Feb 082006
 
Authors: Lee Newville

(Editor's note: This is the first in an occasional series that examines some of the groundbreaking research being conducted in various fields here at Colorado State University)

 

Like a cramped tropical fish store with its gurgling noises and briny odor, Dr. Deborah Garrity's basement-level aquarium hardly seems the environment of life-saving medical advances.

But Garrity, a soft-spoken biologist who often works alone, knows that the estimated 2,000 zebra fish swimming and breeding here are critical for researching United States' leading cause of death.

"Heart disease is the number one killer in this country," Garrity said in a series of recent interviews at her research facilities at CSU.

Unlike research subjects such as rabbits or mice, zebra fish are ideal for study because the embryos they produce from mating are transparent, allowing a scientist an unobstructed view of biological development.

To be clear, the type of zebra fish Garrity studies are not the mystical-looking, black-and-white creatures found at the local pet store. Her zebra fish, native to India, more closely resemble drab-colored guppies.

While not as exciting or seemingly controversial as studying, say, monkeys for human behaviors, Garrity's work with zebra fish has produced results.

In findings published last year in the "Proceedings of the National Academy of Sciences," Garrity announced her discovery of a gene in zebra fish that controls heart rhythms.

"It probably took me about three years to figure out that that was the gene and then another year after that to make it into enough of a story that we understood something about the biology," Garrity said.

This revelation potentially offers details about blood circulation in the human body, and Garrity's ongoing efforts could help move scientists one step closer to extending life.

A GROWING FIELD

Heart disease ranks as society's leading cause of death, especially of women, according to the Centers for Disease Control and Prevention.

�In an effort to learn more about the root causes of heart disease, scientists began studying zebra fish more than three decades ago.

One of the better known American pioneers of this research was the late George Streisinger, biology professor at the University of Oregon, who became interested in zebra fish in the early 1970s "through his hobby of owning tropical fish," according a Sept. 19, 2005, article in the Oregon Daily Emerald.

Streisinger's widow, Lotte, told the Emerald last fall that her husband would be amazed by the advancements in the study of zebra fish.

For example, until 1988 such research at that university occurred in a "corrugated metal Quonset hut across from the science buildings," according to the Emerald article. Today, the work, just as Garrity's does at CSU, takes place at a basement facility inside the science buildings.

Further, the Eugene, Ore., campus was host last year to a two-day international zebra fish conference that attracted scientists from as far away as Japan.

In recent years, the field of zebra fish analysis is growing so quickly that crucial information is widely available on the Internet and in scientific journals. One online database is the Zebra Fish Information Network, also based in Oregon, which allows researchers to search for genetic maps, clones, anatomy resources, and even individual researchers across the country.

In the United States alone "there's around 300 to 350 labs that study zebra fish as a model system," Garrity said.

At a time when it remains difficult to obtain grants for certain scientific research, CSU's Alicia Ebert stressed her belief of the importance of continually forging new frontiers toward better health.

"This is a stepping stone toward understanding the human system. If it has implications in human disease, it's worthy of funding," said Ebert, a doctoral candidate who works with Garrity.

HOW DOES SHE DO IT?

After finishing her doctoral work at Cornell and post-doctorate research at Massachusetts General Hospital, Garrity accepted a post at CSU and funding, which subsequently used to create her aquarium.

In a small, humid space in the zoology department basement (she has a separate laboratory, as well), Garrity packed in and stacked some 400 small tanks for her zebra fish.

When she isn't teaching, Garrity works with the fish to learn about heart defects. Specifically, she is studying genes inside the embryos – the transparent products of males and females that have mated.

Zebra fish fertilize their eggs and sperm externally and the result within 24 hours is an embryo that basically looks like a real fish.

With every experiment on a different heart defect comes a need for a readily prepared fish with specific genes mutations. There are an average of five fish in each aquarium that are useful for studying different genes.

"You have to have a lot of them because you never know when you need to set up fish and get embryos," Garrity explained, referring to the large amount of zebra fish she keeps stocked at a cost of a couple hundred dollars a month in maintenance.

Not every set of breeders, she added, is "going to produce embryos every time."

To obtain the embryos, Garrity puts two adult fish in a special tank that contains a barrier running down the middle. After spending a lonely night apart, Garrity removes the barrier and, if things go right, embryos will be resting at the bottom of that special tank within about 20 minutes.

"What happens is the lights come on and they go through their courtship behavior," Garrity said of the morning ritual. "The males kind of follow the females and rub up against them and eggs are laid and eggs are fertilized."

A protective grate – a honeycomb barrier at the bottom of the tank – shields the fertilized embryos from hungry parent fish. Garrity uses a "happy-face" labeling system on the tanks to identify her most successful breeders.

Once she has obtained the embryos, Garrity places them on a Petri dish and studies the material under a microscope.

In addition to their transparency, zebra fish embryos work well because a heart is not necessary for short-term survival. In all cases, the heart of an embryo begins functioning after one day but isn't necessary for survival until the fifth day of life.

Because the zebra fish embryo is so small during this four-day window, it can survive on a diffusion, or movement, of oxygen from surrounding tank water.

While this is a small window of time, Garrity also uses photographs and videos of the embryos to supplement her research.

Controversy

In addition to her findings on blood circulation, Garrity's efforts have blazed related trails.

Genes that lead to heart defects in zebra fish are so similar to those in humans that mutations, or changes in DNA, in zebra fish can be linked back to heart disease in humans.

The study of Holt-Oram syndrome is such an example. In humans, Holt-Oram is also known as a hand-heart syndrome, a genetic disorder that causes deformities in the upper limbs and heart.

In zebra fish, when the fish are given the same mutation, they exhibit similar abnormalities. While in humans, limb problems can range from to missing thumbs to dwarfed arms, in zebrafish, pectoral predicaments range from undeveloped fins to no fins at all.

Garrity's lab worked on tracing this disease back to its genetic counterparts, called gene mapping.

At the University of Oregon, the use of animals for scientific research, including zebra fish, has caused controversy and stirred several protests.

In May of 2000, a small group from the Students for the Ethical Treatment for Animals marched outside the home of a neuroscience professor who had been using monkeys and mice in his research, according to the Emerald newspaper.

Asked his thoughts on the march, then-University of Oregon Vice Provost for Research Tom Dyke told the Emerald:

"Animal models are the only way to find the type of information we want to get at," he said in 2000. "No treatment of humans has been discovered without animal research."

Garrity said she tries to keep her extensive experiments on animals as humane as possible before they die from the mutations that guide her research, while stressing the importance of using animals to study humans.

"I do think they're absolutely necessary," she said of animal models, adding the experiments "wouldn't be ethical to do on humans."

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