OREGON STATE UNIVERSITY

NEW TRANSGENIC MICE MAY EXPAND RESEARCH, CUT COSTS

12/14/2004

CORVALLIS - Biochemists at Oregon State University have created the school's first transgenic mouse - a genetically modified laboratory animal that will be used to study the role of dietary selenium, and a technological advance for the university that may have huge benefits for a broad range of research.

University officials say this genetically modified mouse should be just the first of many that can be produced in a new mouse transgenic facility they plan to create, which will dramatically cut the costs of certain projects and speed advances in biomedical and other research.

For the moment, the first mouse created by this technology gives OSU an important new tool to work with in studying the antioxidant selenium, which helps protect cells from oxidative stress and appears to play a role in the prevention of cancer or other diseases.

"The creation of this transgenic mouse to use in laboratory research is a significant step forward in important research on selenium, which is currently a subject of intense study in the science community because of its cancer-preventive and other activities," said Chrissa Kioussi, an assistant professor in the OSU Department of Biochemistry and Biophysics.

"But beyond that, we know now that we have the knowledge base here at OSU to use this technology, which is essential to much modern biomedical research," Kioussi said. "OSU now joins the Oregon Health and Science University as the only institutions in the state to have this capability, and this is an important step forward that we very much want to build upon."

Researchers soon hope to create a new facility at OSU that could cost up to $1.5 million, and will include the personnel and equipment needed to create transgenic mice, mostly for biomedical research, and perhaps other animals for agricultural studies. Such a lab requires an injection microscope, embryonic stem cell facility, specific pathogen-free animal house, and other specialized equipment.

Once up and running, the facility will be invaluable, the OSU scientists say.

"Transgenic laboratory animals are a primary tool used in genetic and biomedical research, but creating them is both slow and expensive," said Gary Merrill, a professor of biochemistry at OSU. "It can take 2-3 years to have a genetically modified mouse created in some other laboratory, cost up to $75,000, and even then there's no guarantee you'll get what you need."

The same procedure done "in-house" can cut the costs by 60-70 percent and the time to 18 months or less, the researchers said, and also allow far more control over the experimental process.

"Modern biomedical science is very competitive, and if you're serious about moving your studies along quickly, you really need a mouse transgenic facility," Merrill said. "Having this capability will also help us more readily attract large grants from funding agencies such as the National Institutes of Health, and enhance the university's reputation as a leader in biomedical research."

Until the larger goals are met, the OSU scientists will be busy studying selenium.

In humans, mice and most other mammals, selenium is an essential nutrient. Minimal amounts are needed for life, and larger amounts appear to have a therapeutic effect in preventing cancer, an effect that has been observed in both animal and clinical studies, the OSU researchers said. Yet the same compound can be toxic at very high doses, and very little is known about its actual metabolic function.

"There's a lot we don't know about selenium," Merrill said. "That's what the new mouse is for."

There are about 30,000 proteins encoded by a mammalian genome, the OSU scientists say, but only 25 contain selenium and are called "selenoproteins." Scientists suspect that the therapeutic effects of selenium work through this very short list of proteins.

Through genetic engineering, the OSU researchers were able to delete one or both of the genes for "selenoprotein W," which had been intensively studied during the career of another OSU researcher, professor emeritus Phil Whanger. The scientists suspected it was one of the key selenoproteins, and as soon as they successfully deleted this single protein - one out of 30,000 - they found out just how important it was. Death occurred very early in embryonic development.

"We've already found that mice which lack selenoprotein W will die at day six of their embryonic development," Kioussi said. "This was surprising. We expected the mouse to perhaps develop to adults and maybe have some nutritional defect later in life."

The mice were dying, the researchers observed, at just about the time that the embryo starts to establish a blood supply and become well oxygenated. One obvious possibility, they say, is that this particular selenoprotein plays a key role in protecting cells from the toxic byproducts which unavoidably accumulate during aerobic metabolism.

The gestational stage at which the mouse embryos were dying - an entire mouse pregnancy is only three weeks long - also corresponds closely to the time many pregnant women suffer miscarriages.

"This same protein is found in humans, and clearly it could relate to oxidative stress and degenerative diseases, such as cancer, arthritis, inflammation, and atherosclerosis," Merrill said. "We need to learn about its enzymatic function, how it detoxifies oxygen byproducts, and many other things.

"The new transgenic mouse will give us a tool to do that," he said. "And our new facility, we hope, should open similar doors to research in a lot of other areas."