For some people, the steroid androstenone, a component of male sweat, has a sweet or even pleasant floral scent. Other people can’t smell it at all. But when Leslie Vosshall sniffs it, she recoils in disgust, likening it to the smell of a sweaty armpit.
Vosshall has discovered that a person’s genetic makeup strongly influences the olfactory response to this chemical. In 2007, her lab and that of her Duke University collaborator Hiroaki Matsunami published a report, which revealed that people who hate the smell of androstenone are more likely to carry two good copies of a gene for OR7D4, an olfactory receptor in the nose. Individuals who do not find the smell offensive tend to lack one or both good copies of the gene.
Vosshall, who is on the faculty at The Rockefeller University, believes this research may describe the first known genetic variation underlying individual differences in odor perception. The idea for the experiment was born of the same probing curiosity that has fueled Vosshall’s research on other aspects of smell—the fascinating but least understood of the senses.
However, the majority of her research involves not humans but insects like the vinegar fly, the fruit fly Drosophila melanogaster, and the mosquito. They serve as relatively simple models for probing how the brain and nervous system transform olfactory cues into specific behaviors. Moreover, some of the insects she studies are pests that devour crops or spread infectious diseases, which can have devastating economic and health consequences. The discoveries Vosshall is making about how these insects detect odors and how odors influence their behavior may help researchers identify new ways to fend off the insects.
In the 1990s, as a postdoctoral fellow in the lab of Nobel laureate Richard Axel, an HHMI investigator at Columbia University, Vosshall was excited by the series of landmark discoveries Axel’s group was making about the way the olfactory system detects, encodes, and perceives odors. Working with Axel, she identified a large family of genes in Drosophila that function as odor receptors.
As an independent scientist at Rockefeller, she created a nearly complete map of the fly’s olfactory system and identified odorant receptors in Drosophila larvae. To the surprise and consternation of many in the field, Vosshall found that insects have evolved a set of smell receptors unlike those in humans and other animals. Instead of attaching to G protein-coupled receptors (a large family of transmembrane receptors that sense molecules outside the cell and activate signaling pathways and other cellular responses inside the cell), odorant molecules are detected in insects by transmembrane receptors that seem to function as ion channels.
It has long been known that mosquitoes are attracted to the carbon dioxide that humans exhale; in 2007, Vosshall identified two membrane proteins in fruit flies and mosquitoes that detect this gas. Still, she does not believe carbon dioxide is the only thing that attracts mosquitoes to humans. After all, she says, mosquitoes seem to go after some individuals voraciously while others are rarely bitten—yet everyone emits carbon dioxide. “If it were just carbon dioxide, mosquitoes would be falling into your beer,” she says.
For the past five years, Vosshall’s team has studied how insect repellents containing the chemical DEET ward off mosquitoes and other bugs. Her lab recently showed that DEET confuses insects by jamming their odor receptors. Understanding how the chemical works may help researchers develop compounds that are equally effective but longer lasting or more convenient to use.
As an HHMI investigator, Vosshall would like to make the mosquito a viable model organism for answering scientific questions. She acknowledges that the proposal is a significant departure from her current research, but she believes the time is right for such a giant step. She sees a tremendous opportunity to apply the advanced transgenic technology routinely used in other insect models to aid in understanding the female mosquito’s life cycle and what drives it to bite humans. Likewise, she notes, the wealth of information in the mosquito genome sequence data may help researchers develop, among other things, more targeted, less toxic insect repellents.
One point of attack might be the protein Orco, which Vosshall found is expressed in nearly all olfactory neurons of the fly and acts as a generic coreceptor in tandem with specific odorant receptors. “If you make flies without the orco gene they can’t smell,” she says. “And if you put the gene back into this fly, you cure its smell problem.”
That revelation led to Vosshall’s publication of a research article in early 2008 that showed for the first time how the commonly used insect repellent DEET works. The United States Army discovered it in 1957, and although DEET is highly effective and widely used worldwide, researchers did not know how it worked. Vosshall’s experiments showed that DEET acts on pairs of olfactory receptors that include Orco.
Thus, the Orco gene/protein is a “cornerstone” of insect olfaction, Vosshall adds, suggesting that blocking Orco might be a selective and “clean” strategy for repelling harmful insects. “A medfly, for example, wouldn’t be able to smell citrus crops,” she says. Or in areas of endemic malaria, mosquito netting might be impregnated with a compound that inhibits this vital olfactory protein, effectively “blinding” mosquitoes to the scent of their human targets.
With so many infectious diseases transmitted by insect vectors, Vosshall hopes her research will help lessen the burden of illness in the developing world.