The mosquito’s unbreakable affinity to humans is discussed in a new study that aims to identify ways to diminish the bloodsucking insect’s amazing ability to find human prey.
Leslie Vosshall decided to change her focus from researching harmless fruit flies to a far deadlier animal—the mosquito—more than ten years ago while she was still a relatively inexperienced Howard Hughes Medical Institute (HHMI) Investigator.
She pondered whether her in-depth understanding of the fruit fly’s food-finding abilities could be extended to mosquitoes in order to develop novel approaches to reduce the blood-sucking insect’s uncanny capacity to locate human prey.
As she adds: “I wanted to do something the public could be excited about.”
The impact of her new work would be significant, just not in the way she had imagined. She calls it “a huge, staggering surprise.” Her research has challenged the accepted theory of the neural circuity used by animals in their olfactory systems to detect—and distinguish among—thousands of different smells.
The findings of the study were published today in the journal Cell.
Neuroscientist Christopher Potter of the Johns Hopkins University School of Medicine says, “this is a big deal. It really changes the way we think the insect olfactory system is working.”
More so than was previously believed, the unexpected new finding demonstrates how challenging it is to fool mosquitoes in their obstinate pursuit of human blood. According to Vosshall, who is currently HHMI’s vice president and chief scientific officer, “this is not a good news paper” in the effort to reduce the staggering number of illnesses and fatalities caused by mosquito-borne diseases.
One of the first tasks successfully completed by Vosshall’s HHMI group at Rockefeller University when it focused on the mosquito was the assembly of the insect’s first entire genome. Because the genome was so fragmented, no one had ever attempted genome editing previously, according to Vosshall. Then, Meg Younger, a former postdoc in the lab, took the genome and tried to answer a confusing question. Mosquitoes are drawn to both human body odor and the CO2 that people exhale. But she adds, “but there’s something magical about adding those two ingredients together, where one plus one equals twenty.” The insects become intensely focused and aggressive human hunters as a result of their extreme excitement. So how does the olfactory system combine and greatly amplify the two signals?
Younger reasoned that they might determine which olfactory neurons responded to body odor and which to CO2 and then follow the paths of the signals to the brain to attempt and learn the answer. Therefore, scientists inserted a fluorescent marker protein into the neurons that possessed CO2 receptors and another marker into the neurons that could detect compounds from body odor using the gene-editing tool CRISPR.
At that point, the investigation followed a path that nobody anticipated. Vosshall compares it to “Alice in Wonderland, where nothing makes sense.
Based on the research that Linda Buck (now at the Fred Hutchinson Cancer Center) and Richard Axel (at Columbia University) did with mice, the scientific dogma was that animals’ systems for smelling are very specialized and well-organized. Each olfactory neuron has a single type of receptor that only recognizes a limited range of chemicals and connects to a single component (known as a glomerulus) in the olfactory bulb. According to this reasoning, different types types of neurons would respond to different smells, such as different types for peanut butter, different types for gasoline, and so on. “We as a field were so influenced by Buck and Axel,” adds Vosshall (who was a postdoc in Axel’s lab). “Those were the rules.”
Margaret Herre, a former MD-PhD student in the lab, discovered that individual neurons were packed full of numerous types of receptors, not just one, by examining receptor genes with various fluorescent hues. According to Vossall, they discovered that “all the Buck and Axel rules were thrown in the garbage can by mosquitoes.”
Vosshall’s lab has spent years methodically demonstrating that the results were in fact true using a number of different lines of evidence because they were so unexpected. One PhD student in the lab, Olivia Goldman, used a cutting-edge method called single nucleus RNA sequencing (snRNA-seq) to examine the genes that are activated in specific neurons. The method proved that each neural cell does produce a variety of receptors.
They also collaborated with researchers from the Swedish University of Agricultural Sciences, who had made revolutionary advancements in understanding how to implant electrodes into individual mosquito olfactory neurons and track the cells’ reactions to different odors. The technique also demonstrated that a single mosquito neuron is capable of detecting a variety of smells, including two distinct body odor types—a perfume-like smell and a stinking foot odor—which call for two different classes of receptors. These outcomes “were a huge relief,” according to Vosshall. She admits that “the number of levels of evidence that we used to prove it was intense” since she anticipated significant resistance against her findings.
In fact, “there was a lot of skepticism at first” when word and preprints of Vosshall’s team’s findings went throughout the community, according to Potter. In addition to the overwhelming evidence, similar findings were also coming out of Potter’s lab at Johns Hopkins. In an article they published in eLife in April, Potter’s team, which included fruit flies and mosquito species, claimed that “co-expression of chemosensory receptors is common in insect olfactory neurons.”
Potter says that in the past, the idea that there was only one receptor for each smell and one receptor per neuron was so common that there was no reason to look for more than one receptor.
“Now we know to look for it.”
To survive, insects like mosquitoes need to find humans, thus the evolution of a more complicated olfactory system makes logical sense. Each neuron contains different types of receptors, which enhances the bugs’ capacity to detect exhaled CO2 and the full spectrum of body scents. Additionally, mosquitoes can easily locate blood using their other receptors even when people try to repel biting insects by blocking some of those receptors. Vosshall says, “It is a really good trick.” Mosquitoes have a variety of backup plans.
“Mosquitoes have Plan B after Plan B after Plan B. To me the system is unbreakable,” she adds.
That’s bad news for the endeavor to inhibit receptors in mosquitoes to minimize deaths from diseases like malaria, yellow fever, and dengue. However, Potter continues, another tactic might be to bombard the entire system with different odors.
At the very least, he argues, “we have a more realistic view of what we are up against.”
In the meanwhile, Vosshall hopes to discover whether the more severe receptor complexity is a particular adaptation for those species that solely target humans by contrasting the olfactory neurons of blood-eating mosquitoes with those from strictly vegetarian insect relatives. And as for the mystery that Vosshall first began to look into—how the brain gets a much stronger message when CO2 and body odor are both sensed? Meg Younger, a former postdoc who now works at the lab where she is conducting research at Boston University, is investigating the issue.
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