How We Smell: Odour Molecules and Receptors

You can recognise the smell of coffee, rain on dry ground, a lemon or a gas leak in an instant. Each of those experiences starts with a few molecules drifting into your nose and binding to proteins in a small patch of tissue at the top of the nasal cavity. Smell is chemistry detection at extraordinary sensitivity, and some of its puzzles, like why two mirror-image molecules can smell completely different, are among the most interesting examples of molecular recognition in biology.

What makes a molecule smell?

To be smelled, a molecule must first reach the nose, which means it has to evaporate: it must be volatile. Odour molecules tend to be:

• small, usually with a molar mass below about 300 g mol⁻¹;
• held together by weak intermolecular forces, so they evaporate easily at room temperature (see intermolecular forces);
• at least partly fat-soluble, so they can dissolve in the mucus and interact with receptor proteins.

That’s why large molecules like sugars and salts have no smell: they don’t evaporate. Water vapour, nitrogen and oxygen are volatile but have no smell because we have no receptors tuned to them.

The olfactory system

1. Odour molecules enter the nose, either through the nostrils (orthonasal smell, like sniffing a flower) or from the back of the mouth when eating (retronasal smell).
2. They dissolve in the mucus covering the olfactory epithelium, a patch of tissue a few square centimetres in area high in the nasal cavity.
3. There, they bind to olfactory receptors on the tips of millions of olfactory sensory neurons.
4. Binding activates a G protein, which triggers a cascade that opens ion channels and sends an electrical signal to the olfactory bulb of the brain.

Olfactory neurons are unusual: they’re replaced every few weeks throughout life, and they connect almost directly to brain regions involved in emotion and memory, which may explain why smells can trigger such vivid memories.

About 400 receptors, thousands of smells

In 1991, Linda Buck and Richard Axel discovered the large family of genes that code for olfactory receptors, work recognised with the 2004 Nobel Prize in Physiology or Medicine.

• Humans have about 400 working olfactory receptor genes (and many more broken ones, called pseudogenes). Mice have over 1,000; dogs have many hundreds, which helps explain their superior sense of smell.
• Each olfactory neuron makes just one type of receptor.
• Each receptor can bind several different odour molecules, and each odour molecule can activate several different receptors.

So smell works by a combinatorial code: an odour is identified by the particular pattern of receptors it activates, a bit like a chord made from many notes. With about 400 receptors, the number of possible patterns is enormous, allowing us to distinguish a vast range of smells, though estimates of exactly how many vary widely.

Most natural smells, like coffee or roses, are mixtures of hundreds of different molecules, and the brain recognises the overall pattern.

Shape matters: mirror-image molecules

Many odour molecules are chiral: they exist as two mirror-image forms (enantiomers) with identical physical properties, such as boiling point and density. Yet they can smell different, because olfactory receptors are themselves chiral proteins, like a left-handed glove that fits one hand better than the other.

• Carvone: the (R)-enantiomer smells of spearmint; the (S)-enantiomer smells of caraway (the flavour of rye bread seeds).
• Limonene: the (R)-form is common in orange peel and has a sweet orange smell; the (S)-form has a harsher, more pine- or turpentine-like smell.

These examples show that smell detects not just which atoms a molecule has but how they’re arranged in 3D (see isotopes, ions, isomers and allotropes for different kinds of isomers).

Extraordinary sensitivity: thiols

Some molecules can be smelled at astonishingly low concentrations. Thiols (also called mercaptans), organic compounds containing an –SH group, are among the most powerful odorants:

• Ethanethiol and related sulfur compounds are added to natural gas, which is odourless, so that leaks can be detected. People can smell them at concentrations of roughly parts per billion.
• Skunk spray, the smell of rotten eggs (hydrogen sulfide), and some of the aroma of grapefruit and coffee all come from sulfur compounds.

Humans are particularly sensitive to sulfur compounds, possibly because they often signal rotting food. Humans are also very sensitive to some other molecules, such as geosmin, made by soil microbes, which gives the earthy smell after rain and can be detected at parts per trillion.

Structure–odour relationships

Chemists have long tried to predict a molecule’s smell from its structure. Some patterns exist:

• Esters often smell fruity: ethyl butanoate smells of pineapple, and isoamyl acetate of bananas.
• Aldehydes give many green, fatty or citrus notes; vanillin, an aldehyde, gives the smell of vanilla.
• Amines often smell fishy.
• Large ring ketones (macrocycles) often smell musky and are used in perfumes.

But the rules have many exceptions: molecules with similar shapes can smell different, and very different molecules can smell alike. Because the code involves hundreds of receptors, prediction is hard. In recent years, machine-learning models trained on large datasets have made progress in predicting smells from structure.

Smell and flavour

Most of what we call “taste” is really smell. Your tongue detects only five basic tastes (see the chemistry of taste), but when you chew, aroma molecules travel from the back of the mouth to the nose. Pinch your nose while eating a jelly bean and you’ll taste only sweetness; release it and the fruit flavour appears. That’s also why food tastes bland when you have a cold.

Smell in industry

Smell is big business. The fragrance and flavour industry designs thousands of aroma molecules for perfumes, cleaning products and foods. Many natural smells are expensive to extract, so chemists synthesise the key molecules instead: vanillin, for example, is mostly made synthetically rather than from vanilla pods. Perfumers blend “top notes” (small, very volatile molecules that you smell first), “heart notes” and “base notes” (larger, less volatile molecules that linger for hours), designing a scent that changes as different molecules evaporate at different rates. Food chemists analyse aromas by gas chromatography, sometimes with a human nose sniffing each compound as it leaves the column (see gas chromatography).

Losing the sense of smell

Loss of smell (anosmia) can result from colds, head injuries, some viral infections (it was a common symptom of COVID-19), and ageing. It can also be an early sign of neurodegenerative diseases such as Parkinson’s. Beyond losing the pleasure of food, it’s a safety risk: people who can’t smell may not notice smoke, gas leaks or spoiled food.

Key takeaways

• Odour molecules must be volatile: small, with weak intermolecular forces, and partly fat-soluble.
• Humans have about 400 olfactory receptor types; each neuron has one type, and smells are identified by the combination of receptors activated.
• Receptors are chiral, so enantiomers such as the two forms of carvone can smell different.
• Thiols and geosmin are detected at parts per billion or trillion; thiols are added to natural gas so leaks can be smelled.
• Smell provides most of flavour. For how chemical signals work in general, see hormones as chemical messengers.