Molecular Biology, Neuroscience
The Rockefeller University
Dr. Vosshall is also the Robin Chemers Neustein Professor and Head of the Laboratory of Neurogenetics and Behavior at The Rockefeller University.
Genetics of Innate Behavior in Mosquitoes and Humans
Molecular biologist Leslie Vosshall seeks to understand how an animal’s behavior is guided by integrating sensory input with information about its internal physiological state. Her group studies this problem in both mosquitoes and humans.
For a female mosquito to complete egg development, for example, the insect requires a blood meal. Acquiring that blood from a human is an innate behavior that potentially spreads dangerous infectious diseases carried by the insect. Vosshall has developed CRISPR/Cas9 genome-editing tools for use in the Aedes aegypti mosquito, a vector for dengue, chikungunya, and yellow fever. This technology allows her team to apply a genetic approach to understanding how female mosquitoes integrate sensory cues such as body odor, heat, and exhaled carbon dioxide to hunt their human hosts.
Her group is currently pursuing a number of questions: Why are some people more attractive to mosquitoes than others? How do insect repellents work? How are multiple sensory cues integrated in the mosquito brain to elicit innate behaviors? How do female mosquitoes select a body of water suitable for egg laying? This work provides insights into potential methods to control mosquitoes’ biting behavior.
Vosshall also studies the rules that govern the human sense of smell, which is far less understood than vision or hearing. Her lab’s Rockefeller University Smell Study has screened the sense of smell in more than 3,000 normal human subjects since 2002. Vosshall is using data from the study to investigate central questions in olfaction: How does the sense of smell differ among people? How many different smells can humans discriminate? How does the chemical structure of an odorant relate to its perceived odor? Discoveries in this area have the potential to aid the diagnosis of smell disorders in humans.
Grants from the National Institutes of Health provided partial support for these projects.
When Leslie Vosshall became an HHMI investigator in 2008, she had already made a number of important discoveries about the sense of smell. Much of that work – including the identification of a large family of odorant receptors and the demonstration that insect odorant receptors function differently than vertebrate odorant receptors – had been done in Drosophila vinegar flies, an insect with a century-long history in genetic research.
But by the time she joined HHMI, Vosshall’s curiosity about how smell helps animals respond to their environment steered her attention to a more dangerous insect: the mosquito.
Understanding what drives mosquito behavior is critical, Vosshall says, because these insects are remarkably efficient disease vectors. Notorious for transmitting malaria, yellow fever, and dengue, mosquitoes have now been implicated in additional diseases. When the mosquito-transmitted chikungunya virus arrived in the western hemisphere for the first time in 2014, a million people became infected in the Caribbean and Central and South America within nine months. This rapid disease spread is evidence of the intense motivation of mosquitoes to bite humans, Vosshall says.
“Mosquitoes are machines built to hunt humans,” she says. “My group is trying to understand how they are so incredibly effective at finding us, biting us, and taking a blood meal.”
Vosshall’s research focuses on Aedes aegypti, the mosquito whose bite transmits dengue, yellow fever, chikungunya, and zika viruses. Her team is investigating how these mosquitoes respond to a range of cues that guide them to their human targets, including body heat, odor, and carbon dioxide.
Few resources were available to study the genes and neural networks that drive mosquito behavior when Vosshall began her studies. She set out to change that by making the mosquito a modern genetic model for neurobiology research.
A top priority was finding an efficient way to introduce mutations into specific mosquito genes. The method, which took five years to develop, is enabling Vosshall’s team to identify genes and pathways important to a mosquito’s search for human blood. A mutant mosquito that lacks the ability to smell carbon dioxide, for example, showed that carbon dioxide detection is required to amplify responses to other human cues.
Next, Vosshall wants to see what happens in the mosquito brain as it responds to human cues. Her team has engineered mosquitoes that produce GCaMP6, an indicator of neural activity. Using these insects, the team can investigate how mosquitoes respond to human scent cues, and how these integrate with heat and carbon dioxide. They will also see how the male and female brains differ, because only females bite humans. They’re also interested in how the female’s neural responses change in the days following a successful blood meal – a time when the insect temporarily loses her attraction to humans.
These research tools, along with the lab’s ongoing annotation of the Ae. aegypti genome, are making mosquito research more accessible, and the field is expanding at a rapid pace, Vosshall says. “There’s been a massive acceleration over the last two years in people interested in these important problems. We are excited to be building this field,” she says.