The smelling test

By Laura Spinney

Geneticist Andreas Keller suspects every individual has at least one odorant he or she cannot detect at all - an olfactory 'blind spot', which is inherited along with his or her olfactory apparatus. Photo / Thinkstock
Geneticist Andreas Keller suspects every individual has at least one odorant he or she cannot detect at all - an olfactory 'blind spot', which is inherited along with his or her olfactory apparatus. Photo / Thinkstock

In 2004, American neuroscientists Linda Buck and Richard Axel shared a Nobel Prize for their identification of the genes that control smell, findings which they first published in the early 1990s. Their work revived interest in the mysterious workings of our noses, interest which is now generating some surprising insights - not least that each of us inhabits our own, personal olfactory world.

"When I give talks, I always say that everybody in this room smells the world with a different set of receptors, and therefore it smells different to everybody," says Andreas Keller, a geneticist working at the Rockefeller University in New York City.

He also suspects that every individual has at least one odorant he or she cannot detect at all - one specific anosmia, or olfactory "blind spot", which is inherited along with his or her olfactory apparatus.

The human nose contains roughly 400 olfactory receptors, each of which responds to several odorants, and each of which is encoded by a different gene.

But, says Boris Schilling, a biochemist working for Givaudan, the world's largest flavour and fragrance company, based in Geneva, Switzerland, "unless you are dealing with identical twins, no two persons will have the same genetic make-up for those receptors".

The reason, according to Doron Lancet, a geneticist at the Weizmann Institute of Science in Israel, is that those genes have been accumulating mutations over evolution. This has happened in all the great apes, and one possible explanation is that smell has gradually become less important to survival, having been replaced to some extent by colour vision - as an indicator of rotten fruit, for example, or of a potentially venomous predator.

Once a deleterious mutation occurs in a certain gene, that gene ceases to produce a working receptor and becomes a "pseudogene".

But, Lancet says, although all people may have the same proportion of olfactory pseudogenes, each may have different ones. The result is that every individual has a different genetic "bar code" and a different combination of olfactory sensitivities.

That genetic variability is reflected in behavioural variability, as Keller, with colleague Leslie Vosshall and others, recently demonstrated when they asked 500 people to rate 66 odours for intensity and pleasantness.

The responses covered the full range from intense to weak, and from pleasant to unpleasant, with most falling in the moderate range - a classic bell curve in each case.

The researchers also tested people's subconscious responses to odorants, by presenting them at much weaker doses. At these doses, the volunteers were not conscious of smelling anything, but they did show physiological responses to the odorants, such as an increased skin conductance due to minute increases in perspiration.

"There's a surprisingly large variability in all those measures, and maybe more so in the subconscious than in the conscious measures," Keller says.

One compound that people famously perceive differently is androstenone, a substance that is produced in boars' testes and is also present in some people's sweat.

"For about 50 per cent of people androstenone is nothing," says Chuck Wysocki of the Monell Chemical Senses Center in Philadelphia.

"For 35 per cent it's a very powerful stale urine smell, and for 15 per cent it's a floral, musky, woody note."

Androstenone is a special case, however. Of the specific anosmias that have been identified to date, most affect between 1 and 3 per cent of the population, an example being the inability to smell vanilla.

In 2007, Keller, Vosshall and colleagues linked a specific anosmia for androstenone to the combination of alleles or variants a person inherits of a gene called OR7D4. It was the first such gene-behaviour link to be made in the domain of smell, but it convinced Keller that a person's olfactory blind spots can be directly linked to their genetic make-up.

At the University of Dresden in Germany, Thomas Hummel and colleagues are trying to identify other, similar links by carrying out genetic analyses in people who share a certain anosmia, to find out what receptors they lack. The study, which involves 3000 volunteers, has already revealed that, when it comes to anosmias, not all odorants are equal.

"Specific anosmias are significantly related to the molecular weight of the odour," Hummel says, with anosmias becoming more common as the molecular weight of the odorant increases.

Hummel suspects that the reason is that smaller, simpler molecules are more likely to fit the binding pockets of several receptors, making them detectable even if one of those receptors isn't working. A heavier, more complicated molecule, on the other hand, might only bind to one specific receptor, and so become undetectable if that receptor's gene becomes a pseudogene.

Most of the odorant "partners" of the 400 or so olfactory receptors - the so-called "primary scents" - remain unknown, but perfumers dream of the creative possibilities, if only they knew what they were.

That's because, although each receptor may bind to only one or a very few odorants, triggering an electrical signal to the brain, what the brain perceives is a result of the combination of incoming signals from all receptors.

It's that combinatorial power that creates the richness of our olfactory worlds. Think what a painter can do with three primary colours and a chef with five categories of taste, and imagine what a perfumer could do with a palette of 400 primary scents.

Lancet says that the genetic tools that are now available could help researchers to solve another olfactory puzzle, too: why some people are more sensitive overall to smells than others.

One in 5000 people is born without any sense of smell at all, while at the other end of the spectrum are those individuals who have a higher than average general sensitivity, some of whom may gravitate to the perfume industry.

He suspects that the biological culprits in this case are not the olfactory receptors themselves, which are responsible for specific anosmias, but the proteins that ensure the efficient transmission of the signals elicited by those receptors to higher processing areas in the brain - transmission pathways that are shared by all receptors.

"What is fascinating to me is the idea that we could discover a gene or genes that underlie this general sensitivity to odorants, so that we might be able to 'type' those professional noses and say, 'A-ha, we now understand why you are in your profession,"' Lancet says.

The implications of the new research go wider than smell, however. Most of our sensation of taste comes from the odorants in food stimulating our olfactory receptors.

"The wonderful enjoyment of a fresh tomato is practically only in the nose," Lancet says.

Awareness of individual variation in smell has already filtered through to the wine world, launching a debate about how valuable experts' advice really is, when they may be having different smell - and hence taste - experiences from other people.

The science of smell could even throw light on patterns of human disease. It's now known that many diseases are polygenic - that is, they are the products of the cumulative, small effects of many genes, just as a person's range of olfactory sensitivities is the product of a certain combination of genes and pseudogenes. In both cases, the effect of a single mutation is minimal, and mutations spread fairly easily through a population. With monogenic diseases such as haemophilia, on the other hand, a single mutation is so disruptive that natural selection generally acts to eliminate it from the gene pool, usually by killing an affected individual before he or she reaches reproductive age.

Thanks to Buck and Axel, scientists know a lot more about the genetics of olfaction than they do about most polygenic diseases, and they are now studying the former in order to understand how the latter arise and spread through a population - an inspired piece of lateral thinking which the Nobel Prize committee may or may not have foreseen when they bestowed their honour in 2004.

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