t a preferred cardiovascular model for many applications.
Cardiovascular research, however, is not the only therapeutic area in which rats are often considered superior models to mice. Rats have many behavioral and cognitive characteristics similar to humans as well, and hold the promise to more closely model certain psychotherapeutic and neurological disorders such as Parkinson disease, Alzheimer disease, schizophrenia, and autism.
While there have been many types of genetically engineered mice created to model these conditions, the mouse models used to date are often criticized for their lack of predictivity relative to the human disease. As such, findings often fail to result in target validation and successful translation to disease-modifying therapies in humans.
So, if rats are more like humans physiologically and anatomically, and are better models in certain therapeutic areas, why have they been in the background for so long?
Advances in Genetic Engineering
Over the past three decades, techniques for genetic engineering have allowed for the production of a variety of genetically engineered animals that express myriad human diseases. Unfortunately, some of the techniques commonly used in mice could not be replicated in rats.
Over the past several years, however, technological advances in genetic engineering have allowed scientists to produce targeted manipulations of rat genomes. Such advances include chemical mutagenesis, transposon-mediated mutagenesis, zinc finger nuclease (ZFN) technology, and most recently modification of genes in rat embryonic stem (ES) cells.
This latter approach, developed by a group of scientists led by Qi-Long Ying at the University of Southern California, was long thought impossible in rats due to the fact that ES cells from rats did not maintain their pluripotency in culture. This group successfully used homologous recombination to modify genes in ES cells in 2010.
Implications for Biomedical Research
What does this all mean for the biomedical research community? Supported by the wealth of information collected on the rat to date, these emerging tools are boosting the significance of the rat as an animal model. All together, these techniques have opened the door for new possibilities with the premise of creating more predictive models, which could reduce drug development costs and increase success rates.
Two companies—Transposagen Biopharmaceuticals and Sigma-Aldrich Advanced Genetic Engineering (SAGE™) Labs—have already begun creating and distributing knockout rat disease models. Transposagen, using mobile DNA technology, has made available to the research community over 100 unique knockout lines, and is planning to produce 30,000 unique knockout rat lines in all.
SAGE is using ZFN technology, which generates site-specific, double-stranded breaks in the genome, to create knockout rats for a variety of conditions including diabetes, Parkinson disease, and Alzheimer disease. The firm recently announced a collaboration with the Michael J. Fox Foundation to create a model more representative of human Parkinson disease in the rat.
Will the Rat Really Replace the Mouse?
Genetically engineered rat models could potentially overcome the shortcomings associated with mouse morphology and physiology and, in the years to come, make the rat the model of choice for elucidating gene function and decoding physiological processes. But what practical barriers exist in transitioning to the rat, and how long will it take for knockout rats to be fully embraced by the biomedical community?
While the rat may be the preferred rodent in many contexts, logistical challenges including animal facility setup, housing space constraints, and other financial considerations may slow acceptance of the knockout rat as a mouse alternative.
The scientific community will need to weigh these considerations against the incremental value a disease model in a rat background may provide. Similar to other tools, industry acceptance of genetically engineered rats will require time to develop models, publish results, prove the util