What makes insects hate DEET?

The oily, smelly repellent has its drawbacks, but now researchers think it could hold the answer for a better solution. James Mitchell Crow reports.

Scientists have identified a receptor in a fly’s antennae that is responsible for an insect’s repulsion to DEET.

Off to the great outdoors this summer? Don’t forget to pack your DEET. For many of us, a slathering of oily, smelly mosquito repellent is just the price you have to pay for summer fun.

For more than 60 years, DEET, or N,N-diethyl-m-toluamide, a yellow oil, has been the most effective personal mosquito repellent around, but it has plenty of drawbacks. Besides its chemical smell, some people find that it irritates their skin, and its cost puts it out of reach of people in developing countries who need good protection against mosquitoes that carry dengue and malaria.

But developing an alternative has faced a barrier because researchers haven’t known exactly how DEET worked. Now Anandasankar Ray and his team at the University of California Riverside have identified a receptor in a fly’s antennae that is responsible for an insect’s repulsion to DEET. They have used the finding, published in the October issue of Nature, to identify three candidates for a new mosquito repellent with a grape-like aroma.

What took so long? DEET confounded researchers because it seemed to act in different ways, explains Richard Newcome, of the University of Auckland, who researches animals’ odour receptors. It wasn’t clear whether DEET blocked a mosquito’s odour receptors so it could no longer sniff people out, or perhaps directly repelled the insect through another type of receptor.

“Or it could be that it just generally confuses the insect,” he says. Over the years, different experiments pointed at different DEET mechanisms.

To crack the problem, Ray and his team used fruit flies, which are also repelled by DEET. Fruit flies have long been a favourite research subject but these were a state-of-the-art variety. Their brain cells have been engineered to light up with a green fluorescent hue every time they are active. When those brain cells light-up, researchers can trace the particular sensory organ that is sending the signal.

“We could leave these flies overnight in a test tube containing DEET, come back next morning and see which brain cells were glowing green. Those were the ones activated by DEET,” says Ray.

Tracing the connections of these brain cells, they identified a spot called the sacculus on the flies’ antenna, the site of a receptor called IR40a that appears to deliver an aversive response to DEET. When it was deactivated, the flies no longer found DEET repulsive.

Knowing that IR40a was the target helped Ray in the search for a new type of repellent. Any substitute would also have to activate this receptor. Using a computer algorithm, the team screened thousands of compounds on the computer looking for those with structures similar to DEET.

But because any new compound would have to pass costly, time-consuming regulatory tests to prove it is safe to rub on to skin, they restricted themselves to compounds that were already approved for use as food additives by the US Food and Drug Administration.

From this virtual search, they identified three compounds, also found in plums, grapes and jasmine flowers, that activated the IR40a receptor in fruit flies. These compounds also turned out to be strong mosquito repellents, were cheaper than DEET, and had a pleasant grape-like smell.

“We hope that they can very quickly become useful in places like Africa, Asia and Latin America,” says Ray. “We are planning to set up a company that can very quickly shepherd us through prototypes and the various regulatory steps to get them to the people that need them the most.”

Newcome isn’t ready to declare the DEET case closed quite yet, given the subject’s long history of conflicting results. “DEET might do different things to different species,” he says. But in a way, pinpointing the mechanism doesn’t matter, he adds. “Malaria is still killing half a million kids in Africa every year, so if Ray has some new compounds that are repellents that work, who cares exactly what the mechanism is,” he says.

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