Rats Rising: Using the Rat as a Model Organism for Autism Research
Autism Speaks has partnered with SAGE Labs, a division of Sigma Life Science, to create and validate the first line of rat models of autism. Previous rodent models of ASD, which are important for understanding the biological basis of autism and drug discovery, have used mice. Such models allow scientists to examine the downstream effects of genetic mutations on brain development and behavior. For studies of behavior, learning and cognition, the rat is the animal of choice due to its complex behavioral repertoire. With these new genetically modified rats, the richness of previous behavioral and physiological research can be leveraged and applied directly to autism. These new rat models will now be validated in the laboratories of several scientists who will be studying brain development and behavior of the animals.
Edward Weinstein, Ph.D., the Director of SAGE labs, answers some questions about the new model animals and how they will benefit autism research.
1) Generally speaking, why do we need a rat model of autism when mouse models exist?
Dr. Weinstein: Researchers have been able to create genetically modified mice for the past 25 years, so a large number of mouse models have been created, addressing all sorts of human diseases and disorders. But mice are not always the best model system for every condition. For example, researchers who study ocular disease greatly prefer the rabbit. And the rat is an excellent model for toxicology, cardiovascular, and cognitive research. In the past, researchers would create the best genetically modified mouse model possible to answer their scientific questions. Now they can create the most relevant genetically modified model in whatever species best models the condition they are studying.
2) Why can’t the same technology that one uses to make a genetically modified mouse work with rats?
Dr. Weinstein: Genetically modified mice, also sometimes called knockout mice, are created by making changes to the DNA in a mouse embryonic stem cell. Researchers tried unsuccessfully for decades to develop rat models using the same technology. SAGE labs has developed a new technology, called zinc finger nuclease technology, which allows us to create knockout rats without the use of embryonic stem cells.
3) Can you describe how the Sigma technology works in a manner accessible to our community?
Dr. Weinstein: The technology is actually fairly straightforward. We create an enzyme called a zinc finger nuclease (ZFN), which has been especially constructed to target a specific gene. We can then inject that ZFN into a one-cell rat embryo where it will bind the targeted gene and cause a break in the DNA. This effectively “knocks out”, or inactivates, the gene. The one-cell embryo is then transferred into a surrogate rat and 21 days later you have a genetically modified rat that is born. This genetically modified rat will be exactly like every other rat, with the exception of the inactivation of that one specific gene that was targeted. Part of the beauty of this technology is that it not only works for creation of genetically modified rats, but also mice and rabbits. It should work in virtually any animal model system.
4) What do you see are the next steps in using genetically modified rats for autism research?
Dr. Weinstein: We have worked to create a suite of genetically modified rats that we hope will be useful for autism research. The real challenging work, however, comes in the validation of the models. Testing these rats to see if there really are behavioral differences in them will be key to determining their usefulness.
In addition, autism research is still at the stage where new genetic links are continuously being uncovered. We hope to continue to serve the research community by expanding our platform of autism models as rapidly as possible.
5) Genetics is only one component of the autism puzzle. Research has identified environmental agents that either alone or in combination with a genetic vulnerability lead to the altered neurodevelopment we see in autism. Can environmental and gene-environment interaction questions be posed using these new rats?
Dr. Weinstein: We get kind of hung-up when we say “genetic model.” We absolutely can do these experiments. Using the genetically modified rats, we can carefully time exposures both in utero and during early post-natal life. Gene-environment interactions are extremely important to understand and we hope that researchers will seek answers to those questions with these new autism model rats.
6) Why did you partner with Autism Speaks for your foray into rat models of genes important in autism?
Dr. Weinstein: We have a lot of expertise in the use of Zinc Finger Nucleases and the creation of genetically modified animals. However, we don’t have the in-depth expertise or background in autism that is necessary for determining which are the best models to create. Working with Autism Speaks has been critical from a scientific aspect. Also, members of Autism Speaks are so well connected to the research community, you know that when you get scientific advice from Autism Speaks, you are getting advice from an entire field of researchers.
We look forward to sharing the results of the behavioral and physiological evaluations of these new rats as scientists begin working with them.