On the prowl for genetic similarities that might throw light on newly sequenced regions of the human genome, scientists are taking a fresh look at nearly every form of life, from bacteria to various exotic species of insects, fish, and mammals.
Each researcher has a favorite place to dig in this genetic gold rushand many are striking rich lodes of information. The newly examined life forms cannot yet match the usefulness of model organisms such as yeast, worms, flies, or mice. But for certain types of experiments, a fresh cast of characters is gaining respect.
The brilliantly colored, 1 1/2-inch-long zebrafish (Danio rerio), is one of the rising stars, drawing the attention of more than 1,000 scientists in 250 labs around the world. Tropical fish of this sort are common in home aquariums, but despite pioneering work by researchers in Oregon in the 1980s, zebrafish were largely ignored by biologists until Christiane Nüsslein-Volhard, a tenacious German scientist, put them on the map.
Nüsslein-Volhard had been the driving force behind the systematic search for Drosophila mutants (for which she shared the Nobel Prize in Physiology or Medicine in 1995). In the early 1990s, she started an equally ambitious screen for mutant zebrafish. By 1996, her team at the Max Planck Institute in Tübingen and another group headed by Wolfgang Driever and Mark Fishman at Massachusetts General Hospital in Boston had collected more than 1,800 zebrafish mutants with specific defects in blood, kidney, or heart formation.
Zebrafish are vertebrates, like mice, and therefore closer to humans than either flies or worms (zfish.uoregon.edu). Unlike mice, however, zebrafish can be bred and maintained very cheaply. A female zebrafish will typically produce hundreds of eggs at a single laying. These eggs are easily fertilized. The resulting embryos, which are translucent, grow outside the mother's body, so mutants can be observed at every stage of development.
"When you work with other organisms, you are looking at snapshots," remarks a zebrafish researcher. "With zebrafish, you can see development as a real-time process."
Impressed with these advantages, Leonard Zon, a Hughes investigator who was studying blood disorders at Children's Hospital in Boston, asked Nüsslein-Volhard if she would give him some mutant zebrafish. She obliged, providing 39 mutant embryos that failed to form red blood cells normally; as could be seen under the microscope, their red cells were either too pale or too few.
Zon's team mated the mutant zebrafish to each other and then analyzed their offspring. In short order, the researchers found fish equivalents of three human blood diseases: porphyria, a genetic condition in which red blood cells burst open, causing a severe anemia; another form of congenital anemia; and thal-assemia, which results from defects in the production of hemoglobin.
In fact, six different zebrafish strains were found to have some equivalent of human thalassemia, "but only one of these mutants is linked to globin [the component of hemoglobin that accounts for the color of red blood cells]," Zon says. "So there must be five other genes that regulate globin expression, yet nobody knew about them." He hopes to "go on a fishing expedition" soon to isolate these and other "novel" genes.
Even though fish have cold blood and human blood is warm, the two kinds of blood are "very, very similar," he says. "The program is highly conserved."
So, apparently, are the programs for growing a heart, kidney, and other organs. Mutant fish embryos have already provided examples of 100 abnormalities in heart development. In the cardiovascular research center at Massachusetts General Hospital, for instance, Mark Fishman is studying a zebrafish embryo that was named "Santa" for its big heart, and another one, "Slo Mo," whose heart beats too slowly. Both defects also occur in humans, but their causes are more likely to be tracked down in zebrafish.
Zon, meanwhile, has prepared a map of known zebrafish genes that can be compared with genetic maps of mammals, including humans. He wants to promote what he calls "genomic ping-ponging"the increasingly popular process of going back and forth between different species, using the information from one to fill gaps in the other.
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Leonard Zon points to a zebrafish mutant swimming in a tank in his lab. As he explains to Eric Liao, a student researcher, the fish was found to have the equivalent of thalassemia, an inherited blood disorder.
Photo: Larry Maglott for Children's Hospital