The smells of silence

THE MILITARY triumphs of Emperor Napoleon Bonaparte have been chronicled in great detail. Also well chronicled is the tempestuous love life he and his wife Josephine had for decades. Devoted to her, he would take time out during his military campaigns to write to her regularly. In a rather famous one of these, he wrote: "Beloved, I shall return in two weeks. Do not bathe until I come back. I want you to smell the same as when I left you". Reading this, one gets the impression that he had a queer sense of smell. The notion gains strength when we also read that he detested perfumes. In today's parlance, he was an olfactory freak.

Of the five senses, that of smell or the olfactory sense is the least understood. Many animals possess a keener sense of smell than we do. The dog is reputed to be able to smell a single molecule. When we consider that the air around us is full of molecules of all sorts — some smelly and some odourless, to capture that particular one, recognise and react to it is literally a needle-haystack enterprise. Not only should the olfactory system be extremely sensitive, but it should also be discriminatory and identify one odour from another.

We are gradually beginning to understand the basis of operation of the olfactory system. The primary condition is that the material being smelt must be in the vapour state — not in the liquid or solid state. This is so because the molecule has to travel or waft its way to the sensory organ of the organism. I use the term sensory organ here because while it is indeed the nose in many animals, it is the tongue (forked or otherwise) of the snake and other reptiles. Of course in these instances, we do not use the words smell and nose, but the principle and the process are the same.

And what are these? The detector system is invariably a receptor surface on which the odour molecule lands. This surface is generally a protein molecule. Each receptor molecule presents its own characteristic surface of a given shape. Only that odorant molecule can sit or fit there whose shape complements that of the receptor surface. This is the `glove fits, wear it' model, or the lock and key idea that the German chemist Emil Fischer propounded a century ago with regard to enzymes. It is interesting how the same idea or principle repeats in different situations in biology. A large polymer molecule — be it protein, DNA, RNA or polysaccharide — adopts a particular three-imensional shape in its `native' state in the cell or tissue. What this shape would be is determined by the temperature, pressure, concentration, other molecules in vicinity, pH and so forth — the so-called ambient conditions. This shape does not always have to be regular or pretty like the DNA double helix or the collagen triplex. Indeed, the shapes (or the conformations as it is termed) are quite diverse — each molecule with it own surface pockets, grooves, patches and crevices. And each such shape has a receptor surface into which only an appropriately shaped partner molecule can fit.

Herein is the secret of biomolecular specificity. Variety in shape leads to the multitude of specific interactions. The fields of immunology and vaccines, pharmacology and drug action, and nutrition and metabolism are all manifestations of this principle of shape complementarity. And it appears that the sense of smell also uses this principle. Variety might be the spice of life, but so is repeating a well-working formula. The strategy here is to keep the formula going and build variations on the theme as needed.

As the river of evolution flows, not only do organisms develop custom-made adaptations, but they also jettison some properties in favour of others. You lose some but gain some. We get glimpses of these events in evolutionary history when we read the DNA sequences in the genomes of organisms. Thanks to the advances in the technology of reading DNA sequences, the genomes of many organisms have already been read and deposited in public-access repositories. And those of many more, for example wheat, the cow, dog, buffalo, chimpanzee and so on, are being sequenced and the data continually deposited in these databanks. This advance has given rise to a new field called comparative genomics which, as the name indicates, is concerned with studying the similarity and differences between the information contained in the genomes of different organisms. Comparative genomics offers, to date, the most eloquent evidence for the theory of natural selection and Darwin's theory of the origin of species. How aptly Omar Khayyam wrote: "The moving finger writes, and having writ moves on"!

Such comparison of genetic information content, particularly that concerned with the genes for smell, has given us interesting insights. Mr. Yoav Gilad, a Ph.D. student working with his Prof. Doron Lancet and another student Orna Man of the Weizmann Institute, Israel, collaborated with Prof. Svante Paabo of the Max Planck Institute of Evolutionary Anthropology in Leipzig, Germany and analysed the olfactory genes of the mouse, rhesus monkey, orangutan, chimpanzee and humans. The results, published in the March 18 issue of the Proceedings of the National Academy of Sciences, U. S. show that as many as 60 per cent of the 1000 genes responsible for smell perception are disabled or disrupted in us humans. These disrupted gene sequences are called pseudogenes. They are `pseudo' because they resemble the real gene in appearance (the sequence of bases) but not in action. They are not expressed and translated to yield the appropriate receptor protein. A pseudogene is one that does not do what the real one does. It is thus a useless item of baggage that the organism carries — a vestige of history, an heirloom of no utility.

When Gilad and associates analysed the DNA sequences of the 1000 genes super-family which encode the olfactory receptor proteins in mammals, they found that about 200 of these turn out to be inactivated in the mouse. What this means is that an ancestor of the mouse, the tiny one-inch-long Hardocodium wui that lived 150 million years (Myr) ago, might have been a super-smeller. As the mouse evolved from this ancestor, it lost 200 of the smell genes and became a less efficient sniffer. However, the mouse did gain some other traits — size, stamina, to name but two.

As we move in evolution from the mouse to monkeys and apes, we traverse a time zone of 100 million years. And the number of pseudogenes, or olfactory receptor genes silenced in the rhesus monkey, the orangutan, gorilla and chimp, increases to about 32 per cent. Over millions of years, though, this olfactory loss only doubled at best. Our closest relative, the chimpanzee, still has a pretty efficient sense of smell — not as good as the mouse but pretty good.

When the researchers looked at the olfactory gene repertoire in humans, they were in for a surprise. The fraction of olfactory receptor genes silenced in man is as high as 54 per cent, almost twice that of the chimp or gorilla and thrice that of the mouse. Now the human-mouse separation is about 110 Myr, but the human-ape distance is hardly 3-5 Myr. Why this dramatically large decline in olfactory sense in such a short time? This drop appears to be a purely Homo Sapiens feature. At the cost of olfactory sensitivity, we humans have gained better colour vision, better vocalization, and the capacity to tell other humans by facial appearance than by smell (Napoleon, listen!), and so on. We are, I would like to believe, brainier than the mouse or the monkey.

D. Balasubramanian