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March 25, 2005
The Prognosis for Research on Model Organisms
Though more than a million described species live on Earth, most
basic knowledge about the properties of cells has come from study of
just a few “model organisms,” including the bacterium
Escherichia coli, the yeast Saccharomyces
cerevisiae, the nematode worm Caenorhabditis
elegans, the mustard plant Arabidopsis thaliana, the
fruit fly Drosophila melanogaster, and the mouse Mus
musculus. But investments in biomedical research often are
justified through their potential applications to human disease. As
researchers increasingly gain the ability to study diseases directly in
humans, will research on model organisms decline?
That's unlikely, say Stanley Fields, a Howard Hughes Medical
Institute investigator at the University of Washington, and Mark
Johnston at Washington University School of Medicine in St. Louis, in
an article published in the March 25, 2005, issue of Science
entitled, “Whither Model Organism Research?”
“Funding pressures and calls for translational research are orienting research toward humans and human diseases. But there’s still a lot to be gained by studying model organisms.”
Stanley Fields
“Funding pressures and calls for translational research are
orienting research toward humans and human diseases,” said
Fields. “But there's still a lot to be gained by studying model
organisms.”
With that said, however, Fields and Johnston believe that within the
next few decades, research into model organisms will reach a pivotal
juncture. Starting with yeast and progressing through the more complex
organisms, the basic biology of model organisms will be
“solved,” they said. In other words, biologists will
understand, at least in outline, all of the basic mechanisms of the
cell, including the functions of nucleic acids and proteins, the
signaling pathways by which cells communicate, and the selective
expression of subsets of genes.
“Our contention is that at some point, no basic biological
processes in these organisms will be obscure,” said Fields, who
has spent much of his career studying genetic processes in yeast.
“Within twenty to thirty years, for example, we predict that
there won't be key biological processes in yeast that we don't
understand, even if we don't know every detail of those processes. At
that point, we will have to face the fact that we have been very
successful in what we set out to do, and we'll have to move
on.”
“Some people will say that to speak in terms of a `solution'
is ridiculous, but I believe they are wrong,” said Johnston, also
a specialist in yeast genetics. “Of course, you can always find
more detailed questions to answer. But the basic biology of these
organisms will be understood at a reasonable level of
detail.”
Once that biology is understood, the character of model organism
research inevitably will change. In some cases, the quantity of
research on an organism may decline, as happened with E. coli in
the 1980s. However, Fields and Johnston insist that model organisms
will remain critical to future investigations of human biology, for
five main reasons.
First, model organisms will continue to provide insights into basic
cellular processes, even after the organisms' basic molecular
mechanisms have been solved. For example, when a human gene involved in
a disease is identified, researchers often will be able to examine the
function of a homologous gene in model organisms. “For basic
cellular processes, you want to work with the simplest organism that
carries out that process,” said Fields.
Second, biologists will continue to use model organisms to examine
disease processes more directly. For instance, Alzheimer's disease,
Parkinson's disease, and Huntington's disease all involve misfolding or
aggregation of proteins, and similar molecular malformations occur
naturally or can be induced in yeast, worms, and flies. Model organisms
have genes involved in aging that may play analogous roles in humans.
Studies of yeast will shed light on diseases caused by single-celled
organisms, just as studies of fruit flies could help control the
mosquitoes that carry malaria.
Third, model organisms will be essential to understanding the
complex biological networks that control life processes. Basic cellular
processes such as DNA replication involve elaborate molecular
mechanisms with many components acting in multiply connected ways.
Studying how these networks operate “will bestow upon biologists
the predictive powers and design capabilities long held by physicists
and engineers,” Fields and Johnston write. In particular, study
of molecular networks will be essential in understanding complex
diseases, which result from the effects of many genes and environmental
influences working together. “Model organisms will be the proving
ground for studies of complex diseases, which is the frontier in
biology,” said Johnston.
Fourth, critical questions of biological variation and diversity
will be investigated using model organisms. Biological traits can
change depending on small differences in large numbers of genes. These
relationships will need to be understood in model organisms before
diversity in other organisms can be understood, said Fields and
Johnston.
Fifth, model organisms will remain the proving ground for developing
and testing new technologies. Already, model organism research has led
to the ability to isolate and manipulate genes, purify and characterize
proteins on a large scale, and profile and control gene expression.
Indeed, the more that is known about model organisms, the more useful
they will be in developing new technologies, and “the people who
had the biggest impact on biology have been the people who have
developed new tools,” said Johnston.
“Ten or twenty years from now we probably wouldn't come up
with the same list” of potential uses for model organisms, said
Fields. “Other areas that we could have mentioned include
infectious diseases, the development of immunity, and ecological
systems — how organisms fill niches.” As Fields and Johnston
write in their paper, exploring these and other research areas, both in
model organisms and in the great many largely unstudied organisms,
“is certain to occupy [biologists] for a long time.”
According to geneticist Maynard Olson at the University of
Washington, Fields and Johnston's paper is “interesting,
constructive, and provocative.” It asks “new kinds of
questions,” which helps push biological research in new
directions.
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