COMMENTARY
Model organisms: comparative physiology or just physiology?
Kevin
Strange, Associate Editor
American Journal of Physiology- Cell Physiology, Vanderbilt University Medical Center, 21st Ave. S & Garland St., Nashville, TN 37232-2520, (E-mail: kevin.strange{at}mcmail.vanderbilt.edu), December 2000, Volume 279 (48)
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ARTICLE |
A new field referred to as "functional genomics" (or, from a
physiologist's perspective, "physiological genomics") has emerged in the wake of genome sequencing. Functional genomics is defined as the
assignment of function to identified genes and, importantly, the
elucidation of the organization, integration, and control of networks
of proteins that give rise to specific biological processes. It is
widely recognized that the significant challenges posed by attempts to
define the genetic basis of physiology necessitate the study of
experimentally more manipulable "model organisms" (2, 5,
6).
What is a model organism? In the very broadest sense, a model organism
can be defined as any organism that provides an experimental platform
for the study of a biological problem. However, in the post-genome
sequencing era, the term "model organism" has taken on a more
explicit meaning. Model organisms are "simple" organisms that
provide unique experimental advantages for defining gene function.
These advantages include a short life cycle, cellular and molecular
manipulability, and the ability to carry out relatively straightforward
and rapid genetic analyses of complex physiological processes. Model
organisms include, but are not limited to, bacteria, yeast,
Arabidopsis, Caenorhabditis elegans,
Dictyostelium, and Drosophila.
C. elegans serves as a superb example of the experimental
advantages that are afforded by model organisms. The nematode genome was the first metazoan genome to be fully sequenced (5).
Genome sequencing allows for the identification and rapid cloning of genes and cDNAs of interest. It also allows comparison of genes in
evolutionarily divergent organisms. Such comparisons yield important
and experimentally testable clues about biologically conserved functions.
DNA microarrays of the entire C. elegans genome have
recently been developed by Stuart Kim and coworkers at Stanford
University (http://cmgm.stanford.edu/~kimlab/wmdirectorybig.html),
making it possible to identify the complement of genes expressed in
specific cell types, different worm developmental stages, and mutant
worm strains. A genome scale map of protein-protein interactions is currently being developed for C. elegans (13).
This map will provide invaluable clues for elucidating gene function
not only in C. elegans but also in mammals and other
organisms. C. elegans exhibits remarkable "molecular
manipulability." It is relatively straightforward, rapid, and
economical to associate genes with physiology by generating mutant and
knockout animals and transgenic worm strains expressing reporter
molecules and mutant or foreign proteins (3, 8-10).
By using double-stranded RNA-mediated gene interference approaches
(4, 7, 11), investigators can effectively "knockout"
the function of a targeted gene by performing an overnight experiment.
The average life span of C. elegans is about 2-3 wk.
This short life cycle coupled with the ease of crossing and
self-fertilizing individual worms provides the basis for powerful
genetic analyses of complex physiological processes (1).
Adult nematodes have 302 neurons. The interconnections between these
neurons have been fully mapped providing investigators with the first
and only complete wiring diagram of an animal's nervous system
(14). In addition, a complete cell lineage map that
defines cell fate from fertilized egg to 959-cell adult worm has been
developed (12). These tools allow detailed study of such
fundamental processes as cell division, cell-fate determination,
embryogenesis, and the behavior and development of neural circuits.
Ion channels and solute transporters are essential players in cellular,
organ, and whole organism physiology. Defining the regulation, specific
roles, and molecular structure of these proteins represents the leading
edge of the field of membrane transport biology. Model organisms give
membrane transport physiologists a powerful new set of experimental
tools. Papers published under this Special Topic utilize model
organisms to characterize the physiological functions and regulation of
ion channels and solute transporters. The experimental strategies
employed by the authors of these papers will include state-of-the-art
molecular and genetic approaches as well as classic electrophysiology,
cellular imaging, and transport assays.
The utilization of model organisms for studies of basic physiological
processes is a rapidly expanding field at the leading edge of
biological research. My goal in organizing and editing this section is
to stimulate cross talk between model organism biologists and
vertebrate physiologists. By doing so, I hope that novel physiological
insights gained from model organisms will be more rapidly translated
into experimentally testable hypotheses in mammals. Similarly, I hope
that vertebrate physiologists will begin to exploit the experimental
advantages of model organisms to address basic problems relevant to
mammalian physiology. Completion of genome-sequencing efforts has
revolutionized biology and taught us that there is an extraordinary
degree of conservation of genes among widely divergent species. What we
learn about function in a model organism can clearly be leveraged into
deeper understanding of the genetic basis of human physiology and pathophysiology.
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