© Dennis Kunkel Microscopy, Inc.
New questions, methods, and philosophies are creating opportunities for novel organisms to take their places in the model organism ark. Genome sequences, transcriptome profiling data, and high-throughput technologies are providing a springboard that can propel a hitherto unfancied creature into the forefront of research. Continued progress on genome sequencing will enhance comparative evolutionary approaches. The chicken's genetic sequence, for example, could be published by year's end. Comparing chicken and human DNA will illuminate important sections of the human genome.1
The excitement emanating from the life sciences arena is attracting those from the other side. "You are seeing a lot of people coming into the field from physics, data mining, statisticians, all being drawn by the genomic scale of information," says Gad Shaulsky, Baylor College of Medicine. Herbert Levine, a physicist who studies Dictyostelium discoideum at the University of California, San Diego, says: "Even physicists are coupled to the rest of the world, and you can't help but notice that a lot of the excitement and new things that are happening are at the biology end."
The numerous databanks containing gigabyte after gigabyte of model organism information entice scientists to do multiple-species research. "If you're not switching between model organisms, you are going to lose out completely, because there is no one model organism that is going to answer problems completely," says Lisa Stubbs, Lawrence Livermore National Laboratory.
MODELING THE MODELS One species with a multidisciplinary following is Dictyostelium, and those who model biological systems find it fascinating. The chemotaxis mechanism that it uses to form spiral waves, as it transitions from a collection of single cells into a multicellular slug, is relatively simple and well defined. Says Levine: "That phase of the Dictyostelium life cycle is very attractive to people from physics or math because you have a system where many cells are interacting with each other, but the interaction is pretty simple, mediated by a known chemical [cyclic AMP]. Also, they aren't touching each other as would be the case in development in any other organism. This gives you a place to start, where you really have a hope of saying things quantitatively." (Levine notes that biological physics is the second most popular specialization area among graduate students in his department. Moreover, the National Science Foundation's physics division is funding UC-San Diego's new biophysics center; the earlier grant came from the biology division.)
Dictyostelium cells propagate in the soil as free-living amoebae, gobbling up bacteria by phagocytosis. But when food becomes scarce, they stop growing and develop into an integrated multicellular organism. Roughly 50,000 cells aggregate into a mound, form a cellulosic sheath, and undergo cell differentiation to form distinct tissues. An orchestrated process of morphogenesis and cell differentiation produces a fruiting body, with dormant spores aloft a cellular stalk.
Shaulsky also studies slime. These social amoebae, he says, demonstrate the diverse biological processes that are common to many eukaryotes. "We have cloned and sequenced 48 genes from independent communication mutants," he says. The genes are believed to represent at least two different communication mechanisms: secreted signals that are essential for proper cell-type divergence and proportioning; and a cell-cell adhesion mechanism that facilitates communication during early development.
The Dictyostelium genome is currently being sequenced.2 Sequencing has revealed that some new mutants are novel membrane proteins. Molecular analyses and microarray profiling have uncovered additional information about the gene function. "The [secreted] signal is required about halfway through development, after cell-type divergence has occurred," says Shaulsky.
Courtesy of Xenbase.com
LEAP FROG The frog is used to study induction (the interaction between tissue A and tissue B, which changes the developmental fate of the latter) because its huge embryos grow externally. Researchers can manipulate the embryos surgically or chemically, which allows them to observe the developmental effects. One little leaper, Xenopus laevis, is a workhorse of developmental biology; a single mating can rapidly produce thousands of embryos. However, applying genetics is virtually impossible, because X. laevis is a tetraploid organism. It takes a year to reach sexual maturity--a near eon to geneticists. "People who love genetics want to see [genetics used] everywhere," says the University of Virginia's Rob Grainger. "The fact that X. laevis didn't have extensively developed genetics was always seen as a defect in the model."
About eight years ago, frog researchers turned to Xenopus tropicalis, a smaller frog with 10 chromosome pairs and closely related to X. laevis. X. tropicalis reaches sexual maturity in less than three months and has a diploid genome, making it amenable to genetic manipulations. An informal consortium of Xenopus lovers secured funding from the National Institutes of Health for an X. tropicalis genome sequencing project. "[The] community is making Xenopus more attractive ... because genetic approaches are so important to the NIH way of thinking," says Grainger.
Xenopus researchers want to make mutant frogs with developmental defects. For example, the first mutants being studied include those affecting left-right body axis. This "axis can be switched around or randomized, which can be lethal," says Grainger. "We've been able to get some hints about the genes that might be involved ... [we can] learn so much more than you could in a mouse."
MULTIPLE-MODEL MAVENS Some believe that it's not the organism per se that matters, but its genes and biological processes. Yeast researcher Joanne Engebrecht at State University of New York, Stony Brook, has already made the transition. "I became interested in Caenorhabditis elegans because I could do some things that I couldn't do in yeast," she says. She had learned a lot about the regulation of DNA replication between meiosis and mitosis in yeast. "But I really wanted to get at mechanisms," she recalls. So she took a sabbatical in Anne Villeneuve's lab at Stanford University, where she learned to inject labeled nucleotide precursors into worm gonads and apply the powerful cytology of C. elegans.
Vicki Chandler, University of Arizona, Tucson, is also comfortable hopping between organisms. "I will work on anything I can use to address the biological problems I'm trying to solve." She is involved in collaborative projects using Arabidopsis, maize, petunia, and rice, to study chromatin structure and plant color. She says it is easy to bring a new system into her lab when expert colleagues are available to help her students learn the ropes. She also enjoys collaboration with those who use other organisms. "Different scientists bring different expertise, knowledge, and history to the table, and the synergies are great," she says.
An investigator need not actually work with multiple organisms to benefit from comparative approaches. Salamander researcher David Gardiner at UC-Irvine does comparative biology the old-fashioned way: He looks at results in other systems to formulate and test hypotheses about regeneration. For example, he was struck by similarities between salamander limb regeneration and planaria body regeneration. (The flatworm planaria lives in fresh water.) As salamander limbs regenerate, the animal first makes the tip of the new limb and then fills in the middle. Likewise, when a planaria is halved, the leftover tail first makes a new head and then fills in the rest of the body. These similarities led Gardiner to propose that regeneration highlights important, conserved mechanisms. "Maybe there is a general concept of how regeneration works; you make the boundaries first and then you fill in the middle," he says.
GENOMES GALORE As various genome projects are finished, data availability will enhance comparative evolutionary approaches. "When someone sees something new ... the first questions will be, 'Does it work the same way in birds or zebrafish?'" says Jerry Dodgson, who studies the chicken genome at Michigan State University. This kind of evolutionary reconstruction generates testable hypotheses and insights into conserved biological mechanisms.
These comparative computational strategies can lead to remarkable discoveries. "Now that the genome project in Dictyostelium is nearing completion, they are finding ... genes in Dictyostelium and mammals that are not present in worms or flies," says Jeff Williams, University of Dundee, Scotland. Researchers can no longer draw broad conclusions about biological mechanisms that are based purely on morphological similarities or evolutionary distances, he says.
BEYOND GENOMICS Some researchers think it is worth struggling with alternative models that offer unique perspectives despite experimental challenges. For example, Kelly Drew, University of Alaska, studies hibernating squirrels for information about treating stroke, head trauma, and heart disease, as well as cyropreservation of organs. "One thing we get right away from studying their biology is that they use multiple adaptations in concert to allow them [to survive extremely low blood flow]. If we can mimic each of these [adaptations] a little bit, we might get a better effect than if we just tried one," she says.
Clearly, biological questions will drive the future: When the current models can't solve a particular problem, researchers will be looking beyond their cages and fish tanks. Whether tomorrow's investigators are scanning the skies or shoveling the soil, the ark will have room for any model that can help solve life's mysteries.
Mignon Fogarty (firstname.lastname@example.org) is a freelance writer in Santa Cruz, Calif.
1. See www.nature.com/nsu/030428/030428-5.html
2. A. Kuspa et al., "The promise of a protist: The Dictyostelium genome project," Funct Integr Genomics, 1:279-93, 2001.