The Molecular Biology of Smell 
Richard Axel, M.D. — Investigator 
Dr. Axel is also Higgins Professor of Biochemistry and Molecular Biophysics and of Pathology at Columbia 
University College of Physicians and Surgeons. He received his undergraduate degree from Columbia 
College and his M.D. degree from the Johns Hopkins University School of Medicine. He then came to 
Columbia University as a resident in pathology at the College of Physicians and Surgeons. He held 
fellowships in Columbia's Institute of Cancer Research (in Sol Spiegelman's laboratory) and the 
Department of Pathology. Dr. Axel is a member of the National Academy of Sciences. Among his many 
honors are the Eli lilly Award in Biological Chemistry and the Richard iounsbery Award from the 
National Academy of Sciences. 
PERIPHERAL neurons in vertebrate sensory 
systems respond to environmental stimuli 
and transmit these signals to higher sensory 
centers in the brain, where they are processed to 
allow the discrimination of complex sensory in- 
formation. Mammals possess an olfactory sensory 
system of enormous discriminatory power. Hu- 
mans, for example, are thought to be capable of 
distinguishing among thousands of distinct 
odors. Even subtle alterations in molecular struc- 
ture of an odorant can lead to profound changes 
in perceived odor quality. How is this diversity 
and specificity accomplished? The detection of 
chemically distinct odors presumably results 
from the association of odorants with specific re- 
ceptors on olfactory neurons that reside in spe- 
cialized epithelium in the nose. The brain must 
distinguish which receptors or which neurons 
have been activated to allow the discrimination 
among different odorant stimuli. What mecha- 
nisms have vertebrates evolved to allow the recog- 
nition of this huge array of odorant molecules? 
How does the brain know what the nose is smell- 
ing? Insight into these problems is likely to de- 
pend on the isolation and characterization of the 
odorant receptors expressed in the nose. 
We have recently identified an extremely large 
multigene family whose members are likely to 
encode a diverse family of odorant receptors. We 
have determined the sequence of 30 genes and 
have deduced the protein sequence of 30 differ- 
ent putative olfactory receptors. The olfactory 
proteins are clearly members of a superfamily of 
receptors that traverse the membrane seven 
times. Analysis of the proteins reveals structural 
features that may render this family particularly 
well suited for the detection of a diverse array of 
structurally distinct odorants. 
These olfactory proteins can be divided into 
several different subfamilies that exhibit signifi- 
cant divergence in the region of the receptor mol- 
ecule thought to interact with the odorous li- 
gand. These observations suggest a model in 
which each of the individual subfamilies encodes 
receptors that bind distinct structural classes 
of odorants. Within a given subclass of odorous 
ligands, the members would recognize more sub- 
tle variations among odor molecules of a given 
structural class. As such, this superfamily of mole- 
cules would be uniquely suited to its putative 
role in the fine discrimination of odor molecules 
of subtly different structures. 
The isolation of this large family of genes en- 
coding the receptor molecules immediately pro- 
vides one solution to the problem of olfactory 
perception. How do we recognize so diverse an 
array of odors? At one extreme, we would argue 
that the recognition of diverse odorants could be 
accomplished by a small number of promiscuous 
receptors, each capable of interacting with sev- 
eral structurally distinct odor molecules. Alterna- 
tively, olfactory perception would result from 
the presence of a large number of different recep- 
tor molecules, each capable of interacting with 
one or a small number of specific odorants. The 
size of the gene family we have characterized 
suggests that there are indeed a very large number 
of odorant receptors, each capable of interacting 
with a small number of odorous ligands. These 
observations are in sharp contrast to other sensory 
systems, such as vision or touch, where discrimi- 
nation of sensory information is accomplished by 
a rather small number of receptor modalities. 
How then does the brain distinguish which re- 
ceptors or which neurons have been activated to 
allow the discrimination between different odor- 
ant stimuli? In other sensory systems, such as vi- 
sion and touch, neurons in the brain are orga- 
nized in a topographic map that identifies the 
position of a sensory stimulus. Thus the position 
of a given neuron in the brain is used to define the 
location of a sensory stimulus within the external 
environment. Olfactory processing does not ex- 
tract spatial features of the odorant stimulus. Re- 
lieved of the necessity to encode information 
about the spatial localization of a sensory stimu- 
lus, the olfactory system may use spatial segrega- 
tion of sensory input solely to encode the identity 
of the stimulus itself. Recent data utilizing the 
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