Zebrafish and the Cure for Muscular Diseases
August 19, 2013 | by Brian Short
John Kuwada’s zebrafish lab feels like a pet store, with rows and rows of foot-and-a-half-long fish tanks linked together with white PVC piping. Two large rooms are filled wall-to-wall with shelves, and the shelves are filled with aquaria, each labeled with masking tape. Tank lids are stacked in tidy piles in the rare empty spaces between units, and the zebrafish themselves ignore Kuwada and me until we come within arms reach of them. They are hoping, Kuwada tells me, that we are bringing them food. Sorry, not this time.
Kuwada is hoping that the zebrafish can bring him something, too. That is, a deeper knowledge about how human muscles and minds form and work. And he has good reason to think that they will.
A professor in the Department of Molecular, Cellular, Developmental Biology in LSA, Kuwada recently published a paper with Hiromi Hirata of the National Institute of Genetics in Japan, linking a specific genetic mutation with a sometimes fatal muscular disease. Studying this gene, called STAC3, which encodes a protein by the same name, could lead to treatments that might help cure a range of muscular and neurological diseases.
But in order to get those big cures, Kuwada will need to study some little fish.
Meet the Zebrafish
Zebrafish aren’t precisely cute. They are small—only a few inches long—with big, bright eyes that make them look perpetually surprised. Zebrafish get their name from the alternating light and dark stripes running the length of their bodies. They tend to dart quickly one way and then another, as if they’ve just forgotten something important in a different part of the tank.
Zebrafish are useful models for scientific research because they have a genome that has been fully sequenced with essentially all the genes mapped, making it quicker for scientists to document and define mutations. Zebrafish also develop very fast—going from a fertilized egg to a moving embryo in less than 24-hours—and the embryo is transparent, allowing researchers to observe every phase of growth.
“We performed what’s called a mutagenesis screen,” Kuwada explains, “which is a process by which you randomly generate mutations. I’m interested in all genes that affect either the development or the function of various neural circuits.
“So I mutagenized a bunch of zebrafish and screened for fish that weren’t behaving normally.”
Mutagenesis is just the beginning of the research process. After that, the real work begins.
“So you have fish that have a mutant gene that results in misbehavior, but we don’t know at the beginning what that gene is,” Kuwada continues. “You use a combination of genetics and various kinds of genome sequence resources that allow you to map genes and identify what those genes are. In some cases, a single gene took us two years to identify. In other cases, it’s only taken us about two months.”
While Kuwada and his team were observing the mutagenized zebrafish, they noticed some of them had trouble moving.
“When we touched these fish, they just didn’t swim very well. So then we went through this process and discovered that the defective gene was a muscle gene, but a very novel gene that hadn’t been described previously. And so we decided to go ahead and study it.”
When Kuwada’s team searched the human analogue of the defective zebrafish gene, they discovered a link between a similar genetic defect and a disease known as Native American myopathy (NAM).
Building the Cures
The STAC3 gene is found in a region of the 12th chromosome in humans, an area that had been previously linked to NAM, a muscular disease that affects members of the Lumbee tribe of North Carolina. According to Kuwada, 35 percent of the people affected by the disease die before turning 18. The research that uncovered the link between the STAC3 gene and NAM not only allows for the development of possible treatments of that disease, but could lead to further genetic discoveries and treatments in the future.
“We’re getting ready to try, based on this information that we’re collecting now, to go back to a screen,” Kuwada says. “And this time we’re not going to screen for fish that don’t work very well, we’re going to screen by putting different chemicals in that may make those fish more normal.”
A pharmaceutical or genetic remedy may still be a long way off, but this phase of research is crucial to understanding how diseases work in order to prevent, treat, and cure them later on.
“The goal, then,” Kuwada says, “is that this may be the first step in developing these kinds of therapies.”
Photos: Rob Hess