May 19, 2003 MADISON - Ever a favorite of biologists because of its record as a model to understand ailments like diabetes and cancer, the lab rat lost its luster as a research tool during the past decade because it defied attempts to manipulate its genome in a prescribed way.
Now, using a novel combination of tried-and-true techniques, scientists have created the first "knockout" rats, specifically rats whose genomes have been stripped of genes that suppress breast cancer. The development, reported today (May 19) by a team of scientists from the University of Wisconsin-Madison in online editions of the journal Nature Biotechnology, promises to restore the rat to biomedical prominence.
"People have tried for more than 10 years to produce a knockout rat," says Michael N. Gould, a professor of oncology at UW-Madison's McArdle Laboratory for Cancer Research and in whose laboratory the work was conducted.
For 100 years, he explains, the rat was the model of choice for many biomedical scientists. But a decade ago, when knockout technology was first widely deployed in the mouse, the sturdy rat was dethroned. Researchers rushed to take advantage of the biomedical possibilities of an animal model whose genome could be manipulated at will, adding or subtracting genes to gain surprising insight into a host of diseases and potential treatments.
The rat, says Gould, had been "compromised by the lack of a full genetic toolbox. Over the last 10 years, the government and drug companies have invested a lot in bringing the rat up to speed. But one of the last major elusive tools for our toolbox was the ability to knock out genes."
The ability to add or subtract genes to an animal's genome lends powerful insight into the basic mechanisms of disease. New methods of disease prevention and treatment in humans, as well as a better basic understanding of development, physiology and pathology have resulted from the ability of scientists to manipulate genes in living animals.
Prior to the advent of the knockout mouse, the rat was "the model of choice for studies in physiology, pathobiology, toxicology and neurobiology," says Gould. "Anybody that gave up rats because there wasn't a knockout technology will likely want to go back" to using them.
The advantages of rats, Gould says, lie in their larger size and the plethora of disease models developed for it during the past century. "This technology gives us the opportunity to use rat models with a modern genetic approach."
For Gould, who studies the genetics that underpin breast cancer, the return of the rat spells new research opportunities because the disease manifests itself differently in the two animals.
"Tumors in the rat have a spectra of hormonal responses that is similar to the human response," he says. "It is our hope that by studying the disease more extensively in rats, we may be able to develop models for prevention and therapy."
Keeping scientists from making rat knockouts was their inability to use rat embryonic stem cells to produce rats, which could be genetically modified, as mouse stem cells are routinely used to make knockout mice. Moreover, no rat has even been produced using nuclear transfer or cloning techniques, another method by which researchers can selectively modify an animal's genome.
The development of the world's first knockout rats by Gould's lab was accomplished using techniques well know to biologists, but that had never before been used in combination with the goal of producing a knockout. Scientists have long known that it is possible to randomly disrupt an animal's genome by injecting certain chemicals. These mutations can then be passed to future generations through simple breeding. By screening the DNA of the progeny of the mutant rats using a method that can accurately pin down changes that occur to functional genes, Gould's group was able to selectively breed out two different knockout rats whose genomes each lacked a gene known to suppress breast cancer.
"None of the technologies we're using are novel," Gould says. "The novelty is how they are combined."
The technique has been patented by the Wisconsin Alumni Research Foundation.
In addition to Gould, lead co-authors of the Nature Biotechnology paper include Yunhong Zan and Jill D. Haag.
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