A trillion scents, one nose

The mammalian nose is a work of evolutionary art. Its millions of nerve cells, each tailored with just one of thousands of specific odor-chemical receptors encoded in the genome, can collectively distinguish a trillion distinct scents. Those sensations, in turn, inform many behaviors, from assessing food options to discerning friends from foes to sparking memories.

Today, in the journal Nature, a research team led by scientists at Columbia's Zuckerman Institute describes a previously undetected mechanism in mice -- starring the genetic molecule RNA -- that could explain how each sensory cell, or neuron, in mammalian noses becomes tailored to detect a specific odor chemical.

For example, there are sensory neurons in our noses that bear receptors uniquely tuned to detect ethyl vanillin, the main odorant in vanilla, and other cells with receptors for limonene, lemon's signature odorant.

"How sensory cells in the nose make their receptor choices has been one of the most vexing mysteries about olfaction," said Stavros Lomvardas, PhD, a Roy and Diana Vagelos Professor and Chair of Biochemistry and Molecular Biophysics and Herbert and Florence Irving Professor of Neuroscience at Columbia's Zuckerman Institute and the Vagelos College of Physicians and Surgeons, and corresponding author on the paper.

"Now, the story behind our sense of smell, or olfaction, is becoming clearer, and also more dramatic."

The sense-refining drama he is referring to unfolds entirely within the minuscule confines of each olfactory neuron's nucleus, where the cell's chromosomes and genes reside.

There, in a Squid Games-style, winner-takes-all competition, a developing cell's myriad olfactory receptor genes vie with each other in a process that winnow them down, in stages, first to handful of finalists and then to a single winner.

The prevailing gene is the one that determines the cell's odorant sensitivity.

In their study, Dr. Lomvardas and his team uncover details of the final stage of this process when the winner emerges from the finalist genes.

"It's basically a battle between a 1000 contenders," said Ariel Pourmorady, the paper's first author and an M.D.-Ph.D. candidate at the Zuckerman Institute in the Lomvardas lab.

The action is exceedingly complex and involves a dizzying cast of molecular characters.

Playing roles that either dial up or down each gene's ability to produce olfactory receptors are a variety of gene-regulating molecules.

By gathering into various alliances within the genome, these molecular players help turn specific genes on or off.

Also in the fray is another set of molecular hubs that reshape portions of the genome in ways that favor specific receptor genes.

When his team first observed these in the genome in 2014, Dr. Lomvardas dubbed them "Greek Islands" because they reminded him of islands in the Aegean Sea.

"It turns out that the genome has a certain spatial organization in the nucleus and changes in this structure are pivotal when it comes to which genes are expressed into proteins, like olfactory receptors," said Pourmorady.

"We are learning just how important this process is within maturing olfactory cells."

In their new Nature paper, the researchers summon a trove of data from mouse studies pointing toward RNA as the linchpin molecule in the olfactory system's gene-choosing mechanism.

RNA is most known as the go-between molecule that translates the genetic code embodied in DNA into protein molecules with specific cellular jobs, like detecting odorants.

Using sophisticated techniques for analyzing changes in genome structure as cells mature, however, the researchers say their evidence points to a pivotal second role for the RNA.

"It looks like the RNA the cell makes during gene expression also is altering the genome's architecture in ways that bolster the expression of one olfactory receptor gene while also shutting down all the others," Pourmorady said.

Big gaps in this genome-controlling story remain, but the researchers say the outline

is becoming more defined. It starts with maturing olfactory cells, which initially express many receptor genes at those genomic hubs where gene-regulating molecules and complexes, including Greek Islands, converge.

Then the RNA winnows the contending olfactory-receptor genes down to one.

The particular hub in each cell where the molecular stars align to produce the highest amount of RNA wins the competition.

At this hub, receptor-gene expression soars. But, like a slinky saboteur, RNA from that same hub may wind its way to all the other hubs.

In those locations, the RNA causes shape changes in the genome that shut down gene expression.

The result is a nose's worth of mature olfactory neurons, each of which bears on its surface only one odorant receptor.

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Making sense of scents: Deciphering our sense of smell

Breaking a longstanding impasse in our understanding of olfaction, scientists at UC San Francisco (UCSF) have created the first molecular-level, 3D picture of how an odor molecule activates a human odorant receptor, a crucial step in deciphering the sense of smell.

The findings, appearing online March 15, 2023, in Nature, are poised to reignite interest in the science of smell with implications for fragrances, food science, and beyond. Odorant receptors -- proteins that bind odor molecules on the surface of olfactory cells -- make up half of the largest, most diverse family of receptors in our bodies; A deeper understanding of them paves the way for new insights about a range of biological processes.

"This has been a huge goal in the field for some time," said Aashish Manglik, MD, PhD, an associate professor of pharmaceutical chemistry and a senior author of the study. The dream, he said, is to map the interactions of thousands of scent molecules with hundreds of odorant receptors, so that a chemist could design a molecule and predict what it would smell like.

"But we haven't been able to make this map because, without a picture, we don't know how odor molecules react with their corresponding odor receptors," Manglik said.

A Picture Paints the Scent of Cheese

Smell involves about 400 unique receptors. Each of the hundreds of thousands of scents we can detect is made of a mixture of different odor molecules. Each type of molecule may be detected by an array of receptors, creating a puzzle for the brain to solve each time the nose catches a whiff of something new.

"It's like hitting keys on a piano to produce a chord," said Hiroaki Matsunami, PhD, professor of molecular genetics and microbiology at Duke University and a close collaborator of Manglik. Matsunami's work over the past two decades has focused on decoding the sense of smell. "Seeing how an odorant receptor binds an odorant explains how this works at a fundamental level."

To create that picture, Manglik's lab used a type of imaging called cryo-electron microscopy (cryo-EM), that allows researchers to see atomic structure and study the molecular shapes of proteins. But before Manglik's team could visualize the odorant receptor binding a scent molecule, they first needed to purify a sufficient quantity of the receptor protein.

Odorant receptors are notoriously challenging, some say impossible, to make in the lab for such purposes.

The Manglik and Matsunami teams looked for an odorant receptor that was abundant in both the body and the nose, thinking it might be easier to make artificially, and one that also could detect water-soluble odorants. They settled on a receptor called OR51E2, which is known to respond to propionate -- a molecule that contributes to the pungent smell of Swiss cheese.

But even OR51E2 proved hard to make in the lab. Typical cryo-EM experiments require a milligram of protein to produce atomic-level images, but co-first author Christian Billesbøelle, PhD, a senior scientist in the Manglik Lab, developed approaches to use only 1/100th of a milligram of OR51E2, putting the snapshot of receptor and odorant within reach.

"We made this happen by overcoming several technical impasses that have stifled the field for a long time," said Billesbøelle. "Doing that allowed us to catch the first glimpse of an odorant connecting with a human odorant receptor at the very moment a scent is detected."

This molecular snapshot showed that propionate sticks tightly to OR51E2 thanks to a very specific fit between odorant and receptor. The finding jibes with one of the duties of the olfactory system as a sentinel for danger.

While propionate contributes to the rich, nutty aroma of Swiss cheese, on its own, its scent is much less appetizing.

"This receptor is laser focused on trying to sense propionate and may have evolved to help detect when food has gone bad," said Manglik. Receptors for pleasing smells like menthol or caraway might instead interact more loosely with odorants, he speculated.

Just a Whiff

Along with employing a large number of receptors at a time, another interesting quality of the sense of smell is our ability to detect tiny amounts of odors that can come and go. To investigate how propionate activates this receptor, the collaboration enlisted quantitative biologist Nagarajan Vaidehi, PhD, at City of Hope, who used physics-based methods to simulate and make movies of how OR51E2 is turned on by propionate.

"We performed computer simulations to understand how propionate causes a shape change in the receptor at an atomic level," said Vaidehi. "These shape changes play a critical role in how the odorant receptor initiates the cell signaling process leading to our sense of smell."

The team is now developing more efficient techniques to study other odorant-receptor pairs, and to understand the non-olfactory biology associated with the receptors, which have been implicated in prostate cancer and serotonin release in the gut.

Manglik envisions a future where novel smells can be designed based on an understanding of how a chemical's shape leads to a perceptual experience, not unlike how pharmaceutical chemists today design drugs based on the atomic shapes of disease-causing proteins.

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Chemical cocktail in skin summons disease-spreading mosquitoes

Mosquitoes that spread Zika, dengue and yellow fever are guided toward their victims by a scent from human skin. The exact composition of that scent has not been identified until now.

A UC Riverside-led team discovered that the combination of carbon dioxide plus two chemicals, 2-ketoglutaric and lactic acids, elicits a scent that causes a mosquito to locate and land on its victim. This chemical cocktail also encourages probing, the use of piercing mouthparts to find blood.

This chemical mixture appears to specifically attract female Aedes aegypti mosquitoes, vectors of Zika as well as chikungunya, dengue, and yellow fever viruses. This mosquito originated in Africa, but has spread to tropical and subtropical regions worldwide, including the U.S.

This new research finding, and how the team discovered it, is detailed in the journal Scientific Reports. "Though others have identified compounds that attract mosquitoes, many of them don't elicit a strong, rapid effect. This one does," said Ring Cardé, UCR entomologist.

Mosquitoes use a variety of cues to locate their victims, including carbon dioxide, sight, temperature, and humidity. However, Cardé's recent research shows skin odors are even more important for pinpointing a biting site.

"We demonstrated that mosquitoes land on visually indistinct targets imbued with these two odors, and these targets aren't associated with heat or moisture," Cardé said. "That leaves skin odor as the key guiding factor."

Given the significance of odor in helping mosquitoes successfully feed on humans, Cardé wanted to discover the exact chemicals that make our scent so potent for the insects. Part of the equation, lactic acid, was identified as one chemical element in the odor cocktail as long ago as 1968.

Since then, several studies have identified that carbon dioxide combined with ammonia, and other chemicals produced by humans also attract these mosquitoes. However, Cardé, who has studied mosquitoes for 26 years, felt these other chemicals were not strong attractants.

"I suspected there was something undiscovered about the chemistry of odors luring the yellow fever mosquito," Cardé said. "I wanted to nail down the exact blend."

Methods that chemists typically use to identify these chemicals would not have worked for 2-ketoglutaric acid, Cardé said. Gas chromatography, which separates chemicals by their molecular weight and polarity, would have missed this acid.

"I think that these chemicals may not have been found before because of the complexity of the human odor profile and the minute amounts of these compounds present in sweat," said chemist Jan Bello, formerly of UCR and now with insect pest control company Provivi.

Searching for mosquito attractors, Cardé turned to Bello, who extracted compounds from the sweat in his own feet. He filled his socks with glass beads and walked around with the beads in his socks for four hours per odor collection.

"Wearing the beads felt almost like a massage, like squeezing stress balls full of sand, but with your feet," said Bello. 'The most frustrating part of doing it for a long time is that they would get stuck in between your toes, so it would be uncomfortable after a while."

The inconvenience was worth the investment. Bello isolated chemicals from the sweat deposited on the sock beads and observed the mosquitoes' response to those chemicals. In this way, the most active combination emerged.

Future studies are planned to determine whether the same compound is effective for any other mosquitoes, and why there is such variation in how individuals are apt to be bitten. "Some are more attractive than others to these mosquitoes, but no one's yet established why this is so," Cardé said.

Though this discovery may not lead to insights for the development of new repellants, the research team is hopeful their discovery can be used to attract, trap, and potentially kill disease-spreading mosquitoes.

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Smells like ancient society: Scientists find ways to study and reconstruct past scents

In a new call for action paper published in Nature Human Behaviour, researchers from the Max Planck Institute for the Science of Human History in Jena, Germany, discuss the importance of scent in human history and address how and why experts might investigate smells from the past.

In recent years, millions of people worldwide have suffered the loss of smell due to COVID-19. Even those who have avoided infection with the new coronavirus experience the world of scent differently now due to the very masks that provide protection from the virus. This loss of olfaction has highlighted the important role of smell in how we perceive and navigate the world, and underscored the connections between olfaction and mental and physical health.

Scent has always been an integral component of the human experience, but up until now, the past has remained largely odorless. Most scents come from organic substances that decay quickly, leaving little for archaeologists to investigate thousands of years later. Now a team of researchers from the MPI for the Science of Human History is looking for new ways to bring the smellscapes of the past back to life and using smell to study past experience, behaviour, and society.

"Tracking scent in the deep past is not a simple task," says Barbara Huber, the lead author of the paper, "but the fact that history records expeditions of discovery, wars, and long-distance exchange to acquire materials with strong olfactory properties -- like incense and spices -- reveals how significant scent has been for human kind."

Understanding the sensorial dimension of human history and the use of odorous and aromatic substances can contribute knowledge about many aspects of the past -- including ritual, perfumery, hygiene, cuisine, trade and commerce. But because scent is part of how we experience, understand and navigate the world, ancient scents can also provide insight into more general aspects of the past, from social hierarchy and social practices to group identity.

"Scent is a powerful and underappreciated aspect of human experience," notes Professor Nicole Boivin, senior author of the study and Director of the Department of Archaeology at the MPI Science of Human History "Smells reach our brain fairly directly and motivate us in critical ways -- whether to avoid danger, identify something that is good for us, or remember something from our past, for example."

"Using only traces of scented substances preserved in archaeological artefacts and features," adds Huber, "novel methods are revealing the powerful odours that were a cardinal feature of ancient lived realities, and that shaped human action, thoughts, emotions and memories."

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Where does the special scent of thyme and oregano come from?

Thyme and oregano are not only popular herbs for cooking, but also valuable medicinal plants. Their essential oils contain thymol and carvacrol which impart the typical flavors and are medically important. A team from Martin Luther University Halle-Wittenberg (MLU) and Purdue University in the USA has now fully identified how the plants produce these two substances. The results could simplify the breeding process and improve the pharmaceutical value of thyme and oregano. The study appears in the journal Proceedings of the National Academy of Sciences.

Thymol, which is mainly extracted from thyme, has secretolytic, antibacterial and antispasmodic properties. The plant is therefore often used in tea for colds, cough syrups and as an herbal remedy for bronchitis. In contrast, oregano contains particularly high levels of carvacrol, which has similar properties. Its smell is often associated with pizza sauce and other Mediterranean dishes. Both substances are chemically closely related and are produced by thyme and oregano in multi-stage processes. "It's like a production line in a factory: Every step needs to be coordinated and the desired product only emerges when the steps are carried out in the right order," explains Professor Jörg Degenhardt from the Institute of Pharmacy at MLU. Instead of machines, specific biomolecules -- enzymes -- carry out this work in special glands on the surface of the leaves.

Together with researchers from Purdue University in the USA, the team in Halle decoded the individual production steps, thereby solving a decades-old mystery. "For a long time it was assumed that p-Cymene was an intermediate product of thymol and carvacrol synthesis. However, it was chemically not feasible for thymol or carvacrol to ultimately be produced from this substance," says Degenhardt. In fact, normal production of the two substances does not produce any p-Cymene at all, but rather an extremely unstable intermediate product. "This is only present for a few moments in the plant cells, which is why observing it is so difficult. However, it represents the hitherto missing step in the synthesis of the two substances," says Degenhardt. The processes start out the same for both thymol and carvacrol; only in step four do different enzymes that produce the respective substances come into play. In a fifth step, thymol and carvacrol can be further converted to thymohydroquinone and thymoquinone, which have anti-inflammatory and anti-tumour effects.

The researchers were also able to use these new findings to genetically reprogramme a species of tobacco, the model plant N. benthamiana, to produce thymol. "Even though this only happened in small quantities, it meant that we were able to fully understand the synthesis pathways and the associated enzymes," summarises Degenhardt.

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New research 'sniffs out' how associative memories are formed

Has the scent of freshly baked chocolate chip cookies ever taken you back to afternoons at your grandmother's house? Has an old song ever brought back memories of a first date? The ability to remember relationships between unrelated items (an odor and a location, a song and an event) is known as associative memory.

Psychologists began studying associative memory in the 1800s, with William James describing the phenomenon in his 1890 classic The Principles of Psychology. Scientists today agree that the structures responsible for the formation of associative memory are found in the medial temporal lobe, or the famous "memory center" of the brain, but the particular cells involved, and how those cells are controlled, have remained a mystery until now.

Neuroscientists at the University of California, Irvine have discovered specific types of neurons within the memory center of the brain that are responsible for acquiring new associative memories. Additionally, they have discovered how these associative memory neurons are controlled. We rely on associative memories in our everyday lives and this research is an important step in understanding the detailed mechanism of how these types of memories are formed in the brain.

"Although associative memory is one of the most basic forms of memory in our everyday life, mechanisms underlying associative memory remain unclear" said lead researcher Kei Igarashi, faculty fellow of the Center for the Neurobiology of Learning and Memory and assistant professor of anatomy & neurobiology at the UCI School of Medicine.

The study published today in the journal Nature, reports for the first time, that specific cells in the lateral entorhinal cortex of the medial temporal lobe, called fan cells, are required for the acquisition of new associative memories and that these cells are controlled by dopamine, a brain chemical known to be involved in our experience of pleasure or reward.

In the study, researchers used electrophysiological recordings and optogenetics to record and control activity from fan cells in mice as they learn to associate specific odors with rewards. This approach led researchers to discover that fan cells compute and represent the association of the two new unrelated items (odor and reward). These fan cells are required for successful acquisition of new associative memories. Without these cells, pre-learned associations can be retrieved, but the new associations cannot be acquired. Additionally acquiring new associations also requires dopamine.

"We never expected that dopamine is involved in the memory circuit. However, when the evidence accumulated, it gradually became clear that dopamine is involved," said Igarashi. "These experiments were like a detective story for us, and we are excited about the results."

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