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  • richardmitnick 10:15 am on March 20, 2017 Permalink | Reply
    Tags: Angelman’s syndrome, , Autism Spectrum Disorder, Cerebellin 1 (CBLN1), Chemogenetics, Circuit Breaker, , Isodicentric chromosome 15q, , The gene UBE3A   

    From HMS: “Circuit Breaker” Autism Studies 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    March 16, 2017
    JACQUELINE MITCHELL

    1
    ktsimage/Getty Images

    Harvard Medical School researchers at Beth Israel Deaconess Medical Center have gained new insight into the genetic and neuronal circuit mechanisms that may contribute to impaired sociability in some forms of autism spectrum disorder.

    Led by Matthew Anderson, HMS associate professor of pathology and director of neuropathology at Beth Israel Deaconess, the scientists determined how a gene linked to one common form of autism works in a specific population of brain cells to impair sociability.

    The research, published today in the journal Nature, reveals the neurobiological control of sociability and could represent important first steps toward interventions for patients with autism.

    Anderson and colleagues focused on the gene UBE3A, multiple copies of which cause a form of autism in humans (called isodicentric chromosome 15q). Conversely, the lack of this same gene in humans leads to a developmental disorder called Angelman’s syndrome, characterized by increased sociability.

    In previous work, Anderson’s team demonstrated that mice engineered with extra copies of the UBE3A gene show impaired sociability, as well as heightened repetitive self grooming and reduced vocalizations with other mice.

    “In this study, we wanted to determine where in the brain this social behavior deficit arises and where and how increases of the UBE3A gene repress it,” said Anderson, who is also director of the Autism BrainNET, Boston Node.

    “We had tools in hand that we built ourselves. We not only introduced the gene into specific brain regions of the mouse, but we could also direct it to specific cell types to test which ones played a role in regulating sociability,” Anderson said.

    When Anderson and colleagues compared the brains of the mice engineered to model autism to those of normal—or wild type—mice, they observed that the increased UBE3A gene copies interacted with nearly 600 other genes.

    After analyzing and comparing protein interactions between the UBE3A regulated gene and genes altered in human autism, the researchers noticed that increased doses of UBE3A repressed Cerebellin genes.

    Cerebellin is a family of genes that physically interact with other autism genes to form glutamatergic synapses, the junctions where neurons communicate with each other via the neurotransmitter glutamate.

    The researchers chose to focus on one of them, Cerebellin 1 (CBLN1), as the potential mediator of UBE3A’s effects. When they deleted CBLN1 in glutamate neurons, they recreated the same impaired sociability produced by increased UBE3A.

    “Selecting Cerebellin 1 out of hundreds of other potential targets was something of a leap of faith,” Anderson said. “When we deleted the gene and were able to reconstitute the social deficits, that was the moment we realized we’d hit the right target. Cerebellin 1 was the gene repressed by UBE3A that seemed to mediate its effects,” he said.

    In another series of experiments, Anderson and colleagues demonstrated an even more definitive link between UBE3A and CBLN1. Seizures are a common symptom among people with autism including this genetic form.

    Seizures themselves, when sufficiently severe, also impaired sociability.

    Anderson’s team suspected this seizure-induced impairment of sociability was the result of repressing the Cerebellin genes. Indeed, the researchers found that deleting UBE3A, upstream from Cerebellin genes, prevented the seizure-induced social impairments and blocked seizures ability to repress CBLN1.

    “If you take away UBE3A, seizures can’t repress sociability or Cerebellin,” said Anderson. “The flip side is, if you have just a little extra UBE3A—as a subset of people with autism do—and you combine that with less severe seizures, you can get a full-blown loss of social interactions.”

    The researchers next conducted a variety of brain-mapping experiments to locate where in the brain these crucial seizure-gene interactions take place.

    “We mapped this seat of sociability to a surprising location,“ Anderson explained. Most scientists would have thought they take place in the cortex—the area of the brain where sensory processing and motor commands take place—but, in fact, these interactions take place in the brain stem, in the reward system.”

    Then the researchers used their engineered mouse model to confirm the precise location as the ventral tegmental area, part of the midbrain that plays a role in the reward system and addiction.

    Anderson and colleagues used chemogenetics—an approach that makes use of modified receptors introduced into neurons that respond to drugs but not to naturally occurring neurotransmitters—to switch this specific group of neurons on or off.

    Turning these neurons on could magnify sociability and rescue seizure and UBE3A-induced sociability deficits.

    “We were able to abolish sociability by inhibiting these neurons, and we could magnify and prolong sociability by turning them on,” said Anderson. “So we have a toggle switch for sociability. It has a therapeutic flavor; someday, we might be able to translate this into a treatment that will helps patients.”

    The researchers thank Oriana DiStefano, Greg Salimando and Rebecca Broadhurst for colony work and the HMS Neurobiology Imaging Facility (NINDS P30 Core Center Grant #NS07203).

    This work was supported an American Academy of Neurology Research Training Fellowship, the National Institutes of Health (grants 1R25NS070682, 1R01NS08916, 1R21MH100868 and 1R21HD079249), the Nancy Lurie Marks Family Foundation, the Landreth Family Foundation, the Simons Foundation, Autism Speaks/National Alliance for Autism Research and the Klarman Family Foundation.

    See the full article here .

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  • richardmitnick 8:14 am on August 26, 2016 Permalink | Reply
    Tags: , Autism Spectrum Disorder, ,   

    From UCLA: “UCLA-led study sheds new light on the complex genetics of autism” 

    UCLA bloc

    UCLA

    August 25, 2016
    Jim Schnabel

    1
    The UCLA-led study uncovered more than a dozen potential new autism spectrum disorder risk genes, one of them linked to delays in language ability. Dr. Richard Feldman/National Cancer Institute

    A new study led by UCLA scientists shows that in families with multiple children on the autism spectrum, the pattern of genetic factors is different from that seen in families with just one affected child.

    The study focused on genetic changes known as copy-number variations (CNVs), which are losses or gains of normal DNA. Previous research has linked non-inherited CNVs, which originate as defects in the sperm or egg cell from which the affected child is conceived, to autism spectrum disorder in children whose siblings are not affected.

    The research findings included the discovery of more than a dozen promising new candidates for genes linked to the risk of autism spectrum disorders, highlighting the complexity of genetic factors in the disorders. The findings provide a better picture of how genetic variation contributes to autism disorders, and could perhaps point to a possible new target for future therapies. The study appears in the Aug. 25 issue of the American Journal of Human Genetics.

    The researchers found that, among children with an autism spectrum disorder who have siblings with autism disorders, inherited copy-number variations had a stronger influence than non-inherited CNVs. This was expected, but had previously not been demonstrated.

    Although the researchers expected inherited factors to appear to play a greater role in families in which more than one child has an autism spectrum disorder, they were surprised by another observation in these families: When an affected child has an inherited genetic variation that is known to be an autism spectrum disorder risk factor, it is seldom the case that all his affected siblings have that same variation.

    “It’s actually the exception rather than the rule,” said principal investigator Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics at the David Geffen School of Medicine at UCLA. “So for example, there are families in which only two of three kids have the rare CNV inherited from the parent, yet they all have been diagnosed with an autism disorder. One might have expected all three to inherit this major risk factor.”

    The study arose from a long-running project by Geschwind and collaborators to gather DNA and clinical data on families with more than one child with autism spectrum disorder. These are known as “multiplex families.” Most autism genetics studies have focused on families with just one affected child, known as “simplex families,” because researchers predicted that certain types of disease-related DNA changes were in principle easier to detect in such families.

    The relative exclusion of multiplex families, which account for about 11 percent of families with children who have an autism spectrum disorder, may have distorted the picture of how DNA changes contribute to autism disorders. Most obviously, cases of autism spectrum disorder diagnosed in siblings, which appear to run in the family, would be expected to result more from heritable genetic variations than non-inherited CNVs. Heritability is the extent to which genetic differences contribute to observed physical differences.

    One possible explanation for the finding that autistic siblings in a family usually do not all have the same disease-linked genetic variation, Geschwind said, is that lightning has indeed struck twice — in the form of an unlucky non-inherited mutation that accounts for an autism spectrum disorder in a child who lacks inherited risk factors found in siblings.

    Another possibility is that the autism spectrum disorder arises in the siblings mostly from other, harder-to-find factors, for example common or rare inherited variation in many genes, so that the presence or absence of a large, inherited copy-number variation influences only the severity of the disorder.

    The analysis is based on the final collection of data on 1,532 ASD families, which is known as the Autism Genetic Resource Exchange. About 80 percent of the families in the database are multiplex.

    “This is the largest study of its kind in families with multiple autism spectrum disorder children, and it shows that looking at such families can provide significant new insights,” said Geschwind, who is also a professor of neurology and psychiatry.

    Of the potential new autism spectrum disorder risk genes discovered by the researchers, one of them, NR4A2, is linked to some rare cases of autism disorder with delays in language ability. The language connection, Geschwind said, fits with a previous finding from his laboratory that NR4A2 is expressed in the human brain in areas involved in language development, specifically the temporal lobe.

    Geschwind emphasized that the complex genetic underpinnings of autism spectrum disorder in multiplex families need to be better characterized with larger studies of these families. “There are a lot of multiplex families out there waiting to be studied, but unfortunately it seems there is no effort now to study these families on a larger scale,” Geschwind said.

    The lead author of the study, who performed most of the analyses, was Virpi Leppa, a postdoctoral researcher in the Geschwind Laboratory.

    The research was part of a collaborative effort including researchers from Yale University, University of California, San Francisco, Washington University at St. Louis, and other institutions.

    Funding was provided by the National Institute for Mental Health (R01 MH081754, R01 MH100027, R01 MH074090, R01 MH06454701S1). The Autism Genetic Resource Exchange was initially supported by the Cure Autism Now foundation, which later merged with another organization, Autism Speaks.

    See the full article here .

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  • richardmitnick 8:24 am on July 18, 2016 Permalink | Reply
    Tags: , Autism Spectrum Disorder,   

    From Harvard: “Neurodiversity: The Benefits of Recruiting Employees with Cognitive Disabilities” 

    Harvard University

    Harvard University

    11 Jul 2016
    Roberta Holland

    Employers are increasingly finding fresh ideas and insights by recruiting workers with Autism Spectrum Disorder and other cognitive disabilities. Gary Pisano and Robert Austin discuss their case study, “SAP SE: Autism at Work.”

    There’s a new frontier in diversity programs focused not on race or gender but on cognitive ability.

    The growing interest in neurodiversity—hiring people with cognitive disabilities like Autism Spectrum Disorder (ASD)—is motivated by companies looking to tap into a largely unnoticed labor pool at a time when many bemoan the lack of skilled workers.

    ASD is an umbrella term for several cognitive impairments, including Asperger syndrome. The United States Centers for Disease Control estimates one in 68 children have been diagnosed with ASD. Globally the estimate is one in 100.

    Social difficulties are one of the hallmarks of ASD, making it hard for those with ASD to make it through a traditional hiring process. Roughly 60 percent of people with ASD have average or above average intelligence, yet 85 percent are unemployed.

    “Their intellectual horsepower is quite high,” Harvard Business School’s Gary P. Pisano says of the ASD population. “They do things differently and they behave differently, but the question is, can you turn that into a virtue? That’s part of the thinking on this idea of neurodiversity; that we do better when we mix people who think differently or are wired a bit differently.”

    AUTISM AT WORK

    Pisano, the Harry E. Figgie Jr. Professor of Business Administration, and his former HBS colleague Robert D. Austin, Professor of Information Systems, Ivey Business School, delve into the growing neurodiversity initiative at software behemoth SAP in their case study SAP SE: Autism at Work.

    1
    Software testing is exacting and requires precision, so can be a good fit for people with Autism Spectrum Disorder. Source: maciek905

    Started in 2011, the Autism at Work program grew from what was a side project by the head of SAP Labs in India into a companywide effort to have 1 percent of its workforce comprised of individuals with ASD. V. R. Ferose, then managing director of SAP Labs, was inspired after hearing about Specialisterne, a Danish software firm with 75 percent of its workforce diagnosed with ASD. Ferose, like the founder of Specialisterne, has a son diagnosed with ASD.

    Specialisterne is what Austin calls the “gold standard” of neurodiversity. The software testing and consulting firm was founded in 2004 by Thorkil Sonne after Sonne’s young son was diagnosed with the disorder. From inception, it was a for-profit business, relying on employees’ talents, not diagnoses, to attract clients.

    “Software testing is extremely exacting and requires a lot of precision, but it’s also kind of mind-numbingly repetitious,” says Austin. “It’s important to do it correctly, but it’s very difficult to keep your attention on it well enough to do it correctly.”

    Austin wrote a case study on Specialisterne while at HBS in 2008, and invited Sonne to an executive education program for CIOs.

    “He’s the only person I’ve ever seen in an executive program at Harvard get a standing ovation,” Austin says, adding that some listeners were driven to tears. “It was quite an experience.”

    CIOs were excited by how the concept fits together, matching employers in need of talent with a group that has been largely unemployed or unemployed. It’s not a “charity thing,” Austin says.

    “There are possibilities here to do something that is socially good and yet is still being very responsible to the business,” Pisano says.

    “Whether this is the beginning of a bigger movement, I really don’t know, but I hope it does change some things. The prevalence of this kind of condition is actually quite high in our society, so it’s a real shame if we are not engaging those people.”

    NEURODIVERSITY IN PRACTICE

    Sonne and Specialisterne have helped several companies set up neurodiversity programs, including SAP. Partnering with Specialisterne almost implies a seal of approval, offering reassurance for companies worried about accusations of exploiting a vulnerable population, Austin says.

    Anka Wittenberg, SAP’s head of diversity and inclusion, was so impressed by Ferose’s effort that in 2013 she worked to build on that success across the company. The program expanded beyond India to Germany, the United States, Brazil, Canada, the Czech Republic, and Ireland. So far about 100 people have been hired for jobs including software developer or tester, business analyst, and graphic designer, and pay is commensurate to what others in those jobs earn.

    Many participants came to the program with advanced degrees and even holding patents but little, if any, work history. Pisano explains that many of those candidates wouldn’t make it through the interview process or wouldn’t bother applying because they didn’t think they’d get hired.

    Because people with ASD often don’t sell themselves well, the SAP program begins with a less intimidating hangout, during which candidates work individually on Lego Mindstorms projects escalating in difficulty. They then move on to team challenges, followed by a five-week training period developed by Specialisterne.

    So-called soft skills training, like social interaction and professional norms, is a crucial piece provided by public or private organizations already working with the ASD population. Issues other new hires might not have to think about can stymie a new hire with ASD. For example, when the CEO sends out a companywide email, are you supposed to reply? That’s where the soft skills training comes in.

    After landing a job, Autism at Work participants are given mentors and team buddies—existing SAP employees who volunteer—as well as a job and life skills coach usually provided by a partner group. SAP employees also received autism awareness training in what Pisano calls “a lot of internal selling.”

    Other companies that either have programs or are starting one include Towers Watson, Hewlett Packard Enterprise in Australia, E-Y, and Microsoft, Austin says. SAP and other tech companies have agreed informally to share qualified candidates in situations when an individual has completed training but the company doesn’t have a job for them.

    RETHINKING TALENT MANAGEMENT

    Just published, the SAP case study hasn’t made its way to the classroom yet. Both professors believe it holds valuable lessons for MBAs. Pisano focuses on organizational issues, given the complex and multi-layered process required. He wants students to think beyond the feel-good nature of the program and dig into how to build a successful, scalable program.

    “The superficial answer is it’s win-win, and it can be win-win,” Pisano says. “But they can also be win-lose, or lose-lose. Everybody can come out worse if you don’t think through how to do these things well.”

    For Austin, the main takeaway is rethinking how to manage people and talent. He points to SAP’s analogy that individuals are like puzzle pieces with irregular shapes.

    “One of the things that we’ve done historically in human resource management is, we’ve asked people to trim away the parts of themselves that are irregularly shaped, and then we ask them to plug themselves into standard roles,” Austin says. “SAP is asking itself whether that might be the wrong way to do things in an innovation economy. Instead, maybe managers have to do the hard work of putting the puzzle pieces together and inviting people to bring their entire selves to work.”

    That approach can benefit other forms of diversity like race, gender, and sexual orientation.

    “Innovation is about finding ideas that are outside the normal parameters, and you don’t do that by slicing away everything that’s outside the normal parameters. Maybe it’s the parts of people we ask them to leave at home that are the most likely to produce the big innovations,” Austin says.

    Related Reading
    The Surprising Right Fit for Software Testing

    See the full article here .

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    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
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