When you choose to publish with PLOS, your research makes an impact. Make your work accessible to all, without restrictions, and accelerate scientific discovery with options like preprints and published peer review that make your work more Open.


Making sense of the fifth sense: What we know about smell

By Cici Zhang

“I avoid applying sunscreen unless it’s absolutely necessary. The smell of it always brings me back to my semester on the sea.”

For my friend, she’s talking about a memory of sailing and marine biology and someone special, a memory that’s too precious that it makes her sad to realize it’s in such a distant past. My friend’s description of how the smell of sunscreen evokes distinct memories of her semester at sea demonstrates how powerful the sense of smell can be.

I’ve read about smell before. Smell is the fifth sense, probably the most primitive sense in primate evolution, and it’s also the one people usually ignore until they get a stuffy nose and at the same time lose their appetites somehow. Psychology researchers have long before started to use odor to subtly manipulate participants’ mood, almond odor for good mood and pyridine for bad. The connection between smell and memory is found in everyone’s life too. It could be the perfume aroma of your first lover, the chlorine smell of that old swimming pool, or the vanilla scent of your grandma’s house… I can never describe it better than Proust, as he writes in his novel Remembrance of Things Past:

“But when from a long-distant past nothing subsists, after the people are dead, after the things are broken and scattered, still, alone, more fragile, but with more vitality, more unsubstantial, more persistent, more faithful, the smell and taste of things remain poised a long time, like souls, ready to remind us, waiting and hoping for their moment, amid the ruins of the rest; and bear unfaltering, in the tiny and almost impalpable drop of their essence, the vast structure of recollection”.

There is so much more to learn about the fifth sense. How do we get to smell and recognize different odors? Why does smell so tightly relate with our emotion and memory and sensual experience? What will go wrong if we lose our sense of smell? What makes one a better or more sensitive smeller?

From something in the air to something in the brain

As early as 1833, people already had some sense about how olfaction, the sense of smell, works: “Olfaction, the sense, by which we perceive the impressions made on the olfactory nerves by the odorous particles suspended in the atmosphere” (R. Dunglison, A new dictionary of medical science and literature. II. 102/1). Indeed, smells are low molecular weight and volatile chemicals. When inhaled with a breath of air, they pass through the nasal passages, and make contact with the endings of olfactory nerves being buried in a yellow mucous membrane called olfactory epithelium. At these nerve endings sit our olfactory receptors, millions of them, busy identifying more than 10,000 odors.

These basic facts were known for a while, but the question “how” had remained mysterious to scientists until 1991. Linda Buck and Richard Axel, working at Columbia University, discovered that there are about 1000 olfactory receptor types to decode the airborne chemicals into smells, and that each receptor type is represented by a different gene. Based on this finding, researchers are able to use molecular biology and genetic strategies to further study human olfactory system. In 2004, this groundbreaking finding led Buck and Axel to win the Nobel Prize in Physiology or Medicine, “for their discoveries of odorant receptors and the organization of the olfactory system.”

So now we have a bunch of odor molecules (the natural rose scent is said to contain over one thousand molecules) that reached our olfactory receptors. Although these molecules’ adventure in this “physical” world is finished, their afterlife in another form has just begun. Once bound to olfactory receptors, these molecules elicit neural impulses (generator potentials) in the receptors. These impulses, through olfactory nerve axons, travel to two blueberry-sized brain structures designated for processing smell information. These structures are called the olfactory bulbs, one on each side of the frontal brain, sitting around seven center meters above each nostril, just behind our eyes.

Once an odor molecule reaches olfactory receptors, the molecules release neural impulses in the receptors, where they then travel to olfactory bulbs (pictured) which process the smell information. Graphic courtesy of Wikimedia (https://upload.wikimedia.org/wikipedia/commons/4/41/Head_olfactory_nerve_-_olfactory_bulb_en.png).
Once an odor molecule reaches olfactory receptors, the molecules release neural impulses in the receptors, where they then travel to olfactory bulbs (pictured) which process the smell information. Graphic courtesy of Wikimedia.

From the olfactory bulb to the rational and emotional brain

The olfactory bulbs then send odor signals to higher brain cortex, which is responsible for conscious thought processes, and to the limbic system, which generates emotional feelings. Among anatomists, limbic system has sometimes been referred to as the rhinencephalon, which literally means the “nose-brain”. The anatomical fact that olfactory bulbs are at close proximity and with tight interconnections to amygdala, the emotion center, and to hippocampus, the memory center, makes it less surprising for us to experience strong association between scent and recollection, or scent and mood.

Studies done in laboratory animals have shown other interesting relationships and even causality. In a PLOS ONE study published in 2013, neuroscientists in Mexico investigated why olfactory dysfunction is seen so frequently in the early stages of Alzheimer’s disease (1). Researchers found that amyloid beta, the to-be-blamed protein for gradual destruction of an Alzheimer’s brain, not only impairs memory but also inhibits olfactory bulb activity in rats and their ability to smell, in a concentration-dependent manner. As for the cause and effect between smell and mood, in the 1970s, researchers had started to use olfactory bulb ablation as a depression model to examine drugs that might alleviate symptoms. Such model is based on the observation that rats with olfactory bulb removal lose interest in their food, toys and other activities that normally excite them: some behaviors that are strikingly similar to what people experience during depression.

Life without sense of smell

In humans, the loss of smell has a medical term, anosmia. Anosmia can be caused by brain injury, infection, aging, or rarely some people are born without a sense of smell. Such patients have typical complaints about difficulties with cooking, low interest in eating and are subject to hazardous events. In a 2012 PLOS ONE article by researchers working in the University of Dresden Medical School in Germany, 32 patients with congenital anosmia were assessed and compared against control healthy subjects (2). After confirmation of condition with psycho-electrophysical measurements and brain imaging, these patients were asked to fill out different questionnaires in wide domains of daily life related to olfaction. The researchers found that besides enhanced social insecurity and increased risk for household accidents, these patients also display increased risk for depressive symptoms, indicated by higher scores in Beck Depression Inventory (BDI) compared to controls. Other reports and writings also exist to suggest that there is correlation between anosmia and depression-induced suicide.

To make a more vivid case about what anosmia feels like, I need to quote from expert and masterpiece. Diane Ackerman, a bestselling poet, essayist and naturalist, writes about an accident-caused anosmia in her book A Natural History of the Senses (40,41):

On rainy night in 1976, a thirty-three-year-old mathematician went out for an after-dinner stroll. Everyone considered him not just a gourmet but a wunderkind, because he had the ability to taste a dish and tell you all its ingredients with shocking precision…As he stepped into the street, a slow-moving van ran into him and he hit his head on the pavement when he fell. The day after he got out of the hospital, he discovered to his horror that his sense of smell was gone…Seven years later, still unable to smell and deeply depressed, he sued the driver of the van and won…In those seven years, he had failed to detect of smoke when his apartment building was on fire; he had been poisoned by food whose putrefaction he couldn’t smell; he could not smell gas leaks. Worst of all, perhaps, he had lost the ability of scents and odors to provide him with heart-stopping memories and associations. “I feel empty, in a sort of limbo,” he told a reporter.

The abovementioned story is not only tragic but also leads to another question about smell: why someone, like the mathematician before his van-accident, has a better nose to smell, just as having a “perfect pitch” to sound?

Individual differences in the sense of smell

It is said that the average human nose can distinctively identify between 10,000 and 40,000 different smells. For someone working in the fragrance industry, the professional “noses,” they “may be able to discriminate upward of 100,000 odors…with training” (Herz 22). Indeed, it is truly amazing to hear such a professional, Roy Desroachers, describes what a highlighter smells like during an interview with Boston Public Radio in 2013 (5):

“The first thing you get is that you get a moderate intensity of solvent note, which is probably ethyl acetate, or banana-like amyl-acetate. And underneath that you’ve got some other fruity notes that are part of that solventy. They are [usually] citrus notes. And in this case it’s more like lemon, or grapefruit or orange. There also is a little bit musty smell…”

While we might be able to become supersensitive to smells with training, another interesting question is whether there is more innate individual difference in the fifth sense, behaviorally and biologically.

Differences between women and men’s olfactory sensitivity reportedly exist, at least in a subset of odors being tested. A group of Brazilian researchers, in collaboration with University of California San Francisco (UCSF), attempted to explain such a behavioral difference by comparing the number of cells in the postmortem olfactory bulbs of male and female subjects. In their paper published in PLOS ONE in 2014, these researchers found that while not differing in weight, females’ olfactory bulbs have 6.9 million neurons while males only have 3.5 million (6). The non-neuronal cells in females’ bulbs, such as glial cells that maintain homeostasis and provide protection for neurons, are also significantly higher in number: 38.7 percent more than those in males’ bulbs. As olfactory bulb is the first stage of odor stimuli processing in the brain, such a difference in cell number could prepare future study to further investigate any sex difference in structural organization and functional impacts. Those studies might eventually answer questions like why female and male differ in identification, familiarity, and recognition of odors.

While I’m writing this post in a local café, the awakening coffee smell gradually gets replaced by an oily smoky scent lurking out of the kitchen area. Maybe it’s time to go back to my apartment and cook something better, I sniffed the not so pleasant smell and said to myself. It could be an easy Chinese dish I grew up eating and learned from my Mom, with an aroma that reminds me everything so wonderful about home.


1.Alvarado-Martínez R, Salgado-Puga K, Peña-Ortega F (2013) Amyloid Beta Inhibits Olfactory Bulb Activity and the Ability to Smell. PLoS ONE 8(9): e75745. doi:10.1371/journal.pone.0075745
2. Croy I, Negoias S, Novakova L, Landis BN, Hummel T (2012) Learning about the Functions of the Olfactory System from People without a Sense of Smell. PLoS ONE 7(3): e33365. doi:10.1371/journal.pone.0033365
3. Ackerman, Diane. A Natural History of the Senses. New York: Knopf Doubleday Publishing Group, 1990. Print.
4. Herz, Rachel. The Scent of Desire: discovering our enigmatic sense of smell. New York: HarperCollins Publishers, 2007. Print
5. Professional Smeller: Nose is World’s ‘Most Sensitive Instrument’ http://wgbhnews.org/post/professional-smeller-nose-worlds-most-sensitive-instrument
6.Oliveira-Pinto AV, Santos RM, Coutinho RA, Oliveira LM, Santos GB, Alho ATL, et al. (2014) Sexual Dimorphism in the Human Olfactory Bulb: Females Have More Neurons and Glial Cells than Males. PLoS ONE 9(11): e111733. doi:10.1371/journal.pone.0111733

Leave a Reply

Your email address will not be published. Required fields are marked *

Add your ORCID here. (e.g. 0000-0002-7299-680X)

Back to top