Saturday, July 21, 2012

Read Between The Lines

A very interesting study was just released that showed that disruptions of the immune system can lead to the behaviors of autism, at least in mice.  There are quite a few write ups of the actual results, such as herehere, here, or here, so I won't try to add anything to these already good reviews.

Instead I want to go for gross oversimplification of the findings because the pattern it suggests is, in my humble opinion, a good guide to what autism actually is for many people.  Ready?

1. Mother's immune system is given a swift kick.
2. Child's immune system is thrown out of balance.
3. Child develops behaviors of autism later in life.

and, most importantly -

4. Correcting the child's immune system reduces the autistic behaviors.

Of course this is all in mice and doesn't automatically translate into humans.  But given all of the evidence of immune disruptions in autism I strongly suspect that we will see some effective evidence based therapies for autism that target these disruptions within the next ten years.

You can call this pattern anything you want but the key elements are that something is biologically out of balance in people with autism and that correcting the imbalance can lead to "recovery" from autism.

Read that last sentence again because I feel that it is the key to putting together all of the things we know about autism. Instead of the current idea that autism is a fundamental part of who a person is (i.e. it is written into their genetic code), this model suggests that autism is a state that a person's body is in. There is still room for genetic mutations in this model but these mutations are important insofar as they make it easier for a person to get into a disrupted state.

I could write pages and pages about how this model fits into what we know about autism but since I don't have that much time nor I am not under the delusion that anyone would actually want to read that, I will just quickly hit the highlights.

1. The "genetic" model of autism is a bust.  There is no single mutation or group of mutations that occur in any sizable part of the autism population.  The mutations that have been found can be significant for the people who have them but I think they are really just background noise in the larger discussion of what causes autism.

2. The number of people with autism is increasing rapidly.  There are a number of reasons for this increase but it isn't really possible to deny that there has a real and substantial increase in the number of people who have autism.

3. There are many, many, many biological disruptions that are seen in substantial subsets of people with autism.  I always have to laugh when people dismiss these disruptions as unimportant (or "co-morbid") because they only appear in like 30% of people with autism and then turn around and trumpet the latest genetic finding as significant when it appears in maybe 1% of people with autism.

4. There is substantial evidence from other related conditions, such as Retts, Fragile X, SLOS, Wilsons disease, and the group of conditions called inborn errors of creatine metabolism (just to name a few), that correcting the biology corrects the condition even when there are genetic mutations present.

All of these ideas fit nicely into the model of autism as a biological disruption.

You don't have to have some genetic mutation that is "causing" autism, all you need something strong enough to push a person out of equilibrium.  And something that is strong enough to do that could likely cause the random but almost unique mutations that are seen in autism.

The number of people with a specific genetic disorder isn't likely to change rapidly but biologically induced disorders certainly can and do.  If you want a model of that consider Pink's disease.  It came, it rapidly rose, and then, once the cause was found, it disappeared just as quickly as it appeared.

The same can be true for the autism epidemic if get our collective heads out of our asses and stop thinking of autism as some permanent thing and instead consider it as an imbalance that can and should be corrected.

(Before anyone decides to leave a less than polite comment suggesting that I am calling people with autism defective, calling them less than typical people, or wants to suggest that I don't like my children, don't waste your time.  I am not saying, implying, or suggesting anything of the sort.  If you want to interpret my words to mean that then you are certainly entitled to your opinion, but I will ask you to take your stupidity elsewhere.  Serious comments - even if you want to tell me I am completely wrong - are always welcome. )

22 comments:

  1. Today's guest post by Jenny McCarthy!

    ReplyDelete
    Replies
    1. What an intelligent response - so witty, yet lacking real substance. So, anonymous, do you have any actual thoughts to add or are you just here to heckle?

      Delete
    2. Science isn't done by reading between the lines. You're indulging in the worst kind of speculation. You're politically smart enough to know that you shouldn't identify with Jenny McCarthy even where you agree with her, but a loon is a loon.

      Delete
    3. Science is done by coming up with a hypothesis and then testing that hypothesis through some sort of experiment. The initial hypothesis is very much speculation until it is proven.

      But I am not a scientist nor do I have a massive budget for doing experiments. I can only draw conclusions from what I read and what I can infer from that. So yes, most things that you read like this are going to be at least partially speculation.

      Then again, this really isn't just idle speculation on my part either. I have three children with autism that have documented disruptions in their immune systems. We have roughly four or five years worth of tests on each on them (1-2 tests per year) that show a constant pattern of disruption.

      As for agreeing with Jenny McCarty, I'm not sure where you think I am agreeing with her. I think her main riff is vaccines and yeast and I didn't get into that at all. Maybe she says something similar to the above but I wouldn't know because I don't pay that much attention to what she says.

      Delete
    4. Okay, we can lower our standards to blog discussion. Your first two points are wrong. The genetics of autism aren't 'noise', as we can trivially see by looking at families with autistic lines. And we don't know if the prevalence is rising. The numbers are going up but there are lots of possible reasons for that. No one doing actual science on autism will say that it's increasing, because we simply don't know. So the problem with you speculation is its axioms are wrong.

      Delete
    5. "Okay, we can lower our standards to blog discussion"

      Well, this is a blog.

      "The genetics of autism aren't 'noise', as we can trivially see by looking at families with autistic lines."

      A few points here.

      First, try and find a family where a child, parent, and grandparent all have a diagnosis of autistic disorder. There are plenty of families that have multiple children and there are plenty of families where a parent or other family members have self-identified as having autistic traits and/or are so high function as to make a diagnosis silly. But there are extremely few families were multiple generations have full autistic disorder.

      Second, assuming there are such families, there are other methods of inheritance that aren't "genetic" such as epigenetic inheritance.

      Third, my identical twin daughters have different mutations, some of width have been included in published research (although not called out as a cause). By definition, these mutations cannot have been inherited because then they would both have the same mutation.

      Fourth, many of the mutations that have been linked to autism are de novo which means that they weren't inherited either. If they weren't inherited then some external factor caused them.

      "And we don't know if the prevalence is rising. The numbers are going up but there are lots of possible reasons for that."

      If you don't find recent data such as what the CDC
      has published to be convincing then I don't know what to tell you.

      If you take the same measurement in the same way over a large span of years and get a higher number each time (as the CDC has done) that strongly suggests that the number is actually increasing.

      Or how about the recent result where one of the CDC's ADDM sites took another look at an earlier birth year (1992) and found the same prevalence in the group as they did the first time? Even though later birth years had a much higher prevalence? That suggests that prevalence is stable by birth year which would not be the case if the primary factors were social.

      There is a limit to what social factors such as awareness can do - at some point the numbers should be slowing down and yet they show no sign of doing so.

      Delete
    6. It's hard to find generations all diagnosed because diagnosis has only recently become routine, however the personal reports of autistics regarding their families are numerous and convincing.

      "If you don't find recent data such as what the CDC
      has published to be convincing then I don't know what to tell you."

      It's not me, it's every scientist I'm aware of who studies autism. Nobody knows for sure whether the rate is increasing.

      Delete
    7. "however the personal reports of autistics regarding their families are numerous and convincing."

      You complain about me not sticking to scientific levels of evidence and then you cite anecdotal stories based on extremely spotty historical records as evidence? That is like speculation squared.

      If you find people talking about family members possible showing traits of autism to be convincing then you must also believe the stories of parents who say their child regressed after getting a shot.

      That is at least someone talking about their own experience rather than a person with a social communication disorder speculating about a social communication disorder that someone else has.

      "It's not me, it's every scientist I'm aware of who studies autism. Nobody knows for sure whether the rate is increasing."

      The world was flat right up until the moment it wasn't. Up until last year many scientists would have told you identical twins both almost always have autism even that there were more than enough hints in the literature that that wasn't the case.

      There is more than enough evidence and hints in the literature that the real prevalence of autism is increasing, you just have to be willing to dismiss the party line and consider the data with an open mind.

      Delete
    8. Family members calmly noticing that other family members are on the spectrum are far more reliable than parents freaking out over vaccinations. Parents freak out, they're unreliable.

      I'm not aware of a party line among scientists. If you think about it and follow the money, some people would have a reason to promote the idea that autism is increasing (look at Autism Speaks' hysterical adverts and pleas for donations), but I can't imagine a reason to promote the idea that autism may not be increasing.

      Delete
    9. So your position is that parents are just freaking out but other, non parental, family members can have reliable observations? What happens when a person is both a parent and observing another family member?

      Can I, who am a parent, reliably make observations about other family members who are not my children or am I unreliable because I have children?

      Do you hear the sound of logic sobbing quietly in the corner?

      "I can't imagine a reason to promote the idea that autism may not be increasing"

      Well, here is a reason for you.

      If the party line was that autism was increasing there would be huge public outcry (at least in the US) about finding out what the problem is. And since vaccines are very much tied to autism in the public mind I can almost guarantee that if a public health official announced that autism was really increasing that vaccine usage would plummet.

      Delete
    10. I think you understood my point about parents and you're being facetious, unless you think parents freaking out over vaccinations are being rational.

      What party line do you think Jon Brock and Dorothy Bishop are following?

      Delete
  2. M.J....Pink's disease was a selective disease. It chose only 1 out of 2,000 children who used mercury teething powders. One thousand, nine hundred and ninety nine kids showed no reaction to the teething powders...yet still they have been taken off the shelves for over 50 years. That is a causality in .05% if kids, hardly enough to bother over. Yet, we did.

    ReplyDelete
    Replies
    1. And if you brought back those same teething powders Pink's disease would likely reappear. The condition can be selective and induced at the same time.

      Although I don't think anyone ever got to the bottom of why certain kids would get it while others would not. The literature I have read seemed to suggest that there something other than dose involved.

      Delete
    2. I think I read 1 in 500 babies who used that teething powder got Pink's disease.

      Delete
    3. We also don't know how many children were mildly affected by the teething powder without being ill enough to be diagnosed. There could have been a lot of sub-clinical effects. For example, if one effect were reduced immune system function, there could have been increased infectious illness in toddlers that never would have been connected with teething powders. To assume that all of the consequences of a toxic exposure were spotted at the time is a form of unrealistic optimism.

      Delete
  3. I think this is an exciting study and the doors it can open into research. I most sincerely hope that there will be some "effective evidence based therapies...that target these disruptions in the next ten years." Genetics is the wrong path to be pursuing, and this research is definitely heading in the right direction. Thanks for the research and work you do.
    Here is a link you may find interesting.
    http://www.thenewstribune.com//2012/07/22/2222908/tiny-bubbles-big-possibilities.html?storylink=fb

    ReplyDelete
  4. Hehe.

    Child's immune system is thrown out of balance.

    Indeed, it would seem to be an example of developmental programming of the immune system. Not just that, but the immune system was thrown out of balance in a particular direction, a state predisposed towards increased inflammation. This is entirely consistent with your last posting and the papers that I posted in a response. This is a big deal and is going to be a profoundly difficult problem for the Internet-At-Large who continue to insist that studying thimerosal or studying the MMR can inform us about the entire vaccine schedule.

    But given all of the evidence of immune disruptions in autism I strongly suspect that we will see some effective evidence based therapies for autism that target these disruptions within the next ten years.

    Why wait ten years though?

    Intravenous immunoglobulin treatment of children with autism

    Since autism has been associated with immunologic abnormalities suggesting an autoimmune cause of autistic symptoms in a subset of patients, this study was undertaken to investigate whether intravenous immunoglobulin (i.v.Ig) would improve autistic symptoms. Ten autistic children with immunologic abnormalities, demonstrated on blood tests, were enrolled in this study. Their ages ranged from 4 to 17 years, with two girls and eight boys. Eight children (1 female and 7 male) historically had undergone autistic regression. Intravenous immunoglobulin, 200 to 400 mg/kg, was administered every 6 weeks for an intended treatment program of four infusions. In five children, there was no detectable change in behavior during the treatment program. In four children, there was a mild improvement noted in attention span and hyperactivity. In none of these children did the parents feel that the improvement was sufficient to warrant further continuation of the infusions beyond the termination of the program. Only in one child was there a very significant improvement, with almost total amelioration of autistic symptoms over the time period of the four infusions. Once the treatment program was completed, this child gradually deteriorated over a 5-month time period and fully reverted to his previous autistic state. In this treatment program, five children had no response to intravenous immunoglobulin. In the four children who showed mild improvements, those improvements may simply have been due to nonspecific effects of physician intervention and parental expectation (ie, placebo effect). However, in one child there was a very significant amelioration of autistic symptoms.

    Go figure! The potential underlying mechanism of action, reduction in inflammation / re-programming of the immune system is very similar to what was described by Patternson in the bone marrow transplant study from a functional standpoint. Bone marrow transplants are more persistent (and a ton more of a hassle / intrusive than the already a big hassle / intrusive IVIG).

    You don't have to have some genetic mutation that is "causing" autism, all you need something strong enough to push a person out of equilibrium.

    Yes!

    While this was a neat study, I'm a bit more skeptical on the idea that immune mediated treatments will be able to cure autism; in some patients, maybe, and in others, I think they'll help somewhat. But I think there are some patterns in brain development that can't be undone; our brains undergo some once in a lifetime changes during early development that can be affected by peturbations in the immune system, and they can't be undone by treating the immune system later on. How much these differences are pathological in autism is an open question, but the answer to that question will help determine what level of help our children might see from a targeted treatment in the future.

    Nice write up.

    - pD

    (4096 char max == stinky)

    ReplyDelete
    Replies
    1. Hi pD,

      I saw the list of links on the last post and I did spend some time looking through them, so thanks (I guess I forgot to respond).

      "But I think there are some patterns in brain development that can't be undone; our brains undergo some once in a lifetime changes during early development that can be affected by peturbations in the immune system, and they can't be undone by treating the immune system later on."

      I agree with most of what you are saying but this part I don't know about. There are quite a few conditions that were once thought to be permanent that have been proven not to be so. To use my favorite examples of Rett's and fragile x, both conditions were thought to be permanent but recent results are showing that isn't the case.

      The brain is a marvelous machine and I don't think we entirely understand how it works and how it can adapt. The simple fact that it can still function rather well in the face of adverse conditions is a testament to how adaptable it can be.

      Maybe it is wishful thinking on my part, but I really want to believe if you can remove the imbalance the brain will, over time, revert to what it should be.

      Delete
  5. From María Luján
    Now, I wonder
    What are the aspects of the brain that may be recovered "associated to plasticity" and what are the aspects of the brain that may be not recovered" and therefore changed if insults at key developmental windows took place?
    I do think that this is the most unknown of this situation; now if there was a substantial insult associated to inflammation, oxidative stress, microglial activation and other systemic issues the trajectory that was being done was changed in such as way that the same trajectory can not be re-assumed. But are there pathways to "recover" in such a ways that compensation effects can be operational?

    ReplyDelete
  6. From María Luján
    Recent manuscript
    Hum Mol Genet. 2012 Jul 26.Individual common variants exert weak effects on risk for Autism Spectrum Disorders...Anney R. et al
    we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). ..
    Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele-score results, it is reasonable to conclude that common variants affect ASD risk but their individual effects are modest.
    Now, what is then the meaning of findings that may explain near 1 % ?...

    ReplyDelete
  7. I'm new to this site....also anonymous but you all can call me Bern. Since Autistic/Aspergers people do very well on a gluetin-free diet then doesn't it make sense that an abundance of gluetin in an Autistic/Aspergers patient would have other ill affects. I'm referring to the presence of an over abundance of it causing clot formation. Hence, making any heart transplant very dangerous to say the least. Reducing the gluetin in these people's diet does wonders and diminishes at least 75% of Autism/Aspergers affects.

    ReplyDelete
  8. Why do doctors say that people with autism should be institutionalized? Is it because of the fact that their odd thinking, behavior, and obsessions can eventually do them in if they are not monitored? Bern

    ReplyDelete