How Mosquitoes Are Drawn to Human Skin and Breath

Female mosquitoes, which can transmit deadly diseases like malaria, dengue fever, West Nile virus and filariasis, are attracted to us by smelling the carbon dioxide we exhale, being capable of tracking us down even from a distance. But once they get close to us, they often steer away toward exposed areas such as ankles and feet, being drawn there by skin odors.

Why does the mosquito change its track and fly towards skin? How does it detect our skin? What are the odors from skin that it detects? And can we block the mosquito skin odor sensors and reduce attractiveness?

Recent research done by scientists at the University of California, Riverside can now help address these questions. They report on Dec. 5 in the journal Cell that the very receptors in the mosquito’s maxillary palp that detect carbon dioxide are ones that detect skin odors as well, thus explaining why mosquitoes are attracted to skin odor — smelly socks, worn clothes, bedding — even in the absence of CO₂.

“It was a real surprise when we found that the mosquito’s CO₂ receptor neuron, designated cpA, is an extremely sensitive detector of several skin odorants as well, and is, in fact, far more sensitive to some of these odor molecules as compared to CO₂,” said Anandasankar Ray, an associate professor in the Department of Entomology and the project’s principal investigator. “For many years we had primarily focused on the complex antennae of mosquitoes for our search for human-skin odor receptors, and ignored the simpler maxillary palp organs.”

Until now, which mosquito olfactory neurons were required for attraction to skin odor remained a mystery.  The new finding — that the CO₂-sensitive olfactory neuron is also a sensitive detector of human skin — is critical not only for understanding the basis of the mosquito’s host attraction and host preference, but also because it identifies this dual receptor of CO₂ and skin-odorants as a key target that could be useful to disrupt host-seeking behavior and thus aid in the control of disease transmission.

To test whether cpA activation by human odor is important for attraction, the researchers devised a novel chemical-based strategy to shut down the activity of cpA in Aedes aegypti, the dengue-spreading mosquito.  They then tested the mosquito’s behavior on human foot odor — specifically, on a dish of foot odor-laden beads placed in an experimental wind tunnel — and found the mosquito’s attraction to the odor was greatly reduced.

Next, using a chemical computational method they developed, the researchers screened nearly half a million compounds and identified thousands of predicted ligands. They then short-listed 138 compounds based on desirable characteristics such as smell, safety, cost and whether these occurred naturally. Several compounds either inhibited or activated cpA neurons of which nearly 85 percent were already approved for use as flavor, fragrance or cosmetic agents. Better still, several were pleasant-smelling, such as minty, raspberry, chocolate, etc., increasing their value for practical use in mosquito control.

Confident that they were on the right track, the researchers then zeroed in on two compounds: ethyl pyruvate, a fruity-scented cpA inhibitor approved as a flavor agent in food; and cyclopentanone, a minty-smelling cpA activator approved as a flavor and fragrance agent.  By inhibiting the cpA neuron, ethyl pyruvate was found in their experiments to substantially reduce the mosquito’s attraction towards a human arm. By activating the cpA neuron, cyclopentanone served as a powerful lure, like CO₂, attracting mosquitoes to a trap.

“Such compounds can play a significant role in the control of mosquito-borne diseases and open up very realistic possibilities of developing ways to use simple, natural, affordable and pleasant odors to prevent mosquitoes from finding humans,” Ray said.  “Odors that block this dual-receptor for CO₂ and skin odor can be used as a way to mask us from mosquitoes.  On the other hand, odors that can act as attractants can be used to lure mosquitoes away from us into traps.  These potentially affordable ‘mask’ and ‘pull’ strategies could be used in a complementary manner, offering an ideal solution and much needed relief to people in Africa, Asia and South America — indeed wherever mosquito-borne diseases are endemic.  Further, these compounds could be developed into products that protect not just one individual at a time but larger areas, and need not have to be directly applied on the skin.”

Currently, CO₂ is the primary lure in mosquito traps. Generating CO₂ requires burning fuel, evaporating dry ice, releasing compressed gas or fermentation of sugar — all of which is expensive, cumbersome, and impractical for use in developing countries.  Compounds identified in this study, like cyclopentanone, offer a safe, affordable and convenient alternative that can finally work with surveillance and control traps.

Researchers find that ‘peanut butter’ test can help diagnose Alzheimer’s disease

A dollop of peanut butter and a ruler can be used to confirm a diagnosis of early stage Alzheimer’s disease, University of Florida Health researchers have found.

Jennifer Stamps, a graduate student in the UF McKnight Brain Institute Center for Smell and Taste, and her colleagues reported the findings of a small pilot study in the Journal of the Neurological Sciences.

Stamps came up with the idea of using peanut butter to test for smell sensitivity while she was working with Dr. Kenneth Heilman, the James E. Rooks distinguished professor of neurology and health psychology in the UF College of Medicine’s department of neurology.

She noticed while shadowing in Heilman’s clinic that patients were not tested for their sense of smell. The ability to smell is associated with the first cranial nerve and is often one of the first things to be affected in cognitive decline. Stamps also had been working in the laboratory of Linda Bartoshuk, the William P. Bushnell presidentially endowed professor in the College of Dentistry’s department of community dentistry and behavioral sciences and director of human research in the Center for Smell and Taste.

“Dr. Heilman said, ‘If you can come up with something quick and inexpensive, we can do it,’” Stamps said.

She thought of peanut butter because, she said, it is a “pure odorant” that is only detected by the olfactory nerve and is easy to access.

In the study, patients who were coming to the clinic for testing also sat down with a clinician, 14 grams of peanut butter — which equals about one tablespoon — and a metric ruler. The patient closed his or her eyes and mouth and blocked one nostril. The clinician opened the peanut butter container and held the ruler next to the open nostril while the patient breathed normally. The clinician then moved the peanut butter up the ruler one centimeter at a time during the patient’s exhale until the person could detect an odor. The distance was recorded and the procedure repeated on the other nostril after a 90-second delay.

The clinicians running the test did not know the patients’ diagnoses, which were not usually confirmed until weeks after the initial clinical testing.

The scientists found that patients in the early stages of Alzheimer’s disease had a dramatic difference in detecting odor between the left and right nostril — the left nostril was impaired and did not detect the smell until it was an average of 10 centimeters closer to the nose than the right nostril had made the detection in patients with Alzheimer’s disease. This was not the case in patients with other kinds of dementia; instead, these patients had either no differences in odor detection between nostrils or the right nostril was worse at detecting odor than the left one.

Of the 24 patients tested who had mild cognitive impairment, which sometimes signals Alzheimer’s disease and sometimes turns out to be something else, about 10 patients showed a left nostril impairment and 14 patients did not. The researchers said more studies must be conducted to fully understand the implications.

“At the moment, we can use this test to confirm diagnosis,” Stamps said. “But we plan to study patients with mild cognitive impairment to see if this test might be used to predict which patients are going to get Alzheimer’s disease.”

Stamps and Heilman point out that this test could be used by clinics that don’t have access to the personnel or equipment to run other, more elaborate tests required for a specific diagnosis, which can lead to targeted treatment. At UF Health, the peanut butter test will be one more tool to add to a full suite of clinical tests for neurological function in patients with memory disorders.

One of the first places in the brain to degenerate in people with Alzheimer’s disease is the front part of the temporal lobe that evolved from the smell system, and this portion of the brain is involved in forming new memories.

“We see people with all kinds of memory disorders,” Heilman said. Many tests to confirm a diagnosis of Alzheimer’s disease or other dementias can be time-consuming, costly or invasive. “This can become an important part of the evaluation process.”

How neurons enable us to know smells we like and dislike, whether to approach or retreat

Think of the smell of freshly baking bread. There is something in that smell, without any other cues – visual or tactile – that steers you toward the bakery.  On the flip side, there may be a smell, for instance that of fresh fish, that may not appeal to you. If you haven’t eaten a morsel of food in three days, of course, a fishy odor might seem a good deal more attractive.

How, then, does this work? What underlying biological mechanisms account for our seemingly instant, almost unconscious ability to determine how attractive (or repulsive) a particular smell is?  It’s a very important question for scientists who are trying to address the increasingly acute problem of obesity: we need to understand much better than we now do the biological processes underlying food selection and preferences.

New research by neuroscientists at Cold Spring Harbor Laboratory (CSHL), published in The Journal of Neuroscience, reveals a set of cells in the fruit fly brain that respond specifically to food odors. Remarkably, the team finds that the degree to which these neurons respond when the fly is presented different food odors – apple, mango, banana – predicts “incredibly well how much the flies will ‘like’ a given odor,” says the lead author of the research paper, Jennifer Beshel, Ph.D., a postdoctoral investigator in the laboratory of CSHL Professor Yi Zhong, Ph.D.

“We all know that we behave differently to different foods – have different preferences. And we also all know that we behave differently to foods when we are hungry,” explains Dr. Beshel. “Dr. Zhong and I wanted to find the part of the brain that might be responsible for these types of behavior. Is there somewhere in the brain that deals with food odors in particular? How does brain activity change when we are hungry? Can we manipulate such a brain area and change behavior?”

When Beshel and Zhong examined the response of neurons expressing a peptide called dNPF to a range of odors, they saw that they only responded to food odors. (dNPF is the fly analog of appetite-inducing Neuropeptide Y, found in people.) Moreover, the neurons responded more to these same food odors when flies were hungry. The amplitude of their response could in fact predict with great accuracy how much the flies would like a given food odor – i.e., move toward it; the scientists needed simply to look at the responses of the dNPF-expressing neurons. 

When they “switched off” these neurons, the researchers were able to make flies treat their most favored odor as if it were just air. Conversely, if they remotely turned these neurons “on,” they could make flies suddenly approach odors they previously had tried to avoid. 

As Dr. Beshel explains: “The more general idea is that there are areas in the brain that might be specifically involved in saying: ‘This is great, I should really approach this.’ The activity of neurons in other areas in the brain might only take note of what something is – is it apple? fish? — without registering or ascribing to it any particular value, whether about its intrinsic desirability or its attractiveness at a given moment.

Sex, Smell And Science – The Genetics Of Olfaction

No two people smell exactly alike. That is, noses sense odors in individual ways. What one nose finds offensive, another may find pleasant, while another might not smell anything at all. Scientists have long known the way things smell to us is determined by our genes.

Now, two studies appearing in the journal Current Biology (1, 2) have identified “the genetic differences that underpin the differences in smell sensitivity and perception in different individuals.” And while some of these differences merely help determine our culinary preferences, others appear to play a subconscious role in how we choose our sexual partners.

For the first study, 200 people were tested to determine their sensitivity to 10 different chemical compounds commonly found in foods. The researchers found four of the ten odors had a genetic association. These were malt, apple, blue cheese, and a floral scent associated with violets.

The research team, led by Sara Jaeger, Jeremy McRae, and Richard Newcomb of Plant and Food Research in New Zealand, used a genome-wide association study. Their first task was to identify which test subjects could smell each chemical compound and which could not. They then searched the subjects’ genomes for areas of DNA that differed between these people.

“We were surprised how many odors had genes associated with them. If this extends to other odors, then we might expect everyone to have their own unique set of smells that they are sensitive to,” explained McRae

“These smells are found in foods and drinks that people encounter every day, such as tomatoes and apples. This might mean that when people sit down to eat a meal, they each experience it in their own personalized way.”

They further found there is no regional differentiation. A person in one part of the world is just as likely to be able to smell a particular compound as a person in another part of the world. In addition, sensitivity to one compound does not predict the ability to smell another compound.

The genes that determine our ability to perceive certain odors all lie in or near the genes that encode olfactory receptors. These receptors occur on the surface of sensory nerve cells in the upper part of the nose. A particular smell is perceived when these receptor molecules bind with a chemical compound wafting through the nose, causing nerve cells to send an impulse to the brain and producing our sensation of smell.

For the violet smell, caused by a naturally occurring chemical compound known as β-ionone, the researchers were able to pinpoint the exact mutation in gene OR5A1 that determines whether the smell is perceived as floral, sour or pungent, and whether it is found to be pleasant.

These findings might have future marketing value. According to Richard Newcomb, “Knowing the compounds that people can sense in foods, as well as other products, will have an influence on the development of future products. Companies may wish to design foods that better target people based on their sensitivity, essentially developing foods and other products personalized for their taste and smell.”

SEXY OR STINKY?

A separate study was conducted by Leslie Vosshall of the Rockefeller University Hospital. Humans have about 1,000 genes that influence smell, and around 400 of these are responsible for sensing a particular odor molecule.

Testing 391 human subjects, Vosshall studied olfactory responses to two closely related steroids, androstenone and androstadienone, which are found in male sweat. People generally have strong reactions to these steroids, finding them either sweet and florally or rank and noxious. The gene 0R7D4 determines the intensity of these odors as well as the perception of them being either pleasant or repulsive.

According to Vosshall’s report: “People who found the smell repulsive were more likely to have two functional copies of OR7D4; those who perceived it as a more mild smell tended to have one or two impaired copies of the gene.”

This study is part of the larger goal of understanding how genetic and neuronal factors influence behaviors.

A 2002 study published in Nature Genetics provided more insight into the effect of male pheromones on women. This study looked at the link between women’s preferences for the odors given off by men and a group of genes called the Major Histocompatibily Complex (MHC) which contribute to a persons’ immune response.

In this experiment, a group of 49 women were asked to smell 10 boxes. Some of the boxes held t-shirts worn by men with different MHC genes, and others contained familiar household odors such as bleach or cloves.

The t-shirts were worn by men who slept in them for two nights and avoided contact with other scents during that time, even to the point of avoiding other people. According to the report, “the women were then asked to rate each scent based on their familiarity, intensity, pleasantness and spiciness, as well as choose the one odor which they would choose if they had to smell it all the time.”

What the researchers found was the women did not choose the scents of men whose genes were similar to their own, nor did they choose those whose genes were too dissimilar. The women showed no preference for odors from men who had the same genes as their mothers, but did show a preference for odors from men who shared genes they inherited from their fathers.

Scientists believe there are two reasons for preferring a mate whose MHC genes are different than one’s own. One is that it would tend to create offspring with more genetic diversity and thus more robust immune systems. The other is it helps to avoid inbreeding.

Of course, when people choose their mates, there are a number of social factors that come into play as well. However, studies have shown married people tend to have different types of genes than their spouses.

So, the next time you like the way a person smells, keep in mind it may mean you have complementary genes.

The discerning fruit fly: Linking brain-cell activity and behavior in smell recognition

Behind the common expression “you can’t compare apples to oranges” lies a fundamental question of neuroscience: How does the brain recognize that apples and oranges are different? A group of neuroscientists at Cold Spring Harbor Laboratory (CSHL) has published new research that provides some answers.

In the fruit fly, the ability to distinguish smells lies in a region of the brain called the mushroom body (MB). Prior research has demonstrated that the MB is associated with learning and memory, especially in relation to the sense of smell, also known as olfaction.

CSHL Associate Professor Glenn Turner and colleagues have now mapped the activity of brain cells in the MB, in flies conditioned to have Pavlovian behavioral responses to different odors. Their results, outlined in a paper published today by the Journal of Neuroscience, suggest that the activity of a remarkably small number of neurons — as few as 25 — is required to be able to distinguish between different odors.

They also found that a similarly small number of nerve cells are involved in grouping alike odors. This means, for instance, that “if you’ve learned that oranges are good, the smell of a tangerine will also get you thinking about food,” says Robert Campbell, a postdoctoral researcher in the Turner lab and lead author on the new study.

These intriguing new findings are part of a broad effort in contemporary neuroscience to determine how the brain, easily the most complex organ in any animal, manages to make a mass of raw sensory data intelligible to the individual — whether a person or a fly — in order to serve as a basis for making vital decisions.

Looking closely at Kenyon cells

The neurons in the fly MB are known as Kenyon cells, named after their discoverer, the neuroscientist Frederick Kenyon, who was the first person to stain and visualize individual neurons in the insect brain. Kenyon cells receive sensory inputs from organs that perceive smell, taste, sight and sound. This confluence of sensory input in the MB is important for memory formation, which comes about through a linking of different types of information.

Kenyon cells make up only about 4% of the entire fly brain and are extremely sensitive to inputs triggered by odors, in which only two connections between neurons, called synapses, separate them from the receptor cells at the “front end” of the olfactory system.

But in contrast to other regions of the brain, such as the vertebrate hippocampus, the sensory responses in the MB are few in number and relatively weak. It is the sparseness of the signals in the Kenyon cell neurons that makes studying memory formation in flies so promising to Turner and his team. “We set out to learn if these signals were really informative to the animal’s learning and memory with regard to smell,” Turner says.

In particular, Turner’s group wanted to see if they could link these signals with actual behavior in flies. The team used an imaging technique that allowed them to view the responses of over 100 Kenyon cells at a time and, importantly, quantify their results. They found that even the very sparse responses in these cells that are triggered by odors provide a large amount of information about odor identity. Turner suspects the very selectiveness of the response helps in the accurate formation and recall of memories.

When the researchers used two odors blended together in a series of increasingly similar concentrations, they found that two very similar smells could be distinguished as a result of the activity of as few as 25 Kenyon cells. This correlated well with the behavior of the flies: when brain activity suggested the flies had difficulty discerning the odors, their behavior also showed they could not choose between them.

The activity of these cells also accounts for flies’ ability to discern novel odors and group them together. This was determined in a “generalization” test, in which the degree to which flies learned a generalized aversion to unfamiliar test odors could be predicted based upon the relatively similar activity patterns of Kenyon cells that the odors induced.

“Being able to do this type of ‘mind-reading’ means we really understand what signals these activity patterns are sending,” says Turner. Ultimately, he and colleagues hope to be able to relate their findings in the fly brain with the operation of the brain in mammals.

A new study of the sense of smell lends support to a controversial theory of olfaction: Our noses can distinguish both the shape and the vibrational characteristics of odorant molecules.

The study, in the journal Physical Chemistry Chemical Physics, demonstrates the feasibility of the theory – first proposed decades ago – that the vibration of an odorant molecule’s chemical bonds – the wagging, stretching and rocking of the links between atoms – contributes to our ability to distinguish one smelly thing from another.

“The theory goes that when the right odorant binds to its receptor, the odorant’s molecular vibration allows electrons to transfer from one part of the receptor to another,” said University of Illinois physics and Beckman Institute professor Klaus Schulten, who conducted the analysis with postdoctoral researcher Ilia Solov’yov and graduate student Po-Yao Chang. “This electron transfer appears to fine-tune the signal the receptor receives.”

(Watch a video about the research.)