Autism’s Plot

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Erika wants to know about the state of autism research. “How is the field doing in terms of rigorous science?” she asks. “What is the most promising theory about how autism develops?”

The first question’s easy to answer: pretty damn well. In 2008 (the last time a good survey was done), autism research reaped $144 million in tax dollars and $78 million from private funds. That’s a helluva lot of interest in a disorder that is diagnosed in 1 percent of the population. In no small part because of this investment, autism science is constantly making headlines. In just the past month, seven gangbuster autism papers have come out in the likes of Nature, Nature Genetics, Science Translational Medicine and Neuron.

The other question, about smart theories of autism, is one I’ve been trying to sort out for awhile.* No answer is wholly satisfying, but I’ll tell you a bit about recent findings and how I see them fitting into a bigger picture. The short version: autism can begin with one of hundreds, if not thousands, of different glitches during fetal development, all of which eventually result in a similar kind of abnormal wiring in the brain. It’s like roots, separate yet impossibly tangled, which, with water, sun, and time, give way to an awesome, immutable tree.

If I had to choose one thing that’s responsible for the lack of understanding in autism, it’s the fact that none of the trees look the same — to the point where it’s difficult to pin down the essence of tree-ness. My metaphor is failing.

Here’s what I mean. Autism is defined by impaired communication, social problems and repetitive behaviors. Ideally, the diagnosis comes after a highly trained clinician observes a child for several hours and then checks off a sufficient number of little boxes under each of these three categories.

That system means that a boy who bangs his head on walls and does not speak and will never have a job might get put in the same psychiatric bucket as a gadget geek and bestselling author. As I’ve heard countless times from parents of children with autism and the scientists who study them: If you know one kid with autism, you know one kid with autism.

The behavioral diagnosis does imply, though, that there is some entity, called autism, that exists across this befuddlingly diverse group. Which finally brings me to what’s been so exciting about autism science in the past couple of years. With the help of genetic screens, protein analyses, brain scans and mouse models, scientists are finding some biological signatures that crop up in many individuals on the autism spectrum. And many (though not all) of those signatures have similarities that could (could) be used to develop effective treatments.

The all-important synapse

What are the signatures? I’m trying not to write the longest-ever LWON post, so I’ll just mention one famous old idea. It’s called the ‘connectivity theory‘ of autism, and it says that the autism brain has A) long-range connections (think between regions) that are too weak, and B) short-range connections (think within one region) that are too strong. Initially, the theory was supported by a few small studies in which researchers looked at postmortem brain tissue or brain scans of people with autism.

More recently, a growing number of groups have backed up the theory with genetic and molecular studies. They argue that abnormal connectivity across the whole brain stems from improper signaling between individual cells. The signaling is hugely dependent on the molecular make-up of the synapse, the junction between neurons. And the synapse, it turns out, is the star of many of the new papers.

For example, a study published last month found that synapse-related genes tend to be expressed at lower levels in autism brains compared with controls. (Gene expression is a way of measuring when and how DNA gets turned ‘on’ to make RNA and, eventually, proteins.)

In another study, published last week, researchers took a few proteins that are damaged in autism-related syndromes — such as fragile X, tuberous sclerosis and Phelan-McDermid — and investigated hundreds of other proteins that interact with them. They found that dozens of them work together in the dendritic spine, the part of the synapse that receives electrical signals.

To some readers, I suspect, none of this will seem all that exciting. The connectivity theory, like all of the others, has lots of holes. More poignantly, these exciting scientific advancements haven’t led to more than a handful of promising autism treatments. I feel cynical sometimes, too.

The situation is cheerier if you consider that many of the recent breakthroughs in autism came from molecular tools — such as fine-grained genetic screens — that have only been around for a few years. As the technology continues to improve, researchers should be able to describe more and more of autism’s myriad roots, and hopefully, eventually, its tree.

**

Images from Martin LaBar, via Flickr, and Wikimedia Commons

*Full disclosure: Since 2007, I’ve written frequently for SFARI.org, an autism news website supported by the Simons Foundation. The foundation gives large grants to the best and brightest in the autism field, and the investment has paid off in spades: much of the work mentioned above was funded by SFARI.

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14 thoughts on “Autism’s Plot

  1. Thanks for this very useful integration of research findings.
    For anyone who’d like more data on amount of research on autism, I did a comparative survey of (a) number of research papers and (b) amounts of NIH funding, for several neurodevelopmental disorders, including autism. Autism comes out with the lion’s share. You can see the data in my PLOS One paper:
    http://tinyurl.com/2wgbvtq

  2. For many children autism is far more complicated than described above. Many children have severe biological problems which manifest themselves in bowel disease, serious allergies, PANDAS and so on.

    This post also leaves out the importance of environmental factors. This area of research is yielding the most promising information. Hertz-Pinchero, Pessah, Jill James, Adams, Martha Herbert…this work is uncovering immediate causation factors.

  3. Hi Autism Mom,

    Actually, you’re bolstering my point. Some children with autism have GI problems; others don’t. Some have allergies. None of the trees look the same. (The causal link between autism and GI problems is not by any means proven; ditto for allergies.)

    I should have mentioned that those thousands of roots almost certainly include some environmental and developmental factors…we just have little idea (so far) about what those are.

  4. The problem with the ‘connectivity theory’ in autism is that the ‘connectivity theory’ has now been invoked in all the major neurodevelopmental disorders, autism, schizophrenia, ADHD, intellectual disability and so on. The connectivity theory has also been invoked to explain Alzheimer’s and Parkinson’s Disease.

    The connectivity theory might be more logically thought of as being associated with a broad spectrum of neurodevelopmental and neuropsychiatric diseases but is not a diagnosis specific theory.

    The same problem exists in autism environmental research. High prevelance rates, far beyond general population rates, of co-occurring autism has been linked to cerebral palsy, pre mature and low weight babies, rubella virus, prenatal exposure to alcohol, thalidomide, valproate acid, aterial switch surgery, newborn encephalopathy and severe pediatric constipation. However, as is the case with gene findings, the high rates of co-occuring autism, which appears to be about 7-8% in these enviromental studies, is also not a diagnosis specific finding.

    One of the interesting findings in the autism genome studies is that the gene risks for autism are also found in genome studies in schizophrenia, ADHD, intellectual disability, childhood language disorders and so on.

    The most intriguing discovery in genetic studies in autism is that in the single-gene disorders and copy number variations with high rates of co-occurring autism such as Downs Syndrome, Tuberous Sclerosis, Williams Syndrome, Klinefelter Syndrome, Pheland-McDermid Syndrome, Timothy Syndrome, 16P.2 Syndrome and many many others, the mutation is seldom inherited and these mutations are the consequence of a germ-line reproductive error (egg or sperm) or an error early in fetal development.

    Transgenerational inheritance in these conditions canc and does occur and in such conditions as Williams Syndrome, Angelmans Syndrome and Prader-Willis Syndrome, Tuberous Scerosis and 16P.2 syndrome, but the geneticists have not been able to explain why the parents are seldom affected by the mutation.

    Fragile X Syndrome is the only major genetic syndrome with high rates of co-ocurring autism that follows a Mendellian pattern of inheritance but even in Fragile X co-occuring autism is not found in all cases.

    I agree with Sir Michael Rutter that despite advances in many areas of research we are no closer to understanding the causes, preventions or treatments of autism then we were a decade ago.

  5. Virginia;
    A final thought on the connectivity theory as far as autism is concerned. There are a number of groups that are studying the named genetic syndromes with high rates of co-occurring autism including Rett Syndrome, Tuberous Sclerosis, Phelan-McDermid syndrome and Fragile X Syndrome. These groups have formed alliances with the drug manufacturers and have genetically enginereed mice by knocking out the gene associated with the named genetic syndrome.

    In the case of Rett Syndrome, they have created mice with mutations in the MECP2 gene associated with Rett Syndrome. They have introduced a novel drug therapy that appears to reverse some of the physical symptoms observed in Rett Syndrome such as ‘hand-washing’, gait ataxia and breathing problems.

    http://ghr.nlm.nih.gov/condition/rett-syndrome

    The claim is that aberrant synaptic connections are at the root of Rett Syndrome and the the MECP2 is abnormally expressed in the brain and introducing drug therapy that normalizes MECP2 expression in the brain may repair the aberrant synaptic connections, reverse the symptoms and ‘cure’ Retts Syndrome. The discovery of drug therapies that may reverse some of the physical symptoms is a remarkeable achievment in itself, but these researchers have gone way beyond their initial research and are now claiming the aberrant synaptic connections between healthy neurons (connectivity theory)are at the root of all neurological disease including Rett Syndrome, idiopathic autism, schizophrenia, bi-polar disorder and Parkinson’s disease.

    http://www.nytimes.com/2007/02/20/health/20rett.html?adxnnl=1&adxnnlx=1308654507-l83Gew68rXL8Ck+DJzzPwA

    They are now claiming that if you can cure Rett Syndrome it may be applicable to all neurological disease which they claim are caused by aberrant synaptic connections and miscommunication between normal neurons.

    http://www.youtube.com/watch?v=RyAvKGmAElQ

    In order to claim that the autistic brain is relatively intact and that aberrant synaptic connections (connectivity theory) are the only neuroanatomical variations in the autistic brain they have to ignore or dismiss decades of neuroanatomical research.

    http://brain.oxfordjournals.org/content/127/12/2572.long

    It is not only miscommunications between intact neurons in the autistic brain, the neurons themselves are damaged and these structurally damaged neurons have been found thoughout the autistic brain.

    Think about the astonishing claims made by the Rett Syndrome researchers they claim that they are on the cusp of developing a magic bullet that may cure all neurological diseases in humans.

    A great deal of scepticism is in order for these astonishing claims.

    None of these groups are using control mice. In the case of Retts Syndrome what are the consequences of a drug therapy that ‘normalizes’ MECP2 brain expression when applied to a mouse, or human, that does not have an MECP2 mutation and currently has normal MECP2 brain expression? What are the consequences of disrupting normal MECP2 brain expression?

  6. Nice analysis. I like your tree metaphor and I quote again your excellent short version: “autism can begin with one of hundreds, if not thousands, of different glitches during fetal development, all of which eventually result in a similar kind of abnormal wiring in the brain. It’s like roots, separate yet impossibly tangled, which, with water, sun, and time, give way to an awesome, immutable tree.”

    Just one crucial correction: the tree is very mutable too.
    I am a little disappointed you stay in the roots when you try and go for a big answer rather than looking at the awesome tree. I am trying to talk about the mind as the clue to the brain rather than the other way round – but I would say that, wouldn’t I?

    I tried to make this argument in my SFARI piece https://sfari.org/news-and-opinion/viewpoint/2011/uta-frith-why-i-am-obsessed-with-this-cognitive-thing
    Clearly I am missing something in not getting my message across.

  7. Hi Uta,

    Thanks so much for reading and thinking about this. The reason I call the tree immutable is because autism doesn’t go away…people may learn to compensate (especially after many years or decades), but it’s a lifetime condition.

    As for my emphasis on the roots…I agree that the tree is probably more important, but I think all of the excitement in the field over the past couple of years has been related to genetic and molecular studies. (For better and for worse…) The roots are certainly where drug developers begin.

  8. Is it possible that there is no *single* disease called autism and the fact that we have a single diagnostic category in the DSM fools us into thinking that it corresponds to something that is actually out there in the world? Is it possible that abnormal connectivity, high intraindividual variability, and sensory processing problems are not disorder-specific because we’re carving up the diagnostic map in the wrong way? Maybe we should not only split up “autism” more finely, but look for commonalities *across* developmental disorders?

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