Written by
Ahmed El Hady
Dec. 5, 2022

Anyone of us has experienced at least once the bite of a mosquito.  Beside being unpleasant, it is a very mysterious behavior: Why are some mosquitos attracted to humans? While most mosquitos are opportunistic willing to get blood from any sources, it is only Aedes Aegypti that evolved to bite and consume human blood exclusively.   An important anecdote of this behavior is that it is sexually dimorphic: only females bite while males are attracted to the host and do not bite.  The blood that the female consumes is crucial to make eggs.  Mosquitos targeting humans cause diseases as they are a major viral vector for yellow fever, dengue, chikungunya, and Zika fevers.

The question of the specific targeting of humans by Aedes Aegypti was on the mind of neuroscientist and evolutionary biologist Lindy McBride for long time. She leads the McBride lab at the Princeton Neuroscience Institute where she is investigating genomic and neuronal basis of behavior and the molecular mechanisms by which behaviors evolve using mosquitoes as a model system.  She got her Ph.D. in Population Biology from the University of California at Davis in 2008 under the mentorship of Drs. Michael Turelli and Sergey Nuzhdin and then conducted postdoctoral research in neurogenetics and behavior with Dr. Leslie Vosshall at The Rockefeller University. She started her own lab at Princeton in 2014, where she holds a joint position in the Princeton Neuroscience Institute and the Department of Ecology and Evolutionary Biology.  By bridging neuroscientific and evolutionary biology investigations, she can study behavioral evolution on an unprecedented mechanistic level showing how evolution has refined the capabilities of animals in this case Mosquitoes to adapt to their ecology. 

The lay person does not usually think of mosquitos as having complex processing abilities but those fascinating insects have brains that contains approximately 220,000 neurons.  These neurons are organized in 60 nerve centers called glomeruli. This collective of neurons “Glomerulus”  is capable of processing sensory inputs translating it into the amazing ability of mosquitos to search and exploit their targets.  The main sensory input that mosquitoes depend on is olfaction.  As neural processing and coding are one of the major research focuses at Princeton Neuroscience Institute, the research agenda of Lindy’s lab lie at the heart of this mission by studying an evolutionary conserved behavior and how neural circuits were tuned to process and code information accordingly. A recent study in Nature from the McBride lab showed that Aedi Aegypti’s glomeruli are specifically tuned to compounds rich in human odor, solving a long standing mystery.  “ This study lies at the core of what my lab is interested in and opens up endless possibilities to study evolutionary shaping of sensory processing“ said Lindy when I interviewed her about the paper.

Zhilei Zhao, a geneticist with a Bachelor degree from Peking University, joined Lindy’s lab as a PhD student. They both embarked on the challenging journey to decipher the mysteries of Aedes Aegypti’s exclusive attraction to human odor. The main question was to be able to detect which neurons in the mosquito brains are activated when exposed to odors. “I had to learn so many new techniques and delve into research areas that I was not familiar with, I have neither done neuroscience or studied odors before “ Zhilei admitted. Despite the challenges, Zhilei was up to the mission. He genetically engineered mosquitos that express calcium sensors that light and increase their fluorescence whenever they are active. He built a custom designed imaging equipment that allowed him to image the mosquito brain and to deliver human or animal flavored air.

Human and animal odors share so many compounds, but the ratios of those different compounds is what makes human odor distinct. A hypothesis that one could think of is that mosquitoes are attracted not to a particular compound but a blend of those compounds. The first major step was to determine the blend of components that give human odor its uniqueness.  The team has shown that human odors are enriched in two main chemical compounds decanal and undecanal.  For the curious, Zhilei mentioned to me that to get human odors, one recruits volunteers and have them not shower for two days then lie naked in a Teflon bag to avoid cotton, polyster or any clothing to distort the odors.  For other mammalian odors, one can get it from animal hair or wool or fur. In this study, graduate student Jessica Zhung along with former research specialists Alexis Kriete and Azwad Iqbal collected samples from rats, guinia pigs, quail , sheep and dogs in order to provide a set of odors to be tested.

The imaging setup that the team built is able to detect which glomeruli are activated when mosquitos are exposed to different odors. From the perspective of the mosquitoes, they are tethered under a two photon microscope that looks through their brain and the air around them change its odor from an epoch to the next, thus their sensory experience is controlled. The odors are puffed through a wind tunnel. To their surprise, Lindy and her team found that only two glomeruli are pretty active, one was broadly tuned responded to human odors along with other mammalian odors and the other had a pretty specific activation by human odor. The one glomeruli sensitive to human odors is especially sensitive  to decanal and undecanal that are  long-chain aldehydes probably originating  from unique human skin lipids.

A complex odor stimulus gets converted to a simple neural code that researchers can read out through neural activity in a glomerulus. A simple, elegant solution to what one would think is a complex daunting task. It is indeed a daunting task if you try to design a machine learning algorithm from scratch to perform a similar task. Often evolution offers simple solutions that tends to breed and sustain over time improving survivability of a species. Moreover, oftactory processing is a pivotal example of convergent evolution: from mice to insects, one observes that glomeruli and combinatorial information processing forms that basis to detect olfactory cues in the environment.  The ubiquity of these mechanisms is providing inspiration to build artificial noses for odor detections. Evolution can help us design the next generation of nature inspired artificial intelligence.

“Evolution is fun. Look at Aedi aegyptis  from what the name suggested it might have originated in ancient Egypt and propagated in west Africa and was domesticated by human. It thus evolved its reliance on human blood by its association with human as during the expansion of the Sahara desert, human remained the sole source for blood to these mosquitos, they have retained this ability since then. They moved around the world because of trade since 400 – 500 years ago “ Lindy remarked on the fascinating evolutionary history of Aedi Aegyptis. 

Of concern to many people around the world is finding ways to control mosquitos that target human. Studies, like this one published by the McBride lab,  are very crucial to find ways to attract mosquitos and get rid of them for example the McBride lab has patented a mixture of decanal and undecanal that was proven to be efficient in attracting mosquitos.

As for what comes next, the discovery made by Lindy McBride and her PhD student Zhilei paves the way to understand the neuroscience of specific targeting of humans by Aedi Aegyptis.  Glomeruli are the first relay station in the mosquito brain for the sensory information. The next steps aim to delineate how this information is relayed next building up the complete neural pathway that process and encode human specific odors.  “ There are many brain structures we think will be involved such as mushroom body and the lateral horn “ Lindy remarked.

After finishing his PhD, Zhilei moved to Cornell University  continuing on the path of investigating behavioral evolution . He is currently studying the fascinating ability of parrots to vocalize and imitate human speech  asking how evolution has shaped parrots’ ability to perform this complex linguistic functions.

Lindy and Zhilei’s work are part of a growing trend in neuroscience that focuses on bridging evolutionary biology, ecology along with neural mechanisms. Often times, neural dynamics are studied in highly artificial settings or in the context of behaviors that animals do not do in nature.   From c.elegans to drosophila to rodents to non-human primates, technological and conceptual advances are paving the way to study the neuroscience of natural behavior.