Researcher Uses New Genetically Engineered Mice to Better Understand Autism
Early in his career as a scientist, Matthew P. Anderson, M.D., Ph.D., director of neuropathology at Beth Israel Deaconess Medical Center, was searching for a research field off the beaten path. "I saw this emerging childhood disease of the brain, and there was just very little known about it," he recalls. "Many of the people that I trained with in neuropathology and neurology probably thought at the time that I was a little bit crazy. It just didn't exist. There was no field."
Autism, which only 10 years ago was at the periphery of psychology and pediatrics and not a popular subject for scientists, is a developmental disorder that appears in the first three years of life and affects the brain's normal development of social and communication skills. Within the last five to eight years, diagnoses and awareness of the complex disorder have skyrocketed. "The autism spectrum became a common place to put a lot of somewhat diverse conditions which share these behav-ioral traits: impaired communication, reduced social interaction, and increased repetitive behaviors," says Anderson. Today the Centers for Disease Control and Prevention estimates one in every 88 children and one in 54 boys in the United States is autistic.
Anderson, who works in both the Department of Neurology and the Department of Pathology at BIDMC, is on the leading edge of the relatively new and extremely active research field to understand the genetic components of the debilitating social disease. Last year he made a major breakthrough when he developed and published his work on a genetically engineered mouse model for autism, which comes closer to mirroring all of the core symptoms of the disorder in humans than any before. The model, which produces quantifiable and easily replicable results, provides a preliminary understanding of the abnormalities that may lead to autism and can serve as an important tool for future use by scientists and clinicians, including Anderson, to test potential genetic components of the disorder and possible drug therapies targeting those genes.
The Nancy Lurie Marks Family Foundation, which has previously supported Anderson's work on immune system responses related to autism, recently gave him a $1 million gift to support his research in addition to a $440,000 grant to research genetic forms of autism using mouse models. "Matt Anderson brings to autism research not only an impressive background in molecular biology but a rare and much-needed biomedical perspective," says the foundation's director and chief scientific officer, Clarence Schutt, Ph.D. "This enables him to carry out incisive experiments that bridge geno-mics data with the subtle and varied observations of physicians and neuroscientists. He will soon publish several path-breaking papers on autism that will accelerate the pace of translating basic research into improved clinical practice."
Philanthropic foundations and grass-roots organizations are at the heart of support for investigational research into novel disorders, like autism. With this groundwork, Anderson's laboratory has grown into a multi-dimensional force in the field, focused on genetically engineering mice, recording behavior measurements, studying neurocircuits, and, now, molecular work to understand pathways involved in gene regulation. "We have some quite intriguing genes that we are looking at now," he says. "We are looking at a variety of genes that are copy number variations in autism, and we think it is going to provide insight into the evolution of the human brain."
The advances in autism research are coming fast thanks to improve-ments in modern technology. Recent implementation of microarray hybridization technology, which provides the ability to look at the whole genome simultaneously on a chip, enabled scientists to identify deletions and duplications in the linear structure of our genome. "What they found were these micro duplications and deletions are present in these autistic kids," Anderson says of previous research. "These are things you couldn't see with the standard cytogenetic method they had before. That's why we can see these now suddenly."
In developing his mouse model, Anderson focused on isodicentric chromosome 15 or idic (15), a chromosome abnormality that had been linked to traits of autism. Individuals with idic (15) have 47 chromosomes instead of the normal 46 with extra genetic material on chromosome 15. "We focused on a region of the chromosome that was duplicated or triplicated in autistic kids, which is 15q11-13," he says. Three percent of all cases of autism are associated with mutations in this region, making it the most abundant genetic form of classic autism.
With approximately 40 genes to investigate, Anderson and his team had a clue where to look. "Ube3a is a gene that we suspected might be responsible," he explains. Deletions and mutations of this particular gene are associated with Angelman Syndrome, a disorder in children characterized by intellectual disability, epilepsy, and intriguingly, excessive laughter, smiling, and personal engagement-the opposite traits of autistic kids. "We thought too little might cause an overly social child, while too much might suppress social interaction," Anderson says. He introduced extra copies of the Ube3a gene into the mice and showed problems with social behavior that mimicked autism in humans. "We were able to recreate impairments of verbal communication, social interaction, and repetitive behavior," he says.
Anderson admits even he was skeptical when they first planned to record social behavior in mice, but it turns out they are extremely social ani-mals. "We saw that if you put two mice together that have never seen each other, they will talk to each other," he explains. "If you put two female mice together, they talk more than two male mice. So we focused on females, and we found with the extra copies of the gene, their communication was impaired." They investigated social interaction in a three-chambered cage. Normal mice showed a preference to interact with other mice, but the autistic mice were oblivious to the other mouse in the cage. "They didn't show an aversion to that mouse, but instead, complete indifference," he says, also noting that if there was an inanimate object in the cage instead of a mouse, the autistic mice showed a strong preference for exploration, similar to an autistic child. Finally, observations of self-grooming were more than three times the amount of a normal mouse, which demonstrated excessive tendencies and signature repetitive behavior.
Anderson and his team have already used these autistic mice to investigate potential circuit malfunctions in the brain. "We found that there was a selective impairment of glutamatergic synaptic transmission, which is the main excitatory neurotransmitter of the brain," Anderson says. "We don't yet know that the defect is the cause of their problem. There is much more work to be done, but as we get these clues, then we can guess at what treatments might help to make the system work better." And as they move this and other lines of research forward, they have a robust mouse model to work with and test potential treatments.