Why We Still Don’t Know How Smell Works

Despite centuries of study and advancement in technology, human understanding of how we perceive scents remains surprisingly incomplete. Our capacity to detect and identify countless odors has shaped cultures, driven commerce, and deeply influenced human relationships. Yet, at the heart of it, scientists still debate how smell fundamentally operates. Two main theories dominate this discussion: the shape theory and the vibration theory.

Shape Theory: Lock and Key

The most widely accepted and oldest explanation for how we perceive scent is the shape theory, often described metaphorically as the "lock-and-key" mechanism. This theory suggests that olfactory receptors in the nasal cavity are specifically shaped proteins designed to detect molecules of corresponding shapes. When an odor molecule fits into the receptor perfectly, it triggers the receptor to send a signal to the brain, which interprets it as a specific smell.

This lock-and-key idea has intuitive appeal because it parallels how many biological processes function—enzymes and substrates, neurotransmitters and receptors, antibodies and antigens—all rely heavily on structural compatibility. Shape theory neatly explains why chemically similar molecules can smell similar and why structurally distinct molecules often smell entirely different.

However, the model has significant limitations. A notable example is the case of enantiomers—molecules that are mirror images of each other, like left and right hands. Enantiomers often have identical physical and chemical properties, including shape, but can smell dramatically different. Take carvone, for instance. The (R)-enantiomer of carvone smells like spearmint, while the (S)-enantiomer smells like caraway. Their molecular structures are nearly identical, yet our brains perceive them as entirely different scents. This discrepancy challenges a purely shape-based model.

Another example involves musks. Some musk compounds with vastly different molecular shapes can still produce a nearly identical musky odor. Conversely, nearly indistinguishable molecules like androstenone and its closely related isomers can evoke different responses: some people perceive them as pleasant, others find them foul, and some smell nothing at all. Such inconsistencies hint at complexities in olfactory perception that shape theory alone struggles to explain.

The underlying assumption of shape theory is that molecular recognition depends solely on how well a molecule's geometry fits into a receptor. In biochemistry, this is referred to as molecular docking. In this framework, an odorant docks into an olfactory receptor in the same way a key fits into a lock. Once bound, the receptor undergoes a conformational change, activating a signal transduction cascade that ultimately sends a message to the brain.

You can try the simple game we made below to get an idea of this theory. You can drag the shapes and rotate them using the buttons. Find a way to fit them into the receptors, and you'll find out what scent the brain perceives. Of course, this is highly simplified. It is simply a way to visualize the theory.

Research into docking theory has revealed additional factors that might influence receptor activation, such as molecular flexibility, charge distribution, and the presence of water molecules in the receptor site. These nuances complicate the simple lock-and-key model, implying that while shape is crucial, it's not the whole story. Factors like how the molecule twists, bends, or polarizes in the receptor pocket may all play roles in determining what we smell.

Some variants of shape theory, like the induced fit model, propose that olfactory receptors are not rigid locks but more like adaptable gloves that mold slightly to fit incoming molecules. This adaptation could allow structurally similar molecules to evoke different olfactory responses depending on how the receptor reshapes itself around the odorant. Still, even these refinements fall short of explaining all anomalies.

Ultimately, shape theory provides a foundational framework for understanding olfaction but leaves many puzzles unsolved. These unexplained phenomena have led scientists to explore alternative or complementary models—most notably the vibration theory, which suggests a different approach entirely to how our brains interpret molecular encounters.

Vibration Theory: An Alternative

In the 20th century, the vibration theory emerged as an intriguing alternative. Proposed initially by Malcolm Dyson in the 1930s and revived later by biophysicist Luca Turin, this theory postulates that receptors detect molecular vibrations rather than shapes. Each molecule vibrates at a specific frequency, and these frequencies determine the perceived scent. According to vibration theory, the receptor proteins act like spectroscopic detectors, tuned to sense these frequencies directly.

This theory accounts well for anomalies unexplained by shape theory, such as isotopic variation. Turin demonstrated that molecules identical in shape but differing slightly due to isotopic substitutions (atoms of different weights) could smell differently to highly sensitive noses. Vibration theory provides a compelling explanation for such phenomena, suggesting receptors detect vibrational frequencies rather than shape alone.

Despite these strengths, vibration theory remains controversial. Critics argue it lacks clear biological evidence detailing how olfactory receptors detect molecular vibrations and translate these frequencies into signals comprehensible to the brain. Scientists continue seeking direct experimental evidence that could decisively prove or disprove this theory.

The Persistent Mystery of Anosmia

Further complicating our understanding of smell is the phenomenon of anosmia—the complete loss or impairment of the sense of smell. Conditions like anosmia really show how little we truly understand about olfaction. People with anosmia typically suffer disruptions in their olfactory receptors or the neural pathways connecting the nose to the brain. The recent COVID-19 pandemic, which induced anosmia in millions globally, is a very clear example of it. However, despite intense scientific scrutiny, exactly why the virus impacted the sense of smell—and the intricate biology behind why recovery varied so drastically—remains incompletely understood.

One potential explanation involves inflammation. Some researchers propose that COVID-19-induced inflammation around the olfactory epithelium disrupts the environment needed for receptor neurons to function properly. This inflammation may impair signal transmission even if the receptors themselves are undamaged. However, this theory doesn’t fully explain why some individuals regain their sense of smell within weeks, while others experience long-term anosmia with no structural damage apparent.

Another hypothesis focuses on the sustentacular cells—non-neuronal support cells in the olfactory epithelium. SARS-CoV-2 appears to infect these support cells rather than the neurons directly. Damage to these cells could disrupt the functional environment necessary for olfactory neurons to operate, indirectly silencing smell. Yet, while this helps explain temporary anosmia, it struggles to clarify persistent cases or selective smell loss.

Some researchers suggest the issue lies further downstream in the brain, particularly in the olfactory bulb or even higher cortical regions involved in odor interpretation. Brain imaging studies of long-COVID patients with persistent anosmia have found changes in olfactory bulb size or activity levels. This central damage theory could account for cases where the peripheral olfactory system appears structurally normal but fails to function.

These competing explanations show that anosmia may not have a single cause but rather a spectrum of disruptions. The causes may range from peripheral inflammation to central neural rewiring. Such complexity is difficult to square with a purely shape-based or vibration-based model of smell. Both theories focus heavily on molecular recognition at the receptor level but overlook the vast neural architecture required to interpret those signals. The brain doesn’t just receive odor data—it processes, prioritizes, remembers, and even suppresses it.

Anosmia research further challenges the simplistic views of both shape and vibration theories. Why does damage to certain pathways lead to permanent anosmia while others recover fully? Why can some individuals smell only specific molecules but not others? These inconsistencies point to a much more intricate mechanism behind smell than either theory currently fully captures. A complete understanding of olfaction may need to incorporate receptor biology, neural circuitry, immunology, and even genetics to account for the full diversity of human smell perception. Indeed, it is a very complex problem to solve.

Implications for the Perfume Industry

The debate surrounding how smell works is far more than academic; it deeply impacts the perfume and fragrance industry, which hinges on our sense of smell to create compelling products. Perfumers, despite their deep expertise, rely on a combination of experience, intuition, and trial-and-error rather than purely scientific principles. A clearer understanding of how olfactory receptors function could revolutionize fragrance design, allowing perfumers to predict precisely how a given molecule or blend will be perceived.

Should vibration theory prove correct, for instance, fragrance houses might pivot to engineering molecules based on their vibrational frequencies, enabling a much higher precision in scent creation. Alternatively, if shape theory holds true, molecular modeling software and AI models could significantly enhance fragrance innovation by efficiently matching molecular shapes to receptor types.

Currently, perfumers must still navigate the art and science of scent creation without definitive biochemical guidelines. This blend of artistry and unpredictability partly explains why fragrance remains profoundly subjective—one scent can evoke a powerful emotional response in one individual and none at all in another. This is similar to the way art works. What one might see in art is something to hold dear to the heart, but another could see the same artwork as nothing but a waste of time and space.

A Future of Exploration

Ultimately, the persistent uncertainty around how smell works invites continuous exploration and innovation. As scientists continue to probe these competing theories and confront the unsolved like anosmia, the implications extend far beyond biology or perfumery alone. Smell is intimately connected to memory, emotion, and even survival. It is something that is deeply embedded in the human experience. And yet, perhaps the pursuit of decoding olfaction is as futile as trying to quantify why we love a painting or a song. Maybe trying to break down the art of scent into chemistry and code risks stripping away its mystique, its subjectivity, even its beauty. Or maybe it doesn’t. Maybe understanding it more deeply will only deepen our appreciation for scent and unlock untapped creative potential. Perhaps we’ll discover many new scents that we humans collectively enjoy that have yet to be found. We don’t know yet.

But one thing is for sure, that the pursuit for the answers will surely carry us forward. Perhaps, in doing so, we are also inching closer to understanding what it means to be human. Because to decode scent is to peer into the very architecture of memory, intimacy, and imagination. And maybe—just maybe—the future of olfaction won’t just redefine how we bottle fragrance, but how we experience the world, how we connect with one another, and how we remember. In scent, there is science. But there is also wonder. And in it, something uniquely human.