Science from a fishbowl

Zebra fish: A clear embryo makes it a favorite for biologists scientists seeking clues to human disorders of the brain, skeleton and circulatory system.

March 15, 2000|By Jonathan Bor | Jonathan Bor,SUN STAFF

Near a lab stacked to the ceiling with fish tanks, Shannon Fisher focuses a microscope on an embryo that is only hours old. A remarkable thing comes into view: a two-chambered heart pumping a column of pale-red blood.

Over the space of two days, she watches one eye divide into two, a brain separate into lobes and folds, and a spine unfurl and sprout a tail. Finally, a baby zebra fish with all its parts wriggles away.

To scientists interested in the wondrous changes that occur when a fertilized egg develops into a complete organism, this is a thing of beauty. It is made possible by a convenience of nature: The embryo is crystal clear, a window to the emergence of life.

The embryo's clarity has made the zebra fish, long a staple of the home aquarium, a new favorite for biologists seeking to understand how organisms develop from a single cell. Because fish and humans share many genes, scientists are increasingly studying the striped fish to answer key questions about how people are put together.

"It's such a beautiful system and so easily accessible," Fisher said at the Carnegie Institution, a Baltimore biological research center where she worked until recently.

"Everything happens so quickly," said Fisher, who studies skeletal development. "You can go in a 24-hour period from a single cell to a miniature fish that has all the major organ systems, cells that know what they're supposed to become, all in the right place."

Or the wrong place.

At Carnegie and elsewhere, scientists are breeding fish with strange mutations that could offer clues to human disorders of the brain, skeleton, muscle and circulatory system. Among the 20,000 fish at Carnegie, one can find fish without tails or with multiple tails, fish with dots rather than stripes, fish with long, lustrous tails, and fish so pale their stripes are barely visible.

After the first week of life, they lose their transparency. But even then, they can be anesthetized in a chemical bath, and X-rayed in a device that resembles a copy machine. The adult fish are no more than 2 inches long -- about the size and shape of minnows -- and have black stripes that run the length of their bodies.

From flies to fish

Marnie Halpern, a biologist who runs Carnegie's fish laboratory, came to zebra fish 10 years ago from the world of fruit flies, an insect whose genetics have been studied for a century. As a graduate student, she studied the flies to learn how nerve cells connect to muscles.

Last year, her world changed when she saw a presentation by an Oregon scientist who had identified a zebra fish embryo with a mutation known as "spade tail." Cells that were supposed to populate the midsection migrated to the tail, giving the fish a short, sickly look. The embryo was so compromised that it died before hatching.

"It was the first time a zebra fish mutant was shown," said Halpern. "When I saw it, I knew this was a system I had to work with."

Halpern studied with the scientist, Dr. Charles Kimmel, at the University of Oregon before coming to Baltimore in 1995. Kimmel has trained many of the scientists who have fanned out and established zebra fish laboratories of their own. Until recently, practically everyone in zebra fish studies seemed to know everyone else, personally or by reputation.

In the past few years, "the field has exploded," said Halpern. There are more than two dozen laboratories in the mid-Atlantic region. In Baltimore, the Johns Hopkins University and the University of Maryland also have zebra fish labs, although Carnegie's is by far the largest.

Biotechnology companies have begun mining the fish for clues to new treatments for human disease.

The field received a huge boost in the early 1990s when Christiane Nusslein-Volhard, a German biologist who won a Nobel Prize for discovering the genes that shaped fruit fly development, turned much of her laboratory over to zebra fish. She has more than 700,000 fish.

In 1996, Nusslein-Volhard and scientists at the Harvard Medical School published a guide to zebra fish mutations that lists defects in nearly every aspect of development, many of which have analogies in humans.

The fish offer advantages besides clear embryos. They multiply fast. A pair can produce hundreds of babies in a week and thousands in a few months. They are cheap to raise, survive in treated tap water and can be housed 70 at a time in tanks the size of breadboxes.

The eggs develop outside the mother's body, so scientists can watch an embryo's development without sacrificing mother or baby. That is a distinct advantage over mice, the vertebrates used most widely in genetic studies, which develop inside the mother's womb.

"One of the problems with the mouse embryo is that you can't see it," said Laura Roman, a Hopkins scientist who is studying zebra fish for clues to cleft palate and other facial abnormalities. "You end up having to sacrifice the mother, and you're killing the embryo, too, so you'll never see cell movement."

Producing mutants

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