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TITLE:  It's a knockout
        First rat to have key genes altered
SOURCE: Nature, by Helen R. Pilcher
        http://www.nature.com/nsu/030512/030512-17.html
DATE:   May 19, 2003

--------------------- archive: www.gene.ch/genet.html --------------------


It's a knockout
First rat to have key genes altered

Researchers have altered genes in rats to create strains with genetic
characteristics of their choosing - a long-sought tool for studying disease.

The animals, called knockout rats, were stripped of a gene that
suppresses breast cancer in humans and will help researchers to unravel
the genetics of the disease1.

"It is our hope that, by studying the disease more extensively in rats,
we may be able to develop models for prevention and therapy," says
Michael Gould of the University of Wisconsin-Madison, who created the rats.

Future knockout rats will help researchers study other cancers and
diseases such as diabetes and hypertension, says Gould.

The humble rat, a lab stalwart for the past 100 years, took a back seat
in the 1980s. It was during that decade that researchers developed the
ability to manipulate mouse genes at will - and some 5,000 knockout mice
resulted. Rats however, proved to be a tougher proposition.

Mice knockouts are created when genetically modified stem cells are
implanted into pregnant females and allowed to develop. Rat stem cells
are more difficult to culture, and fail to develop in the womb.

Yet mice may not be the best model for many human diseases. Breast
cancer, for example, is best studied in rats, says Gould. "Tumours in the
rat have a spectra of hormonal responses that are similar to the human
response," he says.

Rats are also bigger than mice - making them easier to work with - and
their physiology and behaviour are well understood. Their creation is "a
badly needed development for research", says rat researcher Iain Robinson
of the British National Institute of Medical Research at Mill Hill, UK.

Getting ratty

The team produced strains of rats that carry altered versions of the
brca1 and brca2 genes. Women with similar faulty genes have an increased
risk of developing breast cancer.

Mice with one copy of the faulty gene fail to develop cancer, whereas
some women do. The rats are young, so it's too soon to know if they will
develop tumours, says cancer researcher Alan Ashworth of the Institute of
Cancer Research in London. If they do, they will prove to be a valuable
tool for breast-cancer research, he says.

They may also provide a model for a deadly form of anaemia, says
Ashworth. Like some of the rats, sufferers of the disease Fanconi anaemia
carry two copies of an altered brca gene.

Gould's team bypassed the stem-cell approach by injecting male rats with
a chemical that causes DNA to change at random. The rats were allowed to
reproduce, and the mutations were passed on to their offspring. By
screening the offspring's DNA, the researchers were able to pinpoint
changes in key genes.

The two-step technique is "extremely elegant", says mouse geneticist
Monica Justice of Baylor College of Medicine in Houston, Texas, yet it
may have its limitations. Genes cannot be added or activated by the
method - they can only be altered at random. "It will be a useful
additional tool, but it's unlikely to replace the mouse as a genetic
tool," Justice argues.

References

* Zan, Y. et al. Production of knockout rats using ENU mutagenesis and a
yeast-based screening assay. Nature Biotechnology, published online,
doi:10.1038/nbt830 (2003).

 


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