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A changing sense of smell

Genetic and environmental influences shape the sensory organ located at the back of the nose

If you spend a prolonged period of time exposed to a certain smell, you may become more efficient at detecting it. This might not seem surprising and may even bring to mind other senses, like hearing—for example, those quiet sounds in a house that only those living there can perceive and identify. But the mechanism of smell is apparently much more remarkable, if scientists’ observations in mice are applicable to other animals, including humans. “The cellular and molecular construction of the olfactory epithelium depends on genetic instructions and also changes with life experience,” says biologist Fabio Papes, professor at the University of Campinas (Unicamp). He and colleagues in the United Kingdom and United States have analyzed the strong genetic component that is responsible for shaping the olfactory system, described in a paper published in the journal eLife on April 25, 2017. They also found that this sensory organ is modulated by the environment. And that’s news.

Genetics undeniably plays a major role in the complexity of smell: more than 5% of the genes in the human DNA are devoted to producing an array of molecular receptors, expressed by olfactory neurons (see Pesquisa FAPESP Issue No. 155). This means that the scent-detecting organ located at the back of the nasal cavity is made up of around 400 kinds of cells, each specialized in recognizing a molecule. “Our eyesight relies on only three types of cells,” Papes offers by way of comparison. This is a big investment, particularly since smell is not the primary human sense. Approximately 1,000 genes encode smell receptors in mice—the model used by the Unicamp professor and his colleagues. “This is one of the largest multigene families in existence,” says Papes. Complex smells trigger diverse chemical receptors, activating combinations of cells in the nose. This detection strategy is what makes it possible for us to identify an astronomical number of scents (see image above).

Researchers used two strains of mice to unravel how genes and the environment contribute to shaping the sense of smell, which is responsible for evaluating food quality, potential sex partners, and nearby competitors and predators. The catch was that all representatives of both strains were genetically identical, so it was almost as if the experiment had been performed on two individuals, each with a number of clones.

In one of the experiments, the researchers housed both strains of mice in the same environment and then compared their olfactory organs. Led by geneticist Darren Logan, the team at the Sanger Institute in England sequenced the RNA of the entire olfactory epithelium and thus obtained the most thorough characterization to date of the genetic activity of the organ as a whole. “It’s the world’s biggest sequencing center,” says Papes, explaining how this unprecedented feat was possible. The researchers were consequently able to show that the physical structure of this odorant detection center varies between mouse breeds even under standardized environmental conditions, indicating that the receptor cells found in each strain are the product of genetic differences.

Even so, the nasal epithelium is anything but rigid. “It’s one of the few places in the body where there is ongoing neurogenesis over the course of a lifespan,” the Unicamp professor says. This particular feature stems in part from the fragility of the tissue. Neurons in the nose are exposed to outside air, unlike the extremely well-protected cells in the brain. Whenever a toxic substance enters the nose—like fumes on a busy street—the neurons are attacked and sometimes killed. With each cell lasting only a few months on average before it is replaced, this accounts for the variance over the long term.

It turns out that these replacements are neither random nor predetermined, according to the experiments conducted at Unicamp and Sanger. To create a controlled, homogeneous gestational environment, the researchers transferred embryos from both strains of mice into surrogate females and then returned the litters to mothers from their same strains—but with one exception: each foster litter received a single pup from the other strain.  This experimental design was based on the principle that genetically distinct mothers have distinct ways of influencing the sensory experience of their offspring, for example, through the scent of their milk. After reaching adulthood, the mice were analyzed in four groups according to strain and environment: pups from both strains raised by mothers of the same strain and pups from both strains raised by mothers of the other strain (see infographic below).

The experiment made it possible to detect subtle differences in the profile of gene expression in the olfactory epithelium of mice living in different environments, a sign that the environment also plays a role in building the organ. “This hadn’t been predicted,” says Papes. There was a major technical challenge in detecting this variation, since every type of odorant affects only a few cells in the nose. This explains why such a large-scale, in-depth analysis could only be performed now that genetic analysis resources have grown more sophisticated.

A mutable nose
The experiments also delved deeper into the changes that occur over the course of a lifetime by exposing adult mice to four odorants with known detector cells, such as the scent of banana or cloves. The odorants were added to the animals’ water so they would smell it whenever they drank. Although exposure was not ongoing, it was extended over a period of six months. Subsequent sequencing showed certain genes to be more active, which was interpreted as reflecting an increase in the number of cells carrying the four odorant-specific receptors. Gene expression levels returned to normal after only six weeks without odorized water.

“This was the first extensive quantification that determined that the number of olfactory neurons expressing each one of the 1,000 types of olfactory receptors varies among different strains of mice,” says Bettina Malnic, a biochemist at the USP Chemistry Institute (IQ-USP) and one of Brazil’s leading experts on the neurobiology of the olfactory sensory system. While Malnic did not take part in the study, she is particularly interested in the genetics behind olfactory neurons and how the expression of these genes is regulated (see Pesquisa FAPESP Issue No. 220), as evident from her collaboration on a recent review of the literature, published in the journal Molecular Pharmacology.

Fabio Papes/Unicamp The olfactory epithelium of mice puts neurons in direct contact with the air (dark spots are nuclei)Fabio Papes/Unicamp

Life and death
In a study whose findings have been submitted for publication, Malnic’s group used genetically modified mice that were unable to transmit odorant signals to their brains and found that neurons in the epithelium died under these circumstances. “The inability to respond to odorants affects the lifespan of the cells,” Malnic explains, although she has yet to identify the biochemical pathway underlying this cell death. New cells are constantly being produced, but the high mortality rate means the olfactory epithelia of these modified mice are made up of a reduced number of neurons. “Increased gene expression in mice raised in environments where a specific odorant was added, as observed by these researchers, is compatible with the idea that the lifespan of the neurons activated by the odorant was extended,” she suggests.

While conducting her research, Malnic was pleasantly surprised to come across the article by Papes and collaborators before its official publication, thanks to bioRxiv, an electronic repository of preprints (see Pesquisa FAPESP Issue No. 254). “Having access to the study’s findings even before their definitive publication helped enhance the design of experiments already underway at my laboratory,” she says.

The questions raised by these new answers guarantee plenty of work for both teams in the near future. In addition to further investigating the possible mechanisms behind this increased abundance in the receptors used the most—like cell longevity and the regulation of gene activity—researchers will also have to evaluate how this variation over the course of a lifetime and between individuals might alter perception of the environment. Papes suggests that similar plasticity may be displayed by other senses, which have yet to be studied from this angle.

Findings suggest the existence of an adaptive mechanism, in addition to what is already known about sensory memory and habituation (the former is activated when a scent evokes a specific recollection, while the latter occurs when exposure to a stimulus turns off the neurons involved in its interpretation by the brain). “We described a new strategy adopted by the body, where environmental factors modify how the olfactory organ is built, adapting the individual to live in that environment,” says Papes.

Papes also foresees a potential impact in the realm of personalized medicine. “If each person’s senses are distinct, not only because their physiology is different but also because the very cellular construction of their sensory organs is not the same, then we should view each human being as unique from a sensory perspective,” he affirms. From this standpoint, he argues that drugs could be developed to treat sensory disorders or modulate the behavior that these disorders prompt in specific groups of people.

Over the past 20 years, according to Papes, a series of studies has investigated the extent to which smell influences human behavior, like the relation between sexual attraction and body scent. The current findings suggest that new genetic approaches may help us understand this better. One project now underway at the Sanger Institute involves British volunteers in a broad-scale experiment to sequence the RNA of the olfactory organ, map the epithelium genetically, and correlate genes with different types of illnesses and sensory disorders. Papes hopes to take part and include Brazilian samples in the sequenced population. “The country’s social diversity and genetic variability makes Brazilians especially interesting in this type of study.”

Scientific articles
IBARRA-SORIA, X. et al. Variation in olfactory neuron repertoires is genetically controlled and environmentally modulated. eLife. V. 6, e21476. April 25, 2017.
NAGAI, M. H. et al. Monogenic and monoallelic expression of odorant receptors. Molecular Pharmacology. V. 90, No. 5, pp. 633-9. November 2016.