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Health

Pitt fishing for genetic breakthroughs

| Tuesday, Sept. 21, 2004

Unlike Disney's Nemo or Charlie the Tuna, the thousands of zebra fish that live in the University of Pittsburgh's Biomedical Science Tower South don't have cute names.

In fact, an advanced degree in molecular genetics would come in handy when trying to make sense of how scientists classify their hordes of black-and-white striped fish.

Glomus absent M3612, No isthmus, GFP-Lin 1 -- these are just a few of the zebra fish strains researchers at the University of Pittsburgh School of Medicine hope will help them identify genes involved in human disease and understand how people develop from the moment sperm fertilizes egg.

Zebra fish are becoming increasingly popular among scientists -- joining the menagerie of so-called model organisms, such as fruit flies and mice -- to address questions that can't be studied easily in humans.

Last year, Pitt's medical school jumped in by constructing the city's first large-scale zebra fish facility, which can hold about 3,100 tanks and 10,000 fish the size of a pinkie. It is a not-so-dry run for the even bigger, $1.5 million zebra fish system the university plans to erect in the life sciences research center under construction on Fifth Avenue in Oakland.

By spring, the center should house one of the largest zebra fish facilities in the United States, with about 10,000 tanks containing more than 350,000 fish.

"For any large university interested in being on the cutting edge of developmental research, a large zebra fish facility is definitely an asset," said Heather Stickney, a biologist who works in one of the nation's foremost zebra fish labs, at the Stanford School of Medicine in California.

"In many ways, zebra fish are ideal to work with," Stickney said. "They have a lot of the benefits of invertebrate organisms like worms and flies, but they are genetically much closer to humans."

The University of Pittsburgh School of Medicine has recruited five leading zebra fish researchers from prestigious labs at Harvard University and the National Institutes of Health.

These efforts are part of an initiative led by the medical school dean, Dr. Arthur Levine, to make Pitt a hub for zebra fish research, which started at the University of Oregon in the early 1970s and has been making a splash ever since.

"Over the last decade, there has been a growing realization amongst developmental biologists and geneticists that the zebra fish is an unusually useful model for exploring the molecular basis of development," said Levine, who helped to launch a zebra fish facility at the NIH in the early 1990s.

More than 1,000 researchers worldwide now work with zebra fish as a model organism. By the end of next year, this rising star of science will become the third vertebrate to have its genome sequenced, together with the human and the mouse.

So why are scientists so enamored with a tropical aquarium fish you can buy at the local pet store for 60 cents?

One advantage of zebra fish is that, unlike mice, they can be kept together in high densities in a small space, said Neil Hukriede, an assistant professor of molecular genetics and biochemistry who came to Pitt from the NIH almost two years ago.

Designed by research associate Paul Ulanch, an aquarium hobbyist, Pitt's current fish rooms resemble a well-stocked library -- only instead of books, the shelves are lined with clear plastic containers teeming with fish.

Grouped according to size and genetic makeup, the fish are fed a combination of brine shrimp and flake food, usually twice a day. Their water quality and light exposure are regulated to create the perfect conditions for frequent spawning.

Slight changes in temperature, salt concentration or pH trigger an electronic alarm that sends researchers scrambling to make sure the labyrinthine network of water purifiers, filters and pumps is working properly.

Aside from saving space, zebra fish also make useful models because they have backbones. As a result, they are more likely to share genetic similarities with humans than the invertebrate fruit fly, Hukriede said. This means that most zebra fish genes have a human counterpart, or homolog, with a similar function, he said.

But to developmental biologists, the true beauty of the zebra fish lies in its transparent embryos, which grow outside the mother's body instead of in a uterus. Scientists can watch under a microscope as the cells of the embryo divide to form a recognizable fish within the first 24 hours of life.

To find out what genes orchestrate the stages of early development, scientists treat male zebra fish with a chemical that induces mutations in their sperm cell DNA. Then they breed the fish, examine the embryos in later generations for visible malformations, and pinpoint the gene responsible. The next step is to see whether the human version of this gene is mutated in people afflicted by disease.

"The ultimate promise (of zebra fish research) is knowledge that will lead to sufficient understanding of human disease and disorders such that we may be able to prevent them," Levine said.

For example, Hukriede is trying to determine how mutations in two zebra fish genes affect vertebrate kidney development, which could lead to new treatments other than kidney dialysis and organ transplant.

Nearby, in the medical school's ophthalmology department, assistant professor Xiangyun Wei is identifying gene mutations that affect the development of the zebra fish retina.

"If we know the principles of how retinal cells organize, we might in the future be able to engineer an artificial retina," Wei said.

Dr. Nathan Bahary, an oncologist at the University of Pittsburgh Medical Center, is trying to create a mutant strain of zebra fish that has chronic myelogenous leukemia -- a cancer of the bone marrow that results when white blood cells divide uncontrollably. It is associated with mutations in a gene called ABL1, which has a homolog in zebra fish. Bahary hopes to make his fish leukemic by inducing this particular mutation in their DNA.

These fish could be used to test the effectiveness of potential cancer treatments simply by adding the drugs to the tank water, Bahary said.

Bahary also is using zebra fish to study the development of blood and the gut, to determine how to halt the spread of cancer and to search for new treatments for inflammatory bowel disease.

"It's such a good model for so many different things," said Bahary, who is also an assistant professor of molecular genetics and biochemistry.

Zebra fish research is still in its early stages compared with work on the fruit fly and mouse. But Pitt's new facility should position the university's medical school as a leader in the nascent field.

"This has been a useful scientific adventure for others in the world, and it certainly should be for us," Levine said.

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