You spray DEET on your arms, and those pesky mosquitoes leave you alone.

It works.

However,  not everyone wants to use DEET, a synthetic insect repellent. There's that smell, for one thing. "Properties that people do not like in addition to the smell is that DEET is a solvent for plastic," says chemical ecoloigst Walter Leal of the University of California, Davis. "So, one gets eyeglass frames and watchbands dissolved by DEET."

There's also "the misconception that everything synthetic is bad."

So what is it with DEET that repels mosquitoes? What odorant receptor is involved? Mosquitoes, as we know, detect smells with their antennae.

The  Leal lab today (Oct. 27) published research in the Proceedings of the National Academy of Sciences (PNAS) that pinpoints the exact odorant receptor that repels them. They also identified a plant defensive compound that might mimic DEET, a discovery that could pave the way for better and more affordable insect repellents.

“Mosquitoes are considered the most deadly animals on the planet, but unfortunately, not everyone who needs this repellent can afford to use it, and not all who can afford it can use it due to its undesirable properties,” said Leal, an internationally recognized professor in the Department of Molecular and Cellular Biology and co-chair of the 2016 International Congress of Entomology.

For more than six decades, DEET has been known as  the gold standard of insect repellents. More than 200 million people worldwide use the chemical insect repellent, developed by scientists at the U.S. Department of Agriculture and patented by the U.S. Army in 1946.

So when Leal and his team--project scientist Pingxi Xu, postdoctoral scholar Young-Moo Choo, and agricultural and environmental chemistry graduate student Alyssa De La Rosa-- published their groundbreaking research, “Mosquito Odorant Receptor for DEET and Methyl Jasmonate,”  they drew global attention.

In their research, they examined the receptors of the southern house mosquito, Culex quinquefasciatus, which transmits such diseases as West Nile virus.

The researchers set out to investigate two hypotheses regarding DEET's mode of action: activation of ionotropic receptor IR40a vs. odorant receptor(s). “Ionotropic receptor is another family of olfactory receptors, which seem to be the ancestral version when insects were aquatic,” Leal said. “So, the ionotropic receptors normally detect acid, bases, and other water soluble compounds.”

They discovered that the direct activation of an odorant receptor, not an ionotrophic receptor, “is necessary for DEET reception and repellency in Culex mosquitoes.” They also detected a link between DEET and methyl jasmonate, thus suggesting that DEET might work by mimicking a defensive compound from plants.

“Vector-borne diseases are major health problems for travelers and populations living in endemic regions,” said Leal.  “Among the most notorious vectors are mosquitoes that unwittingly transmit the protozoan parasites causing malaria and viruses that cause infections, such as dengue, yellow fever, chikungunya, and encephalitis.”

Leal said that diseases transmitted by mosquitoes destroy more lives annually “than war, terrorism, gun violence, and other human maladies combined. Every year, malaria decimates countless lives – imagine a city of San Francisco perishing to malaria year after year. The suffering and economic consequences in endemic areas are beyond imagination for those living in malaria-free countries. Both natives and visitors to endemic areas want to keep these ‘infected needles' at bay. In the absence of vaccines for malaria, dengue, and encephalitis, one of the most ancient and effective prophylactic measures against mosquito-borne diseases is the use of DEET.”

Dan Strickman of the Bill and Melinda Gates Foundation, not involved in the study, praised the work. “We are at a very exciting time for research on insect repellents,” said Strickman, senior program officer of the Global Health Program's Vector Control. “ For decades, the field concentrated on screening compounds for activity, with little or no understanding of how chemicals interacted with mosquitoes to discourage biting. Use of modern techniques that combine molecular biology, biochemistry, and physiology has generated evidence on how mosquitoes perceive odors.”

Said zoologist Paul Weldon of the Smithsonian's Conservation Biologist Institute, also not involved in the study: “Since DEET is strictly synthetic and not a natural product, it has been challenging to understand the adaptive nature of the response it elicits. It is not as if the compound emanates from, say, spider webs or fishy water, where avoidance by mosquitoes would make sense. Xu et al. have solved the mystery of where the DEET response comes from: it is in response to plant chemical defenses.”

“This, by the way, also explains why the DEET response is widespread, occurring in many arthropods, including those that are not ectoparasitic -- like cockroaches,” Weldon said. The repellence of other arthropods by DEET may have tipped off some of those investigating the DEET response, but I'm not sure that it did. The focus of research on DEET seems to have been with the organisms in which it just so happened to be discovered -- mosquitoes. The Xu et al. study suggests that there is a much broader array of DEET-sensitive organisms than previously suspected. No doubt, this finding will assist further investigations of it.”

Professor John Pickett, Rothamsted Research, UK, also not involved in the study, called the link between the plant compound and synthetic insect repellent, DEET as a “surprising evolutionary link.”

Pickett, the Michael Elliott Distinguished Research Fellow and Scientific Leader of Chemical Ecology at Rothamsted Research and a foreign associate of the National Academy of Sciences, said: “Not only does this work demonstrate that a mosquito response to the gold standard repellent DEET, as well as the more recently developed repellents, is mediated by a specific odorant receptor (OR136 for the southern house mosquito Culex quinquefasciatus) but that the receptor responds specifically also to methyl jasmonate, involved in plant hormone-based defense against insects, which suggests a surprising evolutionary link between these types of insect interactions.”

The UC Davis researchers pointed out that “insect repellents have been used since ancient times as prophylactic agents against diseases transmitted by mosquitoes and other arthropods, including malaria, dengue fever, and encephalitis. They were developed from plant-based smoke or extracts (essential oils) into formulations with a single active ingredient.”

Progress toward development of better and more affordable repellents has been slow, they said, because scientists weren't sure which odorant receptor was involved. Now they are.

Mosquito researcher Anthony "Anton" Cornel, associate professor with the UC Davis Department of Entomology and Nematology, and based at the UC Kearney Agricultural Research and Extension Center, Parlier, provided the mosquitoes that allowed the Leal lab to duplicate his mosquito colony at UC Davis.

Look for more exciting research to come!

 The competition was fierce.

We're talking 800 postdoctoral scholars on the UC Davis campus, 12 finalists and two winners.

Chemical ecologist Zain Syed, who helped discover the mode of action for the insect repellent DEET in the Walter Leal lab, UC Davis Department of Entomology, emerged as one of the two winners.

The occasion: the sixth annual postdoctoral scholar research awards, sponsored by the UC Davis Postdoctoral  Scholars’ Association and the Office of Graduate Studies.

Syed and fellow recipient Izumi Maezawa of the Department of Pathology and Laboratory Medicine, UC Davis Health System, each received a certificate and a $500 cash prize.

So, the next time you’re applying DEET to ward off mosquitoes, you can thank Leal and Syed for why mosquitoes won’t go near you. For the past 50 years, scientists assumed that DEET jams the senses of a mosquito or masks the smell of the host.

Not so. Mosquitoes can smell DEET and they avoid it because it smells bad to them. No jamming. No masking. Just a smell that's not in their comfort zone.

The chemical ecologists identified the olfactory receptor neuron in the antenna that detects the repellent. Their work led to one of the most popular research articles ever published in the Proceedings of the National Academy of Sciences (PNAS). The research paper has been loaded 9317 times from August 2008 through April 2009.  

What this research means is we may see a whole new direction in the development of novel and promising insect repellents.

Syed, a native of India, received his bachelor of science degree in combined sciences (botany, zoology and chemistry) and his master’s degree in agricultural entomology from universities in India. He earned his doctorate in sensory physiology and behavior at the University of Neuchâtel, Switzerland before joining  the Leal lab in 2005. .

 “Zain has an an encyclopedic knowledge of the literature and he designs well-thought experiments,” said Leal, also praising him as “a good mentor to students in the department, college and elsewhere on campus.”

 “Zain is the type of postdoc that every principal investigator dreams about one day having in their own laboratory,” wrote professor Gabrielle Nevitt of Neurobiology, Physiology, and Behavior, College of Biological Sciences, in her letter of support. “He is a dynamo, a maverick and an inspiration to be around….he is one of the most talented, smart and inquisitive individuals I have come across at UC Davis.”

Entomology professor Penelope Gullan, who supported the nomination, said: "As a faculty member in the same department as Dr. Syed, I have watched his research progress and accomplishments over the past four years. His recent achievements have been truly outstanding in terms of significant research findings and publications in highly rated journals."

A dynamo, a maverick and an inspiration: mosquitoes beware!

We know it works, but how?

Just how does DEET work? Does it jam the senses of a mosquito? Does it mask the smell  of the host?

You spray the chemical repellent on your arm and thankfully, those darn skeeters leave you alone.  They need a blood meal to develop their eggs, so off they buzz to find another host, one that's not so inhospitable.

But why do mosquitoes avoid DEET?

Well, they avoid it because it smells bad to them. Yes, they can smell it--that's why they avoid it.

The groundbreaking research, the work of UC Davis chemical ecologist Walter Leal and researcher Zain Syed, is published today in the Proceedings of the National Academy of Sciences (PNAS), which lifted the news embargo at 2 p.m., Pacific Standard Time.

The research contradicts a Science article published in March by researchers at Rockefeller University, New York. The researchers, as other scientists have long believed, said mosquitoes can't smell DEET because it jams the odorant receptors in insect nervous systems.

The Leal-Syed research solidly establishes the real mode of action.

Noted entomologist James "Jim" Miller of Michigan State University praised the Leal-Syed work as correcting “long-standing erroneous dogma.”

Said Miller: "For decades we were told that DEET warded off mosquito bites because it blocked insect response to lactic acid from the host -- the key stimulus for blood-feeding. Dr. Leal and co-workers escaped the key stimulus over-simplification to show that mosquito responses -- like our own -- result from a balancing of various positive and negative factors, all impinging on a tiny brain more capable than most people think of sophisticated decision-making.”

“This new work corrects long-standing erroneous dogma, and shows that recent work on DEET mode-of-action published in the flagship journal, Science, apparently was flat-out wrong,” Miller said. “One of the great attributes of science is that, over time, it is self-correcting."

Leal, past president of the International Society of Chemical Ecology  and former chair of the UC Davis Department of Entomology, said previous findings of other scientists showed a “false positive” resulting from the experimental design. 

Now that we know that skeeters can smell it, this will no doubt lead to better methods of insect control. Or, as Major Dhillon, president of the American Mosquito Control Association and district manager of the Northwest Mosquito and Vector Control District, Riverside, said: ”In the future, this new knowledge can be incorporated into developing new repellents and may be in control strategies for Culex quinquefasciatus and other mosquitoes.”

Those darn female mosquitoes, always in a “Let-us-prey” mood, have clearly met their match: the "why" behind "Let us spray."