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NOBEL FOR MEDICINE, 2004
The Nobel Prize in Physiology or Medicine for 2004
awarded jointily to Richard Axel and Linda B. Buck
for their discoveries of "odorant receptors and the organization
of the olfactory system"
The sense of smell long remained the most enigmatic of our
senses. The basic principles for recognizing and remembering
about 10,000 different odours were not understood. This year's
Nobel Laureates in Physiology or Medicine have solved this
problem and in a series of pioneering studies clarified how
our olfactory system works. They discovered a large gene family,
comprised of some 1,000 different genes (three per cent of
our genes) that give rise to an equivalent number of olfactory
receptor types. These receptors are located on the olfactory
receptor cells, which occupy a small area in the upper part
of the nasal epithelium 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 odours. The cells send thin nerve
processes directly to distinct micro domains, glomeruli, in
the olfactory bulb, the primary olfactory area of the brain.
Receptor cells carrying the same type of receptor send their
nerve processes to the same glomerulus. From these micro domains
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. Therefore,
we can consciously experience the smell of a lilac flower
in the spring and recall this olfactory memory at other times.
Richard Axel, New York, USA, and Linda Buck, Seattle, USA,
published the fundamental paper jointly in 1991, in which
they described the very large family of about one thousand
genes for odorant receptors. Axel and Buck have since worked
independent of each other, and they have in several elegant,
often parallel, studies clarified the olfactory system, from
the molecular level to the organization of the cells.
The olfactory system is important for life quality
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.
A unique odour can trigger distinct memories from our childhood
or from emotional moments – positive or negative –
later in life. A single clam that is not fresh and will cause
malaise can leave a memory that stays with us for years, and
prevent 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.
Olfaction is of central importance for most species
All living organisms can detect and identify chemical substances
in their environment. It is obviously of great survival value
to be able to identify suitable food and to avoid putrid or
unfit foodstuff. Whereas fish has a relatively small number
of odorant receptors, about one hundred, mice – the
species Axel and Buck studied – have about one thousand.
Humans have a somewhat smaller number than mice; some of the
genes have been lost during evolution.
Smell is absolutely essential for a newborn mammalian pup
to find the teats of its mother and obtain milk – without
olfaction the pup does not survive unaided. Olfaction is also
of paramount importance for many adult animals, since they
observe and interpret their environment largely by sensing
smell. For example, the area of the olfactory epithelium in
dogs is some forty times larger than in humans.
A large family of odorant receptors
The olfactory system is the first of our sensory systems
that has been deciphered primarily using molecular techniques.
Axel and Buck showed that three per cent 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.
One type of odorant receptor in each olfactory receptor cell
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 odours 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 colours 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
odours.
Olfactory receptor cells activate micro regions in the olfactory
bulb
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 in mice 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 (see figure).
In the glomeruli we find 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 odour. This
is interpreted and leads to the conscious experience of a
recognizable odour.
Pheromones and taste
The general principles that Axel and Buck discovered for
the olfactory system appears to apply also to other sensory
systems. Pheromones are molecules that can influence different
social behaviours, especially in animals. Axel and Buck, independent
of each other, discovered that pheromones are detected by
two other families of GPCR, localized to a different part
of the nasal epithelium. The taste buds of the tongue have
yet another family of GPCR, which is associated with the sense
of taste.
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