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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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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1.   Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77: 71-94, 1974[Abstract/Free Full Text].

2.   Cowley, AW, Jr. The emergence of physiological genomics. J Vasc Res 36: 83-90, 1999[ISI][Medline].

3.   Fire, A. Integrative transformation of Caenorhabditis elegans. EMBO J 5: 2673-2680, 1986[ISI].

4.   Fire, A, Xu S, Montgomery MK, Kostas SA, Driver SE, and Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391: 806-811, 1998[ISI][Medline].

5.   Hodgkin, J, Plasterk RHA, and Waterston RH. The nematode Caenorhabditis elegans and its genome. Science 270: 410-414, 1995[Abstract].

6.   Kao, CM. Functional genomic technologies: creating new paradigms for fundamental and applied biology. Biotechnol Prog 15: 304-311, 1999[ISI][Medline].

7.   Lin, R, and Avery L. RNA interference. Policing rogue genes. Nature 402: 128-129, 1999[ISI][Medline].

8.   Liu, LX, Spoerke JM, Mulligan EL, Chen J, Reardon B, Westlund B, Sun L, Abel K, Armstrong B, Hardiman G, King J, McCague L, Basson M, Clover R, and Johnson CD. High-throughput isolation of Caenorhabditis elegans deletion mutants. Genome Res 9: 859-867, 1999[Abstract/Free Full Text].

9.   Mello, CC, Kramer JM, Stinchcomb D, and Ambros V. Efficient gene transfer in C. elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J 10: 3959-3970, 1991[Abstract].

10.   Miller, DM, Desai NS, Hardin DC, Piston DW, Patterson GH, Fleenor J, Xu S, and Fire A. Two-color GFP expression system for C. elegans. Biotechniques 26: 914-918, 1999[ISI][Medline].

11.   Montgomery, MK, Xu S, and Fire A. RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegans. Proc Natl Acad Sci USA 95: 15502-15507, 1998[Abstract/Free Full Text].

12.   Sulston, JE, Schierenberg E, White JG, and Thomson JN. The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev Biol 100: 64-119, 1983[ISI][Medline].

13.   Walhout, AJ, Sordella R, Lu X, Hartley JL, Temple GF, Brasch MA, Thierry-Mieg N, and Vidal M. Protein interaction mapping in C. elegans using proteins involved in vulval development. Science 287: 116-122, 2000[Abstract/Free Full Text].

14.   White, JG, Southgate E, Thomson JN, and Brenner S. The structure of the nervous system of the nematode C. elegans. Philos Trans R Soc Lond B Biol Sci 314: 1-340, 1986[ISI].


Am J Physiol Cell Physiol 279(6):C2050-C2051
0363-6143/00 $5.00 Copyright © 2000 the American Physiological Society




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