By Kristen Coughlin
The rat as a model system
Rats were the first mammalian species specifically domesticated to be used in the laboratory. Two centuries ago, the brown rat Rattus norvegicus was used by scientists to understand human physiology and medicine, concentrating on the effects of food and oxygen deprivation. Rats have since been used to answer a wide range of basic science questions in the fields of physiology, immunology, pharmacology, toxicology, nutrition, behavior and learning.
What are the advantages of using rats in human disease research?
Rats are an ideal choice for many labs due to their size and physiological similarity to humans. With the sequencing of the Brown Norway rat in 2004 by the Rat Genome Sequencing Project Consortium, led by the Baylor College of Medicine, it is now known that almost all disease-linked human genes have counterparts in the rat. Now, after advances in gene targeting and gene editing, it is possible to specifically modify the rat genome to produce knockouts and knockins, further enhancing our understanding of human disease through the development of powerful customized CRISPR rat models. Better rat models are likely to decrease drug failure in clinical trials – currently standing at about 90% – which will decrease development costs and time to market. The sequenced genome will also unveil new targets for drug intervention.
Researchers choose rats over other species for a number of reasons:
- The larger size makes handling, sampling and performing procedures easier.
- From a physiological standpoint, more is known about the responses and pathways in rats than in other species due to the wealth of data collected over the years.
- Some results suggest that the rat more accurately reflects human physiology than other species, mimicking human disease more accurately in many cases.
- Behavioural research shows rats are more suited to studies on learning and cognition because they are more capable of learning tasks than other species.
- The rat’s ability to learn, remember, and interact gives them an advantage over other species, allowing for insights into the basic principles behind learning and behavior which can then be translated to human behavior and learning.
- It is now possible to more easily manipulate the rat genome to produce specific gene knockouts and knockins and apply results to our understanding of human disease.
The power of rodent models
The rat has historically been the preferred animal model for biomedical research due to genetic and physiological similarities to humans. In 2001 however with the development of targeted genetic manipulation in mouse embryonic stem (ES) cells, rats took somewhat of a back seat as the rodent of choice for specific gene targeting because this technology was not available in the rat. In mice, ES cells can be maintained in their pluripotent state easily. The same methods that allow this to be so in mice have failed in rats. Rat ES cells are very unstable, with any disturbance leading them to activate, so that they could not be implanted in an embryo and brought to term. The power of mouse models proved to be so clear however that the desire for the same abilities in rat continued to be desired and pursued.
Significant progress was made in 2008 by Professor Austin Smith’s lab at Cambridge, and Professor Qi-Long Ying’s lab at the University of Southern California with the first targeting of rat ES cells achieved. Although the ability to target rat ES cells was then available, doing so was still difficult. It was around this time that gene editing came into being, specifically Zn Finger nucleases and TALENS. Although expensive to produce and not always precise, this became the preferred method to target rats in a specific manner. Then in 2012, CRISPR/Cas9 changed genome manipulation as we know it. With a much less expensive and more precise method for targeting genomes the potential for rats as a model system of human disease can now be fully realized.
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