Sense of Smell Wins Nobel Prize

Medical Authors and Editors: Barbara K. Hecht, Ph.D. and Frederick Hecht, M.D.

Oct 4, 2004 -- Two American investigators Richard Axel and Linda B. Buck have received the 2004 Nobel Prize in Physiology or Medicine for their work on "odorant receptors and the organization of the olfactory system" -- the sense of smell.

In 1991 Axel and Buck jointly discovered a very large family of about one thousand genes for odorant receptors. They have since worked independently and have in elegant, often parallel, studies they have clarified the olfactory system from the molecular level to the organization of the cells.

Dr. Axel is at the Howard Hughes Medical Institute and Columbia University in New York, while Dr. Buck is at the Fred Hutchinson Cancer Research Center in Seattle. The Sense of Smell

The sense of smell has long remained the most enigmatic of our senses. The basic principles for recognizing and remembering about 10,000 different odors have not been understood. Drs. Axel and Buck have "solved this problem and in a series of pioneering studies clarified how our olfactory system works," according to the Nobel Assembly at the Karolinska Institute in Stockholm.

The Gene Family

The gene family that Axel and Buck discovered contains 1,000 or so genes. It is truly a superfamily of genes, accounting for about 3% of all human genes. The olfactory genes in this superfamily gives rise to an equivalent number of olfactory receptor types. These receptors are located on specialized cells called olfactory receptor cells, which occupy a small area in the upper part within the nose and detect the inhaled odorant molecules.

Each olfactory receptor cell possesses only one type of odorant receptor, and each receptor can detect a limited number of odorant substances. Our olfactory receptor cells are therefore highly specialized for a few odors.

Smell Cells

The olfactory receptor cells send thin nerve processes directly to distinct microdomains, called glomeruli, in the olfactory bulb. The olfactory bulb is the primary area of the brain for olfaction. Receptor cells carrying the same type of receptor send their nerve processes to the same glomerulus.

From these microdomains in the olfactory bulb, the information is relayed further to other parts of the brain, where the information from several olfactory receptors is combined, forming a pattern.

Lilacs and Strawberries

Thanks to this olfactory system, we can consciously experience the smell of a lilac flower in the spring and recall this olfactory memory at other times, noted the Nobel Assembly.

When something tastes really good it is primarily activation of the olfactory system which helps us detect the qualities we regard as positive. A good wine or a sunripe wild strawberry activates a whole array of odorant receptors, helping us to perceive the different odorant molecules.

Loss of Sense of Smell

A unique odor can trigger distinct memories from our childhood or from emotional moments later in life. A single clam that is not fresh and makes us sick can leave a memory that stays with us for years, and prevents us from ingesting any dish, however delicious, with clams in it.

To lose the sense of smell is a serious handicap -- we no longer perceive the different qualities of food and we cannot detect warning signals, for example smoke from a fire.

The following sections provide more information about the science of our system of smell and are based upon the press release today from the Nobel Assembly.

Deciphering a Sensory System

The olfactory system is the first of our sensory systems that has been deciphered primarily using molecular techniques. Axel and Buck showed that 3% of our genes are used to code for the different odorant receptors on the membrane of the olfactory receptor cells. When an odorant receptor is activated by an odorous substance, an electric signal is triggered in the olfactory receptor cell and sent to the brain via nerve processes.

Each odorant receptor first activates a G protein, to which it is coupled. The G protein in turn stimulates the formation of cAMP (cyclic AMP). This messenger molecule activates ion channels, which are opened and the cell is activated. Axel and Buck showed that the large family of odorant receptors belongs to the G protein-coupled receptors (GPCR).

All the odorant receptors are related proteins but differ in certain details, explaining why they are triggered by different odorous molecules. Each receptor consists of a chain of amino acids that is anchored into the cell membrane and traverses it seven times. The chain creates a binding pocket where the odorant can attach. When that happens, the shape of the receptor protein is altered, leading to G protein activation.

Each Olfactory Cell is Unique

Independently, Axel and Buck showed that every single olfactory receptor cell expresses one and only one of the odorant receptor genes. Thus, there are as many types of olfactory receptor cells as there are odorant receptors. It was possible to show, by registering the electrical signals coming from single olfactory receptor cells, that each cell does not react only to one odorous substance, but to several related molecules -- albeit with varying intensity.

Buck's research group examined the sensitivity of individual olfactory receptor cells to specific odorants. By means of a pipette, they emptied the contents of each cell and showed exactly which odorant receptor gene was expressed in that cell. In this way, they could correlate the response to a specific odorant with the particular type of receptor carried by that cell.

Most odors are composed of multiple odorant molecules, and each odorant molecule activates several odorant receptors. This leads to a combinatorial code forming an "odorant pattern" - somewhat like the colors in a patchwork quilt or in a mosaic. This is the basis for our ability to recognize and form memories of approximately 10,000 different odors.


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Activating the Brain

The finding that each olfactory receptor cell only expresses one single odorant receptor gene was highly unexpected. Axel and Buck continued by determining the organization of the first relay station in the brain. The olfactory receptor cell sends its nerve processes to the olfactory bulb, where there are some 2,000 well-defined microregions, glomeruli. There are thus about twice as many glomeruli as the types of olfactory receptor cells.

Axel and Buck independently showed that receptor cells carrying the same type of receptor converge their processes into the same glomerulus, and Axel's research group used sophisticated genetic technology to demonstrate the role of the receptor in this process. The convergence of information from cells with the same receptor into the same glomerulus demonstrated that also glomeruli exhibit remarkable specificity.

Conscious of a Smell

In the glomeruli there are not only the nerve processes from the olfactory receptor cells but also their contacts with the next level of nerve cells, the mitral cells. Each mitral cell is activated only by one glomerulus, and the specificity in the information flow is thereby maintained. Via long nerve processes, the mitral cells send the information to several parts of the brain. Buck showed that these nerve signals in turn reach defined micro regions in the brain cortex. Here the information from several types of odorant receptors is combined into a pattern characteristic for each odor. This is interpreted and leads to the conscious experience of a recognizable odor.

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