Article curated by Ginny Smith
From the heady scent of a rose garden on a summer's day to the rumble in our stomachs that can be triggered by wafts of freshly baked bread as we walk past a bakery, smell plays a huge role in our lives. And yet it is probably the most mysterious of our senses. Scientists don't know exactly how we detect different smells, how many of them we can identify, or why they have such a profound effect on our emotions.
We have more genes that code for smell than any other sense, making it highly complicated and intricate. Although we understand fairly well how signals are passed from the nose to the brain, we still don’t know how an aromatic molecule gives away its identity. The main theory for how we smell is the 'lock and key' theory, which suggests the shape of a molecule allows it to fit into a receptor in the nose, triggering the receptor to send signals along neurons to the brain. However, there are various problems with this theory, including the fact that molecules with almost identical shapes but a few different elements in them have very different smells, like the molecules that we recognise as freshly cut grass or rotten eggs. Another problem with this theory is the fact that we don't have enough receptors to code for the thousands of smells that we can detect on a 1-to-1 basis.
One emerging theory is that of molecular vibration. This suggests that it is not the shape of a molecule but how it vibrates that determines its smell. It is supported by the fact that two molecules can smell different if they contain different isotopes- versions of an atom with a different number of neutrons. This changes their vibration but not their shape. Molecules with very similar shapes but different vibrational frequencies can also smell very different. However studies showing these effects have been criticized and the theory is far from being widely accepted.
Because we have far fewer olfactory receptors than many other animals, it has long been thought that the human sense of smell is rather limited- it has even been said we can only detect 10,000 odours. However a recent paper in Science claimed to find that we can actually detect a trillion different smells.
They combined 128 different odour molecules into combinations of 10, 20 or 30 and asked subjects to spot the odd one out when presented with 2 identical mixtures and one different one. They found that people could, on average, spot the odd one out if its components differed by 50%. They then extrapolated to the number of unique, identifiable combinations that could exist, and got to the number: 1 trillion.
However others disagree with their finding, claiming the maths is flawed. By simply varying the number of subjects, or the threshold for significance, and re-analysing the original data, the number of distinguishable smells varied dramatically- from 4,500 to 100 Octillion! The problem comes because smell isn’t easily broken up into categories like, for example, colour, which can be divided by wavelength. Until we work out better how to categorise smell, it seems that the number of discrete scents we can distinguish is impossible to know.
As the centre of conscious smell detection is the olfactory bulb behind our eyes. Here there are millions and millions of neurons with hair-like cilia carrying the receptors. Also found in the nose are a large number stem cells - there to regenerate and replace damaged or aged neurons, and the supporting cells which give the organ its structure. This is unusual: most neurons are not replaced when they die and are not protected so carefully. Similar hair cells in the ear can be destroyed by loud sounds and do not regenerate, which is why hearing problems become more common with age. We still don’t know why the nose is different.
The world of scent
One hindrance to our understanding of smell is the complexity of natural odours. When attempting to synthesise new flavourings, scientists often look to nature for help. But while some smells can be recreated easily, using a single molecule, others are much more challenging.
One of these tricky smells is that of strawberry. Strawberry flavour is made up of more than 350 odour molecules. In tests on 12 key molecules, participants were asked to smell combinations with just one component missing to see whether they still thought it was strawberry. Six molecules were found to be essential to the strawberry flavour; although it lost dimension if the others were missing, it was still strawberry.
It is thought that 20-30 of the volatile molecules that come off a strawberry create its attractive smell, so what do the others do? Some will be there for ripening or preserving it, and some may attract other animals. Although we don’t know why wild strawberries vary so much in their smells, it is likely to have evolved as the strawberry plant spread to different environments, where its survival depended on appealing to different animals that would feed on the fruit and disperse its seeds. What these animals are and what chemicals they like is still a mystery. However, this does imply that, theoretically, we might be able to breed a strawberry that drives us wild, but that birds turn their beaks up at.
Even when we can determine and re-create the exact chemical make-up of something like a strawberry, it can often smell different to the original. This is because the flesh of the strawberry affects the volatility of the compounds, and so how quickly and strongly they reach our noses. To make a truely realistic smell experience we have to recreate not only the proportions of the molecules present but the patterns in which we detect them. To mix “strawberry flavour” in different foods - bread, for example - we may need to use different amounts of our strawberry molecules than are present in the real thing.
Our sense of smell
The human sense of smell is intricately linked with emotion and memory, but how and why this link exists isn’t known. Smells are first processed by the olfactory bulb, then pass through two brain areas linked to emotion and memory: the amygdala and hippocampus. This might explain why scents can be so evocative of past experiences or emotions. Some studies have suggested amygdala activation is linked to smell-triggered emotional memories, but others have found different areas are activated for different types of memory, so it may be more complex than was first thought. Some research has also suggested smell problems could be linked to various disorders including depression and schizophrenia, but it remains to be seen whether olfactory ability could ever be a used for diagnosis or treatment.2
It is very rare, but some people are born unable to smell, thanks to genetic mutations which affect the development of the olfactory system It is known as congenital anosmia, and is estimated to affect 6,000 people in the UK.
Congenital Anosmia can occur alone or it can be a symptom of another genetic condition. Exactly which genes are involved in cases not linked to other conditions isn’t known. One gene which seems to be involved is called Ift88. In mice, knocking out this gene results in the cilia or hairs of their olfactory system being unable to grow, causing anosmia. Researchers were then able to restore the sense of smell in these mice using gene therapy- injecting a virus carrying a working version of the gene into the nose . The mice were then able to use smell to find food. If this finding translates to humans, it might provide hope for anyone whose anosmia is the result of a similar genetic mutation.
Anosmia, whether it is congenital or brought on later in life after infection or head trauma. is a serious social handicap  . Sufferers typically withdraw from social situations like eating out and express feelings of vulnerability and isolation. Men with anosmia typically engage in fewer sexual relationships (3 on average, where the non-anosmic average is 9), and 17% of anosmics score as moderately depressed on the Beck Depression Inventory. Interestingly, most people with disabilities express the same quality of lives as those without after a sufficient time has passed since the onset of the disability, but this doesn’t seem to be the case for loss of smell. This could be due to the links between smell and emotion, or it could simply be that support networks for these sufferers are comparatively poor.2
Some forms of anosmia are treatable (treating the cause of inflammation of the nasal cavity, for example, can restore the sense) but for others there are no cures currently available. But one idea that is giving hope to those with the disorder is that of smell training . Smell training involves sniffing 4 very distinct smells for a few minutes every day while paying close attention to any sensations detected. It works best for those whose anosmia was triggered by a virus, and is most useful when started soon after onset.
No-one knows exactly how it works, but it is thought that the reorganisation of brain networks may be involved. The cells in the nose are also some of the best in the body at regeneration, so it may be that smell training somehow encourages the regrowth of damaged nerves.
Smell can have a profound effect on behaviour, especially for animals that use it to find food, detect predators and trace mating partners. Many animals use not only scent, but also the vomeronasal organ, which detects pheromones and processes “smell signals” that bypass conscious awareness to generate innate responses. The organ is also known as the “sexual nose”. We don’t as yet know to what extent human behaviour is influenced by these invisible smells, or whether we can even detect them.
Whether humans have this organ, and whether it is functional if they do, is a topic of debate. The organ does seem to develop in embryos, but then regresses- some claim any remnants of it in adults are simply vestigial and non functional. This is supported by the fact that the organ can be found in some adults but not others. Research has also shown that the organ doesn’t contain the required nerve cells to detect input or send signals to the brain.
Even if the VNO is non-functional, as many claim, this doesn't mean there is no way humans can detect pheromones-we may use our main olfactory system. Some studies have suggested substances in sweat can alter the menstrual cycle of women, for example, or increase arousal. How these changes happen remains to be seen.
In animals such as mice and fish, evidence suggests that sexual partners are selected for genetic compatibility (healthy offspring and relationship longevity) using smell - but so far we’re not sure whether the same is true for humans. How genetic identity is encoded in smell molecules is also completely unknown. Human leukocyte antigens share genome space with olfactory receptors, suggesting they are inherited together, so may work together in mate selection, or may have done historically. Smell tests on women sniffing men’s shirt did produce results consistent with smelling out genetic compatibility. Interestingly, women also outperform men in smell sensitivity tests, which could reflect enhanced partner choosiness as they bear the greater reproductive burden.
If we can detect it, we don’t know how important genetic compatibility is compared with other factors like personality and appearance. Some feel that the answer may be black or white, with mates either wholly driven by instinct or hardly conscious of it, attributing very little significance to it. However it is more likely it would play a role, amongst other factors. Such a mechanism could certainly explain why people often develop chemistry with date partners who do not tick off much on their list of desirable attributes, and why the perfect partner on paper may just not create that 'spark' of romance.
Smell in Animals
Does cancer smell? According to a 2015 study, a trained scent dog accurately identified whether patients’ urine samples had thyroid cancer or were benign (noncancerous) 88.2 percent of the time. Although this was a relatively small (n=34) study, this could well be indicative of something which can be measured. According to a BBC article, Dr Emma Smith from Cancer Research UK cautioned:
Although there's some evidence that some trained dogs can sniff out the smelly molecules given off by cancers, there have been mixed results on how accurate they are and it's not really practical to think about using dogs on a wide scale to detect the disease. It seems unlikely that western states will consider using animals for such detections (though less wealthy states may do so if it proves to be both cheap and effective) it does open up the possibility of developing an electronic nose, or "E-nose", that can detect such cancers. This would potentially be a lot cheaper and much less invasive than the current technique of fine-needle aspiration biopsy.
This article was written by the Things We Don’t Know editorial team, with contributions from Ed Trollope, Ginny Smith, Johanna Blee, and Rowena Fletcher-Wood.
why don’t all references have links?
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 Bushdid, C., et al., (2014) Humans Can Discriminate More than 1 Trillion Olfactory Stimuli Science 343(6177):1370-1372 DOI: 10.1126/science.1249168
Soudry, Y., et al., (2011) Olfactory system and emotion: Common substrates European Annals of Otorhinolaryngology, Head and Neck Diseases 128(1):18-23 DOI: 10.1016/j.anorl.2010.09.007
 McIntyre, J,C., et al., (2012) Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model Nature Medicine 18(9):1423-1428 DOI: 10.1038/nm.2860
 Karstensen, H., Tommerup, N., (2012) Isolated and syndromic forms of congenital anosmia Clinical Genetics 81(3):210-215 DOI: 10.1111/j.1399-0004.2011.01776.x
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Kollndorfer, K., et al., (2014) Recovery of Olfactory Function Induces Neuroplasticity Effects in Patients with Smell Loss Neural Plasticity 2014:1-7 DOI: 10.1155/2014/140419
Costanzo, R,M., Yagi, S., (2011) Olfactory epithelial transplantation: possible mechanism for restoration of smell Current Opinion in Otolaryngology & Head and Neck Surgery 19(1):54-57 DOI: 10.1097/MOO.0b013e328341e242
 Jun, H.H., et al., (2015) Overcoming the Limitations of Fine Needle Aspiration Biopsy: Detection of Lateral Neck Node Metastasis in Papillary Thyroid Carcinoma Yonsei Medical Journal 56(1):182-188 DOI: 10.3349/ymj.2015.56.1.182