Finding new perfumes to foil a femme fatale

With the notable exception of the West Nile virus, the industrialized world is blessedly free of mosquito-borne diseases. But according to the World Health Organization (WHO), malaria causes over 300 million acute illnesses and kills at least a million people each year, mostly children in developing countries. The WHO estimates that an African child dies of malaria every 30 seconds. “We don’t think about it much in this country,” says John R. Carlson, Ph.D., the Eugene Higgins Professor of Molecular, Cellular and Developmental Biology, “but as a world health problem this is just staggering.”

Carlson, an expert on the sense of smell in insects, has thought about malaria a great deal, and with the help of a five-year, $8.5 million grant offered by the Grand Challenges in Global Health initiative to Vanderbilt University, he and a team of scientists on three continents are launching an ambitious and innovative plan of attack against this dreaded disease.

In 1999, researchers in Carlson’s lab identified the genes that encode the exquisitely sensitive odor receptors found in fruit fly antennae—the first such genetic mapping of any insect olfactory system. The mosquitoes that spread malaria, females of the genus Anopheles, use similar receptors to find their human hosts, and Carlson was eager to apply the techniques he had developed to Anopheles. “After doing all this basic research for many years at Yale,” he says, “I thought we should see whether any of it could be useful in addressing real-world problems.”

Carlson contacted Laurence J. Zwiebel, Ph.D., an associate professor of biological sciences at Vanderbilt who studies mosquito olfaction, and the two collaborated to identify the genes for Anopheles odor receptors in 2001. Because fruit flies are far easier to study in the lab than Anopheles, Carlson’s lab devised a method to place Anopheles receptors in fruit fly antennae, and by 2004 Carlson, in collaboration with graduate student Elissa Hallem, had pinpointed an antenna protein in the Anopheles female that specifically responds to a chemical compound in human sweat.

“That was exciting,” Carlson says, “because it suggested the possibility that we could then identify compounds that either excited or blocked those receptors, thereby inhibiting the ability of the mosquitoes to find us. You could sort of jam the system.”

The discovery came at an auspicious time. In 2003, the Grand Challenges initiative was seeking novel, practical solutions to the world’s most massive public health problems. Zwiebel assembled a proposal to design new repellents and traps that specifically target Anopheles and to test them in field settings in Africa—precisely the sort of “deliverable technology” the initiative was encouraging.

In the wide-ranging project, Zwiebel, the principal investigator, and Carlson will test hundreds of chemical compounds using fruit flies genetically engineered with Anopheles odor receptors to see which elicit the most robust response. Colleagues at Wageningen University in the Netherlands will then assess whether the candidate chemicals actually alter Anopheles behavior. Compounds that pass this test will be analyzed again in specially designed mosquito enclosures in Tanzania. Finally, the repellents and attractants deemed effective will be deployed in villages in the Gambia, a nation in West Africa, to see whether they can reduce the incidence of malaria.

This multi-tiered approach was a good fit with the goals of the Grand Challenges initiative, Carlson says. “They didn’t want just lab research in America. They actually wanted to develop real, practical solutions to these problems, and for that we needed real expertise in the field in Africa.”

Carlson hopes the findings from the new project will prove useful in curbing other mosquito-borne illnesses, such as yellow fever. “With insect-borne diseases, the best way to control the disease is often to control the insect,” he says. “We smell good to the mosquitoes, so if we can understand in molecular detail how the insects are attracted to us, we might be able to devise new means of controlling them.”