Fruit fly, mouse, roundworm, zebra fish, frog—scientists have long turned to the same dozen or so species to answer our most basic biological questions. These species are called “model organisms” because discoveries made by studying them often apply to a broad range of organisms, including humans.
Robert Grainger, a UVA biology professor, uses frogs to reveal how cells come together to form the eye during early embryonic development. For developmental biologists interested in organ formation, the frog is an ideal model species. “Frog embryos have the advantage of being very large, very abundant, and very tolerant of being manipulated, in the sense that you can move tissues around to study what they do and what they make,” says Grainger. Furthermore, embryos can be easily observed through their transparent eggs.
Biologists now look to mutations in genes to identify their roles in organ formation. From a geneticist’s perspective, however, X. laevis has an unfortunate quality. “Most genomes in animals are diploid,” Grainger explains. “They have two copies, just like humans, one from each of our parents. But X. laevis has a duplicated genome so it has four copies of every gene and that makes genetics extremely difficult.”
“If Xenopus was going to survive as a model species,” says Grainger, “the genetics had to come along.”
And so, in the early 1990s, the search was on for a new model frog species, one with large, plentiful eggs, but only two sets of chromosomes. Rana, another frog genus, was considered, but Rana wouldn’t lay eggs well in the lab. Axolotls, which are not frogs at all, but a type of salamander, were also considered, but although they are diploid, their overall genome size is huge—100 times the size of the human genome. Sifting through such a massive genome would be extremely challenging.
Grainger immediately recognized the potential in this newly selected species and had some of the frogs shipped to his lab.
For over a decade now, Grainger has worked to develop tools that make this new model frog invaluable to biologists. His first step was to begin creating what are known as genetic lines. These are frog lineages that share a mutation or gene insertion.
For example, Grainger developed one genetic line where all frogs have a mutation in Rax, an important gene for eye formation. Using these frogs, Grainger can now ask, if the eye does not develop because the Rax gene is inactivated, “what happens to all of the other genes that are involved in eye formation? Are they activated or not?”
“In other words,” he says, “we can begin to understand the pathway of genes that is important in making the eye.”
Frogs from Grainger’s lines are now used by scientists around the world.
In 2002 the Department of Energy’s Joint Genome Institute began sequencing the Xenopus tropicalis genome using a frog from Grainger’s lab. The genome sequence showed that X. tropicalis and humans share many long stretches of one hundred genes or more, making many discoveries in X. tropicalis directly applicable to humans.
The original model frog species, Xenopus laevis, will continue to contribute to scientific research. Using the simpler genome of the new model frog, X. tropicalis, as a template, scientists are beginning to piece together the far more complicated genome of the original model frog.
Grainger now heads the new U.S. National Xenopus Resource at the Marine Biological Laboratory in Woods Hole, Mass. Within the next 5 years, this research facility is expected to house 15,000 frogs.
As scientists embrace the new model frog species, Grainger expects advancements in our understanding of the genes that direct the formation of complex organs like the kidney, pancreas, brain and, of course, eye.
Many of these advancements will directly impact our understanding of developmental diseases in humans ranging from birth defects to blindness. “For example,” Grainger explains, “in eye development we study a gene called Pax6 that is the same gene that is very important in eye development in humans. In humans, when that gene is mutated, it causes a variety of problems in vision. The syndrome generated is often referred to as aniridia because many patients do not have an iris, but it can also lead to eye deficiencies and blindness.” According to Grainger, if we can study the function of genes like Pax6 in the new model frog, we can uncover how these same genes are responsible for diseases in humans.