The story behind our sense of smell is coming into focus

The mammalian nose, a testament to evolutionary art, holds remarkable capabilities beyond just our sense of smell. It harbors millions of nerve cells, each equipped with thousands of specific odor-chemical receptors encoded in the genome, allowing for the discrimination of trillions of distinct scents.

These olfactory sensations guide vital behaviors, including assessing food choices, distinguishing friends from foes, and sparking memories.

Studying our sense of smell

A team of researchers, led by scientists from Columbia’s Zuckerman Institute, unravels a previously unrecognized mechanism in the sense of smell in mice, involving the genetic molecule RNA. This finding may shed light on how each sensory cell, or neuron, in mammalian noses becomes specialized to detect a specific odor chemical.

The study focuses on the diversity of sensory neurons in our noses, which possess receptors tuned to detect unique odorants, such as ethyl vanillin, the primary odorant in vanilla, or limonene, the signature odorant of lemons.

Dr. Stavros Lomvardas is the corresponding author of the paper. He explains the significance of this new insight, saying, “How sensory cells in the nose make their receptor choices has been one of the most vexing mysteries about olfaction. Now, the story behind our sense of smell, or olfaction, is becoming clearer, and also more dramatic.”

The intricate “winner-takes-all” battle

The complexity and drama of sensory refinement occur within the minuscule confines of each olfactory neuron’s nucleus, where the cell’s chromosomes and genes reside. Remarkably, a cell’s olfactory receptor genes compete with each other in a “winner-takes-all” contest.

This fierce competition taking place behind the scenes in our sense of smell occurs in stages, starting with numerous contenders and gradually narrowing down until one receptor gene ultimately prevails, defining the cell’s odorant sensitivity.

Ariel Pourmorady, an M.D.-Ph.D. candidate at the Zuckerman Institute, elaborates on the complexity of this battle for genetic supremacy, “It’s basically a battle between a thousand contenders.”

Dr. Lomvardas and his team provide unprecedented insight into the final stage of this process, unveiling the emergence of the winning gene from the pool of finalists.

“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.”

A diverse cast behind our sense of smell

The intricate process behind our sense of smell involves a diverse cast of molecular characters. Various gene-regulating molecules either enhance or suppress the production of olfactory receptors by influencing specific genes within the genome.

Additionally, there is another group of molecular entities that reshape sections of the genome, favoring specific receptor genes. In 2014, Dr. Lomvardas first discovered these molecular hubs and aptly named them “Greek Islands” due to their resemblance to the islands in the Aegean Sea.

Pourmorady further emphasizes the importance of genomic structure and its influence on olfactory receptor genes. He explained, “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. We are learning just how important this process is within maturing olfactory cells.”

The researchers’ extensive study utilizes data from mouse studies, pointing towards RNA as the central molecule orchestrating the gene-choosing mechanism within the olfactory system.

The role of RNA: A key player

While RNA is primarily known as the intermediary molecule responsible for translating genetic code into proteins, assisting in functions like odorant detection, the researchers present compelling evidence for an additional role played by RNA.

Pourmorady highlights this pivotal function of RNA, saying, “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.”

Although there are still gaps to be filled in our understanding of genome control, the researchers assert that the outlines of this intricate process are beginning to take shape. It all starts with maturing olfactory cells, which initially express multiple receptor genes at specific genomic hubs.

These hubs, coalescing with gene-regulating molecules and complexes, including the Greek Islands, provide the initial platform for receptor gene expression. The RNA then navigates through the contenders, whittling them down until only one gene prevails. This gene’s corresponding hub produces the highest amount of RNA, facilitating receptor-gene expression.

However, the RNA, much like a “slinky saboteur,” ventures to other hubs, contributing to changes in the genome’s structure, effectively suppressing gene expression. Consequently, each mature olfactory neuron in the nose possesses only one odorant receptor on its surface.

Decoding the molecular marvels

Dr. Lomvardas concludes with enthusiasm about the extraordinary progress being made in decoding the molecular and genomic intricacies in our sense of smell within a single cell’s nucleus.

“We are reaching the edge of science fiction when it comes to the molecular and genomic details we now can observe inside a single cell’s nucleus. We need to keep going back in to figure out the rest of this olfaction puzzle,” Lomvardas said.

In summary, this study sheds light on the fascinating mechanics behind smell perception in mammals. The discovery of RNA’s additional role in shaping the olfactory system’s gene expression provides a crucial piece of the puzzle.

As researchers continue to peel back the layers of this intricate process, our understanding of the sense of smell will deepen, leading to new insights and potentially revolutionary applications in the fields of biology and medicine.

The full study was published in the journal Nature.

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