen Agricultural University in Distribution: Coastal areas along the Gulf of 15 others spend their evenings frantically swat- the , a pioneer in the field. Mexico, Caribbean, and Central America. 16 ting them, usually to no avail. If you’re in the He’d like a simple, $1 or $2 trap that peo- Breeding habitat: Has found a unique niche in 17 latter category, you’ve probably wondered: ple in developing countries could affix to the burrows of land crabs. 18 Feeding: Night feeder; host preferences Why me? Is it thin skin? My gorgeous body their doorposts to keep out the mosquitoes unknown. 19 odor? Sumptuous blood vessels begging to that spread deadly diseases. Key targets are Diseases: None known. 20 be punctured? Or is it all between the ears, as Anopheles gambiae, the species that trans- 21 some people say, and you simply fuss and mits , and Aedes aegypti, 22 fret more about mosquito bites? which spreads dengue and yel- 23 Rest assured, it’s not your imagination: low fever. Deinocerites cancer 24 Several studies have shown that to 25 mosquitoes, all people really aren’t creat- Blood, sweat, and 26 ed equal. Besides factors such as heat and For almost a century, re- 27 carbon dioxide, mosquitoes use odors to searchers have been trying to di- 28 find their victims, and ap- vert mosquitoes from their tance and second thoughts about insecticide

29 pear to exude different amounts pursuit of blood. use have sparked a renewed interest in alter- on October 24, 2011 30 of the volatile compounds the The field blossomed in native control methods. 31 insects love. the 1950s, when dozens Scouting for potentially attractive com- 32 By studying mosquito be- of entomologists in pounds, researchers are taking a closer look 33 havior, entomologists are try- several countries set at the more than 300 chemicals present on 34 ing to tease out these favorite out to discover what human skin. Martin Geier of the University 35 smells. It’s a complex story, attracts females—the of Regensburg, Germany, for instance, takes 36 they say. Millions of years of only mosquitoes that skin rubbings and then chemically removes a 37 evolution have resulted in bite—to their hosts. certain group of compounds—say, the ke-

38 sophisticated odor-based Anthony Brown tones or the fatty acids. If one group attracts www.sciencemag.org 39 navigation systems that dif- of the University mosquitoes, it can be further separated into 40 fer greatly from one of Western On- its individual components, he says. 41 mosquito species to the tario in London, To test how compelling single compounds 42 next, depending on where Canada, for in- or mixtures are, researchers use a specialized 43 it lives and which host it stance, built hu- instrument called an olfactometer, whose 44 prefers. Even so, chemical man-shaped steel central part is a Y-shaped wind tunnel. Two 45 and behavioral studies— tanks, which he different odors are blown into the short legs 46 often using human volunteers as called robots, dressed them of the Y; when mosquitoes are set loose at the Downloaded from 47 bait—have helped identify some of the up, and then counted the other end, they fly upwind and, like quiz 48 smells that tempt several mosquito number of mosquitoes that show contestants choosing between two 49 species. And recently, molecular re- landed on them in a forest. doors, decide whether to go left or right. Re- 50 searchers have begun identifying the He found, among other searchers can also fixate mosquitoes, apply 51 receptors that pick up these odors and things, that the robots became miniature electrodes to their nerves, and test 52 translate them into neural signals. more attractive if their skin whether exposing them to a whiff of some 53 Researchers hope to use odor cues was 37°C (the temperature of compound elicits an electrical signal. 54 to lure mosquitoes into the perfect trap the human body) than at low- Recent studies have confirmed what 55 or otherwise outwit them—say, by de- er temperatures, if they ex- Brown and others discovered half a century 56 signing repellents that foul their sense of haled CO2, or if they wore a ago: that for most mosquito species, CO2, 57 smell. Garden parties and golf getaways wet jerkin—or, better still, one heat, and moisture are key attractants. But 58 might be the first beneficiaries; in- soaked in human sweat. these lead a mosquito to any warm-blooded 59 deed, one U.S. company is already By the mid-1960s, animal—bird, cow, or human. That might 60 marketing the $500 to $1200 most research on host be fine for species that aren’t too picky, 61 Mosquito Magnet, which pur- attraction had stopped, such as Culex pipiens, a West Nile vector in 62 portedly attracts mosquitoes Footwork. Anopheles gambiae in part because DDT the United States. But those that dine al- 63 by emitting a compound called (left) bites mainly on the feet made mosquito extermi- most exclusively on humans, such as An. 64 1-octen-3-ol, as well as heat, CO2, and ankles; An. atroparvus nation so easy. Lately, gambiae and Ae. aegypti, need much more

65 and water vapor. prefers the face. however, emerging resis- specific attractants. SOURCE:AND RING CARDÉ MIRIAM COOPERBAND

90 4 OCTOBER 2002 VOL 298 SCIENCE www.sciencemag.org T HE M OSQUITO G ENOME: A NOPHELES GAMBIAE Hunting for cues, Bart Knols, a re- researchers, who joined the field just 2 years tors is produced only in mature females—an searcher in Takken’s group, noticed in 1995 ago, will help make sense of it all. They are important clue that it might be involved in that An. gambiae had a predilection for bit- making some headway: In a study published host seeking. So far, the group hasn’t been ing its victims on the feet and ankles—even on page 176, a team led by Laurence able to link any of the odors known to attract when their entire bodies were exposed. (This Zwiebel at Vanderbilt University in An. gambiae to any of the receptors. Still, the clearly set it apart from related species, such Nashville, Tennessee, has scoured the newly study is a “nice breakthrough,” says Takken, as An. atroparvus, a mosquito from Holland that goes mainly for the face.) A native of the Dutch province of Limburg, Knols also real- Death trap. The Mosquito Magnet’s popularity is ized that foot odor bears a remarkable re- growing in the United States (bottom). Something semblance to the pungent cheese from that much simpler and cheaper is needed to divert region. And sure enough, An. gambiae mosquitoes in developing countries. turned out to be heavily attracted to the smell of cheese. The finding, after making snickering headlines around the globe, led researchers to tempt different mosquitoes. “It became sort of a madhouse,” Knols recalls. “People started taking Limburger cheese all over the world.” But the stinky dairy product turned out to be an acquired taste, he says; just those few mosquitoes that feed primarily on hu- mans were strongly attracted. Knols says the common denominator between feet and cheese is obvious: a bacterium used in cheese production, called , which is a close rel- ative of Brevibacterium epidermis, a bug

known to reside in the warm, humid on October 24, 2011 clefts between human toes. Both turn that might speed the discovery of other, more glycerides into a specific set of break- powerful attractants. down products, such as fatty acids. Takken’s group is now trying to find Building the perfect trap out exactly which products provide Whether chemical lures can be fashioned the draw. into an irresistible mosquito trap, much less Over the years, researchers have one that would be cheap and effective in de- found that individual species have veloping countries, isn’t clear. But there is a

their own idiosyncratic tastes for var- precedent. In many East African countries, www.sciencemag.org ious attractants. Ae. aegypti find lac- simple traps have helped virtually eradicate tic acid—which humans produce on tsetse flies, the carriers of sleeping sickness their skin but other mammals don’t— and a livestock disease called nagana. (One sublime; to An. gambiae, it’s only so- trap consists of a simple black-and-blue so. With ammonia, it’s the other way cloth, baited with acetone and octenol—or, around. And even in Aedes, Geier ex- alternatively, buffalo urine—and sprayed plains, lactic acid alone isn’t all that with insecticide.) attractive; rather, it boosts the appeal Mosquitoes, however, could pose a more Downloaded from of several other compounds. daunting challenge. One tsetse fly produces Complicating matters, explains only a handful of offspring over her life- Ring Cardé of the University of Cali- time, making the population vulnerable to fornia, Riverside, an effective trap de- even a slight increase in mortality. By con- pends not just on the right attractants trast, mosquito mothers can produce hun- but also on the physical properties of dreds of young. It might also be “very dif- the odor plume. Cardé has spent most of his sequenced An. gambiae genome for so- ficult,” says Geier, to produce a trap that career studying how male moths home in on called G protein–coupled receptors, which can compete with the real thing: living, females by navigating pheromone plumes— include odor receptors. breathing humans who emit not just smell AMERICAN BIOPHYSICS CORP. AMERICAN BIOPHYSICS which, from the insect’s viewpoint, consist The team, working with researchers at but also heat and moisture. (A trap could do of a series of small odor filaments swirling the University of Notre Dame in Indiana, the that too, of course, but it would quickly get SCIENCE; through the air. More recent work in University of Illinois, Urbana-Champaign, too complicated and costly.) But even if mosquitoes, carried out by Cardé’s col- and Celera Genomics in Rockville, Mary- they only reduced the number of mos- league Teunis Dekker, suggests that they, land, found 79 odor-receptor candidates, on- quitoes, “traps could have a fantastic im- too, use the fine structure of an odor plume ly five of which had been known before. Of pact,” says Takken. “We all agree that no to navigate, and Cardé believes that the these, 64 were expressed solely in the single measure will ever solve the malaria shape and structure of a plume will deter- mosquitoes’ olfactory tissues—evidence that problem completely.” mine any trap’s efficacy. they’re probably involved in odor recogni- Short of that ambitious goal, traps might

CREDITS: TO G.BOTTOM) (TOP VOGEL/ Takken and others hope that molecular tion. And at least one of the candidate recep- also be effective in monitoring the risk of epi-

www.sciencemag.org SCIENCE VOL 298 4 OCTOBER 2002 91 T HE M OSQUITO G ENOME: A NOPHELES GAMBIAE

1 demics and focusing control efforts. Some Other mosquito-thwarting strategies on chemist Ulrich Bernier of the U.S. Depart- 2 countries already use a relatively unsophisti- the drawing board are clever new repellents. ment of Agriculture in Gainesville, Florida, 3 cated trap developed by the U.S. Centers for If, for instance, researchers could find com- has found some people who are almost nev- 4 Disease Control and Prevention (CDC) to pounds that overstimulate crucial odor re- er bitten. His team has isolated compounds 5 keep track of pathogens. But this trap, which ceptors, they might be able to disorient the from their skin—he declines to discuss 6 relies on just CO2, light, or a combination, insects, dooming them to a life of aimless which ones—that he believes might be a clue 7 catches a motley array of insects—often not buzzing, Zwiebel says. It might even be pos- to the protection. Someday, he speculates, 8 those most relevant to human health. To catch sible, he says, to tinker with the receptors they could serve as a natural, less toxic alter- 9 An. gambiae, says Takken, a human needs to that help mosquitoes find nectar or places to native to DEET. 10 be nearby, and because the attractiveness of lay their eggs. Splashing yourself or your house with 11 people varies, so does the nightly catch. Spik- In the meantime, attraction studies with somebody else’s might not sound 12 ing such a trap with a specific odor blend human volunteers suggest another, more all that enticing. But at the levels needed to 13 could lead to a much better and more repro- down-to-earth approach to keeping mos- keep bugs away, Bernier assures, humans 14 ducible haul, he says. quitoes at bay. Among his human subjects, won’t smell a thing. –MARTIN ENSERINK 15 16 17 NEWS search. When funding is tight, he explains, 18 “people start fighting over whose work is 19 more important.” 20 Lab v. Field: The Case for 21 Sexier science 22 Studying Real-Life Bugs Field studies of mosquitoes, which peaked 23 during the vector biology heyday of the 24 Molecular entomology is all well and good, some researchers say—but 1940s and 1950s, were dealt their first heavy 25 what about studying insects where they live and breed: in the field? blow when DDT and other insecticides 26 promised to end insect-borne disease. By the 27 These querulous observers don’t want to giene and Tropical Medicine puts it, “pass the time insecticide resistance and growing op- 28 sound like curmudgeons. Nor do they want to so-what test.” position to chemical use shattered that

29 take away anyone’s scientific glory. But some For more than a decade now, Curtis and dream, the molecular biology revolution was on October 24, 2011 30 tropical disease researchers say they just can’t other vector ecologists have argued that the well under way, and chasing mosquitoes in 31 get very excited about the sequence of the field of insect-borne diseases—whether the field seemed old-fashioned and obsolete. 32 Anopheles gambiae genome, published in this malaria, dengue, West Nile virus, or Lyme “People just find molecular biology sexier,” 33 issue of Science. To be sure, the sequence disease—is betting too many of its scarce concedes Duane Gubler, chief of the division 34 promises to reveal the inner workings of the research dollars on high-tech work like of insect-borne infectious diseases at the 35 mosquito in unprecedented detail, shedding DNA sequencing and too few on studies of U.S. Centers for Disease Control and Pre- 36 light on everything from its metabolism to in- insect behavior and ecology, the type of vention (CDC) in Fort Collins, Colorado. 37 sect evolution. But skeptics aren’t convinced fieldwork that gets your back sweaty and “It’s seen as the future.”

38 it will actually help control malaria—or, as your hands dirty. To figure out how these Indeed, for the last 15 years or so, molec- www.sciencemag.org 39 Chris Curtis of the London School of Hy- diseases behave, they say, you have to don ular scientists have dominated mosquito re- 40 your boots rather than start your se- search grants and high-profile publications. quencer (see p. 87). Of more than 130 mosquito studies current- The riposte from molecular re- ly funded by the U.S. National Institute of searchers is that ecological studies are Allergy and Infectious Diseases (NIAID), Handsome devil important, but given the lack of only about one in five includes fieldwork, Sabethes cyaneus progress in the fight against insect- while DNA work booms. The World Health Males of this mos- borne diseases, new strategies are Organization (WHO) has also made the Downloaded from quito species, one of needed. “If ecology had all the an- transgenic mosquito one of its top priorities the most beautiful swers, there wouldn’t be molecular A. Foster in fighting malaria. on Earth, display credit: W. biology,” says Anthony James, a The funding shift, some say, created a an elaborate molecular entomologist at the Uni- courtship dance in which they wave one of self-perpetuating cycle: Universities hired their legs and swing their bodies back and versity of California, Irvine. In the molecular researchers because they could forth. They sometimes court other males, too. past few years, the sparring has got- pull in grants, and vector biology depart- ten especially intense over molecu- ments took on a decidedly molecular bent. 41 Distribution: New World tropics, from Belize to northern Argentina. lar biologists’ boldest plan: to con- “The molecular people are multiplying like 42 Breeding habitat: Deep rot holes in trees, trol malaria by releasing transgenic flies,” laments Yale medical entomologist 43 where the low evaporation rate allows breeding mosquitoes (see Morel Viewpoint Durland Fish. Even if they would like to do 44 throughout the dry season. on p. 79). Some ecologists have field studies, he says, young scientists are 45 Feeding: Most likely a daytime biter; hosts dismissed the scheme as a gran- forced to follow the money and end up in 46 unknown (monkeys?). diose folly—a Star Wars of infec- molecular research. 47 Diseases: Not incriminated as a vector, tious disease—that is diverting As a result, studies that could make a dent 48 although a close relative transmits yellow fever money from more “down to in disease transmission are lacking, ecolo- 49 to monkeys. earth” research. James chalks up gists say. Dengue fever, a debilitating and 50 Sabethes cyaneus part of the bickering to the “im- sometimes fatal disease transmitted by a 51 poverished mentality” that af- mosquito species called Aedes aegypti, is a 52 flicts all of tropical disease re- case in point, says CDC entomologist Paul

92 4 OCTOBER 2002 VOL 298 SCIENCE www.sciencemag.org