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Through 69 years of controversy, past the conjectures of cold-hearted parenting or bad vaccinations, we find ourselves in an exhilarating time to study autism. The condition was originally defined only by speech and language abnormalities, social deficits, and a need for uniformity. These characteristics hold true, but the autism we know today is a far more multifaceted spectrum. There is no individual gene mutation that pinpoints the cause of the disorder. Fortunately, state-of-the-art technologies are amplifying our understanding of the complex genetics that underlie Autism Spectrum Disorder (ASD), putting what was once a moving target within reach.
In the Sur Laboratory, we study Rett Syndrome (RTT), an ASD that is accompanied by stunted development and deficits in motor and speech skills. The disorder, caused by mutations in the X-linked gene encoding Methyl CpG Binding Protein 2 (MeCP2), is on the quickly expanding list of ASDs with a known genetic origin. MeCP2 is a vastly important protein that plays a crucial role in regulating the expression of many genes throughout the body, effectively acting as a switch. Its binding to a specific region within a gene determines whether or not the protein it encodes will be produced. As one might expect, any loss of this tightly controlled regulation has drastic downstream effects. Indeed, humans who lack both copies of MeCP2 generally do not survive past gestation. For this reason, those suffering from Rett Syndrome are almost always female, as they have a healthy, compensatory copy of MeCP2 on their second X chromosome.
"It sounds like science fiction and it’s equally fascinating. Working with human neurons has allowed me to appreciate the individuality in neurological disorders. Each patient is slightly different."
The Sur Laboratory is passionate about dissecting the mechanisms underlying cortical development and plasticity. It’s within this context that we explore RTT pathogenesis. Previous work from the laboratory showed that adult mice lacking MeCP2 demonstrate excessive cortical plasticity typical of animals half their age. We believe this to be a demonstration of immature neuronal circuitry, which fundamentally contributes to Rett Syndrome. This is a promising concept – immature networks are not necessarily beyond repair. Accordingly, and with much excitement, we and others have demonstrated that many RTT phenotypes are in fact reversible in mice.
The majority of our laboratory’s Rett Syndrome research has taken place in mouse models that lack a functional MeCP2 protein. Such “knockout” animal models have, for years, paved the way for insight into countless mechanisms of human disorders, including autism. Mice are relatively easy to genetically manipulate and share substantial homology with the human genome. In fact, RTT mice recapitulate a spectrum of human symptomology ranging from obvious growth deficits to the more subtle hand-clasping movements typical of patients. However, whereas the majority of RTT patients have mutations in one region of the MeCP2 gene, most of the RTT mouse models studied harbor drastic mutations that result in a truncated, non-functional MeCP2 protein. This allows for easier phenotypic identification and analysis. However, it does not accurately reflect the variety, subtlety, and complex spectrum of syndromes that RTT patients experience depending on their respective mutation. In order to parse out and investigate these subtleties, one would have to study a genetically accurate human model of disease. When the disease in question resides in the brain, this is no trivial obstacle.
Embryonic stem cells, though a powerful resource for human disease research, are shrouded in ethical controversy. As such, their potential has been restricted. In 2007, a group of researchers found a way to circumvent this issue and in doing so, changed the way we are able to consider studying disease. Scientists in the Yamanaka Laboratory successfully transformed human adult skin cells into stem cells by introducing genes that restore an earlier cellular identity. Once reprogrammed, they are called induced Pluripotent Stem Cells (iPSCs). Their potential – both cellular and investigative – is virtually limitless. Starting from a naïve state, the iPSCs can be differentiated into the cell type of interest. The final product, be it neuronal, cardiac, or other, has the same genetic composition as the person from whom the skin cells were taken. Consequently, with only a skin sample from a patient, we are now able to grow, manipulate, and study human neurons that harbor precise, disease-relevant mutations.
In collaboration with the Haggarty Laboratory at Massachusetts General Hospital, we’ve been developing an iPSC model of Rett Syndrome. We have successfully been able to recapitulate human neuronal and glial development, on a remarkably similar time scale to that of human cortical neurogenesis in vivo. The neurons have a charged membrane; they fire action potentials when we inject current and depolarize them. They make synaptic contacts with one another and elicit spontaneous electrical activity. The glial cells support and regulate neuronal function. And it all happens in a dish a bit bigger than a quarter.
Using these cell lines, we intend to revisit and further explore the Sur Laboratory’s findings of altered cortical plasticity in RTT mice. Cortical plasticity is regulated in large part by a fine-tuned balance of excitatory and inhibitory neurotransmission. Skewing of this balance has been proposed to underlie several ASDs, including Rett Syndrome. We now have the unprecedented ability to assess the development of excitation and inhibition throughout the duration of cortical neurogenesis in human neurons.
It sounds like science fiction and it’s equally fascinating. Working with human neurons has allowed me to appreciate the individuality in neurological disorders. Each patient is slightly different. Some cells grow faster than others. Some have fewer processes. Each, however, is a contribution, and it comes with a responsibility to use the resources that we have available to the best of our ability. Though they are complex and widespread, ASDs have become less of a mystery due to committed research.