The Autism Speaks’ Innovative Technology for Autism (ITA) Initiative has awarded more than $400,000 in new research grants to develop innovative assistive, educational, therapeutic, and diagnostic technologies for persons with autism.
2011 saw a new approach for Autism Speaks’ Innovative Technology for Autism(ITA) Initiative with the running of a student design competition called Autism Connects. The design brief was pretty straight forward: to create technology design ideas for individuals with autism to better connect with the world around them, and to allow individuals who do not have autism to better understand and connect with those who do.
This is a guest post by by Mehreen Kouser, a Dennis Weatherstone Fellow, and Ph.D. Candidate working with Dr. Craig Powell at the UT Southwestern.
This year IMFAR hosted a Scientific Panel titled “Shank synaptic genes in autism: Human genetics to mouse models and therapeutics” organized and chaired by Dr. Craig Powell. This panel consisted of four presentations starting with the unequivocal role of Shank3 in autism and ending with potential treatment strategies in genetically mutated mouse models of Shank3.
Over the past few years , Shank3 has emerged as the new “it” gene for autism. Current estimates suggest that Shank3 errors account for 0.5-2 % of autism diagnoses making it a major genetic cause of autism. Several recent human studies have implicated mutations/deletions/duplications in the Shank family of proteins, especially Shank3, to be involved in ASD and 22q13 Deletion Syndrome. Shank3 is a scaffolding protein that is involved in synapse architecture. Mutations in Shank3 are known to affect synaptic connections between neurons in similar ways to other autism-relevant genes such as neuroligin and neurexin. Thus understanding the role of Shank3 in autism is critical.
The first presenter at this panel was Dr. Catalina Betancur from INSERM in France. Dr. Betancur was a major player in the discovery of Shank3’s relevance to autism. She carefully detailed all known human mutations, deletions, and duplications published since the first paper on Shank3 mutations in idiopathic autism was published in 2007.She also outlined the case for Shank3 as a major causative gene in the symptoms of the 22q13 chromosomal deletion syndrome known as Phelan-McDermid Syndrome. In addition, Dr. Betancur detailed the work of her laboratory and others implicating Shank2, another member of the Shank gene family, in autism.
Dr. Joseph Buxbaum from Mount Sinai School of Medicine in New York was the next presenter. His laboratory was the first to publish a genetic mouse model of Shank3 successfully Shank3. Their Shank3 mutant mouse closely mimics autism-associated mutations in this area of the Shank3 gene. His work focused on the heterozygous mutation of Shank3 gene as this is the state of autism patients with Shank3 mutations. Characterization of this mouse model, clearly suggests that Shank3 plays an important role in synapse architecture, function, and plasticity. Among the most intriguing findings in his presentation was his ability to reverse the manifestations of Shank3 mutation in brain slices treated with Insulin-like Growth Factor-1 (IGF-1). This gives us the much needed hope that Shank3 mutation models of autism will lead to identification of novel therapeutic targets that can be validated in these models.
Next, Dr. Yong-hui Jiang from Duke University in North Carolina presented his work on a genetic mouse model very similar to that of Dr. Buxbaum’s group, but his focus was the homozygous mutation of Shank3 mutating both copies of the gene. He noted that the Shank3 gene is more complex than originally thought, with potentially having as many as six variants or isoforms. His careful analysis of this mutant model clarified that only a portion of Shank3 isoforms are affected by this genetic strategy. He identified abnormalities in synaptic connection morphology in his model. Moreover, his lab characterized this mouse model extensively on autism related behaviors and found them to be impaired in the social behaviors, repetitive behaviors, communication, motor coordination and learning and memory. These results demonstrate that human diseases can be successfully modeled in mice. The hope is that if we can reverse them in mice, treatments for humans are not far away.
Dr. Joao Peca from Guoping Feng’s lab at MIT in Massachusetts concluded the session by presenting a completely different Shank3 mutation in mice. He began his presentation by telling us about another synaptic gene called SAPAP3 and showing us its involvement in a repetitive grooming behavior in mice. He showed that SAPAP3 knockout mice continuously groom themselves and that this behavior can be reversed by putting this gene back into the striatum of mice later in life. He also showed that Shank3 is a strong binding partner of SAPAP3 and their Shank3 mutant mice have the same increase in repetitive grooming behaviors. Like the other Shank3 mutations, this mutant does not affect all forms of Shank3, but may mimic a different human mutation.
This panel set the stage for future advances in the area of Shank3 and autism. Only 4 years after the initial study implicating Shank3 in autism, we now have at least 3 different animal models and 4 publications on these models. Although, we may face grave challenges in sorting through the heterogeneity of mutations, deletions, and duplications and their different consequences, these presenters clearly demonstrate that this strategy will lead to identification of potential therapeutic targets that can be readily tested in animal models.
by Geraldine Dawson, Ph.D., Chief Science Officer, Autism Speaks
In San Diego last week, The International Meeting for Autism Research (IMFAR) celebrated its 10th anniversary. Only a decade ago, prompted by parents, a small group of scientists pulled together the first IMFAR meeting. As program chair of IMFAR’s second meeting in 2002, I recall spreading the submitted abstracts out on a large conference table in my lab; working with my graduate students, we created the conference schedule by moving pieces of paper around the table’s surface! In 2007, when my colleague, Elizabeth Aylward, and I hosted the meeting in Seattle, we were thrilled that 1,000 people attended the conference. This year, only four years later, nearly 2,000 people attended IMFAR inSan Diego, representing a 10-fold increase in attendance in only a decade. The conference not only has changed in size, it has also changed in a number of other significant ways:
Autism as a global challenge
The international scope and participation has grown tremendously. Whereas the first meetings included scientists from Europe and a few from Asia, today’s IMFAR includes scientists from virtually all continents on the globe. Autism Speaks sponsors an annual meeting at IMFAR of the International Autism Epidemiology Network (IAEN), a group now comprised of over 100 scientists from 30 counties! Topics of this year’s IAEN meeting focused on how to deliver services to low resource communities, both in the U.S.and in developing countries. Travel awards were given to 13 international scientists from countries that included Oman, Turkey, Nigeria, Palestine, China, India and Argentina, among others.
Attracting a new generation of scientists
I am especially encouraged by the fact that the number of bright young graduate students and postdocs involved in autism research is rapidly growing. Graduate students and postdocs from diverse fields ranging from neuroscience to education shared their research results and had an opportunity to hear and interact with scientists from a wide range of disciplines. Thirty-seven students received travel awards to IMFAR; they travelled not only from around theUS, but also from the UK, Germany, France, Spain, Canada, Japan, Mexico, Australia, and Israel. IMFAR provides a unique opportunity for graduate students to learn and be motivated to devote their careers to autism research. I was honored to participate in the “Meet the Experts” luncheon which provided an informal venue for students to talk in depth with senior scientists about their careers and areas of expertise.
People with autism and their families have a real presence in the IMFAR meeting
The inclusion of families and individuals on the spectrum as important and influential participants in the planning and conduct of IMFAR has steadily increased over the past decade. Community members are part of every IMFAR committee as well as the program planning. The committee I chaired this year that oversaw the INSAR board elections included a mother of a child with ASD and an adult with Asperger’s syndrome. At the meeting, parents and self-advocates with ASD attended lectures, gave presentations, and made opening remarks. Families with children on the spectrum could be seen throughout the meeting and especially enjoyed the technology demonstrations and booths. Video coverage was managed by Alex Plank, a person on the spectrum who hosts the website Wrong Planet.
Scientific progress provides hope for the future
Finally, I was struck by how both the breadth and depth of autism research has increased over the past 10 years. There are so many ways in which our thinking about autism has changed dramatically. To bring home this point, here are a few of the key themes and topics of research that emerged from this year’s conference:
- We now recognize that autism affects the whole body, not just the brain. Presentations reflecting this theme focused on studies of mitochondrial dysfunction, oxidative stress, sleep, gastrointestinal disorders and nutrition.
- The role of the environment and gene-environment interactions are now recognized as important etiological factors. Examples at this year’s meeting included studies on a variety of pregnancy and prenatal factors (fertility therapies, medication use, gestational diabetes, very low birth weight, maternal infection), neurotoxins (mercury, occupational exposures, air pollution), and specific gene-environment interactions.
- Autism can be recognized in infants less than one year of age, and interventions appropriate for infants and toddlers can alter the trajectory of children’s developmental outcomes. A wide range of new and innovative methods for detecting autism in infants were presented, along with several new methods for treating infants.
- There is an increasing interest in addressing the needs of two previously under-recognized populations of people with autism: adults and nonverbal individuals. I chaired a symposium on nonverbal autism in which scientists presented findings based on EEG that demonstrated that many children with autism who are unable to speak nevertheless have strong intellectual abilities and language comprehension. The same symposium illustrated how speech-generating devices can be effectively incorporated into early intervention to promote communication in children who have not developed speech. Studies on adults with autism were diverse, ranging from those focused on intervention strategies to improve quality of life, to how to promote independence and optimal health.
- The promise that technology holds for improving the quality of life for people with autism is more and more evident. This was especially clear in Autism Speaks’ Innovative Technologies Demonstration. The session was lively as adults and children with ASD and their families tried out the games and communication devices. We sponsored an international student technology design competition that attracted over 120 entries from around the world. I had the pleasure of giving the awards to the top three designs, all of which focused on the theme of helping people with autism connect to the world around them.
- Autism is no longer a “black box” – instead, the puzzle of autism’s underlying biology is being put together piece by piece. Using information gleaned from a decade of genetic research, neuroscientists presented papers that shed light on the role of the immune system in autism, identified several neural signaling pathways affected in autism, and described strategies for helping repair the brain’s synaptic function. One of the keynote lectures focused on the promise of a new technique called “induced pluripotent stem cells” which allows stem cells to be made from skin tissue. These cells are being coaxed into forming neurons and allow scientists to compare precisely the difference between neuronal functioning between persons with and without autism. These insights and technologies are providing clues to new autism drugs which are now being tested in animal models.
While I am happy to see the remarkable progress that has been made over the past decade, I am eagerly looking forward to the next 10 years, knowing that the pace of scientific discovery will only accelerate. I am hopeful that the science of the future will allow us to continue to make even more of a difference in the lives of people with autism of all ages.
Video Credit: Alex Plank
Guest blogger Ruth Carper, Ph.D., Asst. Research Scientist, Center for Human Development, University of California, San Diego
Adults with autism and their families may be interested to know that the scientific community is turning more attention toward understanding the full life course of autism spectrum disorders (ASDs). While a great deal of research is directed toward understanding the causes of the disorder and developing interventions for young children, we still know relatively little about how the disorder is expressed in adults and how autism changes as individuals on the spectrum get older. This year one of the Invited Educational Symposia at IMFAR was dedicated to this topic, and entitled: Adults with Autism Spectrum Disorders: Challenges for Epidemiological and Outcome Research.
The first two speakers Traolach “Terry” Brugha, M.D., and Fiona Scott, Ph.D. come from the UK where they have recently collaborated on studies of adults with Autism Spectrum Disorder. Dr. Brugha and his colleagues conducted a large epidemiological survey to assess the prevalence of ASD among adults living in the general community (published earlier this month in Archives of General Psychiatry, 2011; v. 68(5): pp. 459-466). The rates of ASD diagnosis have been rising rapidly in the last many years and it is generally accepted that at least part of this increase is due to increased awareness of the disorder among pediatricians, educators, and other child specialists, and to improvements in detection and diagnosis especially in individuals who do not have comorbid intellectual disability. However, it is important to remember that this also implies that there may be a large number of adults who could meet the criteria for an autism diagnosis but who have never been diagnosed with a disorder on the spectrum. To address this, Dr. Brugha and his colleagues contacted adults at more than 13,000 residential addresses in a door-to-door Adult Psychiatric Morbidity Survey in England. Using a stratified random sampling approach, 7,461 individuals participated in first phase interviews which included screening for a variety of psychiatric diagnoses. Individuals who met certain criteria on a 20 item screening questionnaire for autism spectrum disorders were selected to participate in more in-depth assessments including the ADOS (Autism Diagnostic Observation Schedule) and ADI (Autism Diagnostic Inventory). After all testing was completed, 19 individuals were determined to have previously undiagnosed autism spectrum disorders which the authors estimated represents of a rate of 9.8 per 1,000 in the general UK population. Importantly, they did not find evidence of any significant differences in rates across age. That is, it appeared that the oldest individuals were just as likely to have a previously undiagnosed ASD as the youngest.
The next speaker was Dr. Fiona Scott of the University of Cambridge, who is also part of the Adult Psychiatric Morbidity Survey in England. Dr. Scott focused on the particular challenges of accurately diagnosing ASD in higher functioning adults who did not have pre-existing diagnoses. ASD is a developmental disorder and accurate diagnosis requires knowledge of the individual’s social, communicative, and behavioral development during early childhood. The APMS study focused on a higher functioning population that may not have sought services during childhood and particularly wanted to include adults of all ages. Accurate diagnosis is particularly challenging in this population because it is often difficult or impossible to acquire accurate information about the early developmental period. Community-living adults in their 50s, 60s, or 70s may not have living parents who can describe their early development and if they do, these parents are being asked to recall subtle behavioral changes from many decades before. Accurate diagnosis may be further hindered by our limited knowledge of the life course of behaviors. The behaviors and abilities of individuals with ASD change as they get older, as part of normal maturation, as a result of the interventions and training that they partake in, and in response to the challenges that they face in daily life. For example, Dr. Scott pointed out the possibility of comorbid psychiatric disorders such as depression that may arise later in life and may make diagnosis less clear. This could be particularly problematic for previously undiagnosed populations such as those in the APMS study who would not have received outside support for dealing with social challenges.
Other diagnostic challenges include gender differences in ASD. The APMS study found a 9:1 ratio between males and females in the rates of ASD whereas most studies of children find ratios closer to 4:1. This may mean that the screening tools that were used need to be modified for use in women or it may be an artifact of the community-dwelling population that was examined. Women with ASD are often more severely affected cognitively than males and require more behavioral support, but individuals living in institutional housing were excluded from the APMS study.
The only member of the panel who was not from the UK was Marsha Seltzer, Ph.D. of the Waisman Center at the University of Wisconsin. Dr. Seltzer has been following more than 400 children and adults with ASD, and their families, for about 12 years. She is evaluating people who ranged in age between 10 and 52 years when they first entered the study and her research group continues to follow them. Dr. Seltzer reported several interesting findings from their series of studies. On average, individuals in her study showed improvement in social reciprocity and reductions in problematic repetitive behaviors and stereotyped interests across the first 6 years of the study. About 30% also showed significant improvements on the Scales of Independent Behavior-Revised which measure self-care and community living skills as well as cognitive and motor abilities. These improvements could be a result of the supports and interventions that the individuals receive in the community or could simply be the natural life-course of the disorder. However, Dr. Seltzer also reported a study that raises the question of whether even greater improvement might be possible if better support structures were provided. In a study that looked selectively at younger adult subjects who were exiting high school they found that, although repetitive behaviors decreased with time, the rate of improvement was much higher while students were still in school, but slowed substantially (or even regressed) after leaving school.
The final speaker was Patricia Howlin, Ph.D. of King’s College in London who provided a broader perspective of the natural life course of ASD across the life span. She reviewed outcome studies from 1967 to the present. These studies tend to classify individual outcomes as “good”, “fair”, “poor” or similar categories based on the level of independence achieved. For example, those who live in institutions are given poorer ratings than those who live by themselves and those who have part-time jobs rate better than those in sheltered employment or day programs. Over the years there appears to have been a slight decline in rates of “good” outcomes compared to “fair” or “poor” outcomes in such studies, but Dr. Howlin pointed out the subjectivity of these ratings and the difficulty of interpreting the effects of service changes such as the move from housing in large institutions to small group homes. Studies have also found that as much as 16% of adults with ASD develop additional psychiatric diagnoses such as depression and obsessive compulsive disorder which may be triggered by life stressors (citing Hutton et al., 2008). But those with good community support may have better outcomes (citing Farley et al., 2009).
The symposium on Adults with Autism Spectrum Disorders presented some important findings on the topic and also pointed out some of the unique challenges to this area of research. Identifying and recruiting this population is not a trivial task but one which must be addressed. Efforts to improve available tools in this area are moving us forward and it is clear not only from this symposium but from other presentations given at the IMFAR meeting — on diagnostic tools targeted at verbal and non-verbal adults, interventions for adults, and changing health status — that this area of research will continue to grow.
Alex Plank of WrongPlanet.net sits down with Peter Bell of Autism Speaks at IMFAR 2011. Peter and Alex have a discussion on a balcony that overlooks the bay. This year’s International Meeting for Autism Research was held in San Diego, the site of the inaugural meeting.
Peter Bell, the Executive Vice President for Programs and Services, reflected in a blog post, ‘Stakeholders Make Their Mark at IMFAR 2011.’
The author is a guest blogger, Ashley Scott-Van Zeeland, Ph.D. and she is a Dickenson Fellow at the Scripps Translational Science Institute in La Jolla.
This was the second year IMFAR hosted an Invited Educational Symposium on Imaging Genetics in autism spectrum disorders. Dr. Susan Bookheimer, a leader in brain imaging and one of the pioneers of imaging genetics, and Dr. Daniel Geschwind a world-renowned autism geneticist, chaired the session. The goals of the symposium were to introduce the principles behind imaging genetics and demonstrate methods by which various researchers are using imaging genetics to discover relationships between genetics and brain function.
The first speaker was Dr. Susan Bookheimer, Professor of Cognitive Neurosciences from UCLA. Dr. Bookheimer gave a broad overview of the use of brain images as quantitative measures for use in imaging genetics investigations. Essentially, neural measurements such as activation or metabolic response, structural volumes, or connectivity measures can be thought of as being one step closer to the mechanism of gene action than broad diagnostic classifications. Therefore, these types of ‘endophenotypes’ are more strongly associated with gene variants and should considerably increase the ability to identify brain-gene relationships.
Dr. Daniel Geschwind, Chair of Human Genetics and Professor of Neurology at UCLA followed with a general primer on genetics to introduce all clinicians, brain imagers, and non-geneticists to the types of genetic assays available. The goal of Dr. Geschwind’s talk was to encourage non-geneticists to consider what is “reasonable” from a genetics perspective when designing studies. He highlighted three main frameworks for imaging genetics studies: 1) Identify genetic factors that underlie normal brain structural and/or functional variation 2) use differences in brain imaging measures to identify disease-associated genes, or 3) use brain imaging as a way understand the neurobiological effects and neural mechanisms of disease-associated genes. He also re-emphasized the issue of statistical power in the search for disease-associated genes, which depends on many factors but can be increased by using brain imaging that likely has larger detectable gene effects than broader phenotypes such as autism diagnosis. He also stressed that the best imaging genetic approaches are hypothesis driven, with known implicated brain regions or neural effects to limit statistical issues caused by testing many genetic markers over many brain regions.
After the introductory talks by Drs. Bookheimer and Geschwind, there were three more talks that went into greater detail about current applications of imaging genetic approaches in the study of autism – the first being by Dr. Joshua Trachtenberg, Assistant Professor of Neurobiology at UCLA. Dr. Trachtenberg presented methods for imaging dendritic growth in animal models. Using cutting edge 2-photon microscopy techniques, Dr. Trachtenberg is able to examine the neurobiological effects of candidate autism risk genes in a living animal. His lab has been working on the PTEN gene, which has been associated with an enlarged brain. In order to determine how PTEN contributes to an enlarged brain, Dr. Trachtenberg is able to selectively alter the PTEN gene in mouse brain after birth and monitor the changes in neural architecture over time. In the PTEN mutant animals, Dr. Trachtenberg observed up to 50% extra growth of dendrites – neuronal structures that receive input from other cells – suggesting a mechanism by which this autism-associated gene contributes to larger brain size. Importantly, he also presented evidence that the dendrites involved in long-range communication circuits are more affected than those involved in short-range circuits – a story that is emerging as a consistent finding across many measures of brain connectivity in autism.
Next, Dr. Declan Murphy, Professor of Psychiatry and Brain Maturation and the Head of Department of Forensic and Neurodevelopmental Science at Kings College in London presented an overview of the state of the field for serotonin genes and imaging genetics. Serotonin is a neurotransmitter involved in both brain function and brain development, and has been associated with behaviors such as aggression, affiliative behaviors, and obsessional behaviors. There are two major serotonin genes that have been the focus of imaging genetics studies – MAOA and 5-HTTLPR. MAOA is involved in the breakdown of serotonin and 5-HTTLPR encodes a protein that transports serotonin into neurons. Both genes have been associated with many neuropsychiatric disorders, including autism. Dr. Murphy presented studies in which activity in the amygdala and fusiform gyrus, regions thought to play a role in autism, was associated with different versions of 5-HTTLPR. However, he noted that although there is some evidence for serotonin dysfunction in autism, the evidence is not conclusive and imaging studies reflect this as well. In structural MRI studies, investigators have found frontal lobe abnormalities associated with the serotonin transporter, though this has not consistently been replicated. Within this talk, Dr. Murphy emphasized that it remains important to search beyond simple gene effects and consider systems-based approaches, developmental effects, gene-gene interactions and pharmacogenetic effects in imaging genetics studies.
I had the great pleasure of wrapping up the session by describing a general framework for pursuing targeted imaging genetics studies in autism, using a recent study that explored frontal lobe connectivity and an autism risk gene, CNTNAP2. As imaging genetics studies can be quite difficult, it is important to begin with well-devised experimental paradigms and testable hypotheses for gene effects. Since CNTNAP2 encodes a protein that is involved in cell-cell interactions and synaptic transmission, we reasoned that CNTNAP2 might be related to neural connectivity. As mentioned by Dr. Bookheimer in the introduction, it is important to use brain imaging as a quantitative measure of brain function or structure. To this end we chose to use a functional paradigm that we knew would elicit activity in regions where CNTNAP2 is expressed during development. We observed differences in frontal lobe activity in both typical children and those with autism depending on which CNTNAP2 allele they carried, and also found differences in connectivity patterns with the frontal lobe such that children who carried the autism-associated risk gene had more local frontal connections and reduced long-range connections. In sum, by leveraging information about the role of CNTNAP2 in the brain , we were able to better understand the mechanism by which CNTNAP2 contributes to increased risk for autism using an imaging genetics approach.
Overall, the application of imaging genetics to autism spectrum disorders is beginning to reveal very interesting neurobiology and I expect we will see more of these types of studies at IMFAR 2012!
Autism Speaks Science Board member John Elder Robison is the author of Look Me in the Eye: My Life with Asperger’s and Be Different: Adventured of a Free-Range Aspergian. You find out more about his IMFAR experience, here, here, and here.
To find out more about ‘Innovative Technology for Autism’ visit here.