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September 2004 Issue

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Zebrafish Lead New Wave of Research

Published September 2004

"Chasing a wild goose in a zebrafish doesn't take very long!" boasts Jay Hove, PhD, an organismal physiologist at UC's Genome Research Institute (GRI).

An assistant professor in genome science, Dr. Hove will admit he's better at mutagenesis than metaphors. But he's making his point that the experimental models he works with are a very quick study.

They reproduce prolifically, and they provide data applicable to a whole spectrum of human diseases in a very short time. And, of course, they're fish--Danio rerio to be polite. And they're little fish--about 1-2 millimeters as embryos (when most of the research is done) and 3-4 centimeters full grown. So feeding and maintaining them doesn't cost an arm and... a fin.

"Let's not underestimate these guys!" says Dr. Hove, who's passionate about the importance of these stripy little critters to biomedical research. So important, in fact, that the GRI's Zebrafish and Medaka Model Organisms Lab, the fifth largest of its kind in the U.S., has the capacity to house over 250,000 of them.

The zebrafish is a freshwater tropical used extensively to study embryogenesis and organ development. Genetic mutants that mimic human disease are increasingly available.

Their rapid life cycle and large clutch sizes-- females can lay up to 200 eggs daily--make them ideal for high-throughput screenings, like those used for drug target identification and validation.

A similar fish, the medaka, also called the rice killifish, is used in parallel with the zebrafish. Medaka are a temperate species and are particularly useful for studies of low-temperature physiology, for examining sex-linked traits, and as environmental "sentinels" of aquatic pollution.

What people don't realize about fish, Dr. Hove says, is how "human" they actually are. All life emerged from the oceans, he points out, and when one considers all animal life on the planet, fish and people are not so evolutionarily and genetically distant. In fact, they share many of the same basic anatomical features.

"Take the heart," he says. "Although fish hearts look different--they have two chambers instead of four, for example--the fundamental processes that determine how those chambers form are likely to be very similar in fish and humans."

Although frequently discounted as being primitive, Dr. Hove points out, fish make up half of all vertebrates "and are an incredibly diverse group of animals that are exceedingly good at what they do."

Changes in the environment, genetic manipulation or chemical exposures that harm humans, he says, are very likely to affect fish in similar ways.

Most people never consider the fact that fish get cancer, diabetes, heart disease and weakened immune systems, he says. They can even suffer from obesity.

What's more, they're cheap and relatively easy to study.

Zebrafish develop so rapidly, says Dr. Hove, the young have a beating heart 22 hours after the sperm and egg get together. That means many of the mysteries of vertebrate development will play themselves out right on the stage of the microscope. Five to seven days after conception, a zebrafish has not only a fully functioning cardiovascular system, but also a working nervous system, liver and kidneys.

Another asset is that zebrafish reproduce externally. The young grow outside the parents, and they're so transparent that with the help of some very sophisticated microscopes Dr. Hove and his GRI colleagues can watch every organ system develop in the embryo.

"We can watch red blood cells as they race through the body," he says, "see inside the heart itself and make measurements that would be very difficult in a fetus growing inside the mom. And we can do it all without dissection, or even touching them.

"We can obviously recreate human diseases in other, more expensive models," says Dr. Hove. "But they are frequently fatal. Many mutant zebrafish survive, allowing us to follow the progression from the earliest stages of development to a point much later than we see in other models."

Because they can be genetically manipulated to fluoresce when specific biological events occur, when cells die or a particular protein is synthesized, for example, zebrafish can provide a fluorescent Ôreadout' to measure how well experimental compounds work.

"This is particularly useful in the early stages of drug discovery," Dr. Hove says. "The fast generation of the fish also allows us to do a lot more work in less time. So we can run down bad leads quickly, because chasing a wild goose in a zebrafish doesn't take very long."

There's a lot of naiveté about fish, Dr. Hove says. Most people simply don't realize that findings from research done in model vertebrate systems frequently translate into useful knowledge about the human condition.

So research on fish makes a lot of sense, says Dr. Hove.

"Imagine how much more we can learn through them," he says, "considering that scientists have won Nobel Prizes for knowledge about human development obtained from worms and flies.”

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