Tuesday, 22 July 2014 09:32

Nontraditional Animal Models—Beyond the Zebrafish, the Other Teleosts

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icefishThe blackfin icefish may hold clues to osteoporosis.
Illustration by Johnny Chang, ASCB.
Fishermen can tell you many tales of the teleosts but most cell biologists know but one—the zebrafish. That's a shame, says John Postlethwait, professor of biology at the University of Oregon, who made his scientific mark with the zebrafish but is a fan of a much wider circle of the teleosts, ray-finned fish whose ranks include nearly all of the important sport or commercial bony fish on Earth. Postlethwait thinks there are discoveries to be made amongst the lesser-known teleosts. Consider the blackfin icefish, a three-foot long, shovel-jawed fish that once almost set an Antarctic research station on fire. The blackfin icefish may hold clues to osteoporosis, he says.

Then there's a tiny aquarium fish, the Gordon–Kosswig cross, a hybrid between the platyfish and swordtail that give live birth to their young. Postlethwait says it could be an invaluable model for researchers studying melanoma. Spotted gar found in the lower Mississippi where it is prized in the making of Cajun "gar balls" could be the perfect liaison between zebrafish research and humans. These species, which are but a handful among the roughly 27,000 other teleost species, could offer unique insights into human diseases, Postlethwait contends.

Postlethwait began his research career as a Drosophila expert, but turned to zebrafish to understand how genes control embryonic development. Zebrafish or Danio rerio, the tiny fish native to the Himalayan region and common in labs, are members of the huge teleost subdivision among bony fishes.

Postlethwait still uses zebrafish to study skeletal development but zebrafish can't supply all the answers he needs. "I wanted a model for understanding the genetic basis for bone mineral density diseases. I looked around for some naturally occurring cases, species where the organisms have a natural osteopenia, that is highly reduced bone minerals. There are a number of [fish] species that have this," he said, and he chose the blackfin icefish, Chaenocephalus aceratus.

Postlethwait explained that the icefish has reduced bone density because its ancestors lived on the bottom, evolving without the swim bladder that helps most fish float. Instead of a swim bladder, natural selection favored ancestral icefish with reduced bone density that allowed them to reach resources higher in the water column. Also, "they're very oily fish," Postlethwait said. "They accumulate lipids, which float on water, which helps them get off the bottom too."

But how does one come by an icefish? You catch them and keep samples, according to Postlethwait, because a live population is tough to keep in a tank. "The icefish was one that, even though it's in a remote place, was more available than many of the other [fish with reduced bone density]. At least you can get to Antarctica and collect the fish with the help of the NSF," Postlethwait explained.

During his Antarctic collecting trip a few years ago, his team decided to try some icefish for dinner. "We asked the cook in Antarctica, and we gave him a big fish to barbecue. About a half hour before dinner the fire alarm went off. Fire is very dangerous there. It's a five-day boat ride to get there, and planes can't land there. So if you have a fire, you are five days in Antarctica with no shelter if everything burns up." With alarms ringing and personnel rushing past, Postlethwait's team waited anxiously for news. "It turns out that when they put the icefish on the barbecue it exploded. There is so much lipid that it simply exploded and caught the galley outside the kitchen on fire," Postlethwait said. Though not good for eating, the icefish did help Postlethwait's lab learn more about the evolution of osteopenia.

Other teleosts have remarkable abilities to model human diseases. Although it's not a model organism he works on, Postlethwait also spoke of the promise that the Gordon–Kosswig cross, a teleost hybrid of platyfish and swordtail, holds towards learning about malignant melanoma tumors. A quarter of the Gordon–Kosswig fishes spontaneously develop melanoma tumors. Melanoma is the most aggressive and deadly form of skin cancer in humans, he said. "The melanoma these fish have is very similar to the human disease. In fact, it's more similar to the human disease than the mouse model of melanoma. These fish have melanocytes in their skin, the mouse doesn't have them in their skin, they have them in their hair. You don't get melanoma in your hair. So the fish makes a better model for that," Postlethwait said.

The zebrafish and icefish are exotics but Postlethwait also works on a fish native to North America that he believes can provide an important link between zebrafish and human disease. The spotted gar, Lepisosteus oculatus, lives in the Mississippi watershed from the Gulf Slopes all the way up to Lake Erie. A hundred of them can also be found thriving in what Postlethwait described as kiddie pools in his lab. "It's an ancient fish and it's really quite important," Postlethwait said. "We found recently that it can allow you take your results from a medical study in zebrafish and apply them more directly to human if you go through this fish.

"We had shown a number of years ago that the [teleost] lineage had experienced a genome duplication. That means every gene in the genome is duplicated. Most of those genes have gone back to single copy. So if you compare a zebrafish to a human, 85% of the genes have a 1:1 correlation, but for 15% of genes—a very important 15%—there is a 2:1 correlation, that is, two [zebrafish] genes to one human," Postlethwait explained. "That can create a disconnect when trying to associate an experiment with zebrafish to human biology."

In 2011, his lab discovered that the spotted gar diverged before the teleost genome duplication. Compared to zebrafish, the gar's genome is more similar to the human, he explained. However, zebrafish are a better model organism because of their small size, their rapid development, and their transparent embryo allows research to see inside. "Now you can use the genome of the spotted gar to connect results that you get in zebrafish to human biology in ways that are impossible without the gar," Postlethwait said.

When comparing zebrafish genes to humans, it can be tough to find orthologs if the genes fall in that duplicated 15%. There have been reports where researchers have concluded that a particular function was specific to humans but now with the gar genome, Postlethwait was able to show that those genes were conserved more widely. "That's going to be important moving forward. Zebrafish workers are going to be able to align their results with human biology through gar," he said.

The gar has one additional advantage. Unlike with icefish or zebrafish, when you're done with your gar experiments, you can have decent dinner. "I have eaten gar. It's not a wonderful fish, but they do eat them in Louisiana," Postlethwait reported.

Christina Szalinski

Christina is a science writer for the American Society for Cell Biology. She earned her Ph.D. in Cell Biology and Molecular Physiology at the University of Pittsburgh.

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