Zebrafish make a big splash

If you look at the range of research models available to scientists today (from fungi to flies to mice and larger), one little guy stands out – a tropical freshwater fish from the rivers of Bangladesh called the zebrafish. While it may be small, this fish is having a big impact on medical science, especially in genetics, stem cell biology, and drug screening, as covered in today’s Wall Street Journal.

As we’ve mentioned previously on Vector, the zebrafish is swimming its way into many research programs, both here at Children’s Hospital Boston and across the country. As a model, they are quite attractive to researchers, in part due to their small size, their fecundity, and their surprising similarities to us (from a genetic standpoint, that is).

Richard White, who works with Leonard Zon in the Stem Cell Program at Children’s Hospital Boston, offers up an explanation for the fish’s popularity:

Happy fish make more fish

But in order to do the research, you have to have the fish. A healthy adult female zebrafish can lay upwards of 300 eggs each week (compare that to the mouse, which might have a single 12-pup litter every month); those eggs will hatch in roughly 72 hours.

There are times, though – if you’re going to run a drug screen on 2,000 chemicals, for instance – you just need a lot of fish, and their natural breeding rate just isn’t enough. To get more fish, you need to understand what a fish wants, what a fish needs.

Christian Lawrence, a fish biologist who manages one of the zebrafish facilities here at Children’s, has spent a long time studying zebrafish breeding behavior and figuring out ways to parlay those insights into techniques that can help breed more fish faster.

“Many factors go into attractiveness,” he tells the WSJ. “They’re generally promiscuous. But I wouldn’t call them indiscriminate.’”

That knowledge, along with an understanding of the fish’s preferred breeding environment, was encapsulated in a new device that Lawrence, Zon, and colleagues developed last year named the iSpawn:

The iSpawn is a specialized fish breeding tank designed to take advantage of the zebrafish’s natural preference for breeding in shallow water. Built to replicate the contours and environment of a riverbank, the tank lets researchers to gather as many as 10,000 zebrafish embryos for research in 10 minutes.

“The iSpawn is going to have a major impact on how researchers work with zebrafish, not only at Children’s but internationally,” says Zon. “The potential savings in time and efficiency is really significant and could speed up our ability to search for therapies through chemical screening.”

Making what’s old new again

One of Children's zebrafish facilities.

Apart from work on genetics, development, and stem cell biology, it’s in drug screening that the zebrafish has really come into its own. Getting a completely untested drug through FDA approval is a long, hard road. So researchers and pharmaceutical companies are increasingly repurposing medicines that have already been approved.

The sheer numbers of fish that can be made available, along with their ability to absorb drugs directly through their skin from the water they’re swimming in, is increasingly making the zebrafish the model of choice for finding new drug treatments or revealing new uses for existing drugs. Just in the last year, zebrafish led the way to an arthritis drug that may help treat melanoma and an asthma medication that may help restore muscle in Duchenne muscular dystrophy (DMD). And in December, doctors at Dana-Farber Cancer Institute announce the results of the first clinical trial to arise from discoveries made in a zebrafish screen.

“The zebrafish have turned out to be ideal for this kind of small-molecule screening in DMD,” says Louis Kunkel, director of Children’s Program in Genomics and lead on the DMD study. “Because we can grow and test so many at a time, we were able to screen 1,200 chemicals very quickly. We are already screening a few thousand more chemicals, and because we’re focusing on ones that have already been approved for human use, we are confident that we will be able to take candidates found in the fish quickly through mouse studies and into the clinic.”