What Genetics Can Tell Us About Comprehending the World Through Smell

By Karen Kreeger, Director of Communications

No two people perceive life through their noses in quite the same way. Biologically speaking, the act of smelling happens pretty much identically every time. Proteins called olfactory receptors at the ends of olfactory nerves at the back of the nasal cavity lock onto chemicals in the environment with each breath, transmitting an electrical signal to the olfactory bulb in the brain.

Humans have fewer types of olfactory receptors than many other species, but we still have about 400 functional ones – much more than we use for color vision – four, or even taste – about 40. To make the study of smell even more complicated, each gene for a smell receptor can have small variations in its chemical makeup that tweak its corresponding protein’s shape and function. This in turn leads to some differences in how experiencing the same odor can vary from one person to the next.

Joel Mainland, PhD, a neuroscientist at the Monell Chemical Senses Center, likes to give the example of the chemical androstenone (a steroid pheromone from boar testes). “We know that some people smell that molecule as urine, some people smell that molecule as sandalwood, and some people don’t smell it at all,” he recently told The New York Times.

Mainland is a senior author on a new study in PLOS Genetics that examined over 1,000 people from the Chinese Han population for variation in odor receptor form and function and how that relates to their perception of 10 different odors. The findings were replicated in a study in which six of the odors, some at different concentrations, were tested in 364 participants from New York City (mostly Caucasian descent), suggesting the study’s results are comparable among different populations and odor concentrations.

The findings of this international research – with Monell collaborators from the Chinese Academy of Sciences, Tongji University, Rockefeller University, and Unilever – were simultaneously fascinating and puzzling.

News coverage in the days after the paper went live bares out the complexity of making sense out the sense of smell, given these headlines, for example:
Body Odor May Smell Worse to You Than Your Ancient Ancestors:” New York Times
Scientists identify how humans detect the smell of body odour and musk:The Guardian
Humans’ Sense of Smell May Be Getting Duller:” HealthDay News

Identifying novel receptors for two of the odors they used – a version of musk used in perfumes and a prime component of human body odor – was a key finding. The remaining odors looked at aldehydes or mixtures that contained aldehydes, a class of chemical used in perfumes, solvents, and flavoring agents.

“We were interested in aldehydes because previous research had shown population differences in pleasantness for aldehydes–Asian populations tended to find them less pleasant than Caucasian populations,” said Mainland. He notes several reasons for a lack of new or unequivocal findings for the aldehyde-containing odors, including that differences in liking for any odor among study participants could be more influenced by cultural factors than genetics. For example, anecdotally, some people in France report that they do not like root beer, presumably because the flavor is used during dental visits and is associated with “medicine” rather than food. “This has nothing to do with genetics,” said Mainland.

The team chose the musk and body odor scents because of evidence from earlier studies that some people have a specific anosmia (the lack of the ability to smell a specific odor) or other variations in their perception for musk or body odor. “For example, George Preti was the main force behind the discovery of 3M2H, a primary component of body odor, and reported that some people were unable to smell it,” Mainland said. Dr. Preti worked at Monell for close to 50 years and passed away in 2020.

Musk scent poses a particular conundrum for researchers. Molecules with very different structures all lead to a perception of musk among study participants. Sensory scientists have been chasing how the olfactory system decodes that puzzle for decades.

For first author Marissa Kamarck, a doctoral student at the University of Pennsylvania working in the Mainland lab, the most exciting finding was the association between the specific musk odor galaxolide and its receptor OR4D6. “It’s unusual for a single receptor to have such a large effect on odor perception. We think individuals with two variant versions of the OR4D6 receptor appear to have a specific anosmia to galaxolide,” she said.

Other findings were also confounding. The part of the study that addressed genetic variation in olfaction over an evolutionary timescale is a bit tricky, say the authors. Individuals with “older” versions of certain receptors that had not changed over the millennia tended to rate a corresponding odor as more intense.

“The reason behind why we tended to see decreased odor sensitivity over the course of evolution is unclear,” said Kamarck. “In general this is likely due to a lack of selective pressure for detecting a certain odor, resulting in a drift away from a functional version of the gene and therefore a working receptor. The results of perception of body odor was the opposite, where the newer version of the gene produced a receptor with increased function.”

The authors emphasize that their results do not show that the overall sense of smell in humans is deteriorating. They explain it this way: Although humans have over 400 working odor receptors, we also have larger brains than most species, so one possibility is that we can make do with fewer sensors.

“We just don’t really know,” said Mainland. “We see that ancestral receptor variants tend to be more functional than more recent variants. While this all points toward a less responsive receptor array, we can’t make a direct jump to a worse overall sense of smell.”

Kamarck adds: “Although we do find that more recent versions of the genes tend to reduce perceived odor intensity, it is not clear what effect this has on real-world smell perception.” This is where the everyday meets the lab: In studying the biology of smell, chemosensory scientists test odors that consist of a single odorous chemical, while odors that we encounter in our daily lives usually consist of tens to hundreds of different compounds.

The body odor experiment is a good example of this point. The team found that the more recent version of the OR51B2 olfactory receptor predicts an increase in intensity perception of the 3M2H component of body odor. While 3M2H is an important compound in body odor, people who are unable to detect it can still perceive the full suite of body odor, a smell composed of many individual chemicals.

Whether the human sense of smell overall is declining or if we’re truly better at smelling body odor is still a mystery, but one thing is certain – the number of questions to explore in sensory science will likely continue to rise.