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标 题: (FW)Linda Buck: 2004 Nobel Prize Co-Reci
发信站: Unknown Space - 未名空间 (Mon Oct 4 21:22:39 2004) WWW-POST

For people to appreciate the work of Linda Buck, this is an overview by Shatz.

Linda Buck: 2004 Nobel Prize Co-Recipient
A Journey into the World of Sensory Perception


By Carla J. Shatz, PhD
Chair, Department of Neurobiology
Harvard Medical School

One of the most important areas of investigation in the neurosciences is the
mechanism of sensory perception. How do we transduce environmental stimuli
such as light, sound, and smells, into a neural signal, and then how is this
signal processed by the nervous system to generate perception? This process
underlies our ability to function in the world, to care for ourselves and to
relate to others, and when we lose the ability to sense the world either
through loss of sensory neurons or via damage to central processing
structures, life is diminished and we become dependent for even the most basic
aspects of daily routine.

Until Dr. Buck's pioneering research, a major mystery was how odors are
transduced by the specialized neurons in the olfactory epithelium of the nose.
She made the extraordinary discovery that a G-protein coupled gene family
encodes approximately 1000 candidate odorant receptors. Her ensuing studies
exploring the organization of these receptors and showing that they can
function to transduce odors has broken open the field and made it possible for
us to understand how smell is processed by the olfactory system. Her studies
show that the strategies used by the olfactory system to process information
are in stark contrast to those used by the visual system, where there are only
four types of receptors (rods and three cone types), and they imply very
different principles of central information processing in the two sensory
systems. Moreover, Dr. Buck discovered a distantly-related gene family that
forms the taste receptors, and she is now beginning to explore their function
as well.

Dr. Buck essentially created the field of molecular mechanisms of olfactory
sensory transduction in 1991, when she was a postdoctoral fellow in the
laboratory of Richard Axel at Columbia, and she has been instrumental in its
evolution thereafter. This field is one of the most exciting and expanding
areas of neuroscience. Her studies of how information from the periphery -
from the individual subsets of odorant receptors - is combined centrally, and
her creative molecular approaches to trace connectivity in the olfactory
system are innovative and necessary steps towards developing new techniques
for exploring the mammalian central nervous system.

Linda Buck, who since 2002 has been a full member at the Fred Hutchinson
Cancer Research Center, joined the faculty of Harvard Medical School in 1991
as an assistant professor of neurobiology located in the Department of
Neurobiology at the Quad. Dr. Buck was advanced to associate professor in
1996, and to professor in 2000. Concurrently, Dr. Buck was also an
investigator of the Howard Hughes Medical Institute. Dr. Buck received her
Ph.D. in immunology in 1980 from University of Texas, Southwestern, in the lab
of Dr. Ellen Vitella. She then spent two years (1980-82) doing postdoctoral
research in immunology at Columbia University College of Physicians and
Surgeons (laboratory of Dr. Benvenuto Pernis), at which time she made a major
career change and moved to the Molecular Neuroscience laboratory of Richard
Axel. From 1982-1991, she conducted postdoctoral research in the Axel lab, and
it was there that she made her groundbreaking discovery of the olfactory
receptor gene family which consists of a large gene family of G-protein
coupled receptors that are selectively expressed in olfactory epithelial
neurons. This discovery, now a classic, (published in Cell,1991, resulted from
a one-woman crusade to clone olfactory receptor genes, which is now the stuff
of legend.

In her own lab at Harvard Medical School, Dr. Buck continued her
groundbreaking studies of organization and function of the olfactory system.
First, a bit of perspective: before Linda's discovery, the problem of
olfactory coding was dense and impossible to unravel. Unlike in the visual
system or the auditory systems, where there is an orderly representation of
the sensory periphery (the retina or the cochlea) conveyed to central
structures that implies an underlying functional organization, such is not the
case in the olfactory system. The first synapse in the olfactory system,
between olfactory epithelial neurons and the glomeruli, represented a Rosetta
Stone of olfaction. Seemingly randomly located olfactory sensory neurons
connect with each glomerulus. Does each glomerulus receive inputs from a
mixture of sensory receptors transducing many different odors, or is there a
single odorant receptor-to-glomerulus connectivity rule? This question had
been debated endlessly in the literature, but without knowing the molecular
identity of the receptors, the question was impossible to answer.

It was this answer that Linda provided as an assistant professor at HMS: each
olfactory sensory neuron expresses one OR (olfactory receptor) gene (Ressler
et al, Cell, 1993), and olfactory sensory neurons expressing one type of OR
gene send their connections to one or at most two glomeruli (Ressler et al,
Cell, 1994). Thus, the olfactory bulb has a fixed spatial map of odorant
quality, and the brain receives information in units defined by individual
olfactory receptors. Without her discoveries, the field would still be stuck
in the dark ages with no way to understand the molecular logic of smell.

Dr. Buck next discovered another related family of G-protein coupled receptors
that are expressed by neurons in the Vomeronasal organ of the nose and likely
encode pheromone receptors. Again, she approached the problem in a beautiful
and systematic fashion, first by showing that like their counterparts in the
main olfactory bulb, receptors in the vomeronasal organ are also likely to
signal using a G-protein coupled cascade (J. Neurosci., 1996). Then she
identified and characterized a multigene family encoding approx. 140 G-coupled
receptors belonging to a family that is quite different from the OR's of the
main bulb (Matsumani et al, Cell, 1997). This family is complementary to
another VNO gene family discovered concurrently by Axel and DuLac. Indeed, the
co-discovery by both the Buck and Axel Labs underscores the quality and
independence of the work Linda conducted.

From these discoveries, Dr. Buck proceeded to address another major issue in
olfactory sensory transduction: what is the response profile of a given
ordorant receptor? For unclear reasons, it is still not possible to express
successfully olfactory receptor genes in heterologous cells. Linda took a very
clever but difficult alternate approach, which was to use calcium imaging to
record the response of individual sensory neurons to known odorants, and then
to use single cell PCR to identify the OR receptor gene expressed by that
neuron. Her results show that there is a combinatorial code for odorant
recognition: one OR can recognize different ororants, and a single odorant is
recognized by olfactory neurons expressing different OR genes (Malnic et al.,
Cell, 1999). This paper may once again change the way that important problems
in sensory perception are studied.

As if her work on olfactory receptors was in and of itself not sufficiently
groundbreaking, Dr. Buck went on to publish another landmark discovery of
candidate Taste Receptors (Matsunami et al, (2000) Nature 404: 601), based on
the knowledge that animals deficient in gustducin, a G-protein coupled
receptor exclusively expressed in taste cells, are defective in taste
perception. In this instance, her search for taste receptors began with clever
"genome mining," and ultimately with the demonstration that in situ
hybridization signals for these candidates are restricted to taste cells in
the papillae. Her discovery coincided with a rival publication from the Zuker
lab (UCSD) which also demonstrated functionally that some members of this gene
family are required for the recognition of bitter.

Linda Buck has been conducting groundbreaking work throughout her career.
Perhaps the clearest assessment of Dr. Buck's impact is that it is impossible
to imagine a course in neuroscience or a textbook of neuroscience that does
not incorporate her work on olfactory receptor genes, their expression
patterns, the corresponding innervation patterns of the primary sensory cells,
and the odorant specificities of the receptor proteins.


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