If you’ve been following autism research in recent years, you have probably read—many times—that familial, or inherited, risk is seldom the whole picture. A few inherited genes are sufficient by themselves to cause autism. But most so-called “autism genes” only increase the risk that an infant will go on to develop this developmental disorder. As is the case in many complex diseases, it appears that autism often results from a combination of genetic susceptibility and environmental triggers.
This is where epigenetics comes in. Epigenetics is the study of the factors that control gene expression, and this control is mediated by chemicals that surround a gene’s DNA. Environmental epigenetics looks at how outside influences modify these epigenetic chemicals, or “markers,” and so affect genetic activity.
It is important to remember that scientists use the term “environment” to refer to much more than pollutants and other chemical exposures. Researchers use this term to refer to pretty much any influence beyond genetic mutation. Parental age at time of conception, for example, is an environmental influence associated with increased risk of autism, as are birth complications that involve oxygen deprivation to an infant’s brain.
Because epigenetics gives us a way to look at the interaction between genes and environment, it holds great potential for identifying ways to prevent or reduce the risk of autism. It may also help us develop medicines and other interventions that can target disabling symptoms. We have written about epigenetics previously on this blog (here and here). So in this answer, I’d like to focus on the progress reported at a recent meeting hosted by Autism Speaks.
The Environmental Epigenetics of Autism Spectrum Disorders symposium, held in Washington, D.C. on Dec. 8, was the first of its kind. The meeting brought together more than 30 leaders in autism neurobiology, genetics and epidemiology with investigators in the epigenetics of other complex disorders to promote cross-disciplinary collaborations and identify opportunities for future studies.
Rob Waterland, of Baylor College of Medicine in Texas, described epidemiological studies and animal research that suggested how maternal nutrition during pregnancy can affect epigenetic markers in the brain cells of offspring.
Julie Herbstman, of Columbia University, described research that associated epigenetic changes in umbilical cord blood with a mother’s exposure to air pollutants known as polycyclic aromatic hydrocarbons (PAHs). PAHs are already infamous for their association with cancer and heart disease.
Rosanna Weksberg, of the Hospital for Sick Kids in Toronto, discussed findings that suggest how assisted reproductive technology may lead to changes in epigenetically regulated gene expression. This was of particular interest because assisted reproduction has been associated with ASD. Taking this one step further, Michael Skinner, of Washington State University, discussed “transgenerational epigenetic disease” and described research suggesting that exposures during pregnancy produce epigenetic changes that are then inherited through subsequent generations.
Arthur Beaudet, of Baylor College of Medicine, discussed a gene mutation that controls availability of the amino acid carnitine. This genetic mutation has been found to be more prevalent among children with ASD than among non-affected children, suggesting that it might be related to some subtypes of autism. Further study is needed to follow up on the suggestion that dietary supplementation of carnitine might help individuals with ASD who have this mutation. Caution is needed, however. As Laura Schaevitz, of Tufts University in Massachusetts, pointed out, studies with animal models of autism suggest that dietary supplementation may produce only temporary improvements in symptoms of neurodevelopmental disorders.
So what does this all mean for research that aims to help those currently struggling with autism? The meeting participants agreed that the role of epigenetics in ASD holds great promise but remains understudied and insufficiently understood. For clearer answers, they called for more research examining epigenetic changes in brain tissues. This type of research depends on bequeathed postmortem brain tissue, and Autism Speaks Autism Tissue Program is one of the field’s most important repositories. (Find more information on becoming an ATP family here).
The field also needs large epidemiological studies looking at epigenetic markers in blood samples taken over the course of a lifetime. One such study is the Early Autism Risk Longitudinal Investigation (EARLI). More information on participating in EARLI can be found here.
Autism Speaks remains committed to supporting and guiding environmental epigenetics as a highly important area of research. We look forward to reporting further results in the coming year and years.
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Read more autism research news and perspective on the science page.
“Got Questions?” is a new weekly feature on our blog to address the desire for scientific understanding in our community. We received over 3000 responses when we asked what science questions were on your mind. We answered a few here and the Autism Speaks Science staff will address the other themes we received in this weekly post.
Scientists have long wondered how experiences during a person’s lifetime can alter behavior and body functioning. In the early 1800’s Jean Batiste Lamarck suggested that giraffes’ necks grew long through many generations of stretching to reach distant leaves. That theory eventually fell to evolution–pressures from the environment selectively amplify or quiet certain traits that are variably present within a population. Later, the DNA code was found to be the mechanism for inheritance and the level at which selective pressure acts.
Today’s scientists see hints of Lamark as they peer into the molecular biology of inheritance.
Consider DNA to be a library of books that encode genes. These “genetic books” must be read so that proteins can be formed from the code. Some genetic books are open and available for reading by the cell’s molecular machinery. Others maybe temporarily unavailable and still others are in the restricted section—essentially permanently unreadable.
Experiences throughout an individual’s life create tags on the genetic code, marking it as available or not for reading. The molecular methods that control the availability of the genetic code are collectively referred to as epigenetic mechanisms. Literally meaning “above the genome”, epigenetic mechanisms tag DNA with different chemical marks, such as methyl or acetyl groups. Certain tags can increase the reading frequency, resulting in more protein building-blocks transcribed from the DNA code, and more of that gene “expressed”. Other tags result in a particular piece of the genetic code to be skipped during reading.
A host of environmental agents and interactions may leave epigenetic marks on the genome. Early life stress, smoking, exposure to toxins may all leave epigenetic marks either creating or removing barriers for protein creation.
Here is where Lamark comes in. Most epigenetic marks are removed before the sperm and egg meet to form an embryo, but sometimes, epigenetic marks remain. This is one mechanism by which environmental exposures can be passed along from parent to child.
The study of epigenetics and gene expression in autism is underway and early findings are exciting. Some of the genetic syndromes associated with autism, such as Angelman and Prader-Willi syndrome, result from epigenetic marks that render one parent’s genetic contributions unreadable. Recently, gene expression studies from the blood and even brain tissue of individuals with autism have shown differences in the activity of patterns of genes that are involved in brain development and function.
This is an exciting area of research and we look forward to sharing more details as we learn more from the science.
Read more about epigenetics on or blog.
Beyond genetics: What the new fields of functional genomics and epigenetics are revealing about autism
Today’s guest post comes to us from Valerie W. Hu, Ph.D. Dr. Valerie Hu is a Professor of Biochemistry and Molecular Biology at The George Washington University Medical Center as well as a mother of a son with ASD. She redirected her research focus towards autism about 5 years ago and has since published 6 papers on the genes and biological pathways associated with ASD. Dr. Hu received her Ph.D. in Chemistry from Caltech and did her postdoctoral research in Membrane Biochemistry and Immunology at UCLA. More information about her research and papers can be obtained at: http://www.gwumc.edu/biochem/faculty_vhu.html
For many years, genetics has followed the traditional approach to identifying genes associated with various disorders, including autism. However, the wide diversity of symptoms and behaviors associated with autism spectrum disorders (ASD) has posed a significant challenge to identifying mutations in one or a few genes that are reliably associated with ASD. More recent attention has focused on copy number variants (CNVs) which are submicroscopic regions of chromosomes that have been found to be lost or duplicated in some individuals with ASD. Together, these studies are making progress in identifying a number of genes that function at the synapse between nerve cells. Nevertheless, the combination of all known genetic mutations still does not account for the majority of autism cases or for the association of non-neurological symptoms observed in autistic individuals.
My laboratory at The George Washington University Medical Center has taken a functional genomics approach to studying genes that may be deregulated in autism. Rather than identify mutations in DNA, our goal has been to identify genes whose activity, as indicated by gene expression level, is altered in order to identify dysfunctional biochemical pathways and impaired cellular functions in autism. Thus, using a method known as DNA microarray analysis to profile gene expression in cells from identical twin pairs who are differentially diagnosed with autism (one autistic, the other not reaching the threshold for an autism diagnosis), sibling pairs where only one sibling is autistic, and unrelated case-controls, we identified many genes whose expression levels (activities) are different from non-autistic individuals. Furthermore, by subtyping the unrelated autistic individuals according to symptomatic severity across over 63 symptoms probed by a commonly used diagnostic assessment instrument (Autism Diagnostic Interview-Revised), we were able to identify gene “signatures” for each of 3 ASD subtypes studied. These signatures not only revealed genes unique to a given subtype of autism, but also overlapping genes that presumably control common symptoms of autism across subtypes. Interestingly, a set of genes that regulate the biological clock (that is, circadian rhythm) were found to be disrupted only in the subtype of ASD exhibiting severe language impairment.
These studies demonstrating different gene expression signatures between identical but differentially diagnosed twins as well as revealing differential expression of hundreds to thousands genes depending on ASD subtype suggest the involvement of “master switches” (or epigenetic mechanisms) in the control of gene expression. Two new studies by our laboratory, published in two different journals on Apr. 7, 2010, suggest that epigenetics may play a significant role in the regulation of gene expression in autism (read a blog from AS staff on epigenetics). In one study, published in the FASEB Journal, we identified chemical tags (called “methyl groups”) on the DNA of individuals with autism that led to gene silencing. This mode of turning off a gene is potentially reversible with the proper drugs if the specific gene can be properly targeted. The second study, which was published in the journal Genome Medicine, reports on the differential expression of microRNA in autism. MicroRNA are recently discovered snippets of RNA (ribonucleic acid), each of which can inhibit the expression (and thus activity) of hundreds of genes. The effects of microRNA are also reversible by treatment with complementary “anti-sense” RNA. While methylation inhibits gene expression at the level of DNA, microRNA inhibits at the level of RNA. These two studies together illustrate two different “epigenetic” mechanisms controlling gene activity in autism that lie beyond genetic mutations.
In the study published in the FASEB Journal, we again used cell lines derived from identical twins and sibling pairs in which only one of the twins or siblings was diagnosed with autism to identify chemical changes on DNA. We then compared the genes that showed changes in DNA tagging (methylation) with a list of genes that showed different levels of expression from these same individuals. The amounts of protein produced by two of the genes that appear on both lists were then investigated in brain tissues from the cerebellum and frontal cortex of autistic and control subjects which were obtained through the Autism Tissue Program. We found that both selected proteins, RORA (retinoic acid-related orphan receptor-alpha) and BCL-2, as predicted by the observed increase in methylation, were reduced in the autistic brain. Although BCL-2 has previously been reported to be reduced in autistic brain, RORA is a novel gene which is relevant to many of the observed deficits in autism. Specifically, RORA is involved in several key processes negatively affect by autism, including Purkinje cell differentiation, cerebellar development, protection of neurons against oxidative stress, suppression of inflammation, and regulation of circadian rhythm.
These results suggest that blocking the chemical tagging of these genes may reverse some symptoms of autism if targeted removal of methyl groups from specific genes can be accomplished. Furthermore, this study, which links molecular alterations in blood-derived cells to brain pathobiology, demonstrates the feasibility of using more easily accessible cells from blood (or other non-brain tissues) for diagnostic screening.
This research is reported in the study, titled “Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain,” which was recently published in the Federation of American Societies for Experimental Biology (FASEB) Journal, and is available online at: http://www.fasebj.org.
In the study published in Genome Medicine, we identified changes in the profile of microRNAs between twins and sibling pairs, again discordant for diagnosis of autism. We discovered that, despite using cells derived originally from blood, brain-specific and brain-related microRNAs were found to be differentially expressed in the autistic samples, and that these microRNAs could potentially regulate genes that control many processes known to be disrupted in autism. For example, differentially expressed miRNAs were found to target genes highly involved in neurological functions and disorders in addition to genes involved in gastrointestinal diseases, circadian rhythm signaling, and steroid hormone metabolism. The study further shows that by treating the cells with antisense RNA antagonists (inhibitors) to specific microRNA or by employing mimics of a particular microRNA, one can reverse the pattern of expression of a given target gene regulated by that microRNA.
This study, titled “Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines” was highlighted as an “Editor’s pick” in the journal Genome Medicine. It is available online at: http://genomemedicine.com/content/2/4/23.
By integrating both DNA methylation and miRNA expression studies with gene expression data, Dr. Hu and colleagues are applying a systems biology approach to understanding this complex disorder.
My work focuses on autism and understanding how genes and environments interplay to cause this developmental disorder. Much of this work is funded by federal grants, but there can be gaps in what these grants can support, especially in new fields of research. Support from Autism Speaks has been amazing in helping fill these gaps.
In particular, Autism Speaks provided important support for two of my current projects. The funding is allowing us to study families with autism and, so, gain insights into interactions between autism risk genes and environment exposures.
The Early Autism Risk Longitudinal Investigation (EARLI) is a national study of families that have at least one child on the autism spectrum and anticipate having more children. By following these high-risk families we seek to identify causes and risk factors—be they genetic, environmental or a combination of both. Information is regularly collected from mothers enrolled in the study, and their newborns receive free developmental assessments until 3 years of age.
The second study is a genome-wide investigation of DNA methylation, or epigenetics. It will allow us to investigate how various environmental exposures can affect gene expression in ways that increase—or potentially decrease—the risk of autism. This study will place special focus on environmental exposures during crucial periods of prenatal brain development.
Autism Speaks realizes the importance of these new areas of research and has put forth great effort to ensure we can explore and, hopefully, uncover risk factors for autism that, over the long term, may lead to prevention and improved treatments.
We continue to recruit study participants. Specifically we are enrolling mothers who have one or more children with autism and who may become pregnant or who are currently less than 28 weeks pregnant. They must live near an EARLI research site (California, Maryland or Pennsylvania). For more details, please visit www.EARLIstudy.org or our Facebook page.
On behalf of the EARLI research team, I want to extend a special thanks to Autism Speaks supporters for helping make this pioneering research possible.
|Office Hours Webchat with Geri Dawson and Joe Horrigan Jan 5. Thanks to the more than 200 readers who joined us. As time allowed answering just a portion of more than 100 questions, we hope you’ll join us again next month—Feb. 2 (first Thursdays) at 3 pm Eastern.|
Thursday January 5, 2012
3:09 Kim Smith
3:59 Suzanne B.
Thursday January 5, 2012 4:11
Beijing Genomics Institute (BGI), the world’s largest genome sequencing organization got its start a little more than a decade ago at a moment when idealism, patriotic fervor and more than a little chutzpah converged to create what one of its founders, Huanming Yang, Ph.D., recently acknowledged was “a Mission Impossible.”
Yang, then with the Chinese Academy of Sciences, promised to complete 1 percent of the Human Genome Project–at the time the biological equivalent of the moon shot of the 1960s. There was just one problem: He didn’t have a gene-sequencing machine!
What followed was one of the most thrilling rags-to-riches stories in modern science. Yang and his colleagues overcame immense technical, financial and political obstacles to deliver the DNA sequence of their portion of human chromosome 3. In doing so, they changed Chinese science forever and built a scientific-industrial juggernaut that now represents 20 percent of the world’s capacity for genome sequencing.
That same can-do spirit was clearly on display when I and Autism Speaks-funded Duke University researcher Yong-hui Jiang, M.D., Ph.D., visited BGI in Shenzhen after the Autism Research Collaboration Development Meeting, co-hosted by Children’s Hospital of Fudan University in Shanghai and Autism Speaks. Not coincidentally, Yang gave the keynote address to the meeting, which ended last weekend.
Today most of BGI is housed in a former shoe factory on a small campus that includes several high-rise dormitories for nearly 4,000 employees. In recent years, the institute has produced such high-impact scientific accomplishments as complete genome sequences of rice and potato plants and the human gut microbiome (our digestive microbes). Through genetic sequencing, it also identified the culprit behind this summer’s deadly E. coli outbreak in Germany. In the face of this public health crisis, BGI marshaled the staff and technology to sequence the entire genome of the toxic bacterial strain in less than three days.
In visiting BGI, I was impressed by more than the arrays of cutting-edge automated sequencers, which run 24/7. I was struck by BGI’s eclectic leadership.
BGI cofounder, Jian Wang, Ph.D., recently scaled Mount Everest, after three attempts over a two-month period. For inspiration he credits BGI’s landmark collaboration with U.S. and European scientists in documenting the rapid evolution of the Tibetan human genome to accommodate life at high altitudes.
BGI executive director Jun Wang, Ph.D., joined the institute when he was 23 and went on to amass 36 publications in Science and Nature over 12 years. For your average researcher, having 1 or 2 publications in Science or Nature is sufficient to secure a tenured position at a top U.S. or European university.
At age 25 years, Yirui Li is leading the bioinformatics efforts of BGI’s recently announced collaboration with Autism Speaks to sequence 10,000 autism genomes. With 16 Science and Nature publications to his name, Li dropped out of China’s elite Tsing Hua University at age 19.
Despite their intellectual firepower, drive and personal and professional accomplishments, they were a down-to-earth group. They thought nothing of coming in on a Sunday to meet with us. Sporting what appeared to be their regular uniform of T-shirts, jeans and flip-flops or running shoes, they looked more like grad students than high-profile executives of a leading international research institute.
Yang and his colleagues also have a refreshingly progressive view on science and its end game. Impatient with traditional distinctions among scientific disciplines–such as genetics versus environmental sciences–they advocate a “trans-omics” approach to scientific development. In their view, decoding the genome is part of a continuum of activities that includes epigenetics, proteomics, cell biology, systems biology and computer science.
Most importantly, perhaps, they see all these activities as integrated and dedicated to “advancing the science of medicine” and “improving the effectiveness of healthcare.” Clearly, they remain driven by the sense of urgency that allowed them to identify and decipher a deadly pathogen by sequencing its entire DNA sequence in three days.
I left BGI inspired by what I saw and heard. The BGI team seemed refreshingly unencumbered by the petty divisions and willful near-sightedness we too often encounter in science and society. They are pursuing a grander vision that I, too, have lost at times. More than ever, I am hopeful that with enough idealism, ambition and even a little chutzpah, Autism Speaks collaborations like this one will soon deliver a better future for all of our families.
After a few drinks and a dinner of simple and very spicy local fare in the BGI canteen, Yang leaned over to me and said matter-of-factly, “We’ll get it done.”
Please visit our science pages for more news and perspective.
As reported last week, a large twin study supported by Autism Speaks compared the frequency with which identical and fraternal twins both share a diagnosis of autism. This approach enabled the investigators to use statistical techniques to calculate the degree to which environmental factors shared by twins contribute to their risk of developing autism. Such factors include conditions in the womb and during birth.
The results of the California Autism Twin study were game-changing because they revealed a much larger environmental influence than had previously been estimated—accounting for about 58% of the risk of developing autism. By contrast, much smaller twin studies had previously suggested that genes largely accounted for a child’s risk of autism.
The results underscore the need to investigate the role that non-inherited risk factors play in the development of autism spectrum disorders (ASD). So what’s being done to help speed this research? And what role are Autism Speaks and its donor dollars playing in this effort?
Autism Speaks has funded over $21 million in the study of environmental risk factors, an initiative we call (obviously enough) the Environmental Factors of Autism Initiative. Already, we have a large body of evidence suggesting that it is not any one environmental factor, but many different factors working together, that elevate the risk and severity of autism in individuals with a genetic predisposition for this condition. In other words, autism is seldom caused by any one thing and neither is it an “all or nothing” condition. Furthermore, different combinations of genetic and environmental risk factors contribute to individual cases of autism.
Within the Environmental Factors of Autism Initiative are ongoing studies focusing on environmental exposures that occur before and during pregnancy and throughout the first year of life—crucial periods for human brain development. These studies look at such possible risk factors as maternal and paternal age, socioeconomic status, season of birth, exposure to chemicals or toxic agents, nutrition and exposure to various pharmaceutical drugs during pregnancy, the difficulty of labor and delivery, and various other forms of prenatal stress. The researchers we support are also investigating the mechanisms by which genes and the environment may interact (so-called epigenetics) and the role of the immune system. We are also supporting large scale epidemiological studies that focus on pregnancy and the first year of life. These include the EARLI study and the IBIS study.
Are you interested in learning more about the studies Autism Speaks is funding with donor dollars? We are proud to debut the new Grant Search function on our website. Please use it to explore past and present research studies by topic or location. And if you or your family is affected by autism, please consider participating in one of our clinical studies.
Everyone knows that some environmental factors can have adverse effects on health, especially early in development. For example, we know that exposure to cigarette smoke is particularly bad for infants and young children, increasing risk for Sudden Infant Death syndrome, respiratory challenges and middle ear infections. While we are still learning what kinds of environmental factors might impact the intricate process of brain development, and exactly how these impacts occur, we all want to know how environmental factors influence risk for autism.
Last week the Society of Toxicology met in Washington D.C. to discuss not only environmental effects, but how they may interact with our genes to confer autism risk. The most popular topic of this 50th anniversary meeting was epigenetics —literally changes made “above the genome”. Different epigenetic changes have the effect of making the genetic code more or less available for reading and the production of proteins. In other words, the environment can actually turn off the functions of genes, resulting in downstream effects on brain and behavioral development.
During a special symposium organized by autism researcher Isaac Pessah, PhD from the University of California at Davis and Cindy Lawler, PhD at the National Institute of Environmental Health Science, , scientists discussed new data and examples of how environmental factors can lead to changes in autism risk. Animal models of autism are essential for carrying out tests such as these, as different amounts of exposure to a particular substance can be carefully delivered and the outcomes observed with all other variables controlled.
Janine LaSalle, PhD at the University of California at Davis studied the effects of a flame retardant on behavioral development and cognitive function. She and her colleagues showed that these cognitive effects, which are similar to those found in autism, are dependent on both the sex of the animal and proper function of epigenetic mechanisms that turn a collection of other genes “on” or “off”.
Researchers in the Tanguay lab at Oregon State University are using the humble zebrafish to study a newly discovered type of gene expression. The research team is studying the effects of alcohol (ethyl alcohol, both the type found in beverages and and as a biofuel additive to gasoline) and a common acne treatment ingredient (retinoic acid, a metabolite of vitamin A ) on gene expression in the zebrafish. They are finding that disruptions in this new type of gene expression (microRNAs) can have surprisingly large effects on the rest of the genome.
We know from many previous studies that duplications or deletions of collections of genes—called copy number variants or CNVs—can be associated with increased autism risk. Scott Selleck, PhD, from Penn State University reported on his study which looked at the genetic background of children in the CHARGE study at UC Davis (http://beincharge.ucdavis.edu/). Individuals with ASD showed increased lengths of CNVs at certain points in the genome. His lab reasons that these CNVs may be areas of what he calls “genomic instability” where environmental chemicals affect gene expression. We need to know more about these CNVs and whether or not they are the reason some individuals are more susceptible to environmental factors in development.
Genes and environment interact, yes, but another important factor is when. Timing of the environmental insult can be crucial. Studies of neural stem cells are showing us that there exist critical periods in the development of these immature brain cells that include times in which cells divide, and also a later time when the immature cells become either neurons or another type of brain cell known as glia. It is at these times when environmental influences might have their biggest effect.
Pat Levitt, Ph.D. from the University of Southern California spoke on how the combination of genetic vulnerabilities and environmental factors can converge to disrupt brain development and function. One example involves the MET gene, which controls the development of a special class of inhibitory neurons. Previous research showed mutations in MET to be associated with autism, especially in individuals with gastrointestinal dysfunction.
Dr. Levitt and his colleagues demonstrated that exposure to chemicals in diesel fuel exhaust also decreases proper expression of the MET protein. This reduction in expression leads to changes in complexity and length of neurons as they reach to connect with other neurons. These changes may contribute to the previously observed effects on brain development. Interestingly, a recent report notes an increased risk for autism in children whose mothers lived within 1000 feet of a major highway during pregnancy.
Autism Speaks is actively supporting a number of research projects investigating the role of epigenetics in autism, including how environmental factors interact with genetic mechanisms to influence behavior. A primary focus of research invited for submission to Autism Speaks in 2011 is the mechanism of gene/environment interactions, including epigenetics.
To read about all the research Autism Speaks is funding in this area, click here http://www.autismspeaks.org/science/research/initiatives/environmental_factors.php.
The Interagency Autism Coordinating Committee (IACC) met on Tuesday, December 14, at the Bethesda Marriott in Bethesda, Md. This is the fifth time the Full Committee has met in 2010. The IACC has made significant progress in the past year in the following areas: 1) releasing the 2010 Strategic Plan for Autism Research (February 3); 2) publishing the 2008 Portfolio Analysis Report (January 19); 3) releasing the 2009 Summary of Advances in ASD Research; 4) hosting first annual IACC Services Workshop, Building a Seamless System of Quality Services & Supports Across the Lifespan (November 8); and 5) updating the 2011 Strategic Plan for Autism Research.
IACC Chair and NIMH Director Thomas Insel, M.D. opened the meeting with a presentation on research developments since the last IACC meeting. Dr. Insel reported that autism was a “hot topic” at the recent Society for Neuroscience meeting with a 30 percent increase in abstracts focused on autism. The meeting also included a Public Symposium, Autism: Progress and Prospects, chaired by Gerald Fischbach, M.D., Scientific Director, Simons Foundation Autism Research Initiative.
The IACC meeting agenda was devoted primarily to consideration of updates to the Strategic Plan for Autism Research. Members of the Strategic Planning Subcommittee presented the IACC with modifications to the existing plan with appendices of new research advances, funding gaps and new research opportunities for each section of the plan. The Committee approved most of the recommendations made by the Subcommittee.
The Subcommittee’s recommendations included objectives to better understand wandering and fever in persons with ASD to Question 2 of the plan.
The Committee voted to retain the title of Question 3, “What caused this to happen and how can it be prevented?” Updates to Question 3 include reference to a Workshop “Autism and the Environment: New Ideas for Advancing the Science,” held September 8, 2010, which was co-sponsored by Autism Speaks and NIEHS. The meeting involved environmental scientists who have successfully identified environmental risk factors for other conditions, such as Parkinson’s Disease, in an effort to develop better strategies for discovering environmental risk factors contributing to the etiology of ASD. The committee voted to accept new research objectives, including in the following areas: epidemiological studies that take advantage of special populations or expanded existing databases to inform our understanding of environmental risk factors for ASD, to include adverse events following immunization (such as fever and seizures), mitochondrial impairment, and siblings of children with regressive ASD; and the role of epigenetics in the etiology of ASD, including studies that include assays to measure DNA methylations and histone modifications and those exploring how exposures may act on maternal or paternal genomes.
Recommendations for Question 4 were also accepted. These included research objectives to assess the effectiveness of interventions and services in broader community settings by 2015; to study interventions for nonverbal individuals with ASD; and to focus on research on health promotion and prevention of secondary conditions in people with ASD. Secondary conditions of interest include overweight and obesity, injury, and co-occurring psychiatric and medical conditions.
The IACC’s review of the Subcommittee’s recommendations for Question 5 included extensive discussion about how the IACC should address issues related to mortality, safety, and health within the IACC. New research objectives were approved to support research on health and safety issues leading to mortality.
The Question 6 recommendations on future needs of adults highlighted the urgent need for additional scientific research specific to this group. In 2010, several national advocacy groups devoted private resources to initiatives on adult services that have been brought to the IACC’s attention.
Finally, Question 7 is focused on the infrastructure and surveillance needs. The committee noted concern in funding availability for these needs. New research objectives were added. These included objectives to establish a robust network of clinical research sites that can collect and coordinate standardized and comprehensive diagnostic, biological (e.g. DNA, plasma, fibroblasts, urine), medical, and treatment history data that would provide a platform for conducting comparative effectiveness research and clinical trials of novel autism treatments; and to create an information resource for ASD service providers, researchers, families, and people with an ASD which serves as a portal to obtain the most recent evidence-based reviews and plans for intervention, services, and support.
“Public input has been critically important to the Strategic Planning process,” says Geraldine Dawson, Autism Speaks’ chief science officer and IACC member. “Based on feedback received from both consumer and professional stakeholders during the Request for Information phase, the recommended Strategic Plan will include new objectives that enhance the focus on environmental factors and lifespan issues affecting adolescents and adults living with autism.”
The afternoon session began with the Public Comments portion of the meeting. Ms. Idil Abdull, parent advocate and co-founder of the Somali American Autism Foundation, thanked the IACC for its decisive action on exploring the Somali autism issue and urged it to sustain this effort. Also presenting during Public Comments was Mrs. JaLynn Prince, President and Founder of the Madison House Foundation, based in Montgomery County, Md. The mission of the Madison House Foundation is to identify the lifelong needs of adults with autism and fill those needs through education, awareness, and advocacy. Mrs. Prince encouraged the IACC to explore the expertise of organizations like the Madison House which have been dealing with adult service issues in local communities throughout the country.
The agenda also included several updates on issues raised during recent meetings. At the October meeting, the IACC asked Autism Speaks, NIEHS and CDC to investigate issues raised concerning the Somali population in Minnesota. Coleen Boyle, Ph.D., Acting Director, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention and IACC Member, Cindy Lawler, Ph.D., National Institute of Environmental Health Sciences, and Autism Speaks’ chief science officer and IACC member Geraldine Dawson, Ph.D. provided an update on their efforts with respect to this issue. It was reported that collectively $350,000 has been committed to begin to study this issue, with Autism Speaks contributing $100,000 to this effort.
In response to a presentation on Wandering and Autism at the October meeting, the IACC created a subcommittee on safety issues the first task of which is to write the secretary of HHS on the recommendations that were made during the meeting. Lyn Redwood, R.N., M.S.N. Co-Founder and Vice President, Coalition for Safe Minds and Co-chair, Safety Subcommittee, and Alison Singer, President, Autism Science Foundation and Co-chair, Safety Subcommittee, reported on the Subcommittee’s recent meeting. The IACC authorized the Subcommittee to proceed with its information gathering in order to finalize the letter to the secretary. To inform this letter, the Subcommittee’s representatives will meet with the Departments of Education and Justice and will develop a Request for Information (RFI) on wandering. It was also announced that Autism Speaks and the Autism Science Foundation will fund a study utilizing the Interactive Autism Network (IAN) on this issue.
Services Subcommittee Co-chairs Ellen W. Blackwell, M.S.W., Centers for Medicare and Medicaid Services and Lee Grossman, President and CEO, Autism Society, reported on their Services Workshop on November 8 and subsequent subcommittee meeting. The goal of the workshop was to determine a set of recommendations to make for the Secretary of HHS. The Subcommittee is using slides from the workshop to inform the recommendations to be sent to the Secretary. The Subcommittee believes another workshop on services will be necessary next year.
Finally, the IACC solicited the input of IACC member Alan E. Guttmacher, M.D., Director Eunice Kennedy Shriver National Institute of Child Health and Human Development, on the implications of the proposed addition to Question 1 of the Strategic Plan to conduct five studies on the ethical, legal and social implications of autism screening research, including at least one study on the implications of potential future genetic testing. The committee agreed to look at what other diseases have done in this area and will convene a workshop next year.
The IACC is scheduled to meet again on January 18 and will finish its update of the Strategic Plan’s Introduction section at that meeting before approving the plan.
Last week, the Senate Environment and Public Works Committee convened a panel of experts to investigate the role of environmental factors in autism spectrum disorders (ASD; link to web archive for video). Although genetic factors are known to contribute to the risk of autism, we also need to understand environmental factors and their interactions with genetic susceptibility.
The dramatic increase in autism prevalence over the last two decades—over 600% during this period—underscores the need for more research on environmental factors. Our understanding of typical brain development combined with what we’ve learned from examining the brains of individuals with autism have focused efforts on the prenatal and early postnatal environment. To investigate environmental factors that may be active during this time, researchers are casting a wide net on potential environmental agents that can alter neurodevelopment, including exposure to metals, pesticides, polybrominated diphenylethers and other chemicals.
Isaac Pessah, Ph.D., Director of the University of California, Davis, Children’s Center for Environmental Health and Disease Prevention, participated in the panel and said in his testimony, “We must identify which environmental exposures and combination of exposures are contributing to increased overall risk in the population and identify the most susceptible groups. Only by bringing together the concerted effort of multidisciplinary teams of scientists can we identify which of the >80,000 commercially important chemicals currently in production promote developmental neurotoxicity consistent with the immunological and neurological impairments identified in individuals with idiopathic autism”.
To help speed an understanding of environmental factors, Autism Speaks is supporting research on several fronts. In 2008, Autism Speaks launched the Environmental Factors Initiative to fund investigators researching aspects of environmental causes and autism.
A collaboration with the National Institute for Environmental Health Sciences (NIEHS) has resulted in a network of 35 international scientists who gathered at this year’s International Meeting for Autism Research (IMFAR) to promote collaboration, identify gaps in our understanding and foster opportunities for innovative research which is discussed in more detail in Dr. Dawson’s 2010 IMFAR recap. This fall, Autism Speaks and NIEHS will co-sponsor a workshop to help identify the most promising strategies and scientific directions for understanding the role of the environment in ASD.
A large collaborative study which will pull together data from six international registries is being funded by Autism Speaks to explore early environmental risk factors for ASD.
Autism Speaks is also leveraging longstanding investments to make the best use of research resources that currently exist. For example, the Autism Genetic Resource Exchange (AGRE), a premiere genetic resource for scientists studying autism, is now collecting environmental data from families to pair with the genetic and medical data. Autism Speaks has partnered with the National Institutes of Health to fund the the EARLI and IBIS research networks to study environmental factors in infants at risk for autism. The EARLI network is following 1200 mothers of children with autism from the start of another pregnancy through the baby sibling’s third birthday. The IBIS network is charting the course of brain development in infant siblings of children with autism. Together with Autism Speaks, these groups are exploring both genetic and environmental risk factors for ASD.
Taken together, Autism Speaks’ investment in research on environmental factors promises to shed light on an important area of autism research that has until recently remained in the shadows. We look forwarding to following the new directions illuminated by the discoveries made possible by these various research opportunities.