The smell of success

Print edition : November 05, 2004

THE sense of smell is perhaps the most complex among the sensory perceptions in animals and humans. Its aesthetic value apart, smell is an essential part of animal behaviour and has a great survival value as well. Evolutionarily, therefore, it is the most primitive sense. But the underlying mechanism that enables recognition and memory of about 10,000 different odours has long been a mystery. How do living organisms detect such a large number of chemicals and how does the brain translate these signals into perceptions that enable distinction between even slightly differing smells?


The olfactory response system has an extraordinary power to discriminate between molecules that are close in structure. For example, although quite similar chemically, the smells of pear and banana that humans perceive are quite distinct.

This year's Nobel Prize for Physiology or Medicine has been awarded to two American scientists who solved this long-standing problem. In a series of pioneering studies, Richard Axel of Columbia University and Linda Buck of the Hutchinson Cancer Research Centre, Seattle, showed in detail how the olfactory system works at the molecular level. They discovered a large gene family, comprising about 1,000 different genes, about 3 per cent of the 30,000 genes in the human genome, which codes for an equivalent number of olfactory receptor (O.R.) molecules. The O.R.s are located on the olfactory receptor cells, which occupy a small area in the upper part of the lining of the nose and detect the inhaled odorant molecules.

These ideas were presented in a fundamental paper published jointly in 1991 when Buck was Axel's student. Axel and Buck have since worked independently and they have carried out several elegant experiments that have clarified the olfactory system, from the molecular level to the organisation of cells. The olfactory system is the first of sensory systems that has been deciphered in the most detailed manner possible primarily using molecular techniques. The Nobel award has been made "for their discoveries of odorant receptors and the organisation of the olfactory system".

When an O.R. is activated by an odorant substance, an electric signal is triggered in the receptor cell and sent to the brain by nerve processes. Axel and Buck demonstrated that the large family of O.R.s are coupled to G-proteins. (G-proteins act as signal transducers, which transmit and modulate signals in cells.) All O.R.s are related proteins but their structures vary slightly so that they are triggered by different odorant molecules. Each O.R. consists of a chain of amino acids that is anchored into the cell and traverses it seven times. The chain creates a pocket into which the odorant binds. The shape of the O.R. then gets altered and that activates the G-protein to which it is coupled. The G-protein, in turn, stimulates the formation of the messenger molecule known as cyclic AMP (adenosine monophosphate). This molecule activates ion channels resulting in the neuron in the cell getting activated.

Axel and Buck showed independently that each of the individual 10 million or so receptor cells expresses only one of the O.R. genes. That is, there are as many types of receptor cells as there are O.R.s. This was highly unexpected. Further, by registering electric signals from a single receptor cell, it was shown that each cell does not respond to only one odorous substance, but to several related molecules - albeit with varying intensity.

Richard Axel and Linda Buck in a laboratary-AP

The olfactory system operates in a manner that is quite distinct from the receptor genes for other sensory systems, points out Axel. We are able to detect several hundred hues in our vision by only three photo receptors encoded by three genes that have an overlapping specificity for different wavelengths of light. In the case of taste, there are only 30 genes. But in the case of smell, there are a thousand genes that code for O.R.s. The implication is that to respond to the vast diversity of molecular structures of odorants we need a large number of genes in our chromosome. And this principle happens to be common virtually to all living species.

Most odours are composed of multiple odorant molecules and each molecule activates several O.R.s. This leads to a combinatorial code forming an `odorant pattern', somewhat like the colours in a patchwork quilt or a mosaic. This mix-and-match system is what enables humans to detect and remember far more scents than they have types of receptors. According to Buck, humans have only about 360 functional O.R.s, yet they can distinguish between thousands of odours. The combinatorial coding scheme and the tremendous variability in the subsets of odorants recognised by different receptors enable us not only to detect a large number of different odours but also to distinguish between them. This would not be possible if there was only one receptor for each odorant.

HAVING determined how smells are detected via the O.R.s, the next question is how does the brain know which O.R.s have been activated? How does the brain know what is the nose smelling? Equivalently, how does the brain space represent chemical structures? Since each cell expresses one kind of receptor gene, the problem of the brain discerning which receptor has been activated has been reduced to the problem of the brain knowing which sensory cells or neurons have been activated. In other sensory systems, this spatial segregation of activated neurons creates a corresponding map in the brain, retaining the spatial order of the activated neurons. But in the case of smell, the brain map was found not to correspond to the spatial distribution of olfactory stimuli in the receptor cells.

In the nasal lining, the neurons that make one of those 1,000 receptors are randomly distributed, but the nerve processes from these neurons converge at a point - a micro domain - in the first `relay station' in the brain thus restoring order to the apparent randomness. Continuing their investigations, Axel and Buck were able to identify this first `relay station'. This is the `olfactory bulb' and is made up of the micro-regions of convergence called glomeruli (see diagram). There are about 2,000 well-defined glomeruli - that is, twice as many as the types of O.R. cells. The point of convergence or the glomerulus for a given O.R. is fixed or invariant in all individuals of a species and, for each of the thousand-odd receptors in the nose of an individual, that point is different. To demonstrate this, Axel and his collaborators used sophisticated genetic engineering techniques in mice. The invariance of the glomerulus for information from cells with the same receptor showed that the olfactory response of living organisms is remarkably specific.

From these glomeruli the information is relayed further, with its specificity maintained, to other parts of the brain, where information from several receptors is combined to form a `pattern'. Buck showed that these nerve signals reach well-defined micro-regions in the brain cortex where the `pattern', characteristic of a given odour, is generated. In other words, individual odours activate a subset of receptors, which in turn will activate a subset of points in the brain space such that the smell is defined by the unique spatial patterns of activity in the brain. It is this spatial map that the brain recalls every time we encounter a familiar smell.

The general principles that Axel and Buck discovered for the olfactory system appear to apply to some other sensory perceptions as well. Three smaller sensory receptor families, localised to a different part of the nasal lining, have been discovered by Axel and Buck independently. One for pheromones, molecules that influence social behaviour, especially in animals, one for bitter tastes and one for sweet tastes. That is, it is primarily the activation of the olfactory system that helps us detect the good or bad qualities of food.

Axel's group further compared that the representation of olfactory information in the brain of a fruitfly, Drosophila melanogaster, which is much simpler than that of a mammal. The functional organisation of the olfactory system was found to be remarkably similar. That is, despite 600 million years of evolution that separate the two species, they seem to have evolved independently to arrive at the same basic solution for the olfactory system. This, Axel says, suggests that this solution is one of a relatively few that solves the essential and complex problem of smell.

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