Walter Leal Lab Discovers Generic Insect Repellent Detector That Could Lead to More Effective Repellents
March 16, 2011
Chemical ecologists Walter Leal (seated) and Zain Syed in the Leal lab. (Photo by Kathy Keatley Garvey)
DAVIS--Researchers in the Walter Leal lab in the Department of Entomology, University of California, Davis, have discovered a “generic insect repellent detector” and its receptor in the fruit fly--research that may lead to more effective and lower-cost products than DEET, the gold standard of insect repellents.
Their work, published March 16 in the open-access, peer-reviewed science journal PLoS One (Public Library of Science), found the sensory organs involved when fruit flies (Drosophila melanogaster) detect and avoid three key insect repellents: DEET, IR3535 and picaridin. They identified the olfactory receptor neuron (ORN) and characterized its receptor, DmOr42a.
“These are tools that can be used for research and development (R&D) aimed at developing better repellents,” said Leal, a chemical ecologist and professor and former chair of the UC Davis Department of Entomology.
“Although DEET is widely used as the first line of defense against mosquito-borne pathogen transmission, there is a high demand for better insect repellents, but the cost of R&D is prohibitive,” Leal said. “With current technologies, it takes about 10 years and $30 million to develop a new repellent. Only about one test compound in 20,000 reaches the market.”
He attributed the high cost/low speed in part “to the need to synthesize all test compounds in large scale for repellency and other tests.”
”This number of test compounds can be dramatically reduced by probing a library of putative repellents with the fruit fly and ruling out those that do not activate the repellent detector,” he said. “Then, a handful of ‘strong candidates’ can be synthesized in large scale for actual repellency and toxicity tests. In short, the fruit fly repellent detector has the potential to expedite and dramatically reduce the cost of development of much needed repellents outperforming DEET.”
Maximillary palps (left) and antenna. Click to enlarge. (Courtesy of Zain Syed)
The research team of Leal, primary author and chemical ecologist Zain Syed, chemical ecologist Julien Pelletier, and undergraduate students Eric Flounders and Rodrigo Chitolina, first found that the fruit fly avoids all three well-known repellents, DEET, IR3535 (a compound known as Avon Corporation’s “Skin-So-Soft Bug Guard”) and picaridin (derived from pepper) and then set out to find olfactory receptor neurons sensitive to those insect repellents. They scanned all olfactory sensilla in the antennae and the mouthpart structure, maxillary palps, using single unit electrophysiological recordings.
The receptor they found “fulfills the requirements for a simplified bioassay for early screening of test insect repellents,” they wrote in the scientific paper.
"In this study, by using established behavioral assays to dissect the mechanism of repulsion in fruit flies, we demonstrated for the first time that Drosophila equally avoid other repellents--picaridin and IR3535," Syed said. "By challenging every type of olfactory sensilla on the antenna and maxillary palps, we identified neurons and then the odorant receptor that detect these repellents."
"This study," Syed said, "adds a new dimension in research towards understanding the molecular, cellular and organismal response to repellents."
Chemical ecologist Coby Schal, the Blanton J. Whitmire Distinguished Professor of Entomology at North Carolina State University, praised the research as “an excellent example of translational research that can lead to a streamlined and less expensive path of discovery of new repellents.”
In earlier research, Syed and Leal identified a DEET-sensitive olfactory receptor neuron in the Southern House mosquito. “Going from the neuron to the receptor, however, is like looking for the proverbial needle in a haystack as the mosquito genome has some 181 olfactory receptor genes,” Schal said.
“In the fruit fly, on the other hand, a wealth of genomic information is available, including detailed maps of neurons, the odorant receptors they house, and the odorant profiles that elicit electrophysiological responses,” Schal said. “For this reason, Leal’s team turned to the fruit fly.”
Schal, noting that the UC Davis researchers found a neuron in the maxillary palps that responds to DEET as well as two other structurally unrelated insect repellents, said the discovery has “very important implications for R&D efforts. This fly sensillum may be used to screen libraries of compounds in the search for new repellents, thus greatly reducing both the effort of primary screens and the number of candidate compounds that move to whole-animal repellency assays and toxicology tests.”
Entomologist Ring T. Cardé, distinguished professor and A.M. Boyce Chair at UC Riverside, heralded the discovery. “There is an urgent need for mosquito repellents that are both safe for humans and highly effect, and so new methods for rapid screening of compounds are welcome,” said Cardé, who was not involved in the research. “Dr. Leal’s finding of a small receptor system in the fruit fly that is sensitive to mosquito repellents is an unexpected discovery. It has the potential to be a generic screening tool that could speed up the search for new mosquito repellents.”
Biologist Paul Weldon of the Smithsonian’s National Zoological Park’s Conservation and Research Center, Front Royal, Va.,said the UC Davis research “opens the door to repellent studies without the use of nuisance arthropods typically requiring quarantine confinement.”
“It may also lead to the identification of new insect subjects for which electrophysiological studies are more conveniently undertaken,” Weldon said.
“For me, it also deepens the mystery of DEET's action, held by some to inhibit or block attraction to host volatiles and, by others, to act as a repellent in its own right. Clearly, the responses of arthropods to DEET and the receptors mediating those responses have evolved to chemicals other than DEET, but it not known what those are. (These) results will no doubt hasten clarification of this and related topics.”
Worldwide, more than 200 million people use DEET to ward off vectorborne diseases. Developed by scientists at the U.S. Department of Agriculture and patented by the U.S. Army in 1946, the synthetic chemical is suspected unsafe at high concentrations, especially among children. Still, it is the main insect repellent used due to the high cost of developing a better one, the scientists said.
Repellents are “prophylactic tools” against such diseases as malaria, yellow fever and West Nile virus. Worldwide, some one million humans a year die of malaria, caused by a parasite transmitted by Anopheline mosquitoes. Malaria threatens half of the world population. Globally, the number of people who contract malaria each year is greater than the U.S. population. Culex mosquitoes transmit such diseases as West Nile virus and St. Louis encephalitis.
The UC Davis research, titled “Generic Insect Repellent Detector from the Fruit Fly Drosophilia melanogaster,” was funded in part by the National Science Foundation. For undergraduate students Eric Flounders and Rodrigo Chitolina, this was their first paper. Chitolina, an exchange student from Brazil, received an undergraduate scholarship from the U.S. Brazil-Higher Education Consortium to work in the Leal lab.
Back in August 2008, the research of Leal and Syed drew international attention when they discovered DEET’s mode of action or how it works. Scientists long surmised that DEET masks the smell of the host, or jams or corrupts the insect’s senses, interfering with its ability to locate a host. The Leal-Syed research showed that mosquitoes actually smell DEET and avoid it because they dislike the smell.
Mosquitoes and other blood-feeding insects find their hosts by body heat, skin odors, carbon dioxide (breath), or visual stimuli. Females need a blood meal to develop their eggs.
--Kathy Keatley Garvey
UC Davis Department of Entomology