Researchers use novel sperm stem-cell technique to produce genetically modified rats

May 27, 2010
Dr. Kent Hamra, assistant professor of pharmacology at UT Southwestern and lead author of a study appearing in the June issue of Nature Methods. Credit: UT Southwestern Medical Center

For two decades, the laboratory mouse has been the workhorse of biomedical studies and the only mammal whose genes scientists could effectively and reliably manipulate to study human diseases and conditions.

Now researchers at UT Southwestern Medical Center have added another experimental research animal to the scientific stable: the rat.

In a new study appearing in the June issue of , UT Southwestern researchers detail how they created 35 new rat "lines," with each type of animal harboring mutations in specific genes. More than half of these mutated genes are associated with biological processes linked to human diseases, including cancer, diabetes, Alzheimer's disease, aberrant and mental illness.

Dr. Kent Hamra, assistant professor of pharmacology and lead author of the study, said the ability to easily, reliably and inexpensively produce genetically modified rats offers tremendous potential for biomedical research for even small laboratories with limited resources. For example, compared to the mouse, the rat is a larger, more intelligent animal; it is often better for biochemistry, pharmacology and physiology studies; and its behavior often is more in tune with that of humans.

"Our studies are focused on sperm-cell biology and fertility genes, but ultimately, we think other scientists will utilize these relatively simple, cost-effective techniques to generate genetically altered rats for use in experiments related to human disease," Dr. Hamra said.

One of the keys to producing the mutated rats was a novel technique Dr. Hamra and his colleagues in the Cecil H. and Ida Green Center for Reproductive Biology Sciences at UT Southwestern developed five years ago to prevent rat sperm stem cells - sperm - from differentiating, or changing, permanently into sperm.

"Getting sperm stem cells to grow in culture was a huge step," Dr. Hamra said. "In these new experiments, we took the next step and genetically modified these precursor cells in culture, selected them for mutations and introduced the cells into the testes of a sterile male rat."

The animal produces genetically altered sperm, resulting in mutant offspring that can be used for biomedical research.

Other methods have been used in limited ways to produce altered rats, but those methods do not involve manipulating stem cells in culture. In addition, genetic methods typically used to modify mice employ the use of the rodents' embryonic stem cells, and these methods have not worked well in other mammals, including the rat, Dr. Hamra said.

The latest work, he said, is proof-of-principle that genetic mutations introduced into mammalian stem cells from species other than mice can indeed be preselected for in culture and passed on to offspring.

Another key to Dr. Hamra's success in producing genetically altered rats came from two co-authors on the study, Drs. Zsuzsanna Izsvák and Zoltán Ivics of the Max-Delbruck Center for Molecular Medicine in Berlin. They developed a method to trigger mutations in specific areas of mammalian DNA. The method relies on deploying a segment of DNA called a transposon, which, when introduced into an organism's DNA, "jumps" randomly around the genome, creating mutations along the way.

"A transposon is nature's simplified way of cutting and pasting DNA in and out of the genome," Dr. Hamra said.

The researchers in Germany developed ways to harness the power of transposons for mammalian species and to control precisely where and how in a given genome they do their mutagenic "hopping." For example, a transposon can be limited to producing mutations only in an area of the genome where scientists think a disease-related gene resides.

In addition to producing actual animals, Dr. Hamra and his colleagues also are now using the transposon method to generate complex libraries of sperm stem cells harboring various genetic mutations. To date, they have about 100 cell lines with different mutations stored frozen in their labs.

"Because testes of a single rat can support sperm production from thousands of individual and because rats are so prolific, these libraries open the door to an economic strategy for high-throughput mutagenesis screens in the rat," Dr. Hamra said.

Explore further: Bulletproof nuclei? Stem cells exhibit unusual absorption property

Related Stories

Researchers derive first embryonic stem cells from rats

Dec 24, 2008

Researchers at the University of Southern California (USC) have, for the first time in history, derived authentic embryonic stem (ES) cells from rats. This breakthrough finding will enable scientists to create far more effective ...

Treating male infertility with stem cells

Mar 02, 2007

New research has examined the usefulness of bone marrow stem cells for treating male infertility, with promising results. The related report by Lue et al, “Fate of bone marrow stem cells transplanted into the testis: potential ...

Rat hair cells found to be true stem cells

Oct 04, 2005

Cells inside hair follicles are stem cells able to develop into the cell types needed for hair growth and follicle replacement, Swiss researchers claim.

Researchers make stem cells from developing sperm

Aug 06, 2009

The promise of stem cell therapy may lie in uncovering how adult cells revert back into a primordial, stem cell state, whose fate is yet to be determined. Now, cell scientists at the Johns Hopkins University School of Medicine ...

Recommended for you

Researchers successfully clone adult human stem cells

Apr 18, 2014

(Phys.org) —An international team of researchers, led by Robert Lanza, of Advanced Cell Technology, has announced that they have performed the first successful cloning of adult human skin cells into stem ...

Researchers develop new model of cellular movement

Apr 18, 2014

(Phys.org) —Cell movement plays an important role in a host of biological functions from embryonic development to repairing wounded tissue. It also enables cancer cells to break free from their sites of ...

User comments : 0

More news stories

Researchers successfully clone adult human stem cells

(Phys.org) —An international team of researchers, led by Robert Lanza, of Advanced Cell Technology, has announced that they have performed the first successful cloning of adult human skin cells into stem ...

Finnish inventor rethinks design of the axe

(Phys.org) —Finnish inventor Heikki Kärnä is the man behind the Vipukirves Leveraxe, which is a precision tool for splitting firewood. He designed the tool to make the job easier and more efficient, with ...

Making graphene in your kitchen

Graphene has been touted as a wonder material—the world's thinnest substance, but super-strong. Now scientists say it is so easy to make you could produce some in your kitchen.