Compiled by Tim
INDEX (click on topic)
Anosmia (loss of smell) Key Facts Odorant binding proteins Role of smell Smell, fear & pain Theories of olfaction Aromatherapy Limbic system Odour code Section of nasal cavity Smell of Money Therapy using smell Body odour Links Perception Smell & ageing Smell in infants Viagra & smell Epilepsy & smell Mate choice Pheromones Smell & health Smell in Space What's NEW in smell? Flavour Memory Receptors Smell & hormones Smell signalling Dogs "sniff" cancer G-protein activation Mums & babies References Smell & mood & sleep TASTE Smell & brain imaging Innate vs. learned smell Nose (inside) Role of calcium Smell & Sex Taste & Smell Ion channels
New article in PNAS tries to refute the "vibrational theory" of smell
Eric Block and others have performed experiments to test the claim that deuterated compounds smell different from their nondeuterated analogues because, although they have the same shape, their vibrational signature is different. The paper in PNAS is focussed on refuting Luca Turin's 2013 PLoS paper "Molecular Vibration-Sensing Component in Human Olfaction
". This new article describes the use of a heterologous gene expression system in which one receptor - OR5AN1 - is exposed to a series of deuterated musks and apparently does not distinguish between deuterated and nondeuterated versions. Luca Turin points out that this does not explain how or why deuterated musks smell different from their nondeuterated counterparts and points out that this cell based expression system is a long way from the human nose.
22nd April 2015
Olfactory ensheathing cells used to help paralysed man walk again
A man who suffered a spinal cord injury following a knife attack has been enabled to walk again. Cells from his own olfactory bulb were taken and grown in culture. They were then microinjected into regions around the spinal cord injury. Two years after the treatment he is able to walk again using a frame..
21st October 2014
Sense of smell a predictor of death
In a study of over 3000 people aged 57-85, 39% of those with anosmia (loss of sense of smell) were dead within 5 years compared to 10% with a normal sense of smell. So, losing your sense of smell is linked in some, unknown way to overall health and longevity. The conclusion is that smell function is linked to health and wellbeing and olfactory function is a marker for mortality.
2nd October 2014
Men are from bacon, women are from lemons
Did you know men and women are different, because they are. They are so different that they even like different things. Men like meat, visual stuff. Women like lemons, feelings. It's a wonder it ever works, because meat and pictures and lemons and feelings go together like a tornado in a teacup without any good smells in it.
21st August 2014
Losing your sense of smell can make you fat and destroy your ibido - Daily Mail articleThe sweet smell of success. Does success really smell sweet?
A panel of 200 of Britons with 'sophisticated noses' sorted through over 100 individual smells from candy floss to urine to identify the aroma
They found the smells of leather, cedarwood and pencil are not associated with successful business people Patchouli, which is popular in joss sticks, is the scent most associated with successful men and women.
12th May 2014
Potential future cure for anosmia - work in mice has shown that stem cells in the nose can grow and develop into smell receptor cells. They can be made to do this by removing a gene that codes for a "brake" to growth in these cells.
Cancer detected by smell - Dogs can be trained to detect cancer (first shown by a UK lab - see below - Dogs sniff cancer) but now a machine is being developed to "sniff" cancer. Metabolomx, a small company in Mountain View, California plans to bring a cancer-sniffing device to market. Dogs have also been trained to detect diabetes on breath.
Is NEW CAR smell dangerous? - what is that "new car" smell? Why do manufacturers go to great lengths to manufacture it?The Ecology Center identified more than 275 chemicals, some of which are associated with allergies, birth defects, impaired learning, liver problems, and cancer. 7th Nov 2012
Perfume ban - The Scientific Committee on Consumer Safety (SCCS) have advised the European Commission to restrict citral, found in lemon and tangerine oil, along with coumarin, found in tropical tonka beans, and eugenol, found in rose oil and about 90 other perfume ingredients. Chanel No. 5 would disappear as would many other famous brands. This proposed ban stems from fears about skin allergies. Perfumers (and most people of good sense) are outraged. The word is that the SCCS is flexing its muscle having been ignored by the International Fragrance Association (IFRA) - but it has gone too far and is now just grandstanding. A new set of EU guidelines will be issued in 2014.
Need to know more?? Then read on..............
1. Hazard warning 5. Flavour detector 2. Memory prompt 6. Appetite control 3. Chemical signalling 7. Mate choice (HLA) detector 4. Antidepressant
Smell is one of the chemical senses, the other being taste. They are so called because they sense chemicals, and smells are, of course, chemicals. With these senses we sample our environment for information. We are continuously testing the quality of the air we breathe (this will alert us to potential dangers, e.g. smoke) as well as using this sense to inform us of other relevant information, such as the presence of food or another individual. The chemicals detected by our sensory systems need to have certain properties. For instance, odour molecules must be small enough to be volatile (less than 300-400 relative molecular mass) so that they can vapourise, reach the nose and then dissolve in the mucus. This tells us that smell, unlike taste, can signal over long distances (an early warning device). We appear to have an innate ability to detect bad, aversive smells. One-day old babies give facial expressions that indicate rejection when given fish or rotten egg odour.
But, is our olfactory system doing more than just giving us warnings? Yes, of course. Amongst other possibilities, it serves a recognition function. We all have our own unique smell (some more pleasant than others! - but that's another story, see "mate choice" below) and can recognise and be recognised by our smell.
Dogs can distinguish between the smell of T-shirts worn by non-identical twins (they couldn't tell the difference between identical twins - presumably because they smell identical!). Children can distinguish between the smell of their siblings and other children of the same age. Babies recognise their own mothers' smell and mothers recognise their own babies' smell. Emotion can be communicated by smell. Dogs and horses are very sensitive to the smell of fear in humans. Recent research has shown that a panel of women can discriminate between armpit swabs taken from people watching "happy" and "sad" films. Men were less good at this. The emotions of others, for example fear, contentment, sexuality, may therefore be experienced and communicated by smell. Memory is often associated with smell. Smell and memory are intimately linked - although this phenomenon is not well understood (see Smell & Memory, below).
How we smell (some estimates suggest we can distinguish around 10,000 different smells - but see "Odour Code" below), why we smell and the impact of smell on our everyday life are poorly understood. We certainly underestimate the importance of smell to our well-being - ask an anosmic (someone who has lost some or all of their sense of smell). Some anosmics suffer from depression and their quality of life is severely affected - at the moment there is little that can be done to help them.
There are suggestions that smell can influence mood, memory, emotions, mate choice, the immune system and the endocrine system (hormones). We can communicate by smell - without knowing it. In fact the sense of smell could be said to be at the mind-body interface.
Why do we like perfumes? Why do we wear perfumes (well some of us anyway)? It is a multi-billion dollar/sterling/yen/yuan industry. What constitutues a pleasant or an unpleasant smell is an intriguing and very personal thing. Have a look at some of the issues - go to the Perfume page
We chose perfumes to express ourselves and just what we want to express may change day to day, or even during the day. You might chose to wear a different perfume going out on a date to going to work. There has been research that suggests we chose a perfume to advertise our immunotype (see Mate choice).
Smells are detected in the nose by the specialised receptor cells of the olfactory epithelium. These are called olfactory receptor neurones.
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In the roof of each nostril is a region called the nasal mucosa. This region contains the sensory epithelium - the olfactory epithelium - covered by mucus. The area of this olfactory region is 5cm2 in humans and 25cm2 in cats. The epithelium contains, as well as the sensory cells, Bowman's glands producing the secretion that bathes the surface of the receptors. This is an aqueous secretion containing mucopolysaccharides, immunoglobulins, proteins (e.g. lysozyme) and various enzymes (e.g. peptidases). Also found in the nasal mucosa is a pigmented-type of epithelial cell: the depth of colour is often correlated with olfactory sensitivity, being light yellow in humans and dark yellow or brown in dogs. Pigment may play a part in olfaction, perhaps absorbing some kind of radiation, like infrared. Finally the nasal epithelium contains the receptor cells - some 10 million in humans (more in rats and cats). They possess a terminal enlargement (a "knob") that projects above the epithelial surface, from which extend about 8-20 olfactory cilia. These cilia do not beat (being non-motile) but they contain the smell receptors.
The olfactory receptor neurone
Olfactory receptor neuron (ORN) is shown in yellow. It has cilia that project from the dendritic knob into the mucus and on which the receptors for odorants are located.
ORNs are embedded in the olfactory epithelium which has a number of other cell types; basal cells are stem cells for ORNs and other epithelial cells and supporting cells provide a glial-like function and may be involved in detemining the composition of the mucus. The ORN has an axon that terminates in the olfactory bulb.
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Odorant receptors (ORs)It appears that there may be hundreds of odorant receptors, but only one (or at most a few) expressed in each olfactory receptor neuron. A large family of odorant receptors was cloned in 1991 by Linda Buck and Richard Axel (Buck and Axel, 1991) and the mRNA encoding these proteins has been found in olfactory tissue. These families may be encoded by as many as 1000 different genes. This is a huge amount and accounts for about 2% of the human genome. In humans, however, most are inactive pseudogenes and only around 350 code for functional receptors. There are many more functional genes in macrosmatic animals like rats. These receptor proteins are members of a well known receptor family called the 7-transmembrane domain G-protein coupled receptors (GPCRs - see Fig. below). The hydrophobic regions (the transmembrane parts) contain maximum sequence homology to other members of the G-protein linked receptor family. There are some notable features of these olfactory receptors, like the divergence in sequence in the 3rd, 4th and 5th transmembrane domains, that suggest a how a large number of different odorants may be discriminated.
Vomeronasal-like receptors (V1RL1) have been found in the human olfactory epithelium (Rodriguez et al. Nat. Genet; 26, 18-19, 2000). This, in theory, could give humans sensitivity to pheromones although it yet to been proved that V1r proteins are involved in pheromone detection - but it's a thought!
TAARs - a new type of receptor has been discovered (Liberles & Buck, 2006) in the mouse that detects volatile amines. These are found in mouse urine and convey information about stress and gender. One has been reported to be a pheromone. Are they found in humans??? Wait and see!
An odorant receptor (7-transmembrane G-protein-coupled receptor)
Odorant receptor. A G-protein-coupled receptor with 7 transmembrane domains. Domains 3-5 are highly variable between the 350 or so human isoforms of this gene and are probably the odorant binding site. The C-terminus and the intracellular loops I2 and I3 function as G-protein binding domains.
The receptor cells are bipolar neurones in the nasal epithelium (see figure "Olfactory Receptor Neuron" above). It is thought that each ORN expresses only one type of receptor (out of the total of about 350). The ORNs are unique to the extent that they are capable of regenerating. They possess cilia which project into the mucus (these contain the receptor proteins) and, at the other end, axons that project to the olfactory bulb. 10-100 axons form up into bundles that penetrate the ethmoidal cribriform plate and terminate in the olfactory bulb, converging on synaptic glomeruli. ORNs expressing the same receptor protein synapse onto the same glomerulus in the olfactory bulb. There are two olfactory bulbs, one in each nasal cavity. In humans there are about 6M receptor cells in each nostril and this rises to 50M olfactory receptor neurons in the rat. The diagram below shows the incoming axons from ORNs (in green) synapsing with glomeruli in the olfactory bulb.
Olfactory ensheathing cells are like glial cells. They are the non-myelinating cells that wrap around (ensheath) olfactory axons within both the peripheral and and central nervous system portions of the primary olfactory pathway. In vivo these glial cells express a mixture of astrocyte-specific and Schwann cell-specific phenotypic features with the former cellular phenotype predominating, but in vitro can assemble a myelin sheath when co-cultured with dorsal root ganglion neurons. Thus, certain in vitro conditions induce ensheathing cells to express a phenotype more like that of a myelinating Schwann cell.
Foetal olfactory ensheathing glial cells (OECs) are thought to have the capacity to regenerate damaged nerve fibers. Neurosurgeon Huang Hongyun, of Chaoyang Hospital, Beijing is using these cells in the hope of repairing neurological damage. Over the past 3 years he has used foetal tissue transplants to treat more than 450 patients. He now has 1000 Chinese and foreign patients on a waiting list, including about 100 Americans, who find him via the Internet or word of mouth. He has also used the procedure to treat strokes, multiple sclerosis, cerebral palsy, and brain injuries with, he says, "equally positive results".
The bulk of his Huang's patients are people suffering from spinal cord injury, followed by ALS, a distant second. He has only treated a few patients with Parkinson disease.
Sour grapes? Hongyun's work is criticised by the West (see Nature 437, pp. 810-811 (6 October 2005) Fetal-cell therapy: Paper chase by David Cyranoski) because he doesn't publish carefully controlled trials. He has however published in Chinese journals but his work has been rejected by the leading medical and scientific journals. He now says he is going to give up trying to convince the Western scientific community. This is our loss and shows a disturbing arrogance and prejudice on behalf of Western scientists.
- Mitral cells are the principal neurons in the olfactory bulb. There are about 45,000 of these cells in each bulb in the rat and around 50,000 in the adult human. They have a primary apical dendrite which extends into a spherical bundle of neuropil called a glomerulus (see below) which receives the input from the olfactory receptor neurons. Their axons merge together to form the lateral olfactory tract. They possess colaterals, involved in negative feedback and positive feed-forward.
- Glomeruli are roughly spherical bundles of dendritic processes - some 25 mitral cells may send their primary dendrites to a single glomerulus - and it is here that they make contact with incoming olfactory nerves (in rodents the branches of 17,000-25,000 olfactory axons). In the rabbit there are about 2000 glomeruli per olfactory bulb.
- Periglomerular cells are involved in lateral inhibition at the level of the glomeruli
- Granule cells are inhibitory interneurones. They receive both contra- and ipsi-lateral input.
- The lateral olfactory tract terminates in the pyriform and prepyriform areas (primary olfactory cortex) from where the primary projection goes to the thalamus (medialis dorsalis). Axons project from here to the neocortex (orbito-frontal). In addition, primates have a pathway that runs via the limbic brain to the hypothalamus and is involved with mood (and memory) and neuroendocrine regulation. This latter pathway is responsible for the so-called "affective" component of smell.
- Centrifugal pathways have a "wipe clean" function to reset the system ready for the next input and also with dis-inhibition. When hungry smells have a greater effect!
- The architecture of the bulb results in 1:1000 convergence of olfactory receptor neurons to mitral cells. Thus a lot of information about individual receptors is thrown away but this increases sensitivity since contributions from many receptors are added together.
Olfactory receptor neurons (ORNs) express one (or a few) type of receptor per cell. Each ORN expressing the same receptor project to the same glomerulus in the olfactory bulb. There is a symmetry in the two bulbs with glomeruli in similar positions receiving input from ORNs expressing the same receptor.
Simon O'Connor and I have just published a review on the Pharmacology of the Olfactory bulb.
Neuropharmacology of the Olfactory Bulb. O'Connor, S. and Jacob, T.J.C. Current Molecular Pharmacology, 2008, 1, 181-190.
Glutamate has been proposed as the olfactory cell neurotransmitter in turtle, toad and in rat – mediating transmission at the first synapse in the pathway (olfactory receptor neuron (ORN)-mitral cell). There is evidence that noradrenaline is a neurotransmitter in the rat olfactory bulb . There is considerable clinical interest in this system because of the number of conditions associated with diminuished noradrenaline activity in which olfactory discrimination is also impaired, including Korsakoff’s disease, normal ageing, Parkinson’s disease and Alzheimer’s disease.
Both behavioral and molecular studies point to a potentially important role of dopamine in olfaction. Parkinson’s patients, who have reduced dopamine levels, also have impaired odour recognition. Injection of dopamine analogues reduces olfactory sensitivity in rats. Dopamine may play an important neuormodulatory role in olfaction by reducing transmitter release from ORNs . Dopamine receptors of the D2 sub-type have been found to modulate input to the olfactory bulb from the olfactory receptor cells in rats and some periglomerular and mitral cells are dopaminergic . D1 receptors are only sparsely expressed in the rat olfactory bulb (glomerular layer, external plexiform, mitral and granule cell layers) stimulate cAMP and are excitatory, whereas D2 receptors which are more prominent in the bulb (ORNs and glomerular layer) reduce cAMP and are inhibitory.
Inhibitory circuits in the bulb have been found to be mediated by GABA and in vitro studies have shown interactions between GABA and glycine.
Various drugs have been demonstrated to have an effect on the sense of smell, in particular drugs that affect calcium channels, nifedipine and diltiazem. These are thought to have their effect by blocking olfactory nerve transmission.
There are no reports in the literature of the effects of glutamate antagonists or GABA or glycine agonists on human olfactory acuity.
1. Berkowicz, D.A. and Trombley, P.Q. (2000) Dopaminergic modulation at the olfactory nerve synapse. Brain Res. 855, 90-99.
2. Berkowicz, D.A., Trombley, P.Q. and Shepherd, G.M. (1994) Evidence for glutamate as the olfactory receptor cell neurotransmitter. J. Neurophysiol. 71, 2557-61.
3 . Mair, R.G. and Harrison, L.M (1991) Influence of drugs on smell function. Chapter 16 in “The Human Sense of Smell “eds. D.G. Laing, R.L. Doty and W. Breipohl, Springer-Verlag, Berlin, pp. 335-359.
4. Hawkes, C.H. and Shephard, B.C. (1998) Olfactory evoked responses and identification tests in neurological disease. Ann. N.Y. Acad. Sci. 855, 608-615.
5. Kratskin, I.L. and Belluzzi, O. (2003) Anatomy and neurochemistry of the olfactory bulb. In "Handbook of Olfaction and Gustation" 2nd edition, ed. R.L. Doty, Marcel Dekker, New York, pp. 139-164
The rostral migratory stream (RMS) is a pathway where newborn neurons are produced in the subventricular region of the brain and then migrate to the olfactory bulb. Curtis et al in Peter S. Eriksson's collaboration have convincingly shown that it does exists in spite of a recent paper claiming that it did not exist in humans (more later....).
Curtis, M.A. et al (2007) Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 315, 1243 49
Neurons from the lateral olfactory tract project to; (1) the amygdala, septal nuclei, pre-pyriform cortex, the entorhinal cortex, hippocampus and the subiculum. Many of these structures form the limbic system, an ancient region of the brain concerned with motivation, emotion and certain kinds of memory. The septal nuclei and amygdala contain regions known as the "pleasure centres". The hippocampus is concerned with motivational memory (the association of certain stimuli with food). (2) Projections are also sent to the thalamus and thence to the frontal cortex for recognition. There are many forward and backward connections between each of these brain centres.
We respond in an involuntary way to smell – this is due to the wiring of the olfactory pathway. The olfactory nerves go first to a primitive region of the brain called the limbic system (Figure below). The limbic system is a collection of brain structures situated beneath the cerebral cortex that deal with emotion, motivation, and association of emotions with memory. Only after this relay has occurred does the information arrive in the higher cortical brain regions for perception and interpretation. Smell is unique among the senses in its privileged access to the subconscious.
The brain - showing the limbic system (coloured)
The limbic system includes such brain areas as the amygdala, hippocampus, pyriform cortex and hypothalamus (see coloured areas in above diagram). This complex set of structures lies on both sides and underneath the thalamus, just under the cerebrum. The limbic system is increasingly recognised to be crucial in determining and regulating the entire emotional 'tone'. Excitation of this, by whatever means, produces heightened emotionalism and an intensification of the senses. It also has a lot to do with the formation of memories and this is the reason that smell and memory are so intimately linked.
Olfactory hallucinations coupled with feelings of deja vu occur in "uncinate seizures", a form of temporal lobe epilepsy, and sometimes there is a generalised intensification of smell. The uncus, phylogenetically part of the "smell-brain" (or rhinencephalon), is functionally associated with the whole limbic system (which includes such brain areas as the amygdala, hippocampus, pyriforn cortex and hypothalamus - the cooloured bits in the figure above), which is increasingly recognised to be crucial in determining and regulating the entire emotional 'tone'. Excitation of this, by whatever means, produces heightened emotionalism and an intensification of the senses.
Preliminary work has demonstrated that smell can be used to reduce the occurrence of seizures in epilepsy. One possible explanation is that because olfactory centres (primary olfactory cortex, entorhinal cortex) are next door to regions where seizures begin in temporal lobe epilepsy, activity generated in these areas by the presentation of a smell prevents the spread of the synchronous activity from the epileptic focus.
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Electroencephalography (EEG) has been used to study olfaction. For more detail press . EEG is used clinically to investigate brain wave abnormalities for example in epilepsy, brain injury and brain tumors. It cannot be used to diagnose brain death since patients with Persistent Vegetative State (PVS - a kind of coma) are alive but may have no brain waves.
EEG can be used to monitor the state of brain arousal, relaxation and alertness. Fragrance manufacturers have for many years been trying to demonstrate that certain smells are relaxing. This can, in theory, be done using EEG. One of the brain-waves measured by EEG is called the "alpha-wave". It has a particular frequency of 8-12 Hz (or waves per sec). Increased alpha-wave activity in your brain is a sign of relaxation (more correctly speaking - a lower state of arousal, since you produce them when you are drowsy and just before you fall asleep). When the eyes are closed there is an increase in alphawaves in the occipital region (back of the head) where the visual cortex lies. The visual cortex is receiving less (no) information and so therefore it "relaxes" In fact it locks onto an oscillatory activity (8-12Hz) thought to be generated in the thalamus. The frontal lobes produce alphawaves in response to relaxation (with the eyes open) and it has been demonstrated that the left front cortex responds to appetitive (pleasant) experience with a decrease in alpha activity. Pleasant experiences seem to cause activity in the left frontal lobe more than the right (NB decreased alpahwaves = increased brain activity).
There are companies that market perfumes with claims that they do relax you. The problem is complicated by the many things that can affect psychological state. But, there are effects that can be measured under certain circumstances (see section on aromatherapy)
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- Molecular shape
- Diffusion pore
- Molecular resonance
- Nose as a spectroscope
1). Molecular shape
Chemists noted that C4-C8 chains of certain aldehydes/alcohols had strong odours and the odour changed as the chain length increased. 6-C benzene ring altered its smell greatly according to where the side chains were situated, whereas larger rings (14-19C atoms) could be rearranged considerably without altering their odour. The "lock and key" hypothesis (Moncrieff, The Chemical Senses, 2nd ed., 1951) was borrowed from enzyme kinetics and applied to smell. He proposed that distinct primary odours had receptor sites. In the early '50s an American, John Amoore, was on a fellowship to Oxford. He proposed a stereochemical theory of smell. Amoore was very complimentary about Moncrieff's (a dour Scotsman) theory. In Amoore's 1952 paper he refers to Moncrieff's book in the opening paragraph. He says,
Go to top"In chapter 12......Moncrieff presents his own theory, which has much to recommend it..in order to be odorous, a substance must possess two properties: (1) volatility; (2) a molecular configuration that is complementary to certain sites on the receptor system".
Amoore went on to propose 7 primary odours because of their high frequency of occurrence amongst 600 organic compounds; camphor, musk, floral, peppermint, ether, pungent and putrid.
These 7 primary odours were proposed to have different shaped receptors corresponding to the shape of the molecules. Moncrieff, in the next edition of his Chemical Senses (3rd. ed., 1967), was not so kind about Amoore and it maybe instructive to quote from the book:
"In 1952, Amoore suggested that there were seven primary classes of odours......The basic idea was that there were seven kinds of olfactory receptor site, places whereon odorant molecules could lodge when adsorbed on the olfactory sensitive area, and that the odorous molecules had shapes and sizes that were complementary to the shape and size of the seven olfactory receptors.....Molecular shape and size certainly play a part, perhaps a main part, in determining odour. But little confidence can be felt in the restriction of odours to seven classes, and particularly to the seven suggested classes. The "proofs" and "predictions" that have been quoted by Amoore are not satisfying...The suggesetion that there are only seven kinds of receptor and seven classes of odour is apparently untenable. Unexpectedly, at the Corvallis, Oregon symposium on Food Flavours in September 1965, much of Amoore's theory was withdrawn. Difficulties had arisen with which it could not cope. So ended apparently one of the many theories of olfaction. Looking back there was never much solid evidence to support it, and there were difficulties all along the line, but it did stimulate a lot of useful thought".
The shape theory has waxed and waned over the years and the notion of primary odours is no longer tenable. (Although without such a concept it is difficult to explain specific anosmias). However, following recent experiments involving the transfection of a cloned olfactory receptor gene (receptor 17) into the rat (Zhao et al., 1998), it was been demonstrated that this receptor only recognised a limited number of odours (aldehydes). Activation was caused by aldehydes 7-10 carbon atoms long, and not to C6 or C11. Since all the aldehydes have the same side group (-C=O) it can be inferred that this particular receptor was responding to chain length (i.e. shape) and not side group. This does not rule out the possibility that other receptors respond to side groups. Nevertheless it is support for Amoore's Shape Theory.
Amoore, J.E. (1952) The stereochemical specificities of human olfactory receptors. Perfumery & Essential Oil Record 43, 321-330
Amoore, J.E. (1963a) The stereochemical theory of olfaction. Nature, 198, 271-272.
Amoore, J.E. (1963b) The stereochemical theory of olfaction. Nature, 199, 912-913.
Moncrieff, J.W. (1967) The Chemical Senses, pp 381-2.
Zhao, H., Ivic, L., Otaki, J.M., Hashimoto, M., Mikoshiba, K. and Firestein, S. (1998) Functional expression of a mammalian odorant receptor. Science 279, 237-241.
2). Diffusion pore
This theory of Davies and Taylor (1959) suggests that the olfactory molecule diffuses across the membrane of the receptor cell forming an ion pore in its wake. The diffusion time and affinity for the membrane receptor determine thresholds. But, it is difficult to explain the different qualities of smell. The problem of frequency coding and stimulus intensity is difficult to resolve. The different odour would cause a different size pore and therefore a different receptor potential, giving rise to a particular firing rate - but in olfaction, stimulus intensity is frequency coded and not the different quality of the odour. However, many odorants are organic molecules that will dissolve in membranes and alter their properties.
Davies, J.T. and Taylor, F.H. (1959) The role of adsorption and molecular morphology in olfaction: the calculation of olfactory thresholds. Biol. Bull. Marine Lab, Woods Hole, 117, 222-238.
3). Piezo effect
This slightly "off the wall" theory was proposed by Rosenberg et al (1968). They believed that the carotenoids (vitamin A, in the pigment of the olfactory cells) combine with the odorous gases giving rise to a semiconductor current. They argued that this curent could activate the olfactory neurons. This theory followed from an earlier paper by Briggs and Duncan who proposed "..it seems reasonable to assume that proetin bound carotenoids of the olfactory epithelium are the receptors of energy from olfactant molecules entering the nasal cavity". Rosenberg an colleagues tested the idea and found a reversible concentration-dependent increase in current of up to 10,000,000 times and proposed a weak-bond complex formation which increased the number of charge carriers. However, there were problems with this theory; (1) receptor cells do not contain the pigment and (2) weakly odorous short chain alcohols gave a greater increase in semiconductor current than smellier long-chain alcohols. Neverthless, several interesting facts remain to be explained;
- vitamin A deficiency leads to anosmia
- the greater the pigmentation (more vitA) of the olfactory epithelium the more sensitive it is to smell
- Briggs and Duncan (1961) treated 56 anosmics with intramuscular injections of vitamin A. 50 patients recovered in part or completely.
As long ago as 1870, Ogle (Med.-chir. Trans. 53, 263-290) proposed that the pigment found in the nasal passages might act to absorb the vibrations of odorous substances and convert them into heat vibration that would activate the neighbouring nerve cells. We still do not know what the pigment is doing in the olfactory epithelium.
Briggs, M.H. and Duncan, R.B. (1961). Odour receptors Nature 191, 1310-1
Rosenberg, B., Misra, T.N. and Switzer R. (1968) Mechanisms of olfactory transduction. Nature 217, 423-427.
4). Molecular vibration
The frequency of many odours is in the infrared (IR). Is this resonance associated with their smell? This idea was suggested by Dyson (1938). Male moths are drawn to candles because the flickery IR emission is identical to that of the female moth's pheromone. Different frequencies of IR could give rise to different smells. If the whole vibrational range was used, up to 4000cm-1, the detection of functional groups would be explained since many compounds with distinctive odours vibrate at around 1000cm-1. There is an immediate problem - that of the body's natural IR heat. Perhaps the pigment acts to absorb this IR radiation. Another problem is that frequency coding is proportional to stimulus intensity in olfaction, so different frquencies of IR could not be converted into different nerve firing frequency.Dyson, G.M. (1938) The scientific basis of odour. Chem. Ind., 57, 647-651.
5). The nose as a spectroscope
This theory, proposed by Luca Turin (1996), originates from the work of Dyson (see above) who suggested that the olfactory organs might detect molecular vibrations.
Turin has proposed that when the olfactory receptor protein binds an odorant, electron tunneling can occur across the binding site if the vibrational mode equals the energy gap between filled and empty electron levels. The electron tunnelling then activates a G-protein cascade. Receptors are therefore "tuned" to the vibrational frequency of particular odorants, rather like cones are "tuned" to particular wavelengths of light.
Nose as a spectroscope
Turin, L. (1996) A spectroscopic mechanism for primary olfactory reception. Chem. Senses 21, 773-791.
- NADPH supplies electrons
- e- can only tunnel if; (1) an odorant fills receptor site, (2) vibrational energy equals energy gap
- e- s flow through protein and reduce disulphide bridge via Zn++
Support for theory
After receiving a heavily prejudiced critique from the editor of Nature Neuroscience (vol. 7(4), 2004, pp 315-6) and a test published in the same issue by Keller & Vosshall that mis-used statistics to find no evidence that subjects can sniff the difference between two isotopes, support for Luca Turin's theory has come from two sources recently. First, Roberts at the 2006 ECRO1 meeting presented data demonstrating that subjects can distinguish isotopes on the basis of smell and second, physicists from University College London have proved that humans could theoretically recognise odour by photon assisted tunneling (http://arxiv.org/abs/physics/0611205, pub.22 Nov 2006).
1abstract to be published in Chem. Senses in 2007
You will read in the literature that we can smell between 4,000 and 10,000 different odours. In fact, no two substances smell exactly alike and the current understanding of smell discrimination means that there is an infinite number of odours to which we would be sensitive.
Each odorant activates a unique set of olfactory receptors. This is its "signature" - a bit like a bar code, although it would be a 3-D bar code since a given odorant would bind to some receptors more strongly than others, so each of the bars would have a height dimension as well.
A recent Science article by Zhao et al. (1998) demonstrated that a recombinant adenovirus can be used to drive the expression of a particular olfactory receptor gene in the rat olfactory epithelium. Electrophysiological recording showed that increased expression of a single gene led to a greater sensitivity to a small subset of odorants. This is exciting because it shows that each olfactory receptor gene codes for a receptor that only recognises a few odorants.
One ORN one receptor type - Studies have shown that each olfactory neuron expresses only one olfactory receptor gene (Nef et al., 1992). It has led to the possibility that the "odour code" could be cracked once we know which receptors are activated by which odours (see Malnic et al., 1999). Then, in theory, any smell could be reproduced artificially. Some companies have set up to do just this. However, before you invest, we know that smell is not as simple as that! Let me give you an example: an orchestra plays a symphony - we know all the notes (they are written in the score) - but recreating that symphony is not just a matter of assembling all the notes, we need to know which instrument is playing each note, when, with what intonation and for how long. Receptor activation depends upon the association/dissociation constants of the odorant with multiple receptors, it causes complex oscillations across the olfactory bulb and, before the brain receives the information for interpretation and recognition, the bulb receives centrifugal input from other brain centres that modifies the neuronal activity and enables smell to interact with other information such as memory, physiological and psychological state.
References for odour code
Malnic, B., Hirono, J., Sato, T. and Buck, L. (1999) Combinatorial receptor codes for odors. Cell 96, 713-723.
Nef, P., Hermans-Borgmeyer, I., Artieres-Pin, H., Beasley, L., Dionne, V.E. and Heinemann, S.F. (1992) Spatial pattern of receptor expression in the olfactory epithelium. Proc. Natl. Acad. Sci. USA 89, 8948-8952.
Zhao, H., Ivic, L., Otaki, J.M., Hashimoto, M., Mikoshiba, K. and Firestein, S. (1998) Functional expression of a mammalian odorant receptor. Science 279, 237-241.
A large number of G-proteins have been found in the olfactory epithelium. The G-s like G protein, G-olf, which has been cloned and is found in great abundance in the receptor cells (as well as in other neurons), stimulates adenylyl cyclase (AC) and both molecules (G-olf and AC) have been localised to the olfactory sensory cilia.
G-olf, a member of the G-s family of G-proteins, activates adenylyl cyclase. Consequently when an odorant binds to a receptor that is coupled to G-olf, the net result is an increase in intracellular cAMP. cAMP binds to and rapidly opens a cation-selective (Na+, K+, Ca2+) channel from the inside of the membrane. These are a class of channel known as cyclic-nucleotide gated (CNG) channels. The cAMP-gated channels have little or no voltage dependence and their activity depolarizies the cell. Ca2+ enters the cells via the cation channel and activates the Ca2+-dependent Cl- channel, causing Cl- to efflux from the cell - another depolarising influence. This would ensure an increase in the firing of action potentials along the axon of the olfactory receptor cell.
There is evidence that another category of G-protein is involved in the activation of the membrane-bound enzyme phospholipase C (PLC). PLC hydrolyses a lipid phosphatidylinositol 4,5-bisphosphate (PIP2) in the plasma membrane, producing inositol trisphosphate (IP3) and diacyl glycerol (DAG). Both IP3 and DAG can act directly on ion channels and also on intracellular Ca2+ stores. It has been proposed, that both cAMP and IP3/DAG systems may co-exist in the same cell. But only cAMP is involved in the transduction of odour since the adenylyl knock-out mouse cannot smell (Wong et al.(2000), Neuron 27, 487-497). The rise in intracellular Ca2+ induced by IP3 might activate Ca2+-dependent Cl- channels which would also depolarise the cell.
Where in the brain is smell? No two papers on brain imaging and olfaction agree on anything. PET studies found greater right orbitofrontal cortex (OFC) activation with odour versus no odour (Small et al,1997). Some fMRI studies also report a right-sided asymmetry (O'Doherty et al, 2000; Sobel et al, 1998; Yousem et al, 1999). O'Doherty et al (2000), showed 6/8 had stronger right OFC activation than left. Using banana and vanillin as stimuli, found right OFC activation in 4/5 subjects and left OFC activation in 3/5. In contrast Zald and Pardo, (2000) found greater left activation with hydrogen sulphide. Left activation was also found by Royet et al (2000) using PET in response to pleasant and unpleasant olfactory stimuli. To add further confusion, Fulbright et al (1998), using fMRI, did not find any OFC activation when comparing pleasant and unpleasant odours - then, a subsequent study by Rolls et al (2003) found that pleasant odours activated the medio-rostral OFC whereas no activity was observed in the OFC for unpleasant odours. Both unpleasant and pleasant odours activated the anterior cingulate cortex and anterior insula (Rolls et al., 2003) but it is a medial activation and doesn't appear to show marked lateralization with the exception that unpleasant odours activated a region of the right OFC. Levy et al (1997) using fMRI found that odour activated the OFC, cingulate gyrus, piriform and entorhinal cortices, hippocampus and amygdala. PET studies found vanillin activated the amygdala, piriform cortices bilaterally and parts of the anterior insula cortex - and caused frontal and right parietal deactivation in women (though not in men). Women exhibited less activation than men in Levy et al (1997) in contradiction to EEG studies in which women showed higher amplitude evoked responses and also to other fMRI studies (Yousem et al., 1999). PET studies showed no such gender differences (Bengtsson et al, 2001). The OFC has been implicated in hedonic differentiation with the activation in the right medial OFC being greater for pleasant than unpleasant odours but the left lateral OFC showed greater responsiveness to unpleasant than pleasant odours (Anderson et al, 2003). The bilateral middle orbitofrontal cortex (OFC), left lateral OFC, right insula, and bilateral anterior/middle cingulate gyri were most frequently activated by odor stimulation (Katata et al, 2009), but, in contrast to Anderson et al, the left middle OFC and right lateral OFC were significantly more often activated in the participants who perceived the odour stimulation as unpleasant, while the right anterior cingulate gyrus was more often activated in those who perceived the odour as pleasant.
In the last few years I have looked at EEG and lateralisation of olfactory brain activation, following the lead of Davidson (1995). However, with the hegemony of brain imaging, and with the confusion outlined above, I haven't had the confidence to publish opposing results.
1. Anderson, A.K., Christoff, K., Stappen, I., Panitz, D., Ghahremani, D.G., Glover, G., Gabrieli, J.D.E., Sobel, N. 2003. Dissociated neural representations of intensity and valence in human olfaction. Nature Neuroscience 6 (2) , pp. 196-202
2. Bengtsson, S., Berglund, H., Gulyas, B., Cohen, E., Savic, I. 2001. Brain activation during odor perception in males and females. NeuroReport 12 (9) , pp. 2027-2033 3. Davidson, R.J., Sutton, S.K. 1995. Affective neuroscience: The emergence of a discipline. Current Opinion in Neurobiology 5 (2) , pp. 217-224
4. Fulbright, R.K., Skudlarski, P., Lacadie, C.M., Warrenburg, S., Bowers, A.A., Gore, J.C., Wexler, B.E. 1998. Functional MR imaging of regional brain responses to pleasant and unpleasant odors. American Journal of Neuroradiology 19 (9) , pp. 1721-1726
5. Katata, K., Sakai, N., Doi, K., Kawamitsu, H., Fujii, M., Sugimura, K., Nibu, K.-I. 2009. Functional MRI of regional brain responses to 'pleasant' and 'unpleasant' odors.Acta Oto-Laryngologica 129 (SUPPL. 562) , pp. 85-90
6. Levy, L.M., Henkin, R.I., Hutter, A., Lin, C.S., Martins, D., Schellinger, D. 1997 .Functional MRI of human olfaction. Journal of Computer Assisted Tomography 21 (6) , pp. 849-856
7. O'Doherty, J., Rolls, E.T., Francis, S., Bowtell, R., McGlone, F., Kobal, G., Renner, B., Ahne, G. 2000. Sensory-specific satiety-related olfactory activation of the human orbitofrontal cortex. NeuroReport 11 (4) , pp. 893-897
8. Rolls, E.T., Kringelbach, M.L., De Araujo, I.E.T. 2003. Different representations of pleasant and unpleasant odours in the human brain. European Journal of Neuroscience 18 (3) , pp. 695-703
9. Royet, J.-P., Zald, D., Versace, R., Costes, N., Lavenne, F., Koenig, O., Gervais, R. 2000. Emotional responses to pleasant and unpleasant olfactory, visual, and auditory stimuli: A positron emission tomography study. Journal of Neuroscience 20 (20) , pp. 7752-7759
10. Small, D.M., Jones-Gotman, M., Zatorre, R.J., Petrides, M., Evans, A.C. 1997. Flavor processing: More than the sum of its parts. NeuroReport 8 (18) , pp. 3913-3917
11. Sobel, N., Prabhakaran, V., Desmond, J.E., Glover, G.H., Goode, R.L., Sullivan, E.V., Gabriell, J.D.E. 1998. Sniffing and smelling: Separate subsystems in the human olfactory cortex. Nature 392 (6673) , pp. 282-286
12. Yousem, D.M., Maldjian, J.A., Siddiqi, F., Hummel, T., Alsop, D.C., Geckle, R.J., Bilker, W.B., Doty, R.L. 1999. Gender effects on odor-stimulated functional magnetic resonance imaging. Brain Research 818 (2) , pp. 480-487
13. Zald, D.H., Pardo, J.V. 2000. Functional neuroimaging of the olfactory system in humans. International Journal of Psychophysiology 36 (2), pp. 165-181
(1) Walter Freeman and his colleagues have shown that every neuron in the olfactory bulbs participates in the generation of olfactory perception (Freeman, Scientific American 1991; 264(2): 78-85). In other words, the salient information about the stimulus is carried in some distinctive pattern of bulbwide activity and not in a subset of specific neurons. In the absence of a stimulus, the pattern of activity across the olfactory bulb has "chaotic" characteristics. However, upon receiving a stimulus the chaotic behavour rapidly assumes a cross-bulbar pattern. This pattern need not be the same each time for the same odour, but may change its characteristics depending upon the previous stimulus. This system allows for odorant conditioning, and also explains how we can be sensitive to odours we have never previously experienced.
(2) Another prevalent view is that the chemical features of the odour are encoded by the glomeruli in the olfactory bulb (see Bozza & Mombaerts, Current Biology 2001; 11: R687-R690 for a good summary). This view is compatible with that of Freeman explained above. Each glomeruli of the olfactory bulb receives the input from only those ORNs expressing the same receptor. Thus each glomerulus responds to one, and only one, chemical feature of the odour. Neighboring glomeruli respond optimally to slightly different features, e.g. increasing carbon chain length or different side groups. The odour is thus represented by bulb-wide activity - glomerular activation - representing those receptors to which the odour binds, as well as the binding affinity - a kind of 3-D bar code.
The pattern of activation of the different glomeruli is then relayed to the primary olfactory cortex - the piriform cortex. The cells in the olfactory (piriform) cortex should each respond to a different glomerulus becoming active. However, Linda Buck has shown (Zhou & Buck, Science; 311, 1477-81, 2006) that there are cells in the olfactory cortex that only respond when two odorants are present and not when each component odour is present on its own. This could explain why odour mixtures can have different odour percepts to the smell of their individual ingredients. In fact, we are rather bad at picking out individual odours in a mixture.
Menstrual synchrony - Further evidence of chemical signalling in humans comes from work by Martha McClintock: armpit swabs taken from donor women at a certain phase in their menstrual cycle and wiped on the upper lip of recipient women can advance or retard menstruation in the recipients depending upon the phase of the donor (Stern & McClintock, Nature (1998) 392, 177-179). We seem to possess the ability to secrete compounds that can relay information about our mood to another person. Can we prove this more directly by experiment? If we know what these compounds are can they be used to alter mood?
- We signal our immune status by smell (see "Smell and Mate Choice" below ) because our body odour is determined by our HLA system [HLA genes determine what is self and non-self].
- Men rate women as more attractive during ovulation and less attractive during menstruation.
- We smell different when we are ill. Some illnesses can be diagnosed by their associated smell (e.g. acetone and diabetes).
Do we believe in HUMAN PHEROMONES? It is a controversial topic and too many people are sloppy with their definition of the concept which was, after all, discovered in moths. The whole area has a bad reputation because of attempts (scams) to commercialise compounds that "attract members of the opposite sex". However, evidence is emerging for the existence of human chemical signals although nobody has yet isolated and purified one. The best example to date is the "fear pheromone" and the phenomenon of menstrual synchrony in cohabiting women is proposed as another (see above).
Smell of fear
Dogs and horses can smell fear in humans. Recent work by Denise Chen (Chen & Haviland-Jones, Physiology and Behaviour 1999; 68: 241-250) has demonstrated the ability of underarm odour to influence mood in others. Karl Grammer, in Vienna, has recently demonstrated that the smell of fear can be detected (by women) in the armpit secretions of people who watched a terrifying film (Ackerl, Atzmueller & Grammer, Neuroendocrinol Lett 2002; 23(2): 79-84). The implication of this work is that a chemical signal is secreted in sweat which communicates the emotion. More recent work has demonstrated that the odour of the sweat collected from first-time sky divers activates the amygdala in recipients of that odour. (Chemosensory Cues to Conspecific Emotional Stress Activate Amygdala in Humans. Mujica-Parodi LR et al. 2009 PLoS ONE 4(7): e6415. ).
Experiencing the fear of others.
Sissel Tolaas is an artist who uses smell in her artworks. She says that in the West, smell is thought of in "aesthetic terms-pleasant or unpleasant," whereas in other cultures, body odour is important in detrermining social interactions.
"Since our representations of the world are most of the time scentless, this indeed reinforces the social drive for deodorization of the world," Tolaas said. "We can be tolerant in many ways, but this physicality of not being able to stand each others' smell stops any kind of communication."
In an exhibition at MIT in 2006 Tolaas incorporated the sweat of fear into paint using microencapsulation and painted the walls of the exhibition centre. The wall paint contains synthetic replicas of chemicals characteristic of the sweat generated by individuals with varying chronic phobias. Tolaas, by gaining their trust, persuaded nine men suffering from phobias to collect their sweat when exposed to the source of their phobia.
Visitors to the exhibition had a wide variety of responses: some people didn't want to experience it at all, and some people were very happy to rub the walls and smell. Others found the smell so disturbing they refused to spend any time in the room. Smell accesses the subconscious regions of the brain and evokes memories and moods so this exposure to the smell of other people's fear is a very intimate and personal experience.
Smell and pain. Pleasant smell has an analgesic effect. For most subjects, pleasant odours improved mood and reduced pain unpleasantness perception relative to unpleasant odours. In the pleasant odour condition, the maximum activation of both the left and right ventral striatum was positively correlated with the amount of pain reduction. Because both the mediodorsal thalamus and anterior cingulate are involved in pain affect perception, and activation within the prefrontal areas and periaqueductal grey matter were previously shown to correlate with mood-related pain modulation, it is concluded that the ventral striatum is likely implicated in the analgesic effect of positive mood changes induced by pleasant odours on pain unpleasantness. [Ref: Villemure C, Laferrière AC, Bushnell MC. (2012) Pain Res Manag. 2012 Mar-Apr;17(2):69-74.]
Keller et al. (2007) have shown that single nucleotide polymorphisms (SNPs) - differences in genes of a single coding letter - can give rise to perceptual differences of the same smell. They looked at the steroids androstenone and androstadienone and found different people perceived them differently - some found them pleasant while others found them unpleasant and yet others couldn't smell them at all. In my opinion (TJCJ) this is not the whole story. People can not only learn to smell these two steroids by repetitive exposure but also, they can change their sensitivity and with it their peception of pleasantness2,3. Measurable physiological changes take place as this occurs. This rather undermines the genetic variation work. The truth will out - with more research.
- Keller, A., ZHuang, H., Chi, Q., Vosshall, L.B. and Matsunami, H. (2007). Genetic variation in a human odorant receptor alters odour perception. Nature 449, 468-472.
- Tim J.C. Jacob, Liwei Wang, Sajjida Jaffer and Sara McPhee (2006) Changes in the odour quality of androstadienone during exposure-induced sensitization. Chemical Senses 31, 3-8.
- Boulkroune, N., Wang, L., March, A., Walker, N. and Jacob, T.J.C. (2007) Repetitive olfactory exposure to the biologically significant steroid androstadienone causes a hedonic shift and gender dimorphic changes in olfactory evoked potentials. Neuropsychopharmacology 32, 1822-1829.
Anosmia is a condition in which the sense of smell is reduced or lost entirely. It can be caused by traumatic head injury (e.g. a fall in which the head receives a severe blow) or a virus (a bad cold, or infection of the nasal mucosa). Some people are born without a sense of smell - congenital anosmia, and some develop it as a consequence of another disorder, e.g. Alzheimer's disease. Generally, traumatic head injury causes an irreversible anosmia (although some people have reported a recovery) and viral anosmia is temporary (although some people report long-term effects). Anosmia is not life-threatening and for this reason, and because of a lack of information available to GPs (medics), it tends not to be treated (certainly this is true in the UK). As a result it is hugely under reported - it is much more common that you might imagine. There are a limited number of treatments at centres scattered around the world. For further information go to our ANOSMIA website.
In the UK, FifthSense offers help and advice to those who have problems with their sense of smell.
A fascinating and alarming study by Pinto in Martha McClintock's lab (PLoS ONE 9(9): e107541, 2014) shows that olfactory loss is a predictor of death. In a population of 3000 from 57-85 years old, 39% of those with anosmia (loss of smell) were dead in 5 years compared to 10% of those with a normal sense of smell. This was the greatest predictor of death other than acute liver damage. Why is this? Well, it's not clear but the smell receptor cells are very exposed to the environment and pollution and also to viruses. Viruses can enter the body and get to the brain via the olfactory receptor cells. Also, these cells are constantly renewing themselves so if they stop doing so this is bad news for the rest of the body. Basically the take home story is that the sense of smell is linked in unknown ways to factor(s) influencing our mortality. We should pay more attention to our sense of smell.
Smell of disease
There is anecdotal and scientific evidence to suggest that different diseases have particular smells. Most of us recognise that our smell changes when we are ill. In earlier times doctors placed much more importance on a patient's smell - in particular the smell of their stools.Typhus - sickly odourSmallpox - sweet, pungentDiphtheria - peculiar, penetrating "mousy" smellRheumatism - acid smellDiabetes - sweet (acetone)Plague - sweet smell (?)
Electronic noses are being developed to identify infections and lungs diseases (eg TB).
In a recent study Professor Matts Olsson at the Karolinska Institute gave human volunteers something that activated their immune system and then collected their sweat. Their smell was rated as more unpleasant than controls. It is not know which chemicals are given off to account for this change but we communicate our health state by changing our smell.
Is there a smell of health?
There's money in smell - around $24 billion is spent on scented products per annum in the US alone - but "Money has no smell" (who said this? Answer).
There are many possible commercial exploitations for smell, odour and taste:
- Fragrances tailored to individuals' odour phenotype
- Designer scents and flavours (based on cloning of taste and odorant receptors)
- Technologies to modulate odour/taste (odour/taste-antagonists)
- Mood effects of odours (e.g. volatile steroids)
- Partner preference and fertility (HLA-related human body odours)
- Testing deficits in smell (e.g. in Alzheimer's disease)
- AgroChem - pest management based on odour
(taken from Gilbert and Firestein,"Dollars and scents: commercial opportuities in olfaction and taste" Nature Neuroscience 5, 1043-5, 2002 Nov.)
California-based Pherin Pharmaceuticals, Inc. has clinical trials under way on steroidal compounds for PMS (pre-menstrual tension), social anxiety disorder and appetite stimulation.
Smell therapy and the clinical use of odour is an area for the future (see below Therapy using smell memory).
Smell and memory are closely linked. Smell evokes memories. Damage to the temporal cortical region of the brain - the site of memory - does not affect the ability to detect smell, but, rather, prevents the identification of the odour. We must first remember a smell before identifying it.
What we know about smell and memory:
- Memory - odour memory falls off less rapidly that other sensory memory (Miles & Jenkins, 2000)
- Odour memory lasts a long time.
- The "Proust effect" - odour associated with experience and a smell can recall the memory; smell is better at this memory cue effect than other senses (Chu and Downes, 2000)
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Marcel Proust has lent his name to the phenomenon of memory recall in response to a specific smell (after his descrition of such an event in "Swan's Way") - the "Proust Effect". Whole memories, complete with all associated emotions, can be prompted by smell. This is entirely unconscious and cannot necessarily be prompted voluntarily although countless studies have shown that recall can be enhanced if learning was done in the presence of an odour and that same odour is presented at the time of recall. Useful for exam revision!
Work by Walter Freeman (Freeman, 1991) has shown that smell memory is context dependent and can be modified in the light if new experience, implying that our olfactory sense is continuously dynamic, updating as we live and experience new things.
"As much as 80% of what we call "taste" actually is aroma" (Dr Susan Schiffman quoted in Chicago Tribune, 3 May 1990)
"Ninety percent of what is perceived as taste is actually smell" (Dr Alan Hirsch of the Taste Treatment and Research Foundation in Chicago, quoted in MX, Melbourne, Australia, 28 Jan 2003).
Flavour (smell + taste) is what drives appetite. When we are hungry we have an increased smell sensitivity and after eating this decreases. So you can imagine that some scientists have tried to use this phenomenon to curb appetite, i.e. as a dietary aid. e.g. vanilla patches. Doesn't work.
Smell is more sensitive than taste: threshold for sucrose (taste) is between 12 and 30mM (millimolar) depending upon test used. Strychnine is a very powerful taste (apparently), and can be tasted at 10-6M (one micromolar). As for smell, mercaptan can be detected at 7x10-13Molar. Taking into account the relative volumes needed for taste and smell (you sniff a greater volume of air than you taste a liquid), smell is 10,000 times more sensitive than taste (Moncrieff, R.W. "The Chemical Senses", 3rd ed., Leonard Hill, London, 1967).
Who said "A rose by any other name would smell as sweet"? (Answer)
If we smell (or taste something) before a negative experience, that smell (or taste) is linked to that experience. The memory is very robust. This can be a problem for unpleasant medical treaments, or surgery when the last meal is often associated with the pain or trauma. But this very effect could, in the future, be put to therapeutic advantage; if smell were to be associated with a positive, healing treatment then the smell itself can substitute for the treatment once the link has been reinforced. It works in rats!
Some very interesting research was published recently - insulin was injected into healthy male volunteers once a day for four days and their blood glucose was measured (it fell). At the same time, they were exposed to a smell. On the fifth day they were just given the smell, and, their blood glucose fell (Stockhorst & Gritzmann, (1999) Psychosomatic Medicine 61, 424-435).
A very convincing demonstration of innate response to smell has been reported by Kobayakawa et al (2007). To cut a long story short, they "deleted" some glomeruli in the olfactory bulb (regions where the olfactory receptor neurons project) and mice with certain deletions no longer responded to "fear" smells - they used leopard urine (!) which mice respond to in an aversive manner - although they could still smell the urine and the compounds in it. For comment on this finding see Mainen (2007):
References for innate vs. learned
Mainen, Z.F. (2007) The main olfactory bulb and innate behavior: different perspectives on an olfactory scene. Nature Neuroscience 10(12), 1511-1512.
Kobayakawa, K., Kobayakawa, R., Matsumoto, H., Oka, Y., Imai, T., Ikawa, M., Okabe, M., Ikeda, T., Itohara, S., Kikusui, T., Mori, K. and Sakano, H. (2007) Innate versus learned odour processing in the mouse olfactory bulb. Nature 450, 503-510.
The big question "Is odour discrimination inborn" has been taxing many investigators over the years. Babies tested 50 hours after birth sense odours. Yet, according to Engen and Lipsitt (1965), at this stage they do not discriminate between pleasant and unpleasant odours. For example, anise (pleasant) and asafoetida (unpleasant) both elicit the same kind of mild startlement. This evidence is certainly counter-intuitive and implies that response to odour must be learned. It also contradicts the work by Steiner who demonstrated that neonates (a few hours old) gave aversive facial responses to bad smells and neutral facial responses to pleasant smells (Steiner, 1977; 1979). This work has been repeated and re-evaluated because of some methodological and interpretational problems. Soussignan et al. (1997) found that a malodour (butyric acid) was more effective than vanillin in triggering facial expressions reflecting disgust, whereas vanillin did not trigger more smiling or mouthing movements than butyric acid.
By as early as 3 days a baby can discriminate between a gauze pad worn by his or her own breast-feeding mother and that worn by an another lactating mother used as a control (MacFarlane, 1975; Schaal et al., 1980). There is also evidence from animal studies, such as the fact that merely washing the nipple of a mother rat will eliminate the attachment of her pup. It has been suggested that there are semiochemicals (signalling odours) that elicit suckling behaviour in newborn animals. What complicates this whole area is that there is prenatal olfaction. Thus babies are exposed to chemicals in the womb and this influences postnatal preferences (Schaal et al., 2000). There is clearly experience-dependent learning in the olfactory system, but whether the response to certain smells (in particular malodours) is "hard-wired" is still a matter of debate.
Recent new work from Coureaud et al (2006) on the role of the mammary pheromone has shown that it is an enforcer of early olfactory learning in newborn rabbits. The mammary pheromone promoted learning of neutral odorants paired with the pheromone in single and short trials. The pheromone-induced learning works from birth and induces the pup to imprint the current ambient odour, learning to associate it with breast feeding. Thus mammary pheromone can function as a "cognitive organizer" that promotes early learning of relevant environmental cues.
- Engen, T. and Lipsitt, L.P. (1965) Decrement and recovery of responses to olfactory stimuli in the human neonate. J. Comp. Physiol. Psychol. 59, 312-316.
- MacFarlane, A. (1975) Olfaction in the development of social preferences in the human neonate. In Parent-Infant Interactions (Ciba Found. Symp. 33) Elsevier, New York, pp. 103-113.
- Schaal, B., Orgeur, P., Lecanuet, J.P., Locatelli, A., Granier-Deferre, C. and Poindron, P. (1980) Chemoreception nasale in utero: experiences preliminaires chez le foetus ovin. C.R. Ac. Sci. (Paris) Ser. lll, 113, 319-325.
- Schaal, B., Marlier, L. and Soussignan, R. (2000) Human foetuses learn odours from their pregnant mother's diet. Chem. Senses 25, 729-737.
- Steiner, J.E. (1977) Facial expressions of the neonate infant indicating the hedonics of food-related stimuli. In Taste and Development. The Genetics of Sweet Preferences, J.M. Weiffenbach (ed.). NIH-DHEW, Bethesda, MD, pp. 173-188.
- Steiner, J.E. (1979) Human facial expressions in response to taste and smell stimuli.. In Advances in Child Development vol. 13, L.P. Lipsitt and H.W. Reese (eds.) Academic Press, New York, pp. 257-295.
- Soussignan, R., SChaal, B., Marlier, L. and Jiang, T. (1997) Facial and autonomic responses to biological and artificial olfactorystimuli in human neonates: re-examining early hedonic discrimination of odours. Physiology and Behavior 62, 745-758
- Gérard Coureaud, Anne-Sophie Moncomble, Delphine Montigny, Maeva Dewas, Guy Perrier, Benoist Schaal. (2006) A pheromone that rapidly promotes learning in the newborn. Current Biology 16 (19):1956-61
90% of women tested identified their newborns by olfactory cues after only 10 min-1 hr exposure to their infants. All of the women tested recognized their babies' odor after exposure periods greater than 1 hr. These results suggest that odor cues from newborns are even more salient to their mothers than have been thought heretofore.
Kaitz M, Good A, Rokem AM, Eidelman AI. Mothers learn to recognise the smell of their own infant within 2 days. Dev Psychobiol. 1987 Nov;20(6):587-91.
In a survey of pregnant women carried out by Nordin and colleagues, 76% of pregnant mums report smell and taste disturbances. Increased smell sensitivity is common (67%), less common are qualitative smell distortions (17%) and phantoms smells (14%). All these abnormalities were less common in late pregancy and almost absent after birth. Taste abnormalities were less common (26%) and included increased bitter perception and decreased salt sensitivity.
Nordin, S., Broman, D.A., Olofsson, J.K., and Wulff, M. A longitudinal descriptive study of self-reported abnormal smell and taste perception in pregnant women. Chemical Senses 2004 Jun;29(5):391-402.
Women, particularly women of reproductive age, have a more acute sense of smell than men. The smell sensitivity of most women varies across the menstrual cycle, peaking at ovulation (approx. day 14 of cycle where the beginning of menstruation is day 0). This peak in smell sensitivity coincides with a surge in plasma estradiol (an oestrogen). Estradiol also increases during pregnancy, perhaps explaining why some women report an increase in smell (and taste) sensitivity during pregnancy.
Smell declines with age but postmenopausal decreases in smell sensitivity are not reversed by hormone replacement therapy (HRT)1.
In Kallmann's syndrome there is an impaired sense of smell. Affected individuals have deficient gonadotropin levels (hormones that stimulate the function of the testes and the ovaries). Recent studies demonstrate that GnRH neurons originate in olfactory tissues and migrate to the hypothalamus but fail to do so in Kallman's syndrome. In addition the olfactory bulbs fail to develop.
1Hughes et al. Climacteric. 2002 Jun;5(2):140-50
As we get old our sense of smell declines. This also affects our sense of taste and food will lose its flavour. By 80 years old 80% of people have some major smell dysfunction and 50% are "anosmic" by the standards of young people. Not only do we lose our sense of smell, we lose our ability to discriminate between smells.Women, while also losing smell sensitivity with age, perform better than men at all ages. Patients with neurodegenerative diseases, such as Alzheimer's disease, suffer olfactory losses. Very early stage Alzheimer's patients show a loss of smell sensitivity.
Having done several years of research into this area I have become much more sceptical (and cautious!). Using EEG recording in my lab we have analysed the effect of various odorants (eg vanillin and butyric acid) and essential oils (eg lavender, ylang ylang and rosemary) on the alpha-wave content of the brain activity. The EEG was recorded over the frontal region of the scalp referred to the mastoids, with the eyes closed. Alpha wave activity in the brain is associated with the level of arousal - when you are drowsy or sleepy your generate more alphawaves (eg just before you go to sleep). If the brain is active, this causes "alpha-block", and brain activity changes to high frequency, low amplitude beta waves. So, in some respects alpha wave activity is an index of relaxation - more alpha, more relaxed.
Many studies have purported to show that essential oils have effects on the brain. But, after many attempts, we have been unable to repeat these studies. Instead we focussed on a new way to deliver olfactory stimuli and produced the "Aromapod". This has progressed and we have developed a new device - the Aromalux - that is undergoing commercial development. Check out the Aromalux site.
While it is a commonly held view that smell affects emotion and mood, scientific research has more often reported null effects (63% in the survey of Bone & Ellen, 1999).
The effects of smell on emotion and mood are most likely to be the result of conditioned association. Strong emotional responses to olfactory stimuli are rare or idiosynchratic, much more common are minor mood effects and mild affective states. The mood effects are likely to parallel the hedonicity of the odour (pleasant odours give rise to pleasant mood states while unpleasant odours give rise to unpleasant moods).
Smell and dreams - A recent study in Germany has shown that smell can influence the quality and emotional tone of dreams. Researchers wafted the smell of roses under the noses of sleeping volunteers in the REM phase of their sleep (dreaming phase). They then woke them up and asked them to report on the content and quality of their dreams. While the subjects did not report actually smelling anything during their dreams, the emotional tone of their dream did change depending upon the stimulation. The smell of roses evoked pleasant emotions and the smell of rotting eggs had the opposite effect.
BBC News online Sept 2008
Smell and sleep - A study by Carskadon and Herz (Sleep 27, 402-5: 2004) looked at whether smell could be used as an alarm clock to wake you up. They used peppermint and pyridine (unpleasant fish-like odour) but neither smell acted as a satisfactory wake-up call.
Abstract of Carskadon & Herz paper
We choose our mates on the basis of their smell. Well, we like the smell of genetically favourable partners, from an immune system point of view, and dislike the smell of those whose immune system is too similar to ours. The consequence is that we choose a mate with a very different immune system to ours and give our children the benefit of two different sets of immune genes and this confers greater disease resistance. Evidence for this comes largely from the work of Claus Wedekind (http://en.wikipedia.org/wiki/Claus_Wedekind). Recent work from Martha McClintock's lab in Chicago shows that women are able to detect minute differences in male immunotype by smell (Jacob et al., 2002). Immunotype is conferred by HLA alleles, the genes that confer immunity in humans (the equivalent of MHC in animals), and determines our individual smell (see Body odour). We tend to prefer smell of people who have different HLA alleles to our own. This would mean the offspring of such a match would confer immune advantage - more different HLA alleles would be passed on to the kids giving them a greater degree of immunity. We tend to be repelled by people whose immunotype (HLA alleles) is similar to our own. It looks like we choose our partner on the basis of smell (Wedekind et al., 1997) - well it would be one factor anyway. So, why do we spend so much time, and money, disguising it? Actually, we can probably detect the HLA-related smell in spite of our best attempts to cover it up!
Do perfumes, deodorants hide our body odour and therefore confuse potential partners? No, it appears that we choose our perfumes based on our immunotype - people with similar immunotypes tend to prefer the same fragrance ingredients (Malinski and Wedekind, Behavioral Ecology 12, 140-149; 2001). Malinski and Wedekind proposed that we use perfume to advertise our immunotpye. Interesting.
No smell - no sex! Male mice with a genetic modification that disrupted the function of the olfactory epithelium (lack of cyclic nucleotide gated cation channel CNGA2) failed to show any sexual behaviour towards female mice and did not become aggressive when introduced to foreign males - a situation that normally induces aggressive behaviour.
Mandiyan, VS, Coats, JK & Shah, NM. Deficits in sexual and aggressive behaviors in Cnga2 mutant mice.Nature Neurosci 8, 1660 - 1662 (2005)
Sperm may smell their way to the egg. Smell receptor has been identified in human sperm (Spehr et al., Science 2003). This receptor functions in sperm chemotaxis and may be a critical component of the fertilization process.
Spehr, M., Gisselmann, G., Poplawski, A., Riffel, J.A., Wetzel, C.H., Zimmer, R.K. and Hatt, H. Identifiaction of a testicular odorant receptor mediating human sperm chemotaxis". Science 2003 Mar 28; 299 (5615), 2054-8.
Smell and sexual orientation - In a study of smell preferences, heterosexual and homosexual men and women were asked to evaluate underarm sweat from 24 donors. Gay men and women had body odour preferences that were different from straight men and women. Gay men preferred odours from gay men and straight women, whereas odours from gay men were the least preferred by straight men and women and by lesbian women.
The astonishing implication is that body odour is linked, not only to gender, but also to sexual orientation. How? Good question!
Human body odor may contribute to selection of partners. If so, sexual orientation may influence preference for and perhaps production of human body odors. In a test of these hypotheses, heterosexual and homosexual males and females made two-alternative forced-choice preference judgments for body odors obtained from other heterosexual and homosexual males and females. Subjects chose between odors from (a) heterosexual males and gay males, (b) heterosexual males and heterosexual females, (c) heterosexual females and lesbians, and (d) gay males and lesbians. Results indicate that differences in body odor are detected and responded to on the basis of, in part, an individual's gender and sexual orientation. Possible mechanisms underlying these findings are discussed.
Martins Y, Preti G, Crabtree CR, Runyan T, Vainius AA, Wysocki CJ.
Preference for human body odors is influenced by gender and sexual orientation.
Psychol Sci. 2005 Sep;16(9):694-701.
Viagra (sildenafil) may impair the ability to smell. This may be due to an increase in nasal congestion it is reported in The Journal of Urology1.
Dr Thomas Hummel and colleagues at the University of Dresden Medical School studied 20 healthy, young male volunteers who received Viagra at a 50- or 100-mg dose, or inactive "placebo," and then were exposed to an odor-dispensing device.They then tested the subjects' odor detection threshold, odor discrimination and odor identification ability.
They found that the 100-mg dose caused a decrease in olfactory ability, specifically odor discrimination and odor threshold, compared with placebo. The 50-mg dose, by contrast, had no effect on olfactory function.
They authors concluded that the most likely reason was increased nasal congestion. They mention that previous studies had linked Viagra with a fall in nasal airflow.
1Gudziol, V., Muck-Weymann, M., Seizinger, O., Rauh, R., Siffert, W. and Hummel, T (2007) Sildenafil Affects Olfactory Function. Journal of Urology 177(1), 258-61.
Why do we smell? What makes us smell different?
We all have a unique body odour - our odourtype (except identical twins).
Our apocrine glands, situated in our axillae (armpits), sternum (centre chest), groin, nipples, cheeks, eyelids, ear, and scalp, secrete compounds that are virtually odorless. They become smelly by the action of bacteria - particularly those living in our armpits (yuk!).
threefour theories currently to explain why we all have a unique smell:
- The HLA molecules (see above) themselves (which confer "self" and are unique to each individual) might confer an individual smell. Although they are not very volatile.
- HLA molecules may influence odour by binding unique subsets of peptides, which are secreted and acted on by the bacteria on our skin (e.g. armpits) to make them volatile. These volatile compounds are our smell.
- The HLA genes may influence the specific populations of bacteria living in our axillae. Different bacteria would then metabolise our secretions in different ways to make different smells.
- Co-expression of odour-producing genes lying in the HLA region on chromosome 6.
Dogs can determine the direction of a human odour trail. A study by Hepper and Wells (Chemical Senses 30 (4): 291-298 May 2005) examined how much olfactory information from this trail is required by dogs to determine direction. Six dogs, able to determine direction, were tested on a 21 footstep trail laid on 21 individual carpet squares, one footstep per square, by the same individual wearing the same shoes. Dogs brought in at right-angles to the trail at its centre were able to correctly determine direction better than chance (P < 0.025). Dogs were unable to determine direction when the order of the footsteps was randomized by rearranging the order of the carpet squares. When the individual odour cue was removed, but ground disturbance left, dogs were unable to determine direction, indicating that it was the odour of the individual that was used to determine direction. In the final experiment the number of footsteps made available to the dog was reduced from 21 to 11 and then 9, 7, 5 and finally 3. Dogs were able to determine direction from 5 footsteps but not 3. It was calculated that it takes similar to 1-2 s for the odour information in footsteps to change to provide discernible information that can be used by dogs to determine direction.
A paper by Porter et al (2007) reported a rather bizarre experiment where humans were put into special suits, blind-folded and wore ear protectors to remove sound cues and then were asked to follow a chocolate trail, like sniffer dogs. Two-thirds of the subjects were able to follow the trail. - IgNobel Prize candidate perhaps??
Porter, Craven, Khan, Chang, Kang, Judkewitz, Volpe, Settles and Sobel (2007). Mechanisms of scent-tracking inhumans. Nature Neuroscience 10(1), 27-29.
Cancer sniffing dogs were discovered in the UK. In a UK study (Willis et al, BMJ 2004; 329, p712), dogs were trained to sniff out bladder cancer with 41% success rate. Subsequently in California, dogs were trained to detect breast and lung cancer on breath with a 88-97% accuracy (McCulloch et al Integr Cancer Ther 2006; 5; 3). Now there is some scepticism as to where this work is going. Will dogs detect the early signs of cancer? What if they get it wrong? Who is responsible - the dog, it's trainer, or the medic who interpreted the results? A legal nightmare. So, the most likely use of these dogs is to aid scientists in their quest for the chemicals given off by cancerous cells, or by the body in response to cancer. Then machines can take over.
Research has shown that your olfactory sensitivity depends upon body position. Lie down, and you become less sensitive. [Lundstrom et al., (2006) "Sit up and smell the roses better: olfactory sensitivity to phenyl ethyl alcohol is dependent on body position". Chemical Senses, e-print ahead of publication, doi:10.1093/chemse/bjj025]. Although they give a number of reasons for this phenomenon, it may be as simple as the decreased effect of gravity on the blood pressure, just as for astonauts - see below. And another thing - your sense of smell doesn't sleep. The only sense that keeps guard while you are asleep. Ahhhh....!
Astronauts tend to lose their senses of smell and taste. This is thought to be because to the congestion in the nose resulting from the increased capillary pressure as the heart no longer has to work against gravity. As a consequence the sinuses tends to fill up with fluid, giving rise to a feeling of stuffiness similar to a head cold.
Buck, L. and Axel, R. (1991) A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell, 65, 175-187.
Bone, P.F. and Ellen, P.S. (1999) Scents in the marketplace: explaining a function of olfaction. Journal of Retailing 75(2), 243-262.
Chu, S. and Downes, J.J. (2000) Odour-evoked autobiographical memories: psychological investigations of the Proustian Phenomena. Chemical Senses 25, 111-116.
Freeman, W.J. (1991) The physiology of perception. Scientific American 264(2), 78-85).
Jacob, S., McKlintock, M.K., Zelano, B. and Ober, C. (2002) Paternally inherited HLA alleles are associated with women's choice of male odor. Nature Genetics 30, 175-179.
Miles, C., & Jenkins, R. (2000). Recency and suffix effects with serial recall of odours. Memory 8 (3), 195-206.
Wedekind, C. and Furi, S. (1997) Body odour preferences in men and women: do they aim for specific MHC combinations or simply heterozygosity? Proc. Roy. Soc. Lond. B 264, 1471-9.
Green nosed pigs.
Genetically modified to express a green fluorescent protein in their nostrils.
Another proud moment for science.
moths can smell a single
molecule (of the moth pheromone
insect antennae attached to electronic circuits are being used as odour sensors FACT -flavour is mostly (~75%) smell FACT - we can smell happiness dogs can distinguish non-identical twins by smell - but not identical twins! some people can't smell skunks - and some can't smell freesias all smells are small molecules (less than 350 molecular mass) bloodhounds can pick up a 24 h old trail and identify the person.
If a bloodhound comes across a 20 minute-old trail at right angles,
sniffing for 2-5 steps will give the direction of the trail.
"sniffer rats" have been used to detect
expolosives - but they haven't
replaced their canine cousins!
FACT - everyone has a unique smell (except identical twins)
Go to top
- New research shows some smell response genetically determined (Sep 2007)
- Innate vs. learned smell in humans (28 Nov 2007).
- Rostral Migratory Stream in humans (2 Mar 2007).
- Viagra may decrease ability to smell (Feb 2007).
- Two different lines of support for Luca Turin's smell theory (2006/7)
- Smell important in sex (Oct 2005). Mice without sense of smell (no olfactory epithelium) don't mate.
- Human brain repair?? Olfactory ensheathing cells - used for human brain repair - Dr Huang Hongyun, Chaoyang Hospital, Beijing
- May 2005 - Canine smell feat! Dogs need just 5 human steps to sniff in order to follow the trail
- Humans tracking scent? Jan 2007 - Not to be left out, humans can track scent too! See Porter et al.!
- Summer 2006 - Nobel Laureate Linda Buck does it again! How the brain detects odour mixtures...
- ...and again - discovering new olfactory receptor (trace amine-associated receptors or TAARs)
- Oops, Linda Buck retracts two papers (2010)
- Does NERVE GAS smell? - Sarin is the nerve agent suspected of being used in Syria. It is a simple organophosphorus compound with the formula [(CH3)2CHO]CH3P(O)F. It is a colourless, odorless liquid - so it doesn't smell. It is heavier than air so settles at ground level. It induces muscle spasms and the first symptoms are difficulty breathing, runny nose, drooling. It is very toxic - 500 times more toxic than cyanide. Read Daniel Engber for a bit more.
Here are some selected interesting links:
Olfactory info - an extended tutorial on smell and more links
The Smell Report - A series of carefully researched essays on smell from The Social Issues Research Centre
Walter J. Freeman - interesting Sci. Am. review on the neurophysiology of smell
The Senses - an exploration of the senses for kids
Leffingwell - serious links to many aspects of smell
Who said :
"What's in a name? that which we call a rose
By any other name would smell as sweet"
........................................Romeo and Juliet act 2, sc.2, l.66............................. go back
"Pecunia non olet" (Money has no smell)
Said when quashing an objection to a tax on public lavatories............... go back