January 4, 2011
While attending one of our recent grant review meetings, I listened to the group discussing the merits of a predoctoral fellowship application. They were debating the quality of the applicant's research project when one of the committee members raised a critical point: Had anyone noticed that the letter from the student's faculty mentor showed a lack of understanding of what the student was actually proposing to do? Without a committed and involved mentor, the fellowship was unlikely to be a success.
came from one of our newest members, John Elder Robison, a man on the autism spectrum who joined our scientific review board as a community member in 2010. John's conscientious attention to the details of each application and astute observations make him a valuable member of our board. Along with two parents who also take part in our scientific review boards, John helps remind us why we are funding research and makes sure that each grant we fund has the potential to make a real difference in the lives of people with autism spectrum disorders (ASD) and their families.
Research on adults with ASD to improve outcomes
John's presence also is a reminder that we need to better understand and meet the needs of adults on the autism spectrum. With a half-million adolescents with ASD soon transitioning from high school to adulthood, this need has never been greater. Several 2010 studies focused on adults with ASD. A common finding across this research is that successful transition requires careful coordination among several different service systems. Coordination is often left to parents who unfortunately find that adult services after high school are lacking. Marsha Seltzer and her colleagues1 reported that the transition from high school can be particularly difficult for people with ASD without an intellectual disability, who often lacked structured daytime activities, including employment. They stressed that our current service system is especially inadequate to meet the needs of youths with ASD who do not have an intellectual disability. In another study, Seltzer and colleagues2 reported that, compared to adults with other disabilities, adults with ASD have more unmet service needs and received fewer services. The urgent need for empirically-supported services for people with autism was also highlighted in a workshop sponsored by the Interagency Autism Coordinating Committee (IACC), held November 8, 2010, in Rockville, Md. The first conference on autism and aging was held in 2010 at the University of North Carolina at Chapel Hill. Organized by Joe Piven and funded in part by a generous donation from Gregg and Lori Ireland, this conference identified the huge gaps in our knowledge about the health issues A 2010 study found that the mortality rate in autism is 5.6 times higher than the general population. One of the main causes of mortality –accidents – is preventable. and service needs of elderly people with ASD. One striking finding is that the mortality rate in autism is 5.6 times higher than the general population3. Furthermore, one of the causes of mortality – accidents – is preventable. There are many unanswered questions that need to be addressed through research. What are the most effective ways of preparing people with autism to lead successful, productive, and joyful lives? How can health-related problems, such as obesity and accidents, be prevented? Addressing these questions is one of Autism Speaks' targeted research emphasis areas. Our goal is to identify the factors that lead to better outcomes and develop the most effective service and training programs for adults with ASD. Through advocacy, we hope to translate this research into real solutions for adults on the autism spectrum.
New research identifies environmental risk factors for autism
As we are beginning to understand more about adult development in autism, scientists are making progress in discovering the factors that increase the risk for autism. Research on environmental risk factors and their interaction with genetic vulnerabilities is another one of Autism Speaks' targeted research emphasis areas. Scientists are casting a wide net because there still is relatively little published research in this area. To encourage research on environmental risk factors, Autism Speaks launched a collaborative network of epidemiologists studying environmental factors in ASD. The goal is to facilitate cross-fertilization of ideas and methods, and promote data sharing. At the 2010 International Meeting for Autism Research, over 30 epidemiologists attended the first network meeting. In addition, this fall, we co-funded a conference with the National Institute of Environmental Health Sciences (NIEHS) to discuss strategies for accelerating research in this area. As a new member of the IACC, I was pleased to help craft several new research objectives focused on understanding the role of the environment in the etiology of ASD for the IACC's updated strategic plan for autism research . Many of these recommendations came directly from the workshop we co-sponsored with the NIEHS. Several noteworthy papers on environmental risk factors were published in 2010. Five studies found that premature birth is associated with increased risk for autism4. Exposure to hazardous air pollutants shortly after birth also was found to be a risk factor5. Another study replicated earlier findings that parental autoimmune disease increases risk for ASD6. In this study, Alexander Keil and his colleagues used three patient registries in Sweden to examine data on 1,227 individuals with ASD who were compared to 30,693 individuals without ASD. They found that there was nearly a 50% higher chance of being diagnosed with autism if the parent had an autoimmune disease, such as type-1 diabetes and rheumatic fever.
The mechanisms by which parental autoimmune disease increases risk for ASD are now a focus of further research. What is clear from these and other studies is that the causes of autism are likely to be complex rather than simple and many rather than a few.
The role of the immune system in autism was also highlighted in several other 2010 studies. Paul Ashwood and his colleagues7 from UC Davis studied blood samples obtained from children with ASD and compared them to samples from children with typical development and children with developmental delay without ASD. They found that children with ASD had increased levels of cytokines, small molecules that are secreted by the immune system. Increased cytokine levels were pronounced in children with regressive autism and those with more severe ASD symptoms. Autism Speaks is providing additional funding to Dr. Ashwood, who is exploring ways of identifying early abnormal immune function in young children with ASD. Currently, we are funding over two dozen studies that are exploring the role of immune dysfunction in ASD. Our goal is to understand the underlying biology of ASD so that new, effective treatments can be developed.
Genetic research sheds light on the biology of ASD
Genetic research continues to provide new insights into the causes and underlying biology of autism. Investigators from the Autism Speaks-funded Autism Genome Project (AGP) published a major paper in Nature8 in 2010. Among the important discoveries were several novel autism risk genes. Individuals with autism more often had microscopic deletions in their chromosomes that affected the function of specific genes. The specific deletions (called “copy number variations”) are extremely rare in the general population, and many were “de novo,” meaning that they occurred for the first time in the individual with ASD, and were not inherited from parents. De novo mutations can arise spontaneously through errors in DNA replication or be caused by environmental factors, such as viruses or chemicals.
The AGP investigators next examined whether groups of the autism risk genes have a common function in the brain or operate in the same biochemical pathway. They discovered that some of the gene sets are directly involved in the development of neurons whereas other gene sets are involved in the function of neurons, particularly the ability of neurons to communicate with each other as they form and maintain synapses.
Animal models are often created by inserting or removing autism risk genes in a mouse and studying the impact of the lack of gene function on brain development and behavior. Interestingly, in 2010, researchers reported that the impact of knocking out the gene on brain function and behavior could be lessened by providing early stimulation to the mouse. For example, Giuseppina Lonetti and colleagues9from Italy first showed that mutations in the MeCP2 gene cause impairments in motor, cognitive, and emotional behavior of mice. When these mice were provided with early enrichment, their behavioral deficits were lessened. Furthermore, the enrichment reversed the impact of the mutation on how the brain functioned. The ability of the neurons to form synapses was restored. This validates at a biological level what we know about the positive effects of early behavioral intervention in young children with ASD.
Technology breakthrough will shed light on the biology and treatment of ASD
Progress is also being accelerated by new technologies and methods. One recent technological breakthrough that has opened up a whole new method of inquiry about the brain is a type of stem cell called an induced pluripotent stem cell, or “ iPS cell.” iPS cells, which were first derived in 2006, involve transforming cells, such as skin cells, into stem cells which then have the potential to become other types of cells, including neurons. The significant breakthrough in 2010 was made by Maria Marchetto and colleagues10 at the Salk Institute for Biological Sciences. For the first time, they were able to create neurons in culture which were derived from skin cells taken from individuals with a condition that often results in autism (Rett syndrome). The neurons derived from the Rett syndrome iPS cells were similar to neurons previously characterized in Rett syndrome - for example, they had fewer synapses and did not fire properly. The scientists then used these neurons to test the effects of drugs in recovering the synaptic function. This technology is a powerful new method for understanding how the brain works in ASD, and more importantly, for drug screening and, eventually, for tailoring drug treatments to each individual based on how his or her own neurons in culture respond to that treatment. Truly remarkable.
Mitochondrial dysfunction may be more prevalent in ASD than previously thought
Another 2010 study marked further progress in our understanding of the biology of ASD. In a recent issue of the Journal of the American Medical Association, Cecilia Giulivi, and colleagues11 reported a much higher prevalence of mitochondrial dysfunction in a small sample of children with ASD than had previously been found. Mitochondria are found within cells and contain enzymes that are responsible for producing energy. Unlike previous studies, these investigators studied blood samples, specifically, lymphocytes (white blood cells) which have a higher number of mitochondria. The children with ASD had lower mitochondrial enzyme activity and other indications that the mitochondria were not functioning optimally. Five of the 10 children with ASD had more copies of their mitochondrial DNA than expected, suggesting that the body may be trying to compensate for poor mitochondria functioning. It is not known whether the mitochondrial dysfunction found in this study is a cause or effect of autism. We do know, however, that mitochondrial dysfunction could amplify brain dysfunction because the brain requires a high level of energy and depends on the mitochondria to supply that energy. Autism Speaks has invested in several studies to further our understanding of the role of mitochondrial dysfunction in autism. In 2010, we launched the Bob and Suzanne Wright Trailblazer Awards designed to fund highly novel, out-of-the-box ideas that could potentially have a significant impact on our ability to treat autism. One of those awards went to Robert Naviaux at University of California, San Diego.
In an animal model, Dr. Naviaux is exploring whether mitochrondrial dysfunction influences neuroinflammation and disrupts normal brain development. He will then test whether a novel compound can mitigate the effects of mitochondrial dysfunction on the brain.
Treating medical conditions can improve quality of life
I also want to share with you some of the autism treatment research published in 2010. One of the most significant set of papers was written by Tim Buie and colleagues12, including several physicians who are part of Autism Speaks' Autism Treatment Network (ATN). Based on
“A central difficulty in recognizing and characterizing gastrointestinal dysfunction in ASD is the communication difficulties experienced by many affected individuals.” — Tim Buie, M.D.
a consensus conference, this group published a set of clear recommendations for the evaluation and treatment of common gastrointestinal (GI) problems in children with ASD. These recommendations, which were published in Pediatrics, the official journal of the American Academy of Pediatrics, provide detailed and useful information for physicians regarding how to detect, assess, and treat a variety of GI problems in individuals with ASD. The authors pointed out that “a central difficulty in recognizing and characterizing gastrointestinal dysfunction with ASD is the communication difficulties experienced by many affected individuals.” They further stressed that “care providers should be aware that problem behaviors in children with ASD may be the primary or sole symptoms of the underlying medical conditions, including some gastrointestinal disorders” (italics added).
The need for better assessments and treatments of medical conditions in people with ASD, including GI, sleep, and seizures, among others, was the topic of a 2010 presentation to the IACC. Drawing upon data collected on over 2,000 children who are now part of the Autism Speaks' Autism Treatment Network's patient registry, I reported that 65% of children with ASD experience sleep disturbances, and 14% of those with sleep problems also have seizures. GI problems were also reported in 50% of children, and children with GI problems were more likely to have sleep disturbances, behavioral problems, and a lower health-related quality of life. Other health issues identified include seizures, food sensitivities, anxiety and depression.
It is essential that we continue to fund research that can help address these medical conditions, which have a direct and immediate impact on quality of life for people with ASD and their families. One of our ATN physicians, Beth Malow and her colleagues at Vanderbilt University published a study in 201013 in which she and her colleagues carefully monitored sleep by measuring EEG, eye movements, breathing, pulse, and behavior. They also measured an index of the children's overnight levels of melatonin, a natural hormone secreted by the pineal gland that helps establish circadian rhythms, including our sleep patterns. They found that children with ASD had unusually low levels of melatonin and that lower levels of melatonin were associated with less time spent in deep sleep and more daytime sleepiness.
Future work will focus on the effects of supplemental melatonin on sleep patterns and daytime sleepiness.
New treatments address social impairments associated with ASD
Several 2010 papers described novel treatments that directly address the core social difficulties that are associated with ASD. One example is a study14 demonstrating that adolescents and adult individuals with ASD were more socially engaged after inhaling the hormone oxytocin. Autism Speaks is currently funding a study of 3-17 year old children with ASD on the effects of oxytocin. Another example is a randomized controlled trial (RCT)15 showing promising improvements in social behavior in individuals with Fragile X and autism who were administered Arbaclofen. This drug is designed to improve synaptic functioning by regulating glutamate. Examples of behavioral interventions include a study16 of a brief parent-mediated intervention that was found to improve social engagement in toddlers with ASD, and a RCT17 that demonstrated that a Friendship Training Program improved social skills among second to fifth grade children with ASD. Skills taught in this program included conversational skills, peer relationships, sportsmanship, play dates, and handling teasing. Notably, 87% of children made improvements.
I've been a scientist and clinician working in the field of autism for decades now. During all these years, I've never been more optimistic about the scientific breakthroughs that we will witness in the upcoming years. More than ever before, we have the best scientists in the world focusing their attention on autism. More than ever before, technological advances that can accelerate discovery are moving at an astounding pace. NIH funding levels aren't yet what we hope for, but Autism Speaks is working hard every day to advocate for increased funding, including the reauthorization of the Combating Autism Act, which is badly needed. Ultimately, it is the families we have to thank for any and all progress we have seen and have yet to see. They are the force and the meaning behind the progress we are making.
Thank you for being part of our efforts at Autism Speaks to improve the lives of people with autism and their families. I wish you a happy and healthy 2011!
Chief Science Officer, Autism Speaks
1 Taylor, JL and Seltzer, MM. (2010) Employment and post-secondary educational activities for young adul1ts with autism spectrum disorders during the transition to adulthood. J Autism Dev Disord, July 17 (Epub ahead of print).
2 Esbensen, AJ, Bishop, S., Seltzer, MM, Greenberg, JS, and Taylor, JL. (2010) Comparisons between individuals with autism spectrum disorders and individuals with Down syndrome in adulthood. Am J Intellect Dev Disabil, 115: 277-90.
3 Gillberg C, Billstedt E, Sundh V, Gillberg IC.(2010) Mortality in autism: a prospective longitudinal community-based study. J Autism Dev Disord,40:352-7.
4 For example, Johnson, S et al., (2010) Autism spectrum disorders in extremely preterm children. Journal of Pediatrics, 156: 525-31.
5 Kalkbrenner, AE et al. (2010) Perinatal exposure to hazardous air pollutants and autism spectrum disorder at age 8. Epidemiology, June 17 (Epub ahead of print)
6 Keil et al., (2010) Parental autoimmune diseases associated with autism spectrum disorder in offspring. Epidemiology, 21: 805-8.
7 Ashwood, P. et al., (2010) Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behavior Immunology, August 10. (Epub ahead of print)
8 Pinto D, et al. (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 466:368-72.
9 Lonetti, G. et al. (2010) Early environmental enrichment moderate the behavioral and synaptic phenotype of MeCP2 null mice. Biological Psychiatry, 67: 657-665.
10 Marchetto, MCN et al., (2010) A model for neural development and treatment of Rett Syndrome using human induced pluripotent stem cells. Cell, 143: 527-539.
11 Giulivi, C., Zhang, Y., Omanska-Klusek, A., Ross-Inta, C., Wong, S., Hertz-Picciotto, I,, F., Pessah, I.N. (2010) Mitochondrial dysfunction in autism. JAMA, 304: 2389-2396.
12 Buie T, Fuchs GJ 3rd, Furuta GT, Kooros K, Levy J, Lewis JD, Wershil BK, Winter H. (2010) Recommendations for evaluation and treatment of common gastrointestinal problems in children with ASDs. Pediatrics, 125: Suppl 1:S19-29.
13 Leu, RM, Beyderman, L., Botzolakis, EJ, Surdyka, K., Wang, L. and Malow, BA (2010) Relation of melatonin to sleep architecture in children with autism. J Autism Dev Disord, August 4 (Epub ahead of print)
14 Andari, E et al., (2010) Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Prc Natl Acad Sci., 107: 4389-94.
15 Berry-Kravis, E et al, (2010) Arbaclofen for the treatment of children and adults with fragile X syndrome: Results of a randomized, double-blind, placebo-controlled, crossover study. Presented at the 2010 Meeting of the International Society for Autism Research. Philadelphia, PA.
16 Kasari, C et al. (2010) Randomized controlled caregiver mediated joint engagement intervention for toddlers with autism. J Autism Dev Disord, 40: 1045-56.
17 Frankel, F et al. (2010) A randomized controlled study of parent-assisted Children's Friendship Training with children having autism spectrum disorders. J. Autism Dev Disord, 40: 843.