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Feature Articles : Aug 1, 2011 ( )
Where Will Mice End Up in the Rat Race?
Knockout Rats Attempting to Muscle Aside Mice to Prevail as Dominant Research Model!--h2>
Laboratory mice and rats have been traditional animal models used by scientists for almost 150 years. In fact, the purposeful use of rodents for the investigation of human disease dates back to the mid 19th century.
Today, mice and rats make up 95% of the animals used in biomedical research. These rodents are central to the drug development process in their ability to model certain diseases and predict a drug's performance when administered to humans. They are used across many therapeutic areas for numerous applications including pharmacology and toxicology.
Given their size and physiological characteristics, rats have been the historical models used in preclinical drug discovery efforts. Why? The physiological makeup of rats makes them better suited for research in certain therapeutic areas, and their larger size makes rats more amendable to procedural manipulations.
The popularity of rats as research models may continue to increase even further as the recent emergence of new techniques to create knockout rats now allows researchers to manipulate the rat genome in new ways. Knockout rats have started to gain momentum as disease models and, if this trend continues, may become serious contenders to mouse models in the future.
Utility of Rats as Disease Models
From a physiological perspective, the liver metabolism of rats—in terms of the number and type of liver enzymes—is more similar to humans. The rat is often favored by researchers due to its morphology, which makes it easier to surgically manipulate, dose, and collect samples from. As such, rats are preferred over mice for many ADMET studies.
Physiologists and pathologists may prefer the anatomical characteristics of rats as well. For example, the cardiovascular system of the rat is more similar to humans as compared to the mouse. This, coupled with its larger size, makes the rat 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 th