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From Molecules to Medicine: Thoughts on the 2010 International Meeting for Autism Research (IMFAR) from the Chief Science Officer

By Geri Dawson, Ph.D., Chief Science Officer, Autism Speaks

The evening before the start of the IMFAR conference, in the back room of one of Philadelphia's Chinese restaurants, a young woman was talking excitedly about her research. “I am trying to understand why individuals with autism have so much difficulty with change. I work in the lab but also work in the clinic helping people with autism.” She went on to explain how Autism Speaks' Weatherstone Predoctoral Fellowship Program was influencing her experience of graduate school. “My course work is so demanding that, if I had to be a teaching assistant to support myself, I wouldn't have had any time to devote to research. This fellowship allowed me to spend another year training in different labs rather than going out and getting a full-time job. I am so thankful for that.” Another fellow is studying the role of immune abnormalities in autism spectrum disorders (ASD) while others focus on early detection and language intervention. The dinner was sponsored by Autism Speaks to allow the young fellows to network, share ideas, and hopefully, begin to form their own community of young scientists. From experience, I know that having such a network of colleagues can be very helpful in navigating the challenges of academia.

Animal Models of Autism Symptoms

The first day of IMFAR started out with a keynote address by Jackie Crawley, Ph.D., chief of the Laboratory of Behavioral Neuroscience at the National Institute of Mental Health, who spoke about the development of mouse models for autism. She began by emphatically stating, “We can't make an autistic mouse!” However, she explained that mouse models can be extremely useful for studying autism because mice share 99 percent of their genes with humans and have similar biochemistry and neuroanatomy. And mice are very social beings. They provide valuable “assays” for testing hypotheses about

Jackie Crawley, Ph.D.
NIMH

how genetic mutations influence brain development and function, and also for testing novel drugs. Dr. Crawley described her painstaking work developing behavioral measures in mice that can be used to determine whether a novel drug can alter core autism symptoms. I learned a lot about how mice socially interact and communicate with each other. For example, like most humans, they prefer spending time with one of their peers rather than an inanimate object, they greet each other (by sniffing), and they communicate with a remarkably complex set of sounds, which are ultrasonic and can only be heard with special microphones. Dr. Crawley then showed how mice engineered or bred to have variants or mutations in autism susceptibility genes exhibit a lack of preference for spending time with other animals and fail to vocalize with other mice in the normal manner. Dr. Crawley is now applying these mouse models toward testing drugs that can potentially reduce core ASD symptoms.

Progress with a Precious Resource – Brain Tissue

My next stop was a meeting of scientists using brain tissue to gain deeper insight into the neurobiology of autism. Daniel Lightfoot, Ph.D. and Janet Pickett, Ph.D. from Autism Speaks' Autism Tissue Program (ATP) reported that over 7,000 families of individuals with ASD have registered to donate brain tissue to the ATP. Among the scientists who shared their new findings was Carlos Pardo, M.D. from Johns Hopkins University, who authored the first publication documenting inflammation in the brains of persons with autism. He is now studying how different genes are expressed in the brain, with a special emphasis on genes related to inflammation.

The Challenges of Interpreting Scientific Findings

In the afternoon, it was my turn at the podium as part of a symposium on risk communication organized by Craig Newschaffer, Ph.D. and Michael Yudell, Ph.D. from Drexel University. The goal of the symposium was to discuss the challenges of interpreting and communicating scientific findings related to environmental and genetic risk factors for ASD. For example, when a parent has one child with autism and is expecting a second child, what kinds of risk information should be given to the parent, who should deliver it, and how should it be delivered? How should professionals convey scientific findings that are inconsistent and ambiguous, how should they tailor their communication to different individuals, and how can we make sure that people have access to the latest findings about risks factors for ASD? One common theme was the need to engage the public in the dialogue about risk factors, to have respect for parents' perspectives and beliefs, and to consider how each individual's personal experiences shape their beliefs and attitudes.

IACC Strategic Plan Update

Later that afternoon, Tom Insel, M.D., director of the National Institute of Mental Health, gave an update on the Interagency Autism Coordinating Committee's (IACC) 2010 Strategic Plan for Research. He described the public comments on the 2009 IACC Strategic Plan, noting that many in the community felt there should be more emphasis on researching environmental factors, nonverbal individuals with ASD, adults with ASD and delivery of health services. These have been addressed in the 2010 updated plan which now has almost twice the number of research objectives than the 2009 plan! Dr. Insel also noted that as a result of President Obama's new stimulus funding, an additional $68 million was infused into autism research. As a new member of the IACC, I am looking forward to participating in the 2011 update of the strategic plan.

International Environmental Epidemiology Network

That evening, I was thrilled to welcome over 35 scientists to the inaugural meeting of the International Environmental Epidemiology Network, which is co-sponsored by Autism Speaks and the National Institute of Environmental Health Sciences (NIEHS). The goals of the network will be to share ideas and expertise, identify gaps in knowledge, resources, and tools, define high priority research areas, and develop collaborative projects focused on the identification of environmental risk factors for ASD. Cindy Lawler, Ph.D. and Kimberly Gray, Ph.D. from NIEHS described the successes of a similar network founded to study environmental risk factors in Parkinson's disease and several NIH resources that could be useful, including the NIH Environmental Genome Project. The goal of the EGP is to characterize how specific human genes contribute to environmentally induced disease susceptibility. Also of interest was Dr. Gray's description of the NIH Exposure Biology Program, which aims to develop new technologies for measuring human exposure to chemical or biological agents that may lead to susceptibility to disease or dysfunction. Collaborating with NIEHS, Autism Speaks plans to sponsor this network, scientific meetings, and research funding on environmental risk factors as part of its Environmental Research in Autism Initiative.

Overview of Autism Speaks Science

The next day, I had the pleasure of giving the first talk of the morning during which I described Autism Speaks' 2010 science activities. I described how our funding is directed toward science ranging from basic discovery research to treatment and dissemination. Our targeted research emphasis areas were then outlined, which include (1) risk factors for autism, especially environmental factors and role of gene-environment interactions; (2) methods for very early detection of ASD risk; (3) adult development in ASD; (4) molecular pathophysiology of ASD that can inform research on drug discovery and biomarkers for diagnosis and prediction of treatment response; (5) novel treatments addressing core symptoms and associated medical conditions throughout the lifespan; and (6) dissemination of empirically-validated clinical practices to under-served populations. In addition to providing highlights from our research initiatives, I described a new funding mechanism launched this year called the Trailblazer Award. This one-year, $80,000 award is for highly novel, high risk research that has the potential to transform the way we understand and treat autism. Find out more about Autism Speaks' strategic plan for research.

Innovative Technology for Autism Tech Demo

I then headed over to the Innovative Technology for Autism demonstration sponsored by Autism Speaks and organized by Sophia Colamarino, Ph.D. and Simon Wallace, Ph.D. and Matthew Goodwin, Ph.D. I have to say this was a highlight among highlights! Families mingled with autism researchers and computer scientists to explore the latest technologies. Individuals with of all ages with ASD tried out the new computer

Fun with new technology

programs, applications and toys. An elementary-school-age boy focused intently on the computer while his teacher explained how this computer program had revealed the boy's aptitude for math and reading and allowed him to be integrated into the regular classroom. Other projects included computerized games that teach skills using applied behavior analysis, programs that promote social interaction and communication devices. View higlights from the ITA demo below.

Pharmacological Interventions

The afternoon symposia I attended were on the future of pharmacological treatments for ASD and very early interventions. Evdokia Anagnostou reported new findings on the effects of intranasal oxytocin for improving social cognition in individuals with ASD. Interestingly, people taking oxytocin reported feeling an improved sense of well-being. However, they also tended to engage in more repetitive behaviors. Overall, oxytocin was well-tolerated and the results were encouraging. Randy Carpenter, CEO of Seaside Therapeutics, gave a cogent talk on the pathway from molecular biology to the development of therapeutics. He remarked that the brain is “hard-wired in utero” but that experience is necessary for the fine-tuning and connectivity among synapses. Proper functioning of the synapses depends on a balance between excitatory and inhibitory influences, and glutamate is a neurotransmitter that has an excitatory influence on the synapse (acts as an “accelerator”). He then explained that, in Fragile X syndrome, the genetic mutation leads to the lack of a synapse protein (FMRP) that has a regulatory influence on the synapse (acts as a “brake”). This leads to poor neural network performance because the excitatory influence of glutamate is too high, as shown in the figure below.

Scientists have “knocked out” the FMR1 gene in the mouse, drosophila (small fly), and zebra fish, replicating features of the Fragile X Syndrome. Moreover, they have been able to “rescue” or reverse the features of this syndrome by correcting the functioning of the synapse using different compounds.

Mark Bear, Ph.D. was responsible for identifying the molecular mechanism that has been the driving force behind this work, along with significant contributions from Steve Warren, Ph.D., one of Autism Speaks' scientific advisors. Can similar therapies alleviate symptoms in humans with Fragile X syndrome? In humans with ASD without Fragile X Syndrome? In fact, such clinical trials are currently underway. One study is an open label trial investigating arbaclofen, a drug that has been used to help children with ASD with gastrointestinal problems. Arbaclofen inhibits glutamate and might have broader therapeutic effects. The outcome of a second clinical trial – this one conducted with individuals with Fragile X Syndrome – was reported at IMFAR on Saturday. The results were promising and further studies are now being planned.

Early Intervention

The symposium on very early interventions for ASD was next, and I was among the presenters. In January of 2010, I co-published a study of intensive early intervention in toddlers with ASD. The intervention was based on the Early Start Denver Model; it was provided for two years by trained therapists and parents. We found that children who received the intervention showed significant gains in IQ, language, and adaptive behavior. At IMFAR, we addressed the question of what accounts for children's differing response to early intervention. Specifically, we examined whether children of varying symptom or cognitive levels responded differently to early intervention based on the Early Start Denver Model. We found that children with mild versus more severe ASD symptoms both responded to the intervention, but the children with milder symptoms made greater gains. However, children with higher versus lower IQs (before treatment) responded similarly to the intervention; both made similar significant gains in IQ, language and adaptive behavior. This is very positive news, suggesting that children of all levels of cognitive ability can benefit from early behavioral intervention.

Addressing the Global Challenges of Screening and Diagnosis

That evening, I welcomed 78 scientists from twenty countries to the International Autism Epidemiology Network and IMFAR Diversity dinner co-sponsored by Autism Speaks and the International Society for Autism Research. The topic for the evening was how to address the challenges of screening and diagnosis on a global scale. A lively discussion ensued pertaining to the utility of current methods of autism diagnosis in countries with low resources and very different cultures. New approaches to screening that could potentially be used on a large scale in low resource countries were proposed. Although there were differences in opinion regarding how to address the financial, technical, and logistical challenges of diagnosing ASD in diverse cultures, the end goal was unanimously endorsed – families throughout the world are in need of better services for people with ASD. It was clear that solutions will require on-going collaboration among families, governments, nonprofit agencies, scientists and service providers. The annual meeting of the International Autism Epidemiology Network is one part of Autism Speaks' continuing commitments to this effort.

Treatment Advances through the ATN

The last series of talks I attended was an invited educational symposium featuring Autism Speaks' Autism Treatment Network (ATN), a collaboration of fourteen academic medical centers in the U.S. and Canada committed to addressing the medical needs of children with ASD. Clara Lajonchere, Ph.D. moderated the session which began with a talk by George Fuchs, M.D., a pediatric gastroenterologist, on gastrointestinal problems in children with ASD. Dr. Fuchs began by reviewing the scientific findings on GI prevalence in ASD, including new data on 1,884 children with ASD who are part of the ATN patient registry, which showed that 34 percent of children with ASD experienced GI problems within the last three months and 21 percent suffered from chronic constipation. GI problems are correlated with higher levels of physical, emotional, social, school, and sleep problems. Dr. Fuchs reviewed the recommendations for the assessment of GI problems in children with ASD published in the January 2010 issue of the journal Pediatrics. He further noted that, unfortunately, physicians sometimes miss GI problems in children with ASD as they focus solely on the autism symptoms.

Beth Malow, M.D., a child neurologist and mother of two children with ASD, spoke about sleep problems in children with ASD. Approximately two-thirds of parents of children with ASD report that their child has sleep problems. Based on data from 1,590 children from the ATN patient registry, Dr. Mallow reported similar prevalence rates (65 percent) in children with ASD of all ages, ethnicities, IQ levels and gender. Common problems reported by parents include prolonged time falling asleep and decreased sleep. The

Beth Malow, M.D.

reasons for the high prevalence of sleep problems in ASD are unknown, but possibilities include biological differences in melatonin and certain neurotransmitters such as serotonin, GI problems such as reflux, epilepsy, anxiety, and low iron status which has been associated with restless leg syndrome. Like GI problems, sleep difficulties are associated with daytime consequences, including increased ASD symptoms, mood problems, and higher levels of parental stress. Promising treatments include melatonin and behavioral interventions focused on helping the child to fall and stay asleep. The ATN is currently conducting a randomized controlled trial of a parent-educational program designed to improve children's sleep habits.

Sarah Spence, M.D., Ph.D., also a child neurologist, discussed the role of epilepsy in autism, noting that the ATN registry data suggest that approximately 11 percent of children with ASD have epilepsy. Although treatment of epilepsy is well-established, more controversial is the treatment of abnormal EEG patterns without the presence of clinical seizures. Complex partial seizures are associated with an arrest in behavior patterns, unresponsiveness, and repetitive behaviors, all symptoms that are part of the ASD syndrome. This makes diagnosis of complex partial seizures difficult to detect in children with ASD. Systematic study of seizures in children with ASD is needed. This is one of the goals of the ATN. Daniel Coury, M.D. medical director of the ATN, ended the session with a discussion of the importance of evidence-based clinical guidelines for physicians. He described four guidelines currently being developed through the ATN, including assessment and treatment of GI and sleep problems, EEG assessment of seizures, and medical monitoring for side effects of psychotropic medications.

Moving Science Forward Faster
Looking back on the IMFAR meeting I chaired in Seattle in 2007, I am impressed by how much the meeting has grown (from 1000 to 1800 in three years) and encouraged by the real progress that is being made in developing effective treatments for individuals with ASD. In this brief overview, I didn't have time to touch on the presentations on school-based interventions, social skills, and treatments to promote successful transitions to adulthood. While progress has been made, we have a long way to go. The interventions that have been empirically-validated, such as early behavioral intervention and social skills training, are still out of reach for most families. The medical issues faced by many individuals with ASD and their families are still too often missed by their primary physician, requiring a long journey from doctor to doctor looking for an answer. Too many adults with ASD are unemployed and living at home rather than contributing to society and leading lives with purpose. Let's hurry science! We can do it by encouraging young bright minds to enter the field through fellowships, by funding that out-of-the-box idea that just might lead to a breakthrough, and by providing scientists with the tools and resources they need.