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Zebra fish serve as disease models (10/19/98)

Zebra fish are starting to make a splash among geneticists, and one of those wading into disease studies using the fish is Pudur Jagadeeswaran, PhD, a faculty member at The University of Texas Health Science Center at San Antonio.

His laboratory in the department of cellular & structural biology contains the largest collection of zebra fish in Texas. "We have more than 500 storage units holding 1,700 to 1,800 gallons of water," says Dr. Jagadeeswaran, who earlier this year traveled to Cold Spring Harbor, N.Y., to meet with Harvard, MIT and other scientists studying zebra fish.

The fish are popular study subjects because their embryos are transparent, enabling scientists to study developmental problems, says Dr. Jagadeeswaran, associate professor of cellular & structural biology. "If defects such as heart irregularities or lack of blood formation are present in the embryos, these can be seen and diagnosed," he says.

Zebra fish are a geneticist's dream because practically any genetic defect can be studied. "In zebra fish, genes can be readily mutated or deleted and their functions analyzed," Dr. Jagadeeswaran says. "The fish carry about 85 percent of the genes present in humans. Almost any gene you name, it is there in the fish."

Dr. Jagadeeswaran's research team is studying human hemophilia and has developed a mouse model for one type of the blood-clotting disorder. Zebra fish studies are potentially more cost effective, he says.

The team is studying regulation of blood clotting by various genes and seeks to understand the pathways of biological processes that result in hemophilia, a disorder affecting about 20,000 people in the United States. "The initiation of coagulation is still an unsolved puzzle," he says. "We may be able to give the zebra fish mutations that affect the pathways of initiation of clotting and shed light on them."

Scientists studying zebra fish can perform a technique called "saturation mutagenesis" to observe a host of hereditary disorders simultaneously. By exposing an aquarium full of zebra fish to chemical mutagens (agents that cause mutations) or to gamma radiation, they can introduce random genetic mutations in the fish. This procedure is more difficult to do with other animals such as mice.

"I can generate 100,000 mutant fish for less than a thousand dollars," Dr. Jagadeeswaran says. "But the secret is to find in this 100,000 the exact mutant fish I wish to study. That requires screening."

The research team recently developed very sensitive assays to detect defects in clotting in the fish blood. "It took us several months to figure out how to collect blood samples from fish that are only an inch long," Dr. Jagadeeswaran says. "It was not a trivial thing to do, but we accomplished it."

In addition, through a multistep process, Dr. Jagadeeswaran's team is able to breed fish that express genes for the type of hemophilia under study.

Zebra fish "farming" is an art. Because feeding is important for egg production, the researchers must keep meticulous tabs on nutrition. "Eggs hatch in three days," Dr. Jagadeeswaran says. "For up to five days the larvae are sustained by the 'yolk,' which is like the placenta in humans. Afterward, though, the larvae need nutrients. We provide paramecia and brine shrimp. This period, 15 days long, is called the ‘critical period.' Either you grow the fish fully or lose all of them. This is like a neonatal intensive care unit."

The aquarium water is sterilized continuously by three huge ultraviolet (UV) lamps costing $3,000 apiece. Each lamp sterilizes nearly 200 aquariums. The lab wiring was specially done because of the amount of water and electricity housed.

"This is a lot of work. I never thought I would be entering into this," Dr. Jagadeeswaran says. "Two years ago at Christmas, I bought a 10-gallon tank and a dozen fish, and I thought I was going to conquer this zebra fish research in no time. But I found out differently. We have invested $100,000 on this facility, which actually is a cost savings because we did much of the work ourselves and enlisted aid from students at Health Careers and other high schools who were sent to us by Ms. Rajee Thyagarajan, Northside ISD science coordinator."

Was the work worth it? "I can store 20,000 fish in one lab, whereas I would have to build condominiums to study that many mice," says Dr. Jagadeeswaran, who is considering expanding to 3,000 or more aquariums if space becomes available.

Several Health Science Center investigators are working with zebra fish models. John Sheehan, MD, assistant professor of medicine in the division of hematology, is characterizing the biochemical aspects of blood-clotting factors in zebra fish. Stephen Harris, PhD, associate professor of medicine in the division of endocrinology, is using a zebra fish model to study the functions of bone morphogenetic protein genes.

Promising high school students are working on various fish projects, too. One teenager is collecting leaves from the San Antonio Botanical Gardens and testing them for anti-coagulant (anti-clotting) effects. She makes a leaf extract and exposes the zebra fish to it. If the extract blocks clotting factors, bleeding is evidenced even in normal fish. "This could lead to identification of novel anti-coagulant drugs," Dr. Jagadeeswaran says. "Warfarin, also known as coumadin, came from a clover leaf. In Wisconsin cows ate this leaf and bled, and that's how coumadin was discovered."

The zebra fish research is funded by several grants, including a two-year, $500,000 award from the National Institutes of Health's Small Business Technology Transfer Research Program. Kalgen Inc. is the collaborating small business partner. The work also is funded by the department of medicine's Howard Hughes Medical Institute Research Resources Program grant.

"We have published four papers on zebra fish research and will publish four more soon," Dr. Jagadeeswaran said, adding that some of the papers may be read online at [http://zfish.uoregon.edu/zfin/]. Drs. Sheehan and Jagadeeswaran submitted a review article to be carried in a zebra fish special issue of Methods in Cell Biology.

Dr. Jagadeeswaran took the plunge into zebra fish to save time and money, but also because he is fond of them. "I always mention in my lectures that my attraction for zebra fish comes from my native country, India," he says. "Wild zebra fish are found in the river Ganges in my country."

Contact: Will Sansom (210) 567-2570