About two weeks ago, the National Institute of Health announced part of the government’s commitment to autism research through the ACE projects, or Autism Centers for Excellence. Highly competitive and intensely scrutinized, these 5 year projects all investigates areas of autism aimed at helping people with ASD and their families. This week’s podcast summaries them, discusses how they interact and complement each other, and explains how they are going to affect the lives of people with autism.
This week’s podcast is a throwback from a few months ago which highlighted research using brain tissue of individuals with ASD. To understand the brains of people with autism, researchers need to look at the brains of people with autism. This means people with autism and their families need to learn more about this option so they can be prepared when the time comes. Listen to the podcast to hear how brain tissue research is helping scientists understand autism better, and making a difference in the lives of people with autism now.
During IMFAR, a study was presented that showed that women with very high levels of folate during pregnancy showed an increased risk of having a child with autism. The media took this to mean that taking too many prenatal vitamins caused autism. ugh. This week, those findings are discussed. Also published this week is a well-designed, long awaited study which examines the theory that too little folate in the central nervous system is the culprit behind autism. Too little folate in the brain is not the culprit, and too much in the blood may be coincidental to something else causing autism. It’s important to have a balance so don’t hesitate to take a prenatal if you are trying to get pregnant.
Also, because you may be IMFAR’d out – we highlight the exciting findings that cognitive behavioral therapy for treating anxiety in people with ASD is not only effective in clinical settings, but in school settings. This has implications people with ASD in special needs classrooms who need treatments for anxiety.
Welcome to a very special podcast – the IMFAR 2016 edition with highlights from this year’s International Meeting for Autism Research in Baltimore, Maryland. As you may notice, my voice is different. I was talking so much that I actually developed laryngitis. I’m not proud of myself for talking so much at a meeting where I should have been listening, but I will make sure the text is somewhere on the web so you can read it.
This year, ASF got a lot of help in reporting the findings back to you from our IMFAR travel grantees. ASF provides scholarships for families, students and people with autism to attend IMFAR. They attended the sessions they were interested in, and were nice enough to report back on what they learned. We will be including their reports here.
The meeting started with an IMFAR preconference organized by Dr. Becky Landa at KKI and hosted by Towson University. Next year when the meeting is in San Francisco, and if you live in the Bay Area you should try to attend. The topics covered included: behavioral interventions, feeding issues, medical comorbidities in people with autism and sensory problems. It included the most recent findings by some of the most respected scientists and highlighted applicable findings for parents and teachers. We heard Dr. Peter Gerhardt talk about how people with autism don’t need a community – they need communities. That can be the communities of the grocery store, the bus route, the library, as well as family and clinical communities. But it isn’t just one.
While just about every topic under the spectrum was covered at IMFAR, I can’t remember a meeting that highlighted gene/environment interactions as much. Irva Hertz-Picciotto, an investigator who launched one of the very first studies on the environmental factors in autism for most cases of autism, gave one of the keynotes. She emphasized that the word “causes” in most cases is not scientifically accurate. In fact, the causes are actually a mix of multiple genetic factors and multiple environmental risk factors. And while her examples of environment included toxic chemicals, it’s important to think of environment as the whole of “non-genetic” factors. This can be psychological factors, medical, pharmacological and sociological. There is no single environmental cause, and most cases of autism are not caused by one single genetic cause either (but sometimes they are and I’ll get to that later). People trying to understand the research should know that just because an environmental factor is involved in the causes of autism, that is completely different than the causes of the rises of prevalence. So when you see a graph showing an increase in prevalence on one side and the increase in a risk factor on the other – just ignore it. There are more environmental factors than there are genes and when they are studied individually, just like the effects of individual genes, the effects are small. Looking at the combined effect of multiple genes certainly leads to higher risk factors than individual risk factors. For example, studying the genetic component of autism risk in siblings finds a 20 fold increase but the increased risk because of pesticide exposure is like a 1 ½ fold risk. Over the past 15 years, scientists have been able to narrow down the period of exposure to be during pregnancy, and possibly prior to pregnancy. Everyone thinks about pregnancy but exposures actually affect the sperm and the egg too. It might be hard to realize how much progress has been made in the field, but Dr. Hertz-Picciotto pointed out in her final sentence: “in 2000 scientists knew enough about g x e in autism to put 5 bullet points on one slide. Now it can fill a full hour long talk”.
In addition to Dr. Herz-Picciotto, other environmental health scientists presented in this special panel. Dr. Bruce Lanphear, who is a world respected researcher in lead and IQ in children, showed how it doesn’t take that much of a chemical to lead to large effects on a population. Just because it isn’t a dose of lead that is toxic doesn’t mean it isn’t harmful, so we shouldn’t be focusing on high doses of chemicals. An interesting schematic of the role of environmental factors on outcomes was described: some common exposures may lead to underlying conditions like metabolic problems (obesity, prematurity) that then change gene expression and end up as common outcomes like ADHD, ID and ASD. In a podcast just two weeks ago I presented even more evidence that ADHD, ID and ASD are probably etiologically connected. Different mutations the same genes result in autism and schizophrenia. That siblings share these conditions at a higher rate than non siblings and they certainly share overlapping genes, so it isn’t surprising that their non-genetic causes overlap as well. While the presentation that autism like but not autism specific behaviors were affected after environmental exposures may have seemed out of place to some, it really makes perfect sense. So if you were at the presentation and wondering what Virginia Rauh from Columbia was talking about – autism does not hold a patent on the role of the environment – and studying behaviors seen in autism but are not autism specifically is as important to understand the risk but also the brain pathways involved. The role of gene/environment interactions is more important to study than either alone, because, as discussed at a special interest group on this topic, studying the two together will help researchers better identify and describe both the role of genetics and environment independently. New genes might be discovered if you look at environmental factors on gene expression. Imagine if everyone in an exposure study had their genome sequenced? Then you can more precicely calculate the risk of autism after a certain exposure in people with different genetic mutations. Doing this, interactions between genetics and the immune system and air pollution were discovered. Very preliminary data from a cohort in Boston showed that women with very high folate and B12 levels had an increased risk of ASD. It wasn’t a continuous risk, it was only elevated in the group with the very highest levels of folate, meaning, pretty high – and these high levels could come from dietary exposures and an inability to metabolize folate normally. This study got a lot of press because some media sources suggested that it might be that women take too much folic acid – that is NOT the case.
The rub is always how to detect these environmental factors and what to study. So far, they’ve been done one at a time and while it’s a start, it would take forever if we went one by one. Dr. Dani Fallin, who did an amazing job helping to organize this symposium and the conference, showed the audience some new technologies that are being used to measure prenatal exposures at birth, and some proxy measures of exposures like prenatal smoking. But the list doesn’t stop there. In a special interest group, it was proposed that more research be done on objective ways to measure multiple exposures at once through “omics” assays. This is – combining metabolomics (or the breakdown of chemicals), genomics, epigenomics (which is how genes respond to environmental factors), proteomics (the expression of proteins) and the list goes on and on. Instead of going through the list of exposures, including chemical, psychological, medical, etc. you can do them all at once from a single biomarker. There is of course a tradeoff between getting a lot of information on a few people vs. less information on lots of people. It was pretty amazing to think what can be accomplished in this area if this is a possibility.
Another theme for the meeting was need for training. Systemic-level, community-level and provider-level factors such as culture, limited capacities, provider knowledge and training have been identified as barriers to ASD specialized services. Some demographic factors that predict these barrires include rural community and provider experience. To provide comprehensive screening practices and to deliver evidence-based interventions, service providers require more ASD-specific training, increased knowledge and use of screening tools. Amy Wetherby from Florida State University presented how she is using the Navigation Guide in fur different areas across the US and partnering with a group of African American churches through the National Black Church Initiative. The goal is to educate individuals across cultural and racial lines about autism, how to identify it, what to do about it, and how different parts of the community pay a role in helping people with ASD. Also, different screeners like the BITSEA are being studied specifically in families with different racial and cultural backgrounds to see if they work as well.
Mental health services in those with autism is a big concern in the community, especially in light of a study out of Sweden that shows that suicidality is significantly increased in people with ASD. One mental health intervention developed by Dr. Chlebowski includes treatment planning, active treatment, and progress evaluation protocols for mental health providers. It seeks to bridge the knowledge gap between community therapists and lab science and so far has proven to be a useful and feasible clinical intervention.
These interventions can be developed in the lab, but it takes 17 years for them to be actually used in educational settings. They aren’t really useful until they are effective where people live and in settings that they experience day to day. ASF fellow and early career researcher Jill Locke is looking at an intervention called “remaking recess” and expanding it by providing support to schools to not just give them the manual and hope for the best, but to make sure that teachers and educators get the right tools and use all the parts of the intervention. This means one on one or group support and suggestion of strategies when challenges occur. This intervention is aimed to improve social engagement at recess was shown to decrease solitary play, increase joint engagement and increase social network inclusion. It’s important to make sure that things like increasing joint engagement are leading to real world outcomes.
Another major theme for IMFAR was Innovative treatments for individuals with ASD and across the lifespan. Peter Enticott and Stewart Mostofsky presented on Transcranial Magnetic Stimulation (TMS) in ASD. This is where magnetic waves are presented on the heads of individuals with autism to alter brainwave activity. So far this has only been tested in in adolescents and adults. They noted significant improvements in irritability and repetitive behaviors were found with 16 sessions of TMS. Changes were also seen in social functioning and social anxiety when deep TMS was provided for 10 sessions. TMS seems to have few side effects, but is a burdensome process requiring 5 days per week treatment.
While this isn’t exactly a novel intervention, social cognitive training is now being studied in adults. In this intervention, people are taught to understand the perspective of others, read nonverbal cues and supported to understand social cognition and the emotions of others. They compared it to another intervention and they both worked, but the social cognitive training was even better when it came to employment after 18 months and social responsiveness. In adults, employment is one of those things that is a “real life outcome”, one downstream endpoint of an intervention that measures some sort of functional improvement for some people. In addition to just getting employment, if you are employed you are also more likely to be getting a passive type intervention on an ongoing basis. That is, being in an employment environment around people in a community along with the right employment supports also has shown the potential to be therapeutic. But again people with autism shouldn’t just be thrown into the deep end of the pool with no training or employment coaching or video modeling.
But before most drug interventions can be given to people, they have to be tested first in animal models. These animal models need to show symptoms of autism, in other words they don’t have autism but in order to show that they work for autism they need to target autism behaviors. So, scientists have made mice that have the same mutations as people with autism. I mentioned earlier how very few cases of autism are caused by single genes. However, sometimes they are, like in a mutation of the SHANK gene. People with this mutation have something called Phelan-McDermid Syndrome and these people have a high rate of autism. From the point of view of a clinician, researchers are only going to get to better treatments if they understand the specific features of each individual with autism. One of the ways to subgroup people with autism is to separate them out into groups. One way to dow this may be through risk factors like genetics, so researchers are really targeting these single gene disorders of autism like Phelan McDermid syndrome. Another keynote was given by Guopeng Feng At MIT. ASF funded one of his fellows, Boaz Barak, and Dr. Barak wrote a blog about this topic on the ASF website. Check it out. A complete deletion of the SHANK3 gene, the one associated with autism and PMS was created. These mice show a lot of repetitive and restrictive behaviors compared to those without the mutation. In mice, this means too much self grooming and running back and forth in their cages. The researchers then isolated the brain circuitry that was disrupted in these mice. It went from the cortex to the striatum to the globus pallidus. This brain circuit is crucial for motor behaviors and actually this part of the brain is affected in Parkinson’s disease as well. Of course, Parkinson’s Disease has different symptoms than autism, but both involve motor dysfunction. In the animal model, there are not enough branches of neurons to each other and a lack of a certain type of cells that release a chemical called GABA to turn OFF activity, leading to lack of proper connections from one area of the brain to another. Scientists know that these are important for autism because similar features are seen in the brains of people with autism.
But this talk wasn’t just chit chat about the circuitry involved in mice lacking an autism gene. Dr. Feng’s lab found that turning this gene back on helped reduce these repetitive behaviors. And the earlier this happened, the more behaviors that were affected by the gene mutation, like anxiety and motor coordination, were improved. Another plug for “the earlier the better”! In this example a specific gene was turned on and off, however, this could apply to the more novel treatments like TMS. It does seem to apply to behavioral interventions. This means that certain symptoms of autism can be reversible across the lifespan, and targeting autism-genes through different mechanisms is an attainable goal.
While SHANK seems to be more responsible for motor behaviors, the gene CHD8 is more heavily involved in social behavior. Raphe Bernier and colleagues at UW didn’t find this out with a rat model (although some study could look at that), instead, they examined social behaviors of parents of people with autism and a CHD8 mutation. Looking at family members of individuals with ASD is showing all sorts of interesting things about autism genetics, risk factors, and families. ASF is taking a similar approach to studying protective factors by looing at undiagnosed siblings of people with autism. Because the people with CHD8 mutations didn’t show differences in social behavior, the differences were only seen in the family members, it won’t surprise you to learn that the same goes for the mouse model. They have all sorts of neurobiological issues like an enlarged brain and they show changes in learning and memory but nothing specific to autism. This does NOT mean this gene is not involved in autism. But CHD8 is a gene that controls the activity of other genes so the behaviors may be pretty variable.
It wasn’t all about the science. Tom Insel, who tirelessly led the Interagency Autism Coordinating Committee through many cycles and strategic plans, won the advocate of the year award. Stakeholders were invited to a special lunch where they heard from bestselling authors of In a Different Key : Caryn Zucker and John Donvan. They discussed how the tireless persistence of parent advocates and self-advocates is the reason for the improvement in the lives of people with autism over the past few decades. And for those of you who doubt that the lives of people with autism are getting better – fifteen years ago, a newly diagnosed parent of a child with autism was facing a misdiagnosis and absolutely no access to evidence based services of any kind. They didn’t exist. And forget insurance paying for them. However, I do understand the perspective of some parents and individuals who have not felt that they have benefited from research but want to emphasize that research HAS made a difference. A group of individuals with autism also formed a special interest group, to promote not only the inclusion of people with autism into advising studies about people with ASD but, also those with ASD to become researchers studying autism.
On the insurance front, Dr. David Mandell from University of Pennsylvania was happy to report that the glass is half empty and half full at the same time. It’s half full because people who are eligible for state driven insurance mandates are getting diagnosed and paying less out of their pocket for services than those who are not. On the other hand, these individuals still pay quite a bit and the rates of diagnosis in that group is not keeping up with what it should be. Service providers still have a long way to go, but insurance mandates are necessary to get people the help that they need, and do improve people’s lives.
Of course this isn’t a fully comprehensive summary of everything IMFAR. Spectrum News had an army of people attending sessions and you should check out their site (www.spectrumnews.org) as well as keep checking on the ASF blog for stories written by the investigators themselves on the impact of their findings.
In the 3rd Environmental Epigenetics Webinar co-organized by Autism Science Foundation, the Escher Fund for Autism and Autism Speaks, Dr. Christopher Gregg from the University of Utah discusses genomic imprinting. In 1 hour he describes what it is, how it affects behavior, and how the environment is relevant to this process. If you are confused about genomic imprinting you are not alone, watch this short video that explains it!
You can also find more information about his research here: http://conflictsinthemind.blogspot.com and http://www.neuro.utah.edu/labs/gregg/Welcome.html.
The recent prevalence numbers for autism were stable from 2014 at 1 in 68. However, a disparity in prevalence still exists for those of hispanic or african-american backgrounds. While these groups are under diagnosed, little research has focused on what it is like to have autism and also be from one of these races today. Gazi Azad and colleagues studied friendships during adolescence in people with autism across different racial backgrounds and what they found will sadden you. Also, what goes into that 1 in 68 number? As it turns out premature births accounts for a significant portion. And if you didn’t have a premature birth and still had a child with autism? Remember it accounts for a chunk, not the whole thing.
If you couldn’t make it to the ASF Day of Learning last week, this week’s podcast provides a 10 minute summary. Not the same as being there, but it will do. We will have videos of each presentation up soon, but this provides a quick recap. Researchers from basic science, translational research and those with a clinical perspective provided 12 minute summaries of different research areas. This included studying autism behaviors in mice, the role of single gene disorders to autism where there are hundreds of genes involved, understanding anxiety and technologies in the classroom to mitigate stress reactions, understanding recurrence of autism in the children of siblings with ASD, and resilience in females. The podcast also includes pictures from the event.
Instead of looking at genes associated with the big “autism”, researchers at the University of Miami are considering how genes influence specific autism features present very early on in life. In this week’s podcast, two investigators, Devon Gangi and Nicole McDonald, explore how genetic variants influence behaviors that are not autism, but predictive of autism. Even more intriguing is how these genes regulate the effects of environmental variables on later behavior. While it isn’t autism specifically, this approach may provide a better perspective on all those hundreds of genes associated with an autism diagnosis. Hopefully this will lead to add on therapies to speed up the progress of behavioral interventions.
We are pleased to present the 2nd environmental epigenetics webinar featuring Dr. Dana Dolinoy of University of Michigan and Dr. Carol Yauk of Carelton University in Canada. The presentations are entitled “Environmental Exposures and the Germline: Investigating Causes of Epigenomic and Genomic Errors”.
On Thursday, Autism Science Foundation, Autism Speaks and the Escher Fund for Autism co-organized the 2nd in the series of environmental epigenetic of autism webinars to the community. Dr. Dana Dolinoy of U. Michigan and Dr. Carol Yauk of Carleton University in Canada provided a summary of recent data that showed how environmental exposures affect not just the offspring, but potentially future generations. In addition, common exposures may cause mutation in the cells that form sperm and eggs of humans, influencing multiple generations. This is done through epigenetics or the turning on or turning off of the DNA. The epigenome has been somewhat the ‘forgotten stepchild’ of human genetics, which is slowly changing. The full webinar will also be posted on asfpodcast.org but in case you don’t have time for the whole 2 hours, this is a 10 minute summary. Finally, hear what we really think about the USPSTF statement on universal screening.
Here is the picture I promised in the podcast!