Downloaded from http://science.sciencemag.org/ on December 13, 2016 To test insecticide efficacy, mosquitoes are exposed to strips of treated bed nets. PICK YOUR POISON As mosquitoes develop resistance to pyrethroid insecticides, researchers are forced to look for alternatives PHOTO: JOHN CAIRNS By Kai Kupferschmidt W hen Janet Hemingway started her career in mosquito research in 1977, a child was dying of malaria every 10 seconds. Yet the disease, and the mosquitoes that carry it, were low on the global health priority list. Today, the landscape has been transformed. Scientists at the prestigious Liverpool School of Tropical Medicine (LSTM) in the United Kingdom, which Hemingway now heads, and elsewhere have sequenced the genomes of at least 23 mosquito species, looking for clues that might help them conquer the disease. And malaria has surged to the top of the global agenda. Thanks to a bolus of new funds, SCIENCE sciencemag.org deaths have been halved. And halved again. But one thing hasn’t changed. The world still relies on the same class of insecticides, known as pyrethroids, as it did in 1977. Now, in part because of that neglect, these compounds may be nearing the end of their useful lives as mosquitoes develop resistance to them at alarming rates, and there is little in the pipeline to replace 14 OCTOBER 2016 • VOL 354 ISSUE 6309 Published by AAAS 17 1 Downloaded from http://science.sciencemag.org/ on December 13, 2016 NEWS F E AT U R E S them. “If we don’t do something about this very quickly, we have a public health catastrophe on our hands,” Hemingway says. Pyrethroids have played an outsize role in the global fight against malaria in the last decades. They are the main compounds used to spray the inside walls of homes—so-called indoor residual spraying, or IRS—to kill the Anopheles mosquitoes that transmit the disease. And they are the only insecticides that can be used on bed nets. Much of the global success in fighting malaria has come from these two interventions. In a Nature paper last year, a group led by Simon Hay at the University of Oxford in the United Kingdom estimated that between 2000 and 2015, some 633 million malaria deaths were averted, with 68% of that decline due to insecticide-treated bed nets and 10% to IRS. (Treating people with antimalarial drugs accounted for the remaining 22%.) Pyrethroids have also played a role in the fight against Aedes aegypti, the main mosquito transmitting the yellow fever, dengue, and Zika viruses, even though bed nets are less effective against A. aegypti because it predominantly bites people outdoors and during the day. Pyrethroids have several distinct advantages: They kill mosquitoes efficiently, act rapidly, and, although toxic, are safer for humans than the alternatives. But when the massive rollout of insecticide-treated 172 bed nets began in Africa in the early 2000s—more than a billion have been distributed—little thought was given to resistance, says Maureen Coetzee, director of the Wits Research Institute for Malaria at the University of the Witwatersrand in Johannesburg, South Africa. “Nobody dreamt that insecticide resistance would spread the way it has spread throughout Africa.” Scientists shouldn’t have been surprised, however. An earlier insecticide, DDT, played a major role in driving down malaria cases starting in the 1940s. But in many places, resistance reversed those gains. In Sri Lanka, for instance, malaria was all but wiped out with the help of DDT, but by the end of the 1960s, when resistance was widespread, cases surged to more than half a million a year. By that time, Rachel Carson had highlighted the toxic effects of DDT in Silent Spring, and many nations banned its use. Nor has there been much incentive for companies to develop new mosquitokilling insecticides, which could be used in tandem with existing ones to slow the development of resistance. Most R&D has focused on agricultural chemicals, a far more lucrative market. “No publicly traded company is going to spend the money required to discover and develop and take to the market an insecticide for public health,” says Nick Hamon, who heads the Innovative Vector Control Consortium (IVCC) in Liverpool. “These companies are looking for $100 million in sales every year to have any chance of recouping the money for a new compound.” First detected in Ivory Coast in 1993, resistance to pyrethroids was relatively rare until about 10 years ago, when it began racing across the continent (see map, p. 173). “Some countries are seeing an increase in malaria transmission, and resistance is one of the probable causes,” Coetzee says. It’s hard to be sure, she says, because drug shortages or cutbacks of control programs may also be taking a toll. But Hilary Ranson of LSTM thinks the problem is real and will only get worse. “I think insecticide resistance is a time bomb.” Many scientists have their hopes pinned on new approaches to vector control that would be less likely to run into resistance or prove toxic, such as mosquitoes genetically modified to die young, traps that lure the insects to their death, or insecticidal bacteria or fungi (see Features, pp. 164 and 168). “We need to diversify in terms of the kind of tools that we use to control mosquitoes and not focus it entirely on chemical control,” says Willem Takken, a medical entomologist at Wageningen University & Research in the Netherlands. But Hemingway and other scientists caution that even if these new tools prove their mettle, they are years away at best. The first priority, Hemingway says, is to preserve and imsciencemag.org SCIENCE 14 OCTOBER 2016 • VOL 354 ISSUE 6309 Published by AAAS PHOTO: BETTMANN/CONTRIBUTOR/GETTY IMAGES A fogging machine is tested at Jones Beach in New York in 1945. Mass spraying of DDT led mosquitoes to develop resistance. CREDITS: (GRAPHIC) J. YOU/SCIENCE; (DATA) IR MAPPER SCIENCE sciencemag.org 14 OCTOBER 2016 • VOL 354 ISSUE 6309 Published by AAAS 173 Downloaded from http://science.sciencemag.org/ on December 13, 2016 prove the tools we know work. And to her, Not only are bed nets the best weapon in will crash as well,” Ranson says. The group that means insecticides. the fight against malaria-carrying mosquibegan testing the nets in 40 clusters of vilThat’s why, in 2005, Hemingway started toes, in many countries they are the only lages in Burkina Faso in 2014; results of IVCC, a public-private partnership that one. “Some countries still don’t have IRS the trial should be known in a few weeks. aims to develop entirely new classes of inas part of their program. They view it as “There is a lot riding on this,” Ranson says. secticides and get them on the market in too expensive and difficult to implement,” “If it doesn’t show any improvement, then 5 to 8 years. Since IVCC’s inception, the Ranson says. I doubt there will be any further clinical Bill & Melinda Gates Foundation has kicked From 2011 to 2016, Ranson headed an trials of it.” in more than $200 million, and the U.S. EU-funded project called AvecNet to evalAnother combination net is already Agency for International Development, the uate new weapons to fight mosquitoes and on the market, but it’s not widely used Wellcome Trust, and others have each contake one through a clinical trial. The rebecause its efficacy is still in doubt. The tributed millions. In the meantime, IVCC is searchers eventually chose a net that comnet combines pyrethroids with a chemiscrambling to help scientists find smarter bines pyrethroids with a compound called cal called piperonyl butoxide (PBO). PBO ways to use existing insecticides or compyriproxyfen, which prevents mosquitoes blocks enzymes that help resistant mosbine them with other interventions in a from producing fertile eggs. “The idea is quitoes break down pyrethroids, so, in way that keeps resistance at bay. that if the mosquitoes are fully susceptible theory, the mosquitoes should become With IRS, one option is to switch to an they will be killed by the insecticide, and if susceptible again. Small-scale studies have insecticide from one of the other available they are resistant they will pick up a dose suggested that the nets do work, but there classes: organochlorides, carbamates, and of the sterilizing agent and the population haven’t been any large-scale clinical trials. organophosphates. South Africa went To find new compounds for sprayback to using DDT, an organochloride, ing and nets, IVCC has partnered with Resistance movement after an epidemic of malaria transseveral large chemical companies inmitted by pyrethroid-resistant moscluding BASF, Syngenta, and SumiMalaria mosquitoes that are resistant to pyrethroids have spread across Africa in recent years, stoking fears that malaria cases will quitoes in 1999 and 2000. But many tomo to screen more than 4 million rise again. other countries avoid the insecticide— compounds in their libraries. Over and not just for environmental reathe next few months they will choose Confrmed resistance to pyrethroids, 1993–2003 sons. DDT and pyrethroids also work three to go into large-scale toxicology through a very similar mechanism, testing, Hamon says. Any candidates so some mosquitoes resistant to pyrefor bed nets will have to pass other throids are also resistant to DDT. demanding tests: In addition to beSome countries have switched from ing safe, they will have to survive at pyrethroids to an organophosphate least 20 washes and perform well for NIGERIA BURKINA insecticide called actellic. But actellic 3 years. “We were just very lucky with FASO is four times as expensive, Hemingway the pyrethroid insecticides in the ’70s says. “Fewer houses are getting and ’80s,” Hamon says. CAMEROON sprayed, because the money available Luck may not run out quite as fast IVORY BENIN hasn’t increased fourfold.” And with as many fear. Although resistance COAST many countries switching to the same to pyrethroids is widespread, its compound, there is a danger that resisimpact on public health is still untance will emerge to it as well. clear. Even though a mosquito may Two new mosquito killers could be on survive a dose of an insecticide, the the market as soon as 2017: SumiShield, chemical may weaken it in some way. developed by Japanese company SumiAnd the genes needed for resistance tomo Chemical, and chlorfenapyr, an may take their own toll, perhaps by insecticide mostly used to control cat shortening a mosquito’s life span. fleas, developed by BASF. But both are If the insect survives for fewer than Confrmed resistance to pyrethroids, 1993–now seen as stop-gap measures. Although 14 days, the malaria parasites won’t they are new to public health, these have enough time to mature to the compounds have been used in agristage where they can infect humans, culture for years, so some mosquitoes says Matthew Thomas, an entomoCHAD may be resistant already. And Sumlogist at Pennsylvania State UniverSENEGAL iShield is a neonicotinoid, a class of sity, University Park. “There is some ETHIOPIA compounds that faces public opposievidence to show that things like that tion because it has been implicated in can happen,” Thomas says. the mass die-off of pollinators. Insecticide resistance is going to UGANDA IVORY BENIN Finding replacement insecticides for matter at a certain point, he says— COAST KENYA bed nets is far trickier. Any insecticide “What we don’t know is whether used in a bed net “has to be safe enough we are just approaching that point, CAMEROON TANZANIA that a child can put it in their mouth,” whether it is 1 year away, or five or says Ranson, and only pyrethroids fit the 10.” Defeating diseases like malaria bill. Pyrethroids also have a trait scienmay depend not only on finding tists call excito-repellency: They stimuchemicals to kill mosquitoes, but also 0 3000 late mosquitoes to leave the net. Neither on understanding how the insects Km SumiShield nor chlorfenapyr does that. manage to survive them. j Pick your poison Kai Kupferschmidt (October 13, 2016) Science 354 (6309), 171-173. [doi: 10.1126/science.354.6309.171] This copy is for your personal, non-commercial use only. Article Tools Permissions Visit the online version of this article to access the personalization and article tools: http://science.sciencemag.org/content/354/6309/171 Obtain information about reproducing this article: http://www.sciencemag.org/about/permissions.dtl Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2016 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS. Downloaded from http://science.sciencemag.org/ on December 13, 2016 Editor's Summary