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New Gates Grant Supports CUMC Malaria Research

A better understanding of insects' sense of smell could lead to more effective mosquito repellants
August 27, 2010

The insect antennae started arriving in Filippo Mancia’s lab in March. Long, feather-like antennae from Bombyx mori, the silkworm, arrived first from an entomologist in Rhode Island. Then a box packed with dry ice showed up with the honeybee’s stubby, cylindrical antennae. Eventually, short, bristle-covered antennae from Anopheles gambiae – the mosquito culpable for transmitting malaria in Africa – arrived inside a small brown box.

The Gates Foundation is supporting the research of Filippo Mancia (center), Vanessa Ruta (right), and Caitlin Baptiste (left) that could lead to better mosquito repellants to reduce the spread of malaria.
The Gates Foundation is supporting the research of Filippo Mancia (center), Vanessa Ruta (right), and Caitlin Baptiste (left) that could lead to better mosquito repellants to reduce the spread of malaria.

As a structural biologist, Dr. Mancia, an assistant professor in physiology and cellular biophysics, has always been fascinated by how function follows form, but it’s not the elaborate shapes that compel him to collect antennae from insects all over the world.

Dr. Mancia is drawn instead to a smaller structure present within the antennae, a molecule that may be the key to creating a new type of insect repellant powerful enough to drive away all insects – from malaria-infested mosquitoes to crop-destroying Mediterranean fruit flies.

The molecule, an odorant receptor embedded in every insect’s antennae, has been called the “Achilles’ heel” of insects. “Without this one receptor, insects are essentially ‘anosmic,’” Dr. Mancia says. “Basically, they can’t smell anything.”

“Without this one receptor, insects are essentially ‘anosmic.' Basically, they can’t smell anything.” — Filippo Mancia

Because the receptor, called OR83b, is virtually identical in every insect (“you can take the receptor from an agricultural pest like the corn earworm moth, put it in a fruit fly, and it will work,” Dr Mancia says), a chemical that disables OR83b could make humans “invisible” to mosquitoes that carry malaria or dengue fever, ticks that carry Lyme disease, and make crops invisible to many insect pests.

With a new Grand Challenges Explorations grant from the Gates Foundation, Dr. Mancia and his collaborator Dr. Vanessa Ruta, a postdoc in Richard Axel’s lab, are now trying to unlock details about the OR83b’s shape that could prove critical to the development of an “invisibility” spray.

“A detailed picture of OR83b could be a fantastic guide to developing new insect repellants,” Dr. Mancia says. “If screening identifies a compound that blocks the receptor, knowing the shape of the receptor may allow us to tweak the compound to perfect it.”

The same approach has had successful in the past, most notably in the development of the antiretroviral drugs that transformed treatment for HIV. And other scientists at Columbia University Medical Center and Rockefeller University are already screening tens of thousands of chemicals to find compounds that can block OR83b.

Drs. Mancia and Ruta are now trying to take an atomic-level picture of OR83b, but getting an image of a molecule isn’t as simple as putting a specimen under a powerful microscope and pressing the shutter button.

Instead, the two use X-ray crystallography, a discipline in which images of biological molecules are generated by shining high-energy X-ray beams at crystals of the molecule.

“A detailed picture of OR83b could be a fantastic guide to developing new insect repellants. If screening identifies a compound that blocks the receptor, knowing the shape of the receptor may allow us to tweak the compound to perfect it." — Filippo Mancia

The first step in X-ray crystallography – making the crystal – is often the most challenging. In a process akin to making salt crystals, a solution containing millions of copies of the molecule evaporates, leaving behind crystals in which molecules line up in a three-dimensional lattice.

Image quality depends on crystal quality. In the best crystals, the molecules are perfectly aligned with each other, so any bumps or protrusions in OR83b could ruin an image by throwing the crystal out of order. Since there are slight variations in receptors from different insect species, one bug’s OR83b may produce a smudge, while another bug’s receptor may generate a “high-def” image that reveals the position of every atom.

Drs. Mancia and Ruta have already isolated OR83b receptors from 14 different insects in their search for one with the highest probability of crystallizing. The receptor from Anopheles is the most promising so far. But shipments of other antennae still arrive at the lab, so the two researchers can continue looking for one that might perform even better.

“Ultimately, we hope that the information we get from the OR83b crystals will lead to new ways to cripple insects’ ability to track down their human prey and prevent the spread of malaria, or of any other insect-borne disease” Dr. Ruta says. “Insects navigate their world with olfactory cues, but as visual creatures, we get a lot of information from images.”

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