In one of the first successful attempts at genetically engineering
mosquitoes, Howard Hughes Medical Institute (HHMI) researchers have
altered the way the insects respond to odors, including the smell of
humans and the insect repellant DEET. The research not only demonstrates
that mosquitoes can be genetically manipulated using the latest
research techniques, but paves the way to understanding why the insect
is so attracted to humans, and how to block that attraction.
In 2007, scientists announced the completion of the full genome sequence
of Aedes aegypti, the mosquito that transmits dengue and yellow fever. A
year later, when Vosshall became an HHMI investigator, she shifted the
focus of her lab from Drosophila flies to mosquitoes with the specific
goal of genetically engineering the insects. Studying mosquitoes
appealed to her because of their importance as disease carriers, as well
as their unique attraction to humans.
Vosshall's first target: a gene called orco, which her lab had deleted in genetically engineered flies 10 years earlier.
"We knew this gene was important for flies to be able to respond to
the odors they respond to," says Vosshall. "And we had some hints that
mosquitoes interact with smells in their environment, so it was a good
bet that something would interact with orco in mosquitoes."
Vosshall's team turned to a genetic engineering tool called
zinc-finger nucleases to specifically mutate the orco gene in Aedes
aegypti. They injected the targeted zinc-finger nucleases into mosquito
embryos, waited for them to mature, identified mutant individuals, and
generated mutant strains that allowed them to study the role of orco in
mosquito biology. The engineered mosquitoes showed diminished activity
in neurons linked to odor-sensing. Then, behavioral tests revealed more
changes.
When given a choice between a human and any other animal, normal
Aedes aegypti will reliably buzz toward the human. But the mosquitoes
with orco mutations showed reduced preference for the smell of humans
over guinea pigs, even in the presence of carbon dioxide, which is
thought to help mosquitoes respond to human scent. "By disrupting a
single gene, we can fundamentally confuse the mosquito from its task of
seeking humans," says Vosshall. But they don't yet know whether the
confusion stems from an inability to sense a "bad" smell coming from the
guinea pig, a "good" smell from the human, or both
Next, the team tested whether the mosquitoes with orco mutations
responded differently to DEET. When exposed to two human arms—one
slathered in a solution containing 10 percent DEET, the active
ingredient in many bug repellants, and the other untreated—the
mosquitoes flew equally toward both arms, suggesting they couldn't smell
the DEET. But once they landed on the arms, they quickly flew away from
the DEET-covered one. "This tells us that there are two totally
different mechanisms that mosquitoes are using to sense DEET," explains
Vosshall. "One is what's happening in the air, and the other only comes
into action when the mosquito is touching the skin." Such dual
mechanisms had been discussed but had never been shown before.
Vosshall and her collaborators next want to study in more detail
how the orco protein interacts with the mosquitoes' odorant receptors to
allow the insects to sense smells. "We want to know what it is about
these mosquitoes that makes them so specialized for humans," she says.
"And if we can also provide insights into how existing repellants are
working, then we can start having some ideas about what a
next-generation repellant would look like."
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