OSU continues to look for cause and cures

When researching the origins of and possible cures for cancer and other diseases affecting humans, scientists often turn to animals. Monkeys, sheep, rodents and even fruit flies all have enough genetic similarities to Homo sapiens to make informative models for study.

With their small size, high rate of reproduction and rapid developmental stages, fish offer a powerful vertebrate paradigm for genetic analysis. Previously salmon and rainbow trout ranked among the most popular research fish.

In the past decade, however, zebrafish have become all the rage in biomedical investigations.

"It's increasingly clear that in zebrafish we have an animal model that is inexpensive, easy to work with and extremely useful for study of human cancers," said Jan Spitsbergen, a fish pathologist for Oregon State University's Center for Fish Disease Research. She added that these fish experience a large variety of tumors in almost every major organ.

Spitsbergen and other researchers at OSU, in conjunction with the Brigham and Women's Hospital, the Children's Hospital, the Dana Farber Cancer Institute and the Broad Institute of MIT and Harvard, conducted a study looking at how mutations in the gene B-myb can make zebrafish — and, presumably, humans as well — more prone to developing cancerous tumors.

The findings were published this month in the Proceedings of the National Academy of Sciences. The Zebrafish International Resource Center and the Marine and Freshwater Biomedical Sciences Center also contributed to this study.

Aptly named for their black and white stripes, zebrafish are a tropical species native to Asia and India. They range in length from 2 to 5 centimeters, and they usually weigh between one-quarter of a gram and one-and-a-half grams.

Zebrafish eggs hatch within two days of fertilization, and the fry reach adulthood after about three months. The maximum lifespan of a zebrafish is five years.

Zebrafish produce optically clear embryos that develop ex utero, making it possible for scientists to observe their development better than in almost any other animal species, Spitsbergen said.

She and the other investigators in this study, begun five years ago and funded largely by grants from the National Institutes of Health, compared the incidence rates of tumor growth between wild type and mutant zebrafish when exposed to carcinogens.

The scientists caused genetic abnormalities in some of the zebrafish by exposing them to chemical mutagens. These mutations caused malfunctions in a particular gene known as B-myb, which plays a role in human cell-cycle regulation.

The mutant embryos exhibited genome instability. When placed in baths of carcinogens, mutant zebrafish developed far more cancerous tumors than the control specimens.

The mutant zebrafish also exhibited abnormal cell division. They developed tumors about 7 percent of the time after being exposed to the aqueous carcinogen treatments.

Zebrafish tumors are often so large relative to the fish's mass that they weighed half as much as the fish, Spitsbergen noted. By comparison, the exposed wild-type fish developed tumors only about 3 percent of the time.

Humans are exposed to carcinogens every day, just by eating preserved foods, using wood stoves, inhaling cigarette smoke and firing up barbecues, according to experts.

By studying how genetic mutations leave zebrafish more suspectible to developing cancer, scientists hope to better understand the genetic basis of cancer in humans.

Theo Dreher, chair of OSU's microbiology department, said that there are many similarities among veterbrates, particularly during developmental stages.

"You can't do invasive experiments and gene knock-downs with humans. You can do that with a mouse, but it's really quite complicated. It's a whole lot easier to do with a zebrafish," Dreher said. "A lot of the genes we have — some of which when they malfunction lead to disease states — resemble genes in zebrafish."

Spitsbergen said zebrafish research might one day look at cancer treatments, although for now her focus is on isolating the disease's cause and progression.

Mary Ann Albright covers higher education. She can be reached at maryann.albright@lee.net or 758-9518.