Our “strangest discovery”

The Director of the National Institute of Mental Health, Tom Insel, comments on relevant research advances periodically, and on Aug 24 he had this to say, “The strangest discovery of the summer may be the report of bone marrow transplants resolving the symptoms of autism…in mice. Paul Patterson and his colleagues at California Institute of Technology created an autism-like syndrome in mice by exposing them to immune challenges during mid-gestation.3 Once grown up, these prenatally exposed mice showed immune changes but also increased anxiety, decreased social behavior, and repetitive behaviors. A bone marrow transplant, which replaces the immune system, corrected both the immune response and the behavior. This finding, which was unexpected, is surprisingly similar to another recent paper reporting disappearance of the symptoms of Rett syndrome in mice following a bone marrow transplant.4 Both studies suggest that abnormalities of the immune system may underlie some of the symptoms of these neurodevelopmental disorders.” I’ll have to ask him about the the use of “strangest” here.

Another fun choice of adjectives: “But for me the most disorienting discovery of the summer came from the score of papers in July and August on the microbiome. In the same way that cognitive psychology has redefined how we think about our minds, the microbiome must now redefine how we think about our bodies. Actually the term “our bodies” is no longer accurate. Only 10 percent of our bodies’ genetic material checks out as human DNA: some 90 percent belongs to the trillions of microbes that live on and inside us. If all the cells in our bodies were to take a vote, human cells lose. The reports from the last month begin to map the biogeography of the human body, revealing that we are really a complex ecosystem with regional variation and completely unexpected individual variation in the microbes that make each of us a super-organism. How does this variation influence brain development? What does this variable ecosystem of our bodies mean for the individual differences in our minds? Will the microbiome help us to understand or treat mental disorders? All questions that we can begin to address in the fall.” I think he will be really disoriented when he sees our new paper, which is in review at the moment. Elaine Hsiao will be presenting these new findings on the role of the gut microbiota in the autism-like behaviors of our mouse model. This will be at the Society for Neuroscience meeting in New Orleans Oct. 13-17.

 

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17 Responses to Our “strangest discovery”

  1. Hi Paul Patterson –

    Not to be crass, but this is interesting to me; why was he so surprised when your group and the Rett paper group went to such pains to do bone marrow transplants in mice? I will admit that I’m not completely up to speed on the nuances of rodent bone marrow transplants; but I’m thinking that it isn’t exactly a simple task. It wasn’t like you randomly started with a list of options, and just happened to land on an immunomodulatory method of bone marrow transplants.

    The level of detail in the Rett paper are also significant; not only did they perform bone marrow transplants, but they also had multiple knockouts or half knockout models, and observed a lack of effect if the brain was not irradiated; suggesting that microglia had to be removed before a (time dependent) rescue effect could be achieved. While I love the idea of little lead mouse head shields to observe different effects, the upshot is that clearly there was some significant effort put in at study design time to arrive at a place where we could determine if immunomodulatory effects could alter behavior in well established autism models.

    I don’t think that your group of the Noel Derecki group was all that surprised at their findings, you must have had some notion that you’d see something.

    I eagerly await your new paper! Keep it up!

    – pD

    • phpatterson says:

      I think folks are still generally not on board yet about the involvement of the immune system in ASD and schiz, or even in behavior in healthy conditions. Thx, PHP

  2. Ditto for pD’s comment.. looking forward to the new paper. (you aren’t going to be mentioning anaerobic bacteria or Sutterella by any chance?)

    • phpatterson says:

      Thx Paul. We are currently going over the GI microbiome data – microbiology is rather complicated than I had imagined – I thought thsi was figured out by now! Cheers, P

  3. What he should have said is that this is the most exciting and productive time in Autism research. I sincerely believe we are close to some real answers that then translate into real medical interventions.

    You and your colleagues are appreciated … ps tell Sarkis he is one smart cookie. I enjoyed the video and hope to hear more researchers having that type of ‘fireside’ chat to explain their work.

    Cheers

    • Inasy says:

      Yes, double kudos for remarkable work. As far as the potential for practical medical interventions; someone please tell me where to sign my son up, even just as a guinea pig. Desperate times/desperate measures.

      • phpatterson says:

        High Inasy, The best source of medically reliable trials is clinicaltrials.gov – you can find all kinds of trials for all types of disorders and you can search by geographical area etc. Best wishes for a good one near you. Cheers, PHP

    • Natasa says:

      I agree about this being the most exciting and productive time in Autism research, but not so optimistic when it comes to translating into real medical interventions. I don’t ‘feel’ the will is there to overturn the genetic-lifelong dogma, not on a large enough scale. Hope I am wrong!

      Btw speaking of placentas have you seen recent paper by Kitajima ‘Differential transmission and postnatal outcomes in triplets with intrauterine cytomegalovirus infection’, showing differential transmission of maternal CMV infection and differential postnatal outcomes in triples (one diagnosed with autism later).

      Looking forward to the new paper!

  4. Hi Paul any thoughts on this paper and how it might link in with your own work ?

    http://www.ncbi.nlm.nih.gov/pubmed/23063420

    • phpatterson says:

      HI asdres – This paper provides evidence of yet another immune abnormality in autism. While there is a great deal of overlap between the dendritic cell numbers in ASD and controls, it is interesting that about 1/4 to 1/3 of the ASD subjects have numbers higher than any of the controls. That subpopulation deserves intensive study. Unfortunately, we did not assay for dendritic cells in our mouse study. Cheers, P

  5. Pingback: A Brief Overview Of Glial Priming, How It (Probably) Applies To (Some Cases Of) Autism, And Worrisome Speculation On A Model Of A Low Penetrant Effect « passionless Droning about autism

  6. Natasa says:

    Hi Paul, wondering if you’ve seen this, on ‘autism risk genes’. It seems to nicely tie in to your research!!

    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0048835

    To quote from the paper: “… The above could be suggestive of a link between in utero infections and brain development in the child. Thus, the genetic background by itself would not be enough via this view to cause a deranged developmental process which would rather only occur in the presence of relevant infections… The loss of copy number in the interferon genes suggests a possible reduced expression of such genes when stimulated. Thus, a viral infection would last longer under such a genetic background. … There would therefore be a longer generation of chemokines and other cytokines that could interfere with normal brain development. Further, gain in copy number in chemokines may lead to higher levels of these chemokines and would thus exacerbate the derangement in brain development. “

    (I have quite a while ago suggested someone looked into CC genes in autism, so this pleases me immensely ;) http://www.autismcalciumchannelopathy.com/Conclusion.html)

    I also believe this could well be linked to the brand new finding of increased HERV expression in autism! It would also be great if someone looked into HERV expression in autism parents, including their potential activation in germline. Exogenous retroviruses love to insert themselves and/or mess up host chemokine receptor genes (and I suspect interferon ones?) – this makes me wonder if RV activity (be it exogenous or endogenous) in germ line could result in CC and interferon CNVs seen in autism. Possible?

    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0048831

  7. Natasa says:

    Also interesting that some of those CC polymorphisms are already implicated as being risk factors for pediatric NeuroAIDS in HIV positive children.

    As pediatric NeuroAIDS symptoms (and many or most of phatophysiology) are identical to idiopatic autism it points to a wealth of information from HIV research that could be very relevant to autism …

  8. Natasa says:

    ‘Genetic influence of CCR5, CCR2, and SDF1 variants on human immunodeficiency virus 1 (HIV-1)-related disease progression and neurological impairment, in children with symptomatic HIV-1 infection’ http://jid.oxfordjournals.org/content/188/10/1461.long

    There is lots of literature on CC polymorphisms and general disease risk, clinical course and therapy response in HIV+. Overview: http://www.ncbi.nlm.nih.gov/pubmed/17504215 , and http://www.ncbi.nlm.nih.gov/pubmed/9833747

    Re neurodevelopment – language and social impairments and behavioural manifestation in HIV positive children (esp HAART-naive!), again there is a wealth of literature with detailed description.

    Both these papers are a must read http://jpepsy.oxfordjournals.org/content/21/3/379.long and http://jpepsy.oxfordjournals.org/content/19/1/27.long as they give detailed description of symptoms and behaviours, which are basically IDENTICAL to symptoms and behaviours used to diagnose idiopathic autism. There is also discussion on influence of ART therapy on severity (and sometimes complete reversal!) of impairments in those children.

    A good review http://informahealthcare.com/doi/pdf/10.1080/01460860802272870
    “ … infants who developed AIDS-defining conditions displayed major impairments in language, gross motor, fine motor, cognitive, and social development, suggesting that the decreasing immune functioning in children with HIV predicts impairments in neurodevelopment …”

    Several case studies on effects on therapy on severity of symptoms impairments in communication and socialisation:

    http://www.ncbi.nlm.nih.gov/pubmed/2246704

    http://pediatrics.aappublications.org/content/101/3/e7.long

    http://www.ncbi.nlm.nih.gov/pubmed/15996999

    http://www.ncbi.nlm.nih.gov/pubmed/9651460

    hth

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