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.
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our fourth item, Convergence on PTEN Signaling Pathway, is from Autism Speaks’ Top 10 Autism Research Events of 2007.
Model systems for studying the complex and fundamentally human challenge of autism will be vitally important to solving autism because they allow researchers to study the underlying biology in a manner that is not possible in humans. Finding an animal model system with similar behavioral tendencies as humans allows researchers to study which biochemical pathways break down in autism and, most importantly, how they can be treated. In 2007, researchers added an important new model system to their arsenal, the “PTEN conditional knockout” mouse.
PTEN is a gene that encodes for a protein involved in several critical signaling pathways inside cells, including metabolism, growth and survival. To carry out its cellular duties, PTEN interacts with several other important proteins in a biochemical signaling cascade. Other proteins in this signaling pathway have previously been tied to developmental disorders such as Tuberous Sclerosis and Neurofibromatosis. In 2005, researchers found that within a small subset of individuals with autism and macrocephaly (large heads) 17% had mutations in the PTEN gene. This raised the possibility that disrupting PTEN activity, and the signaling pathways within which it functions, may result in some forms of autism. This year researchers succeeded in using complex genetic manipulations to shutdown the mouse version of the gene (PTEN) in the brain of young mice. Surprisingly, not only did these animals grow larger brains, the mice also displayed abnormal social behaviors and seizures, both of which can be features of autism.
These results provided important data supporting the emerging relevance of cellular signaling pathways to autistic behaviors, and are now focusing some researchers on specific molecules that could potentially become targets for cell-based therapeutics.
Update since this story was first run: Having discovered that disrupting the PTEN signaling pathway leads to autism-associated signs, in 2009 the researchers went on to further show that manipulation of the PTEN signaling pathway can serve as a successful treatment strategy. Making use of these same mice, they found that treatment with a pharmacological inhibitor of the PTEN pathway improved the autism-like pathology of the animals, including unusual social behaviors and seizures. Published in the Journal of Neuroscience, the newest data strengthen the case for focusing on this signaling pathway as a viable target for novel autism therapeutics.