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Three ways to make rat models of disease

December 27, 2010

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Until recently, researchers were unable to manipulate the genes of rats the way they could of mice, limiting advances in some areas where mice don’t exhibit the same characteristics as humans. Now, there are three primary ways to “knock out’’ or inactivate individual rat genes:

ZINC FINGER NUCLEASE
How it works: Synthetic proteins known as zinc fingers can be directed to bind to certain spots in the genome, breaking the DNA strand and removing a segment of it.

Advantages: It can work in multiple species, not just rats, and takes just five months to create a new knockout, compared with 12 to 18 months with other methods.

Status: This technology was developed by SAGE Labs, an initiative within Sigma Life Science, and announced in 2009.

EMBRYONIC STEM CELLS
How it works: The scientist manipulates a very early stage rat embryo to create an embryonic stem cell. Using traditional techniques, researchers then alter a gene by removing or adding a snippet of genetic material. Then, they tease that cell into becoming either an egg or a sperm, and breed the animal enough times to create rat strains that all possess the genetic change.

Advantages: It is quite similar to technologies now used to manipulate the mouse genome, so scientists will be comfortable using it. It allows researchers to modify any gene in a predetermined way and to limit the genetic change to a specific tissue or time during growth.

Status: This had been impossible until recently because rat embryonic stem cells don’t stay in an embryonic state very long. A team at the University of Southern California has now managed to halt stem cell development, allowing enough time to tinker with the genome.

TRANSPOSON MUTAGENESIS
How it works: Using a technique that has been compared with the cutting and pasting of sentences in documents with computer software, scientists move bits of the genome around.

Advantages: This method is the oldest, but also the least flexible because it does not give scientists much control over what they are moving.

Status: Scientists have been manipulating transposons for at least a decade, but their use to knock out rat genes is only about three years old.