passionless Droning about autism

Archive for the ‘Gross Over Simplification’ Category

Hello friends –

There used to be a poker room about twenty miles from my home; it sat above a run down greyhound racing track and smelled like an old shoe on the best day.  But they had poker.   They hosted an accumulating jackpot hand, usually worth a couple of thousand dollars, sometimes quite a lot more, which you could win if you got a royal flush in the current suit; i.e., if the suit was hearts, and you wound up with 10-J-Q-K-A hearts, you’d win the Jackpot.  This could lead to some unusual cost/reward analysis scenarios.

Let’s say you sit down to play and buy in for a hundred dollars.  Then, three hands later, you look at your two hole cards and you have 10-J hearts.  Not really a great hand, but if the board winds up showing Q-K-A hearts somewhere in the next five cards, you win fifteen thousand dollars (or whatever the Jackpot had accumulated to).   Almost everyone folds, but before you get a chance to see the next three cards for the two measly dollars you put up as a blind, an aggressive, serial over-better to your right raises to fifteen dollars.  You are in a tough spot, you know the guy bets like crazy anytime he thinks he can steal a pot, but you still are losing to anyone with a queen.   If you had 10-J spades, or clubs, or mixed, or (nearly) whatever else, this is easy; you dump your shitty cards.  But with your two royal heart cards, you *could* win the jackpot; your odds still totally suck, even if you were getting paid off a thousand to one you still didn’t have the ‘right’ odds to make the call, but if you inhabit a place where losing fifteen dollars won’t kill you, but winning fifteen thousand would definitely be a game changer, the magnitude of the potential winnings must be part of your decision making process.

I called the raise a few times, but never hit the jackpot.  Or even came close.

I keep coming back to the idea of incorporating the scale of potential outcomes when I think about the non event of the hilarious prevalence numbers that came out a while, one in fifty with ‘autism’.  Nobody outside of Journey Autism fucking cared and the responses were depressingly predictable; the media and the Internet skeptics went ‘full awareness’, and found nothing of any alarm in these numbers, the Internet vaccine crazies went ‘full autism’, and assumed the numbers were solely comprised of individuals who would need 24×7 assistance for forever.  It was all a big joke.  Haha.

I don’t know how large the real increase in autism is (the older parental age data tells us unambiguously that some of the increase is non-imaginary), but I do know that as our best efforts at figuring this thing out has left us skipping from one in two hundred and fifty, to one in a fifty in eight short years.  To my eye, this means a real increase of fifty percent (or more!) could easily be hiding in the static and we’d never know.  Most everyone doesn’t seem to care, that is the way of the Prevalence Hookup, quickly embracing whatever prevalence numbers come out, coupling until a set of newer, bigger, even more ‘greater awareness’ numbers come along.

But my thoughts continue to be formed by concept of a sort of missed jackpot opportunity when I see a sense of complacency about our ever growing autism population; it isn’t that I don’t believe that diagnostic changes and the watering down of what a diagnosis means in terms of life skills aren’t affecting rates, those factors are clearly at play, but the ramifications of just “some” of the increase being real seems like a big, big, big deal to me.  When your population of interest is every child, a small real increase means a lot of individual children are affected.  Sure, it is, possible that older parental age is the only recent development that is affecting rates upward, with all of the rest being diagnostics, but I find little comfort in this notion.  If the soft social scientists are wrong, even a little, and there is a true increase in incidence, we may come to regret the solace provided by our collective bobbleheading at the mantra of ‘greater awareness’, for it enabled us to waste a great amount of precious time.

The thing is, it doesn’t really cost us that fucking much to apply more resources to the unimportant, nagging question on the neurodevelopment of a generation of infants.  In 2006, Bush signed the ‘Combating Autism Act’, a bill included a billion of dollars for ‘research, surveillance, and treatment’.  That’s two hundred million a year.  Last year, The Avengers, a stupid and shitty movie, made over a billion dollars.  Now, I know there are other funding sources for research, surveillance, and treatment, but there were also a lot of other stupid movies.

I believe that this prioritization is the equivalent of folding 10-J hearts to a dinky four dollar raise; the knowledge we could gain from a relatively small outlay is worth a lot.  We shouldn’t be worrying about the cost, we should be considering the payoff; the question we are trying to understand, “are today’s infants neurobiologically different than infants of the last generation?” has a difficult to understate payoff. We shouldn’t be embracing reasons to stop playing, we should chomping at the bit to see the next three cards.  This is an easy call.

And yet, there was a collective yawn when the CDC announced 2%.

Funny enough, it was just a few years ago that the UK NHS study of adults found a prevalence of 1%, a finding which was heralded as remarkably strong evidence that autism rates are stable (at the time, 1% was the general value for US children.  Oh well.).  For some reason, the robustness of the NHS adult findings didn’t cause anyone to exclaim that there is a sort of epidemic-lite, what with US kids having autism as twice the rate as NHS adults.  It was a classic case of doublethink; US kids have autism at 2%, England adults have autism at 1%, and autism rates are stable.  (Believing that any of the numbers have validity might be closer to triplethink!)

A while ago I saw an interview with Fombonne on the SFARI site that contained the unsurprising byline: ‘Eric Fombonne says that the new CDC report does not necessarily mean that prevalence is increasing’.   [Note: This was BEFORE the 2% numbers were reported!]  Anyway, he made some interesting points about the messiness of the autism data showing how silly the state by state numbers are; Utah has four times the cases that Alabama does, and utilized different diagnostic methods.  In the text of the interview, he reveals Utah also had very low levels of MR (~ 13% instead of ~ 28%), AND had a creepy low male to female ratio.  Either there is something really weird going on in Utah, or the ‘numbers’ from Utah and Alabama are not measuring the same thing.  It could also be that the numbers are measuring some of the same thing, and there are a couple of weird things going on in Utah (heh).  But the bigger point should be that we shouldn’t expect to get a decent understanding of autism rates at a national level by clumping together Alabama numbers, Utah numbers, and whatever other numbers, shaking up them up, and averaging them out.  Maybe the headline ought to read, ‘Pretty much somewhere between half a percent, and two percent of children might have something a psychologist, or a doctor, or both, have something called autism, the manifestations and lifelong impact of which vary considerably individually and regionally’, or maybe ‘Autism Rates: Your guess is as good as ours!’.

I don’t trust any set of numbers more than an educated stab in the dark.

[Note: for a slightly different take on ADDM numbers, you can see this interview on SFARI, where Walter Zahorodny reports that detailed analysis of NJ data indicates a likely real increase in rates.  Doh!]

I began to wonder; if almost nobody really seems worried about an ‘epidemic lite’, if no almost no one is alarmed that the confidence intervals in our data could incorporate huge numbers of actual people, why am I so concerned?  Is my version of the precautionary principle overly cautious?  I don’t know the answer to these questions, but I think that part of the answer lies within my journey autism, watching my son’s challenges (and triumphs) unfold, and the knowledge that whatever we find about autism incidence, he will be reliant on other people for his survival for his entire life.  That is the gift autism has given him; it doesn’t mean he can’t be happy, it doesn’t mean he can’t experience love, but so far, we cannot detect that autism has provided him anything other than near debilitating OCD, an imperfect sense of dangerous situations, and a lifelong requirement of the kindness and capabilities of others.

I am filled with a pervasive and soul crushing sadness at the possibility of one ‘extra’ child having the same challenges because of changes we have collectively made to the environment, and that is the heart of the semantic dance over how much of the increase is real.  That is the Jackpot.

But, your mileage may vary.  I know that there are some parents and people out there who have challenges as heavy as my son’s, and they don’t share my sense of panic over the issue.  A lot of people credit their autism with benefits.  I won’t discount their experiences.  Part of the reason we don’t see eye to eye may be that we look at the same question, but see different risks, and different payoffs.

– pD

Hello friends –

My son was a ‘gut kid’.  The irony is, for a while, because we were first time parents, we didn’t even know.  My son was flagged for evaluation for autism around a year of age and we met with the autism center people several times between his first and third birthdays, with his official diagnosis coming just after he turned three.  My wife came home from one of the early meetings convinced that his evaluators didn’t know the first thing about our son, autism, or anything else, and that in fact, they might be insane.

 ‘Do you know what those idiots asked me today?’


‘What his shits look like.  My kid can’t talk and they want to ask me about his diapers!’

‘Who fucking cares?

We wound up caring, a lot.  It turns out, this wasn’t a stupid question, it just seemed like one to us.   The answer to their question was that our son was having at least four or six very messy diapers a day, his stools were never firm logs that look like they came from an spherical filter, but always, always more liquid than solid, and frequently contained chunks of identifiable food.  But from our viewpoint, within the context of a child who was not speaking,  hurting himself, and never looked at anyone, the idea that we should be worrying about his shit was the stupidest thing we’d ever heard. 

But.  When we started paying attention, starting reading, and started meeting more people with children with autism, our incredulity waned.  We  tried GF/CF and probiotics.  We paid for lab tests to analyze the bacterial populations in his intestines. We experienced a life saving miracle with anti-fungal agents wherein my son essentially stopped hurting himself over the course of weeks after persistently banging his head dozens of times a day for six months.  For nearly a year we removed all complex carbohydrates from our son’s diet, an intervention that makes GFCF feel like a Sunday afternoon after college but before kids and autism.  We saw changes in our son based on how his GI tract was performing.  For our son, for us, we knew that by some mechanism, what got put in his mouth, and what happened along the way was tightly coupled with how our son felt and behaved.

This is why my vision with spots of rage when I see the ideas of GI and dietary involvement with autism mocked by pseudo-skeptics so rampantly on the Internet.  I cannot stand the thought of a single child continuing to suffer the way I watched my son suffer because they were told that there was no basis of GI interaction in autism.  That thought hurts.

Those biases stated, we are now, finally, starting to see research indicating that in some cases of autism, there are very real, non imaginary differences in GI function.

A few months ago, Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances was published [full, dense, but very cool paper available online].  Here is the abstract.

Gastrointestinal disturbances are commonly reported in children with autism, complicate clinical management, and may contribute to behavioral impairment. Reports of deficiencies in disaccharidase enzymatic activity and of beneficial responses to probiotic and dietary therapies led us to survey gene expression and the mucoepithelial microbiota in intestinal biopsies from children with autism and gastrointestinal disease and children with gastrointestinal disease alone. Ileal transcripts encoding disaccharidases and hexose transporters were deficient in children with autism, indicating impairment of the primary pathway for carbohydrate digestion and transport in enterocytes. Deficient expression of these enzymes and transporters was associated with expression of the intestinal transcription factor, CDX2. Metagenomic analysis of intestinal bacteria revealed compositional dysbiosis manifest as decreases in Bacteroidetes, increases in the ratio of Firmicutes to Bacteroidetes, and increases in Betaproteobacteria. Expression levels of disaccharidases and transporters were associated with the abundance of affected bacterial phylotypes. These results indicate a relationship between human intestinal gene expression and bacterial community structure and may provide insights into the pathophysiology of gastrointestinal disturbances in children with autism.

I’ll admit it.  From the outside, from the don’t-have-a-kid-with-autism-and-GI-problems perspective, that is some dense and seemingly bland stuff.  Essentially children with GI distress and children with GI distress and autism were compared and it was found that there were distinctly qualitative differences regarding the GI function in the groups.  This is validation of what a lot of us have been saying for a long time, that the GI problems our kids were experiencing weren’t coincidental to the autism, but somehow related.

For anyone who has been paying attention to the details of the autism-gut debate, these are dynamite findings.  These observations are the death knell for the overused, oversimplified notion that the GI connection to autism was a function of some kids having autism, some kids having GI distress, and that therefore, some kids with autism also have GI distress.  This research tells us that the reality is not so simple.

This study is the view from the microscope as opposed to the telescope, and took care not to study just anyone with an autism diagnosis, but those with an autism diagnosis and GI distress, problems so severe that invasive procedures to obtain tissue samples from the GI tract was warranted.   This is a critically important facet of the study design in my opinion, a lot of the negative findings in this arena have been epidemiological, and cast the widest possible net, capturing everyone with autism and comparing them with a sample of everyone else.  This is a great strength of the paper; for too long everyone has acknowledged the heterogeneous nature of autism, but few studies have tried to understand differences at a phenotype level.  This paper is different.

As evidence of the non-random population, the autism patient group had a regression incidence of over eighty percent, and nearly as many of the children in both groups were reported to have food allergies.

The details of the findings in the paper get deep pretty fast, but at a high level there were differences found in proteins involved with the digestion of carbohydrates and changes in bacterial populations between the groups, with some differences found with regard to specific locations in the intestine.  Based on these findings, the authors speculate that alterations in carbohydrate processing could result in abnormal bacterial populations by way of altered microbial food availability in parts of the gut.

Based on these findings, we propose a model whereby deficiencies in disaccharidases and hexose transporters alter the milieu of carbohydrates in the distal small intestine (ileum) and proximal large intestine (cecum), resulting in the supply of additional growth substrates for bacteria. These changes manifest in significant and specific compositional changes in the microbiota of AUT-GI children (see Figure 7A–C).

The authors discuss a potential feedback loop of effects of intestinal microbes and nutritional processing, and of the known and potential effects of altered bacterial populations.

Additionally, intestinal microbes can influence the expression of disaccharidases and transporters [59] through the influence of pathogen-associated molecular patterns (PAMPs) and butyrate (a byproduct of bacterial fermentation) on CDX2 expression and activity [60], [61], [62], [63]. In this regard, the observation that CDX2 was decreased in AUT-GI children with increased levels of Betaproteobacteria may be important.

Whatever the underlying mechanisms, reduced capacity for digestion and transport of carbohydrates can have profound effects. Within the intestine, malabsorbed carbohydrates can lead to osmotic diarrhea [64]; non-absorbed sugars may also serve as substrates for intestinal microflora that produce fatty acids and gases (methane, hydrogen, and carbon dioxide), promoting additional GI symptoms such as bloating and flatulence [65].

This is very similar to the underlying theory of the Specific Carbohydrate Diet, impaired carbohydrate digestion promotes bacterial imbalances in the intestine by altered food availability, leading to gastrointestinal distress.

Because of the varied nature of the protein imbalances found and absence of the common alleles associated with such conditions, the authors report that it is unlikely that the underlying cause of the imbalances is genetically based.

In our study, 93.3% of AUT-GI children had decreased mRNA levels for at least one of the three disaccharidases (SI, MGAM, or LCT). In addition, we found decreased levels of mRNA for two important hexose transporters, SGLT1 and GLUT2. Congenital defects in these enzymes and transporters are extremely rare [40], [41], and even the common variant for adult-type hypolactasia was not responsible for reduced LCT expression in AUT-GI children in this cohort. Therefore, it is unlikely that the combined deficiency of disaccharidases (maldigestion) and transporters (malabsorption) are indicative of a primary malabsorption resulting from multiple congenital or acquired defects in each of these genes.

There are a couple of ideas presented on what might be causing the altered disaccharide transporter levels, with food composition intake, immune or hormonal irregularities, and bacterial populations and their associated fermentation byproducts listed as possible candidates.  This study did not attempt to determine if any of these things were actually responsible, but an upcoming paper will also detail qualitative differences in expression of genes involved with inflammation in the autism group.

Regarding bacterial populations found, there were several differences identified by bacterial classification and location as well as some associations with onset of autistic behaviors and GI distress.

Pyrosequencing analysis of mucoepithelial bacteria revealed significant multicomponent dysbiosis in AUT-GI children, including decreased levels of Bacteroidetes, an increase in the Firmicute/Bacteroidete ratio, increased cumulative levels of Firmicutes and Proteobacteria, and increased levels of bacteria in the class Betaproteobacteria.

Stratification of AUT-GI children based on the timing of GI symptom development relative to autism onset revealed that the levels of Clostridiales and cumulative levels of Lachnospiraceae and Ruminococcaceae were significantly higher in AUT-GI children for whom GI symptoms developed before or at the same time as the onset of autism symptoms compared to AUT-GI children for whom GI symptoms developed after the onset of autism and compared to Control-GI children. However, we cannot discern whether changes in Clostridiales occurred before the onset of autism in this subgroup. We can only conclude that increased levels of Clostridiales members in biopsies taken after the development of both GI symptoms and autism are associated with the timing of GI onset relative to autism onset in this cohort. Although the reason for this association remains unclear, this finding may suggest that the timing of GI onset relative to autism is an important variable to consider in the design of future prospective studies investigating the microbiota of children with autism.

I am in love with the appreciation of the subtlety on display at the end, it may not be sufficient to simply categorize by GI and non GI autism, but also by the temporal relationship to onset of behavioral symptoms.  It makes for a messy outlook going forward, but one based on pragmatism as far as coming to valid conclusions.

As is appropriate, the authors end with an admission that we are still largely groping in the dusk about how the microbiome interacts with our tightly coupled systems, but give a variety of reasons to believe that what we do know makes system wide effects reasonable and a relationship with autism plausible.

Metabolic interactions between intestinal microflora and their hosts are only beginning to be understood. Nonetheless, there is already abundant evidence that microflora can have system-wide effects [76], [77], [78], [79], [80], [81], [82], [83] and influence immune responses, brain development and behavior [24], [25], [26], [84], [85].

No kidding!

It should be noted that this paper is a child of a 2010 IMFAR abstract, Intestinal Inflammation, Impaired Carbohydrate Metabolism and Transport, and Microbial Dysbiosis in Autism.  If I understand correctly, another paper is being prepared regarding the findings of intestinal inflammation that will be complimentary to Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances.  I’ll try to post something when it is published.

This study was small, with only twenty two participants, largely as a result of the difficulty in obtaining tissue specimens.  While this does give us cause for caution, it is important to note that this research does not exist in a vacuum, but rather, as a much larger set of research that tell us that the relationship between GI complaints and autism is more than the inceptions of DAN doctors.  Previously, Gastrointestinal abnormalities in children with autistic disorder, performed similar biochemistry and reported broadly consistent carbohydrate digestion problems, ‘Low intestinal carbohydrate digestive enzyme activity was reported in 21 children (58.3%), although there was no abnormality found in pancreatic function.’  Several other papers analyzing fecal samples have reported altered bacterial populations, including Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism, Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity, Fecal lactoferrin and Clostridium spp. in stools of autistic children, and Pyrosequencing study of fecal microflora of autistic and control children, among others.

If the findings from this latest paper are spurious finding based on sample size problems, a lot of other studies are coincidentally finding the same type of thing in the wrong way.   Does anyone think that is likely?

I entered the autism world and online autism debate from a place of seeing with my own eyes the failures of a toddlers GI function and the difficult to overstate changes in that toddler alongside improvements in his GI health.  On one of the first autism blogs on which I participated I got into a discussion (argument?) with a blogger who I came to respect very much, but has since moved on.  I described the fact that my son had six or more diarrhea stools, a day, every day, for months on end, and that when we added dietary changes, probiotics, and later antifungal agents, the changes to his GI function were profound and impossible to misinterpret.  He told me something along the lines that humans were susceptible to illusions and sleight of hand, and I thought, ‘as if not knowing the difference between diarrhea and a log was along the lines of figuring out where the jack of spades went!’.   I couldn’t believe, could not fucking believe, someone would try to convince me that I had imagined my sons problems, and associated recovery.   This wasn’t a sugar pill study where I was asked if my child acted more or less hyperactive, this was a matter of asking myself, ‘How many diarrhea diapers did I change today?  Six?  Or Zero?’  [Repeat once a day for 180 days.]

I doubt this is necessary, but just in case, I will go on the record to state that it is easy, very easy, to tell the difference between a condition of chronic diarrhea and normal GI function.  There might not be a more simpleminded determination to make on Planet Earth or indeed, our perceptible universe.   This is a situation that is susceptible to placebo effects only in the most elaborate imaginations of people who have never experienced chronic GI problems.

From that time on, with nearly zero exceptions, I have become a little less shocked, but a little more saddened by the doublethink style skepticism applied to GI distress and autism in nearly every single conversation I have ever seen on the Internet.  I’ve put some time thinking toward this, why so many otherwise intelligent people house such extreme hostility on a relationship between GI function and autism.  I believe that the Wakefield / MMR autism debacle is at the heart of this disconnect; his ill fated and now retracted paper that launched a thousand Internet scribbles has seemingly forever tied GI complaints and autism to bad science.

It doesn’t have to be this way.  As a community, the vaccine wars and kissing cousin prevalence question has done a lot to fracture us, and very little to unite us.  That is a sad statement, and nothing makes it more unfortunate than the fact that it does not have to be this way.  Wakefield can be wrong about the MMR and there can still be very real differences in GI function in some cases of autism.  We can respectfully disagree about how well our existing prevalence studies inform us on the incidence of autism without also needing to accept a world view where every child with autism has raging bowel problems.

We should have the intellectual honesty to admit that there is nothing inherently dangerous about acknowledging what the data tells us; GI function seems to be abnormal in a subset of children with autism, and the underlying features of that GI distress are qualitatively different than what is found in ‘normal’ children.

–          pD

Hello friends –

These have been rough times for the people who are heavily invested in the kissing cousin theories of autism as a predominantly genetic disorder and the static, or near static rate of autism.  The California twin study that is old news by the time I get this finished showed much different rates of genetic participation than previously believed.  These findings exposed the underlying frailty of gene-based causation theories, namely that some of the most widely referenced studies in the autism literature, studies used repeatedly as a basis for the notion that autism was ‘the most highly heritable neurodevelopmental disorder’, were, in fact, relatively underpowered, and suffered from serious temporal and methodological shortcomings.    

By contrast, the California study looked at two hundred twin pairs, a lot more twins than any previous study and actually performed autism diagnostics on all of the participating children, whereas other studies relied on medical records.  Performing dedicated ADOS diagnosis prospectively on the children allowed the researchers to discern between autism and PDD-NOS, something that not all previous studies were not able to perform, if for no other reason than the DSM-IV wasn’t even released when several of the most often cited studies were published.   This is from the Comment section of the California twin study:

The results suggest that environmental factors common to twins explain about 55%  of the liability to autism. Although genetic factors also play an important role, they are of substantially lower magnitude than estimates from prior twin studies of autism. Nearly identical estimates emerged for ASD, suggesting that ASD presents the same liability spectrum as strict autism.

This is on top of the fact that there is a quiet, but growing acknowledgement of the fact that literally decades of genetic studies have failed to be able to explain more than a fraction of autism cases despite sequencing of tens of thousands of genomes.   This is a very similar situation to a great number of other disorders which we thought we would cure once the human genome was decoded.   [Note: That isn’t to say that we haven’t learned a lot from sequencing the genome, just that we didn’t quite get what we thought we were going to get.]

This ‘double hit’, so to speak, has reached a critical mass such that health officials are making politically shrewd, but refreshingly realistic statements, and dare I say, a sliver of common sense may be about to infiltrate the discussion about autism prevalence.  For example, as pointed out by Sullivan, Tom Insel, head of the National Institute of Mental Health keeps a blog where he recently blogged ‘Autism Spring’, which included this nugget within the context of continued failure of genetic studies to explain any substantial part of autism, “It is quite possible that these heritability estimates were too high. . .” Ouch. (I would recommend the entire blog posting by Mr. Insel.) 

The high heritability estimates, and implicit genetically-mediated cause of autism, are foundational pillars of the argument that autism rates have not changed over time.  Though overused, or used wrongly in many instances, there is a kernel of dispassionate reality behind the statement, ‘there is no such thing as a genetic epidemic’.  Without the crutch of exceedingly high heritability to rely on, the notion of a stable rate of autism loses the only hard science (read: replicable, biologically-plausible), i.e.,genetics, it ever had, and must place complete reliance on the softer sciences (read: unquantifiable, ‘greater awareness’), i.e.,sociology.  This is great news if you love impossible to verify estimates of prevalence and anecdotes about crazy uncle George who would have been diagnosed with autism forty years ago.  However, if you think we should be relying less on psychologists and cultural anthropologists to answer critical questions, and rely more on hard science, this means that the old narrative on autism prevalence holds even less allure than it did in the past, for those of you who thought this was possible.

Before Kid Autism came around, I would occasionally read discussion boards on the creationism versus evolution ‘debate’.  One thing that I noticed was that the creationists would often employ a ‘God of the Gaps’-style argument: anything that couldn’t be explained by science (yet), or anything necessary to support whatever fanciful construct had been erected to protect biblical creation fables, was ascribed to the work of God.  That’s one thing you have to give to God, he (or she!) can handle it all; it didn’t matter what primitive logical test biblical creation was failing to pass, the golden parachute clause was always that God could have just made things that way.  It was a nifty out on the part of the creationists, kind of like a get out of jail free card. The autism prevalence discussion has been working just like this, and the funny part is that the people that are always claiming to have the intellectual high ground, the supposed skeptics, are playing the part of the creationists!  Zing! 

Here is how it works:

Concerned Parent: It sure does seem like there is more autism than there used to be, what with there being X in a thousand kids with it!  That’s much, much more than even ten years ago!  My brothers, sisters and I all knew kids with mental retardation and Down’s syndrome, but we just don’t remember kids like we see today.

Supposed Skeptic: It is diagnostic substitution and ‘greater awareness’; autism incidence has been stable.  The DSM was changed which resulted in more children being labeled.

Concerned Parent:  It sure does seem like there’s more autism than there used to be.  Now there are Y kids in a thousand having autism!  Why does my son’s preschool teacher keep insisting something is changing?

Supposed Skeptic: It is diagnostic substitution and ‘greater awareness’; autism incidence has been stable.  The DSM was changed which resulted in more children being labeled.

Concerned Parent:  What the hell?  Now there are Z kids in a thousand having autism!  When are those genetic studies going to figure autism out, anyway? 

Supposed Skeptic: It is diagnostic substitution and ‘greater awareness’; autism incidence has been stable.  When does the new DSM come out again? 

(Replace X/Y/Z with any progressively larger numbers.)

It doesn’t matter what prevalence number is thrown about–even the astronomical one in thirty-eight figure bandied about for South Korean children didn’t cause so much as a raised eyebrow; the autism equivalent of God of the Gaps, greater awareness and loosening of diagnostic criteria can handle any amount of increase gracefully.  It is the equivalent of an uber-absorbent autism paper towel, capable of soaking up any number of new children with a diagnosis; there is, literally, no amount of an increase that the God of the Gaps can’t handle.   

If, instead the question was posed like this, ‘How much of the apparent increase in autism is real?’, the answer was always, ‘Zero’, regardless of what the current rates of autism were when you asked the question

Then a funny thing happened, a series of studies from several researchers showed a consistent trend of older parents giving rise to more children with autism than younger parents. There were differences between the studies on just how much of an effect an older parent had, but the overall direction of association was clear.  In this instance, there was also the luxury of a plausible biological mechanism that involved the mediator in favor, genetics.  The idea is that advancing age in the parent meant more years for gametes to get knocked by a random cosmic zap or other environmental nastygram and this disturbance created genetic problems down the line for the offspring, a theory I think is probably pretty good.   Once a couple of these studies started to pile up, there was a small shift in the narrative regarding autism prevalence; after all, nobody could bother to try to deny that parents were getting older compared to past generations.  Here is how it looked:

Concerned Parent:  What the hell?  Now there are X kids in a thousand having autism! 

Supposed Skeptic: Greater awareness and diagnostic substitution are primarily responsible for our observations of increased autism, although, ‘a real, small increase’ cannot be ruled out.   

And with that, there was a little less autism prevalence for the God of the Gaps to handle.   It never seemed to bother anyone that implicit in this argument is an impossible to quantify concept ‘small increase’.  If you were to ask someone what rate of autism ‘a small increase’ amounted to with more precision, the answer is whatever amount rises to the level of autism minus the difficult to quantify effect of older parents.  That is some lazy stuff.

Here are some examples of prominent online skeptics discussing the possibility of a true rise in autism.  See if you can detect a pattern.

Here is Stephen Novella pushing The Fairytale in 2009:

While a real small increase cannot be ruled out by the data, the observed increase in diagnostic rates can be explained based upon increased surveillance and a broadening of the definition – in fact autism is now referred to as autism spectrum disorder.

[Here we see the notion that everything can be explained by the God of the Gaps.]

Here is an example of Orac toying around with this filibuster just the other day, in August of 2011:

True, the studies aren’t so bulletproof that they don’t completely rule out a small real increase in autism/ASD prevalence, but they do pretty authoritatively close the door on their being an autism “epidemic.”

These aren’t the only examples, far from it.   Check it out:

It should be noted that the data cannot rule out a small true increase in autism prevalence. (Stephen Novella in 2008)

If the true prevalence rate of autism and ASDs has increased, it has not increased by very much. (David Gorski, 2010)

It should also be noted that all of this research, while supporting the hypothesis that the rise in autism diagnoses is not due to a true increase in the incidence but rather is due to a broadening of the definition  increased surveillance, does not rule out a small genuine increase in the true incidence. A small real increase can be hiding in the data. (Stephen Novella, 2008)

We should have the curiosity to wonder, what, exactly, does small mean in these contexts?  What percentage size increase should we consider small enough to hide within the data?  Five percent?  Ten percent?  What does ‘small’ mean, numerically, within a range?   Is a ten to twenty percent rise in autism rates reason for us to take comfort in the fact that the effect of greater awareness is real?  At what level does the percentage of ‘real’ autism increase mandate more than superficial lip service, more than a paragraph about ‘gene-environment interactions’ at the end of a two-thousand word blog post that takes pride in the intellectual chops of outthinking Jenny McCarthy?  You won’t get anyone to answer this question; they can’t, because they don’t really know what they mean when they say, ‘small’, other than, ‘it can’t be vaccination’. 

How do we know the amount of this increase must, in fact, even be ‘small’?  This becomes especially problematic when we consider the smackdown that the canard of autism as ‘among the most heritable neurological conditions’ has taken as of late.  If the high heritability estimates of autism are incorrect, yet so often repeated as gospel, why should we also assign confidence to the idea that the increase is trivial?  Isn’t one argument the foundation of the other?   Did either really have quality data behind them? 

This is a terrible, awful, horrible, completely fucking idiotic way to address a question as important as whether or not a generation of children is fundamentally different.  We cannot afford the ramifications of being wrong on this, but we seem to find ourselves in an epidemic of otherwise intelligent people willing to accept the pontifications of cultural anthropologists and the feebleness of social scientists on this critical question.   I am not arguing against the realities of diagnostic switching and greater awareness affecting autism diagnosis rates.  But we can understand that while they are a factor, we must also admit that we have little more than a rudimentary understanding of these impacts, and when we consider the implications of being incorrect, the potential disaster of a very real, not ‘small’ increase in the number of children with autism, we shouldn’t be overselling our knowledge for the sake of expedient arrival at a comforting conclusion.   We should be doing the opposite.

If we can’t have the robustly defendable values on autism rates right now, that’s fine, because that is the reality, but we should at least have the courage to acknowledge this truth.  This is the nature of still learning about something, which we are obviously doing in terms of autism, but in that situation, we don’t have the currency of scientific debate, decent data, to be saying with authority that any true increase in autism is small. 

Unfortunately for the purveyors of The Fairytale, things are going to get a lot worse.  The problem is that we are starting to identify extremely common, in some cases, recently more common, environmental influences that subtly increase the risk of autism.  These are further problems for a genetic dominant model and effectively mandate that the ‘small increase’ is going to have to start getting bigger as a measurement, with a correlated decrease in the amount of autism that cultural shuffling can be held responsible for.  Will anyone notice?

By way of example, we now have several studies that link the seasons of gestation with neurodevelopmental disorders including autism and schizophrenia; i.e., Season of birth in Danish children with language disorder born in the 1958-1976 period, Month of conception and risk of autism, or Variation in season of birth in singleton and multiple births concordant for autism spectrum disorders, which includes in the abstract, “The presence of seasonal trends in ASD singletons and concordant multiple births suggests a role for non-heritable factors operating during the pre- or perinatal period, even among cases with a genetic susceptibility.”  Right!  As I looked up some of these titles, I found that the evidence for this type of relationship has been well known for a long time; schizophrenia, in particular has a lot of studies in this regard, i.e., Seasonality of births in schizophrenia and bipolar disorder: a review of the literature, which is a review of over 250 studies that show an effect, and I also found Birth seasonality in developmentally disabled children, which includes children with autism and was published in 1989, which is like 1889 in autism research years. 

Our seasons have remained constant (but probably won’t stay too constant for much longer. . . ), but this still throws a whole barrel of monkey wrenches into the meme of a disorder primarily mediated through genetics. 

More damning for the Fairytale are some studies presented at this year’s IMFAR, and some others just published, that tell us that abnormal immune profiles during pregnancy appear to provide slightly increased risk for autism, roughly doubling the chance of a child receiving a diagnosis.  The groovy part is that the studies utilized both direct and indirect measurements of an activated immune system to draw similar conclusions, a sort of biomarker / phenotype crossfire.

From the direct measurement end, we have Cytokine Levels In Amniotic Fluid : a Marker of Maternal Immune Activation In Autism?, which reports that mothers with the highest decile of tnf-alpha levels in the amniotic fluid had about a one and a half times increased risk for autism in their children.  This makes a lot of sense considering the robustness of animal models of an acute inflammatory response during pregnancy and its impact on behavior. 

Another study, this one from the MIND Institute in California (which I love), is Increased mid-gestational IFN-gamma, IL-4, and IL-5 in women giving birth to a child with autism: a case-control study (full paper). They found that in pregnant mothers, increased levels of IFN-gamma led to a roughly 50% increased risk of an autism diagnosis.  Here is a snipet:

The profile of elevated serum IFN-γ, IL-4 and IL-5 was more common in women who gave birth to a child subsequently diagnosed with ASD. An alternative profile of increased IL-2, IL-4 and IL-6 was more common for women who gave birth to a child subsequently diagnosed with DD without autism.

This study took a lot of measurements, and goes to great lengths to explicitly call for additional analysis into the phenomena.   IFN-gamma is typically considered pro-inflammatory, while IL-4 and IL-5 are considered regulatory cytokines.  In order to determine if these findings were chance or not, the researchers determined if there was a correlation between the levels of IFN-gamma, IL-4, and IL-5, which they reported with very robust results.    Less clear is what might be causing these profiles, or how, precisely, they might give rise to an increased risk of autism.  The interconnectedness of the brain and the immune systemwould be a good place to start looking for an answer to the last question though. 

What about indirect measurements? It just so happens, another paper was published at IMFAR this year that observed the flip side of the coin, conditions associated with altered cytokine profiles in the mother and this study also found an increased risk of autism.  The Role of Maternal Diabetes and Related Conditions In Autism and Other Developmental Delays, studied a thousand children and the presence of diabetes, hypertension, and obesity in their mothers in regards to the risk of a childhood autism diagnosis.   The findings indicate that having a mother with one or more of those conditions roughly doubles the chances of autism in the offspring.  Obesity, in particular, has an intriguing animal model Enduring consequences of maternal obesity for brain inflammation and behavior of offspring, a crazy study that I blogged about when it was published.   A variety of auto immune disorders in the parents have been associated with an autism diagnosis in several studies. 

The obesity data is particularly troublesome for the idea of a ‘small’ increase in autism, just like parents have been getting older, parents have also been getting fatter, waaaay fatter, (and more likely to have diabetes)  the last few decades.  There isn’t any squirming out of these facts.  If, indeed, being obese or carrying associated metabolic profiles is associated with an increased risk of autism, ‘small’ is getting ready to absorb a big chunk of real increase.  But is there any clinical data to support this possible relationship, do we have any way to link obesity data with this autism data from the perspective of harder figures?

It further turns out, there are some very simple to navigate logical jumps between the above studies.  Remembering that our clinical measurements indicated that increased INF-gamma, IL-4, and IL-5 from the plasma of the mothers was associated with increased risk, we can see very similar patterns in Increased levels of both Th1 and Th2 cytokines in subjects with metabolic syndrome (CURES-103).  Here is part of the abstract, with my emphasis.

Metabolic syndrome (MS) is a cluster of metabolic abnormalities associated with obesity, insulin resistance (IR), dyslipidemia, and hypertension in which inflammation plays an important role. Few studies have addressed the role played by T cell-derived cytokines in MS. The aim of the tudy was to look at the T-helper (Th) 1 (interleukin [IL]-12, IL-2, and interferon-gamma [IFN-gamma]) and Th2 (IL-4, IL-5, and IL-13) cytokines in MS in the high-risk Asian Indian population.

Both Th1 and Th2 cytokines showed up-regulation in MS. IL-12 (5.40 pg/mL in MS vs. 3.24 pg/mL in non-MS; P < 0.01), IFN-gamma (6.8 pg/mL in MS vs. 4.7 pg/mL in non-MS; P < 0.05), IL-4 (0.61 pg/mL in MS vs. 0.34 pg/mL in non-MS; P < 0.001), IL-5 (4.39 pg/mL in MS vs. 2.36 pg/mL in non-MS; P < 0.001), and IL-13 (3.42 pg in MS vs. 2.72 pg/mL in non-MS; P < 0.01) were significantly increased in subjects with MS compared with those without. Both Th1 and Th2 cytokines showed a significant association with fasting plasma glucose level even after adjusting for age and gender. The Th1 and Th2 cytokines also showed a negative association with adiponectin and a positive association with the homeostasis model of assessment of IR and high-sensitivity C-reactive protein.

Check that shit out!  Seriously, check that out; increased IFN-gamma, IL-4, and IL-5 in the ‘metabolic syndrome’ group, comprised of people with, among other things, obesity, insulin resistance, and hypertension; the same increased cytokines and risk factors found to increase the risk of autism. 

If we look to studies that have measured for TNF-alpha in the amniotic fluid during pregnancy, we quickly find,  Second-trimester amniotic fluid proinflammatory cytokine levels in normal and overweight women

There were significant differences in amniotic fluid CRP and TNF-alpha levels among the studied groups: CRP, 0.018 (+/-0.010), 0.019 (+/-0.013), and 0.035 (+/-0.028) mg/dL (P=.007); and TNF-alpha, 3.98 (+/-1.63), 3.53 (+/-1.38), and 5.46 (+/-1.69) pg/mL (P=.003), for lean, overweight, and obese women, respectively. Both proinflammatory mediators increased in women with obesity compared with both overweight and normal women (P=.01 and P=.008 for CRP; P=.003 and P=.01 for TNF-alpha, respectively). There were significant correlations between maternal BMI and amniotic fluid CRP (r=0.396; P=.001), TNF-alpha (r=0.357; P=.003) and resistin (r=0.353; P=.003).


What we are really looking at are five studies the findings of which speak directly to one another; a link to metabolic syndrome during pregnancy and increased IFN-gamma, IL-4, and IL-5, a link to obesity and hypertension in pregnant mothers and autism risk, and an increased risk of autism in mothers wherein IFN-gamma, IL-4, and IL-5 were found to be increased outside of placenta.   Further, we have a link between amniotic fluid levels of TNF-alpha and metabolic syndrome, metabolic syndrome in mothers and autism risk, and increased risk from increased tnf-alpha in the amniotic fluid. 

As I have said previously, one thing that I have learned during this journey is that when we look at a problem in different ways and see the same thing, it speaks well towards validity of the observations.  What we see above is a tough set of data to overcome; we need several types of studies looking at the relationship between metabolic syndrome, immune profiles during pregnancy, and autism from different angles to have reached the same wrong conclusion, something that is increasingly unlikely.  We are in an epidemic of obesity and the associated endocrine mish mash of metabolic syndrome, there simply isn’t any diagnostic fuzziness on this.  It is happening all around us.  Even though the total increase in risk is relatively small, the sheer quantity of people experiencing this condition of risk mandates that the numbers game looks favorable towards a real increase in autism.  If we acknowledge this, how can we continue to have faith in the concept that any true increase in the autism rates must be ‘small’?

Is the next argument going to be that besides increased parental age, and heavier or more diabetic mothers, the rest of the autism increase is the result of diagnostic three card monte?  (Just how much is the rest, anyways?)

And even though these studies, and likely more in the future, expose the crystal delicate backbone of the ‘small true increase’ argument, I have great pessimism that the people so enamored with invoking this phrase will ever acknowledge its shifting size, much less the implications of being wrong on such a grand scale.


Hello friends –

There is a lot of over simplification in discussions about autism on the Internet, sometimes I don’t think the people that use them really understand that their points are founded on primitive facsimiles of reality, but other times, I’m pretty sure they do know.  That second group are the ones that really leave me in a confused rage; smart enough to know better (or have had the difference explained to them previously), but continue to rely on utilization of grade school quality parameters to govern complicated and entangled systems.  It seems I’m often wrong when I wonder about the reason people do things (doh!), but when someone otherwise sufficiently knowledgeable relies on the crutch of simplicity because they think it bolsters their argument, I do tend to trust their motives before I consider human fallibility.  It reminds me a lot of politicians, especially Republicans.  [sorry] 

That being said, one of the big simplifications you used to see a lot during the thimerosal wars was this gem:

“The poison in the dose.”

I googled this a bit.  This phrase is attributed to Paracelsus, who Wikipedia tells me is considered ‘the father of toxicology’.  He apparently wrote this:

All things are poison, and nothing is without poison; only the dose permits something not to be poisonous.

Good stuff.  By the way, Paracelsus, who no doubt was pretty smart in his day, was born over six hundred goddamn years ago and the primary observation metrics available to Paracelsus was whether or not something died or not.  Sure, oxygen is deadly in sufficient concentrations, as is water, salt, and everything else, so if we want to have a discussion that allows only for endpoints of livingness or death, the parameters laid out by him are good boundaries.  However, if we would like our conversations to allow for somewhat more subtle changes associated with environmental exposures, something a dispassionate evaluation of the data dictates, we may need to find ways to have conversations that allow for endpoints other than death, and we will need to acknowledge that we have lots of evidence to suggest that there are inputs other than dose that are occasionally meaningful, no matter how this might affect our ability to take comfort in one study or the other.  Even worse, we have actual, real empirical data to suggest there are times when there is an inverse dose relationship.

One of my pubmed alerts somewhat tangential to autism sent me the abstract for Differential mRNA expression of neuroimmunemarkers in the hippocampus of infant mice following toluene exposure during brain developmental period.  It’s a doozy:

Toluene, a volatile organic compound with a wide range of industrial applications, can exert neurotoxic and immunotoxic effects. However, the effects of toluene exposure on developmental immunotoxicity in the brain have not yet been characterized. To investigate the susceptible window to toluene exposure during development and the effects of fetal and neonatal toluene exposure on the neuroimmune markers, gestational day (GD) 14 pregnant mice, postnatal day (PND) 2 and PND 8 male offspring were exposed to filtered air (control; 0 ppm), or 5 or 50 ppm toluene for 6 h per day for five consecutive days. The neuroimmune markers in the hippocampus of PND 21 were examined using a real-time RT-PCR and immunohistochemical analysis. Mice exposed to 50 ppm toluene on PND 2–6 showed significantly increased levels of nerve growth factor (NGF) and tumor necrosis factor (TNF)- mRNAs. In contrast, NGF and brain-derived neurotrophic factor (BDNF) and proinflammatory cytokines TNF-, CCL3, NF-kB, toll-like receptor (TLR)-4, astrocyte marker glial fibrillary acidic protein (GFAP), and microglia marker ionized calcium binding adapter molecule (Iba)-1 mRNAs were increased significantly in mice exposed to 5 ppm toluene on PND 8–12. These results indicate that low-level toluene exposure during the late postnatal period (PND 8–12) might induce neuroinflammatory mediators via TLR4-dependent NF-?B pathway in the hippocampus of PND 21 male mice. Among the three developmental phases, PND 8–12 seems to be most sensitive to toluene exposure. This is the first study to show developmental phase- and dose-specific changes in neuroimmune markers in infant mice following toluene exposure.

Essentially the authors took a bunch of mice exposed them to different amounts of airborne toluene at different days before and after birth, then looked for a variety of changes in immune system markers and neurotrophic factors in the hippocampus.  Toluene was certainly capable of tinkering around with lots of systems that we know are skewed in the autism population.  Curiously, what they found was that there were time dependent changes that had just as much of an impact than dose of toluene; and in fact, much, much lower doses of toluene were capable of causing more robust changes if the exposure occurred during critical developmental windows. 

The authors state that the timeframe of exposures in this study, postnatal days 2 -6 and postnatal days 8 – 12 roughly map to the early and late third trimester of human fetal development, respectively.  I’ve seen similar equivalencies in other papers, some with earlier and later timeframes, but certainly these timeframes are generally within the range that other papers have used.  Consistent with the theme of this post, I’d just say that rat to human is difficult, and rat to human specific brain area and developmental timeframe equivalency is even more difficult.

The authors speculate that the difference in effect may be related to what was happening, developmentally within the brain at the time of toluene exposure that made the impact.  

During this period, hippocampus undergoes an increase in size and a change in excitatory neurotransmission to allow for adult-like synaptic plasticity by the end of the second postnatal week (Dumas, 2005). This transiently heightened level of brain plasticity is shaped byenvironmental factors which have profound effects on this brain growth spurt (Goodlett et al., 1989). Furthermore, during this period, the immune system undergoes maturation to immunocompetence (Dietert et al., 2000).

There are also some stuff about why the hippocampus is a particularly promising target for investigation into effects of toluene exposure. 

Here are a couple of graphs of their findings:







Check that shit out!  During some very specific developmental timeframes, a decreased exposure resulted in increased physiological effect, not only that, the more affected animals received ten times less agent.   Less poison, more effect.  The exact opposite of what Paracelsus predicts.  [Sorry for the formatting/stupid wordpress!]

Saliently towards autism, these graphs just happen to show some measurements that have great functional overlap with findings from autism.  These graphs are for CCL3, an immune bugler of sorts, a chemokine, an agent responsible for attracting components of the immune response, one numeral down for CCL2, aka MCP-1, which we’ve also seen increased in the in autism brains, iba1, a marker for microglial activation, NGF and BDNF, neurotrophic factors that have a variety of signaling and maintenance processes in the CNS, and we have much data implicating altered BDNF levels in autism

Not only did the authors observe an inverted dose relationship, some of the measurements found that the time dependencies are also reversed from what you might expect in that later exposure was worse than earlier exposure.  Environmental exposures do not necessarily follow the linear timelines you might expect.

The idea of an inverted, or skewed dose relationship has actually been explored for some time.  For example, The frequency of U-shaped dose responses in the toxicological literature   

Hormesis has been defined as a dose-response relationship in which there is a stimulatory response at low doses, but an inhibitory response at high doses, resulting in a U- or inverted U-shaped dose response. To assess the proportion of studies satisfying criteria for evidence of hormesis, a database was created from published toxicological literature using rigorous a priori entry and evaluative criteria. One percent (195 out of 20,285) of the published articles contained 668 dose-response relationships that met the entry criteria. Subsequent application of evaluative criteria revealed that 245 (37% of 668) dose-response relationships from 86 articles (0.4% of 20,285) satisfied requirements for evidence of hormesis. Quantitative evaluation of false-positive and false-negative responses indicated that the data were not very susceptible to such influences. A complementary analysis of all dose responses assessed by hypothesis testing or distributional analyses, where the units of comparison were treatment doses below the NOAEL, revealed that of 1089 doses below the NOAEL, 213 (19.5%) satisfied statistical significance or distributional data evaluative criteria for hormesis, 869 (80%) did not differ from the control, and 7 (0.6%) displayed evidence of false-positive values. The 32.5-fold (19.5% vs 0.6%) greater occurrence of hormetic responses than a response of similar magnitude in the opposite (negative) direction strongly supports the nonrandom nature of hormetic responses. This study, which provides the first documentation of a data-derived frequency of hormetic responses in the toxicologically oriented literature, indicates that when the study design satisfies a priori criteria (i.e., a well-defined NOAEL, > or = 2 doses below the NOAEL, and the end point measured has the capacity to display either stimulatory or inhibitory responses), hormesis is frequently encountered and is broadly represented according to agent, model, and end point. These findings have broad-based implications for study design, risk assessment methods, and the establishment of optimal drug doses and suggest important evolutionarily adaptive strategies for dose-response relationships.

We have other examples from the synthetic world that may be of interest to autism.  For example, in Developmental Exposure to Polychlorinated Biphenyls Interferes with Experience-Dependent Dendritic Plasticity and Ryanodine Receptor Expression in Weanling Rats the authors report an inverted dose relationship regarding exposure to PCBs and dendrite growth.

Developmental A1254 exposure significantly enhanced dendritic growth in cerebellar Purkinje cells and neocortical pyramidal neurons among P31 rats not trained in the Morris water maze, which is consistent with our previous observations that similar exposures accelerated dendritic growth in Purkinje cells and hippocampal CA1 pyramidal neurons between P21 and P60 (Lein et al. 2007). In Purkinje cells, this effect was observed among animals in the 1 mg but not 6 mg/kg/day A1254 group, whereas in neocortical neurons, responses were comparable between A1254 groups. The reason for the different dose–response relationship in different brain regions is not known. Possibilities include regional differences in RyR regulation (Berridge 2006; De Crescenzo et al. 2006; Hertle and Yeckel 2007) or differential upregulation of cytochrome P450 enzymes by AhR ligands in the cerebellum versus neo-cortex (Iba et al. 2003), which could result in regional differences in PCB toxicodynamics and toxicokinetics, respectively.


What about situations where we have evidence for an environmental factors already associated with autism?  Neuroinflammation and behavioral abnormalities after neonatal terbutaline treatment in rats: implications for autism found that terbutaline administration at postnatal day 2 -5 resulted in chronically activated microglia and behavioral abnormalities in rodents, but the same dose in days 11 – 14 resulted in no such effect.  Same dose, different time, different outcome.

There is more, lots more, but how many times must a rule fail primitive logical tests before we acknowledge that it’s utility in complex discussions is extremely limited?  This absolutely is not meant as an expose meant to reignite discussions about thimerosal, but rather, to illustrate the dangers of trying to understand complicated rules by leveraging simplistic heuristics.  There’s a lot of that in the autism discussion landscape; it is a dangerous concoction of hubris and faith to think that we can have gain meaningful insight into our shared mystery by applying very simple rules. 

I haven’t seen the ‘poison is in the dose’ canard used for a while now.  Good riddance and long live models that are not exceedingly simple to invalidate.




Hello friends –

There’s been something at the back of my mind for a while now regarding the potential for environmental influences to participate in autism, and indeed, a true rise in the number of children that have developmental problems that I’ve been struggling with articulating elegantly.  The right course came to me while reading threads where the recent autism risk as proximity to highways paper was discussed.   I’m actually not too big on the paper, it is very preliminary, uses some terms that are kind of confusing, and at very best, should be used as a guide for more targeted studies.  For anyone who didn’t see it when it came out, essentially it reported a small increase of risk of having a baby with autism as the pregnant mother lived closer to some types of highways. 

What I liked about this study is that at the core, there was a twinge of a biologically plausible mechanism, specifically, exposure to pollutants during development and consequent interference with neural development.  Examples given in the text including possible endocrine disrupting effects of some types of automotive exhaust, and studies showing altered glutamate expression and associated plasticity defects resulting from pollutants. 


What I didn’t like about the study is that it didn’t include any biomarkers and seemed relatively soft on the definitional terms.  It was essentially a GIS placement and association lookup; lots of data and easy to find phantoms.  A methodologically similar study by Bearman was released a few months previously; purporting to assign a very specific percentage of autism increase (16%) to the spatial proximity of other parents with children with autism, with the idea being that those chatty parents convinced their close neighbors to get their child diagnosed, while those people who more than 500 meters from a child with autism, and therefore don’t talk to as many people, failed to get their child diagnosed.  I came down pretty hard on Bearman and don’t see much difference to apply less skepticism here.  I will note, however, with no small amount of amusement, that when Bearman was discussed, no one seemed too concerned about the lack of control for urbanicity in the ‘skeptical’ realm.  Big surprise.   

The skeptics took the freeway paper apart, or in some instances, took apart a reporter or blogger who was spinning the findings as stronger than they were.  I was more or less in agreement with the skeptics ideas on this one; this paper certainly was not sufficiently strong to make any conclusive statements and as usual, some headlines got it way wrong. 

 On the other hand, according to my underlying principles of subtle change still being meaningful, the humbling complexity of poking around with systems like embryonic development, and the difficult to overstate gulf between what we know and what we think we know about the effects of our reckless introduction of a galaxy of sythentic chemicals into the environment our infants are born into, this study fit in pretty nicely; at the very least as a reason to perform bioinformatic analysis of pregnant women to test for biomarkers of exhaust exposure and cognitive outcomes a few years down the ‘road’.   

It didn’t take long before the gross over simplifications started rolling in though; i.e., ‘If this study is valid, we should have seen the rise in autism when the Interstate program was initiated in the 1950’s!’  [cue laugh track], or ‘I guess I have genes that made me live near an Interstate’.  [cue whoot whoot track] It occurred to me that the Interstate jokes are a good illustration of what is largely wrong with nearly every single discussion on environmental participation you stumble into on the Internet.  On one hand, the notion that unless an environmental study has sufficient power to prove a causal relationship for autism, or indeed, can be shown to be unable to account for all autism cases, it is safe to be mocked, or for the more academically minded, accused of being the result of data dredging.  Similarly, anything showing a glimmer of plausibility that isn’t a genetic finding can lends itself towards showing how worthless the genetic angle is.  These are useful cards to play if your goal is to bash environmental causation theories (and thereby, vaccination causation theories), or if your goal is to bash genetic theories; but ultimately are wastes of time if we want to understand a condition with the murky history and multifaceted manifestations of autism.   The crux of what really bothered me about both sides of the Internet joke is that they each ignore meaningful information that can be offered from the other side.  It is worse than dumb, it is wasteful.

 Stepping away from the environmental end for a moment, I think it is safe to say that everyone is beginning to realize that the hunt for high impact genetic changes that can explain more than a tiny fraction of our autism cases is an abject failure.  While there are some genetic changes, like Fragile X, that confer extremely high risk of autism, the absolute number of people with such changes is relatively simple to determine, and they comprise a vanishingly small subset of the children with autism.  What we do seem to be finding is that there are lots of genetic changes that confer a small risk of having autism, the so called, low penetrance genetic changes.  The idea here is that if you have many, (maybe as many as a dozen or more) low penetrance genes, the cumulative effects build up until a physiological end point is reached wherein autistic behaviors manifest.  I actually like the idea behind low penetrance genes a lot; it makes a lot of our finings of genetics make sense, and I absolutely believe in a strong genetic participation in autism.   

Remember, at the end of the day, genes are nothing more than blueprints for building proteins.  Most genetic alterations don’t involve complete additions, or removals, of proteins, but rather, creation of a little less, or a little more of a protein, or perhaps, creation of proteins that are just a tiny bit different than ‘normal’, sort of like autism itself.   While the environment these proteins enter, or are regulated into entering, starts influencing the eventual biological outcome in the most immediate sense imaginable, the end points of genetics, these proteins and their precise structures are indisputably important in what is happening in everything our bodies do; including, in some instances, have autism. 

Consider the tightly orchestrated formation of the microscopic chasms between neurons, the process of synaptogenesis.  Dozens (or hundreds) of chemicals dance together in order to form the structures in our brains that exchange chemical messengers, neurotransmitters, that literally form the foundation of neuron to neuron communication, and thus, cognition; the physical constructs of thought.  It is a biological cauldron that we are just beginning to comprehend, the mind formingly intricate, time dependent interplay of a chemical deck of cards orders of magnitude more complicated than sequencing the genome. 

The evidence for altered synapses, and modified synaptic function in autism, and most (all?) other developmental disorders is impossible for an intellectually honest observer to deny.  Some of the most commonly found genetic alterations in people with autism involve genes known to participate in the formation, maintenance, or functioning of synapses.  For example, neurexin , shank, and neuroligin, are some well known, or at least, well reported reported genes intimately attached to synapse function also found associated with autism, and our list should also include calcium expression and  adhesion genes (and many, many others).  Each of these genes or processes contribute to the synapse in subtle, but different ways, at different times, and yet we can see that interferences anywhere down the functional class of chemicals is associated with autism.  Yet, very few people, (I’ve read of none), have been found to have a neurixin allele, a shank allele, and a neruoligin mutation.  And there are some people who have the same mutations, but do not exhibit autistic behavior.  There are also a great many people that have no known mutations in any of these genes, and still, receive an autism diagnosis.  What does this tell us?

It should tell us that while there are lots of genetic ways that synapse function can be altered in such a way that autistic behaviors bubble up to the diagnosis endpoint, but more importantly, the critical question need not necessarily revolve around what genes you have, but rather, is synapse function manipulated?  Furthermore, we should be able to conclude that simply having a single modifier (i.e., one shank mutation) go wrong isn’t a guarantee of an autism diagnosis, and thus; the participation of individual mutations is real, but small.  [I would also argue that it is likely that there are a great number of as of yet, undetected genetic misprints that contribute in the same real, but subtle ways.]

Another more accessible example of a low penetrance gene is the MET gene, which produces a protein known to interact with a lot of important processes involved in autism, including brain formation, immune system functioning, and intestinal repair.  There have been a lot of high quality studies on the MET mutations in the past few years including those that report higher incidences of MET mutations in children with autism and gastrointestinal problems, higher findings of MET alleles in autism, association to communication phenotypes and MET expression, replication of above studies, evidence of interaction with other genes known to be associated with autism, decreased expression in post mortem brain tissue, and animal studies showing differential, time dependent expression of MET.  (and many, many others).   

The kicker towards this discussion, howeever, is that the changes to the MET gene are really, very, very common.  Nearly one half of everyone has the low MET production gene, but even still, many more people with autism have it.  So, while it is clearly implicated, other changes are obviously necessary for that particular genetic change to result in autism.  What we are learning about the systems affected by MET, or lots of the genes implicated in autism, is that very subtle changes towards critical processes are sufficient to modify the course of development.  Somewhat counter intuitively, I would argue that the implication of this is compelling evidence (or terrifying news) for those of us with worries about the possibility of an environmentally driven increase in the number of people with an autism diagnosis; indeed, it argues that just like genetics, we must admit the reality that if genes can be low penetrance, so too, then, can environmental impacts.   

For example, back to brain formation.  We know that the neurexin proteins participate in forming our synapses.  But we have evidence that hypo

thyroidism can lead to structural changes during development, and we also know that there is increasing evidence that endocrine disruptors can interferre with thyroid metabolism, or for that matter, a wide range of findings on endocrine disruptors and cognitive function.   Or if we look to pesticides, we have evidence that developmental exposure to diazonon can modify neurotransmitter function, with similar findings are available for other classes of pesticides.  Similarly with heavy metals.

The skeptics would claim with some legitimacy that there are significant dose dependency problems to be addressed before we should start pointing to every experimental slice of evidence of potential harm and claiming that the sky is falling.  But.  What if, in fact, we need only perturb the process of brain development a little bit, and with a little help from other, low penetrance genes or other exposures, developmental trajectories begin to alter?  This would seem to be precisely what we are learning from the genetic angle; it isn’t one big thing incorrectly designed, it is lots of small things.  And while our genetic code has, for the most part, remained stable; our environment today is vastly overpopulated with chemicals capable of minor, but real, effects when compared to yesteryears past.

The search for a single environmental impact with the ability to explain a significant portion of autism diagnosis is as futile as the hunt based on genetics.  This makes for a far messier landscape, but also one that fits my terrifying, over arching principle of the Fairytale of a static (or near static) rate of autism, that our uncontrolled experiment of introducing synthetic chemicals into our environment coupled with widespread social changes with real physiological impacts, a set of experiments absolutely unprecedented in the history of living things on planet Earth, that changes to our offspring are unavoidable.  To suggest otherwise, strikes me as either the height of arrogance, or the depths of ignorance. 

Going back to the freeway study for a minute, I ran into a paper while writing this piece that involves pollutants, interaction with the MET gene, gene x environment interactions, and low penetrance impacts that I think has salience towards this discussion.

 Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET. 

Here is the abstract:


Gene by environment interactions (G × E) are thought to underlie neurodevelopmental disorder, etiology, neurodegenerative disorders, including the multiple forms of autism spectrum disorder. However, there is limited biological information, indicating an interaction between specific genes and environmental components. The present study focuses on a major component of airborne pollutants, polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene [B(a)P], which negatively impacts cognitive development in children who have been exposed in utero. In our study, prenatal exposure of Cpr(lox/lox) timed-pregnant dams to B(a)P (0, 150, 300, and 600 μg/kg body weight via oral gavage) on embryonic day (E14-E17) consistent with our susceptibility-exposure paradigm was combined with the analysis of a replicated autism risk gene, the receptor tyrosine kinase, Met. The results demonstrate a dose-dependent increase in B(a)P metabolite generation in B(a)P-exposed Cpr(lox/lox) offspring. Additionally, a sustained persistence of hydroxy metabolites during the onset of synapse formation was noted, corresponding to the peak of Met expression. Prenatal B(a)P exposure also downregulated Met RNA and protein levels and dysregulated normal temporal patterns of expression during synaptogenesis (!). Consistent with these data, transcriptional cell-based assays demonstrated that B(a)P exposure directly reduces human MET promoter activity. Furthermore, a functional readout of in utero B(a)P exposure showed a robust reduction in novel object discrimination in B(a)P-exposed Cpr(lox/lox) offspring. These results confirm the notion that common pollutants, such as the PAH B(a)P, can have a direct negative impact on the regulated developmental expression of an autism risk gene with associated negative behavioral learning and memory outcomes.


(my emphasis) 

I have to say, finding this paper was a bit of tragic humor for me; it was published in December 2010, with zero fanfare from the press, as opposed to the confounder heavy, Residential Proximity to Freeways and Autism in the CHARGE study, study, which had a thousand similar articles in Google News.  But here we find a superb example of what gets bandied around a lot when in quick passing but rarely with any meat behind the discussion; a real life, experimentally sound version of a gene environment interaction that integrates biologically plausible mechanisms that is able to describe what is observed physiologically in autism with dose responses.  Beautiful.  But, it gets even better.  It just so happens, the classifications of agents in use in this study, polycyclic aromatic hydrocarbons, are generated, in some instances, by car exhaust.  In fact, in Detection of polycyclic aromatic hydrocarbon exposure from automobile exhaust fumes using urinary 1-hydroxypyrene level as an index, the authors conclude in part that “Automobile exhaust fume exposed subjects have a higher risk to be exposed to PAHs than the non-exposed subjects”.   Go figure.

Whatever the problems with the freeway CHARGE study, they pale in comparison to the problems that the notion that because we didn’t observe increases in autism when the Interstate system was constructed, the findings must be spurious.  Similarly, genetic predisposition is an indisputable fact; and knowing which genes are implicated in autism can help us intelligently target environmental factors that might be changing our infants.   

– pD




Hello friends –

The mitochondria discussion in the autism community reminds me a lot about the political discussion in the United States; I know it is important, but it is just so hard for me to care enough to get involved; it mandates walking the plank into an environment dripping in hypocrisy, where highly complicated problems are reduced to black and white meme friendly soundbytes, and discussions that seem a lot more like billboards on different sides of the road than people wanting to discuss anything.   It started with the case of Hannah Poling, the little girl who experienced a dramatic and sudden developmental regression following her vaccinations at age 18 months, a case wherein the federal government conceded that vaccines through likely interaction with a pre-existing defect in mitochondrial function were likely the cause of her developmental trajectory and ‘autism like features’. 

On some parts of the Internet, you’d think that every single child with an autism diagnosis experienced a drastic, overnight regression in development that Hannah Poling did; despite abundant, clear as the day common sense evidence that the onset of autism is gradual in the overwhelming majority of instances. For the most part, I don’t think it was a spin job.  I just don’t think they get it.  Although, I must admit, I do believe that there are a very small, but real, minority of parents who have witnessed similar things with their children.  Hannah Poling is not unique. 

On the other hand, lots of other places you could find people whose online existence is part and parcel with the notion that our real autism rates are static, that the inclusion of less severe children was burgeoning our observed rates of increases, and yet, found the intellectual dishonesty to question if Hannah Poling had autism or not, as if suddenly, in this one particular instance, a diagnostic report of having ‘features of autism’ as opposed to ‘autism’ was meaningful. As if that fucking mattered.  

On the one side there is the failure to recognize any semblance of nuance, of complexity, and on the other, a startling hypocrisy and lack of curiosity.  

A few weeks ago (maybe a few months ago, by the time I finally get this post published, at my rate), a paper came out that reported, among other things, children with autism were more likely to have mitochondrial dysfunction, mtDNA overreplication, and mtDNA deletions than typically developing children.  That paper, of course, is Mitochondrial Disorder In Autism, a new winner in the field of simple to understand, straightforward titles.  The good news is that Mitochondrial Disorder In Autism is another portrait of beautiful and humbling complexity with something to offer an open mind.  Maddeningly, my real world email address received an embargo copy of the paper, which is somehow protected from copy paste operations, meaning most parts from that paper here will be manually transcribed, or more likely, paraphrased.

This is a cool paper, it sheds light on the possible participation of a widely observed phenomena in autism, increased oxidative stress, gives us additional evidence that the broader incidence of mitochondrial dysfunction is significantly very higher in the autism population, and an possible illustration of a feedback loop.

Very briefly paraphrased (damn you, embargo copy!), the authors used samples of peripheral cells of the immune system, lymphocytes, to test for mitochondrial dysfunction.  This is a big step, it allowed the researchers to bypass the traditional method of muscle biopsy, which is both invasive and painful.  It is reminiscent of using lymphoblastoid cells as proxies for neural cells in genetic expressions studies; the type of small, incremental data that can get lost in the headline, but has potentially broad applications.

In Mitochondrial Dysfunction in Autism, according to the authors, lymphocytes were considered sufficient surrogates because they are power hungry and derive a significant portion of their energy needs from oxidative phosphorylation; i.e, mitochondrial function.   It was small study, ten children with autism and ten controls; I’m not clear why such a small sample was used, perhaps the laboratory time and/or dollar requirements involved with detecting mitochondrial dysfunction, even in peripheral cells, mandated that such small numbers be used.  (?)   Perhaps funding could not be obtained for a larger study without some preliminary results, and as is mentioned several times in the text, these findings should be replicated if and when possible. 

Two types of changes to mtDNA were evaluated for, the ratio of the total number of mtDNA to nuclear DNA (i.e., ‘normal DNA’), and the presence of deletions of parts of mtDNA. These changes are a lot different than what we normally think of in genetic studies, and here’s my short story (barely longer than my understanding) of how.  

Each mitochondria has a variable number of mtDNA copies, usually estimated at between 2 and 10.  The understanding on what a relatively higher, or lower number of copies of mtDNA means for an organism is ongoing and nascent; for example, findings of associations with lower mtDNA levels in elderly women and cognitive decline, or finding that mtDNA copy number associate positively with fertility, both of which were published in 2010 (there are, conservatively, a brazillion other studies with a broad range of topics).  Highly salient for our purposes, however, are findings cited by this article, Oxidative Stress-related Alteration of the Copy Number of Mitochondrial DNA in Human Leukocytes, which reports that cells experiencing oxidative stress had increased number of mtDNA copies.  In Mitochonddrial Dysfunction in Autism the authors report an increase in the number of mtDNA copies in the autism group. 

Secondarily, the authors also looked for differences in mtDNA structure, but again in this instance, not in the way that we frequently think about genetic studies; they were not looking for an A replaced G mutation that exists in every gene, in every cell, in the individual, but rather, different structural components that were indicative of damage within the copies of mtDNA.  Thus, it wasn’t so much a case of a blueprint gone wrong, as much of case by case differences in mtDNA; potentially the result of exposure to reactive oxygen species during replication. 

Changes in both copy number of mtDNA (increased), and structure (mostly deletions) were observed in the autism group. 

Up and above changes to mtDNA, several biomarkers of direct and indirect mitochondrial dysfunction were measured, including lactacte to pyruvate ratios, (which have been observed abnormal previously in autism and speculated to be resultant from mitochondrial problems), mitochondrial consumption of oxygen, and hydrogen peroxide production, a known signal for some types of mitochondrial dysfunction.  Several of the biomarker findings were indicative of problems in mitochondrial function in the autism group, including impaired oxygen consumption, increased hydrogen peroxide production, and as noted by other researchers, higher pyruvate levels, with a consequent decreased lactate to pyruvate ratio compared to controls. 

These findings were described by the authors like this:

Thus, lymphocytic mitochondria in autism not only had a lower oxidative phosphorylation capacity, but also contributed to the overall increased cellular oxidative stress.

In plainer English, not only was the ability to produce energy reduced, but the propensity to create damaging byproducts, i.e., oxidative stress, i.e., ROS was increased.  Talk about a double whammy!  There have been a lot of studies of increased oxidative stress in the autism population, one of the first was Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin–the antioxidant proteins, with other titles including, Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism, Oxidative stress in autism, Brain Region-Specific Changes in Oxidative Stress and Neurotrophin Levels in Autism Spectrum Disorders (ASD) and many, many others.  Could mitochondrial dysfunction be the cause of increased oxidative stress in autism?  Could oxidative stress by the cause of mitochondrial dysfunction in autism?  Could both be occurring?

Oxidative stress deserves a free standing post (or a few), but at a high level refers to the creation of damaging particles, called reactive oxygen species by our bodies during the course of many biological operations; including generating energy (i.e., the function of mitochondria).  The graceful management of these particles is essential for normal functioning; too little containment and there can be damage to cellular structures like cell membranes, or DNA.  You can measure these types of damage, and a wide swath of studies in the autism realm have found that on average, children with autism exhibit a state of increased oxidative stress when compared to children without that diagnosis.  A great variety of conditions other than autism, but which you’d still generally rather not have, are also characterized by increased oxidative stress, as are things that you can’t really help having, like getting old. 

(It should be noted, however, that in an illustration of humbling complexity, we are now learning that containing free radicals by all means possible may also not necessarily be a good idea; our bodies utilize these chemicals as signals for a variety of things that aren’t immediately obvious.  For example, there is preliminary evidence that too much antioxidants can cancel out, the benefits of exercise; our bodies were using the effects of exercise as a signal to build more muscle, likewise, we have evidence that oxidative stress plays a part in apotosis, or programmed cell death, and interfering with that may not be a good idea; in fact, it could, participate in carcinogenisis.  There is no free lunch.)

Mitochondrial Dysfunction in Autism speculates that oxidative stress and mitochondrial dysfunction could be linked, either by increased oxidative stress leading to problems in mtDNA replication (i.e., the observed mtDNA problems are a result of aggressive attempts at repair, repair to damage induced by the presence of reactive species), or by deficiencies in the ability to remove ROS; i.e., decreased glutathione levels as observed by James.   This really speaks towards the possibility of a feedback loop, something leads to an increase in oxidative stress that cannot be successfully managed, which causes mitochondrial damage, which leads to problems in mtDNA replication, which in turn, leads to dysfunction, and increased oxidative stress.  Again, from the paper:

Differences in mtDNA parameters between control children and those with autism could stem from either higher oxidative stress or inadequate removal of these harmful species. The increased reactive oxygen species production observed in this exploratory study is consistent with the higher ratio of oxidized NADH to reduced glutathione in lymphoblastoid cells and mitochondria from children with ASD, supporting the concept that these cells from children with autism present higher oxidative stress.  Increased reactive oxygen species production induced by mitochondrial dysfunction could elicit chronic oxidative stress that enhances mtDNA replication and possibly mtDNA repair.

Collectively, these results suggest that cumulative damage and oxidative stress over time may (through reduced capacity to generate functional mitochondria) influence the onset or severity of autism and its comorbid symptoms.




(My emphasis).  More on why a little later.

There is a lengthy section of the paper regarding the limitations of the study, including a relatively small sample set, racial differences between the participants, and the possibility that the number of evaluations made could impact the strength of some associations.  Detangling the arrow of causality is not possible from this paper, and likely involves different pathways in different patients.  None the less, it is additional confirmation of something gone awry in the power processing centers of cells in people with autism.  

This is a pretty small study, from a number of subjects perspective, and the pilot nature of the study is somewhat of a problem in trying to determine how much caution we must use when attempting to generalize the findings to a larger population.  However, on the other hand, if we look towards earlier findings, some of which were linked above, the reports in Giulivi should not really be that surprising. In fact, we should have been amazed if they hadn’t observed mitochondrial problems. 

Here is why:

We have voluminous observations of a state of increased oxidative stress in the autism population; Chauhan 2004, Zoroglu 2004, James 2004, Ming 2005, Yao 2006, James 2009, Sajdel-Sulkowska 2009, Al-Mosalem 2009, De Felice 2009, Krajcovicová-Kudlácková M 2009, El-Ansari 2010, Mostafa 2010, Youn 2010, Meguid 2010, and Sajdel-Sulkowska 2010, all are clinical trials that reported either increased levels of oxidative stress markers, decreased levels of detoxification markers, or both, in the autism group.  There is no way, absolutely no way that children with autism have less oxidative stress, or the same oxidative stress than children without that diagnosis, barring some mechanism by which all of the above studies are wrong in exactly the same direction.  There is just too much evidence to support an association, and as far as I know, (?) no evidence to counter balance that association.  [Please note that the above studies are for biomarker based studies only, I left out several genetic studies with similar end game conclusions; i.e., alleles known to be associated with increased oxidative stress and/or mitochondrial function are also associated with an autism diagnosis.]

We also have just a large body of clinical evidence that tells us that as oxidative stress and mitochondrial function are closely linked, as oxidative stress increases, so too do problems with mitochondrial function and/or replication; Richter 1998, Beckman 1998, Lu 1999Lee 2000, Wei 2001, Lee 2002,  Liu 2003, Liu 2005, Min Shen 2008 are useful examples.  Unless all of these studies, and many more, are incorrect in the same way, and the underlying physical foundations of why oxidative stress would lead to mitochondrial function are also incorrect, we must conclude that a state of increased oxidative stress, as observed repeatedly in autism, leads to a degradation of mitochondrial function. 

It turns out, there also a growing body of evidence linking oxidative stress and/or mitochondrial dysfunction to other conditions with a neurological basis (Rezin 2009), such as schizophrenia, (Prabakaran 2004, Wood, 2009, Martins-de-Souza 2010, Verge 2010Bitanihirwe 2011) or bi-polar disorder (Andreazza 2010, Clay 2010, Kato 2006, Kaikuchi 2005).  Here is the abstract for Oxidative stress in psychiatric disorders: evidence base and therapeutic implications:

Oxidative stress has been implicated in the pathogenesis of diverse disease states, and may be a common pathogenic mechanism underlying many major psychiatric disorders, as the brain has comparatively greater vulnerability to oxidative damage. This review aims to examine the current evidence for the role of oxidative stress in psychiatric disorders, and its academic and clinical implications. A literature search was conducted using the Medline, Pubmed, PsycINFO, CINAHL PLUS, BIOSIS Preview, and Cochrane databases, with a time-frame extending to September 2007. The broadest data for oxidative stress mechanisms have been derived from studies conducted in schizophrenia, where evidence is available from different areas of oxidative research, including oxidative marker assays, psychopharmacology studies, and clinical trials of antioxidants. For bipolar disorder and depression, a solid foundation for oxidative stress hypotheses has been provided by biochemical, genetic, pharmacological, preclinical therapeutic studies and one clinical trial. Oxidative pathophysiology in anxiety disorders is strongly supported by animal models, and also by human biochemical data. Pilot studies have suggested efficacy of N-acetylcysteine in cocaine dependence, while early evidence is accumulating for oxidative mechanisms in autism and attention deficit hyperactivity disorder. In conclusion, multi-dimensional data support the role of oxidative stress in diverse psychiatric disorders. These data not only suggest that oxidative mechanisms may form unifying common pathogenic pathways in psychiatric disorders, but also introduce new targets for the development of therapeutic interventions.

(my emphasis)

Given all of this, one might consider casting an extremely skeptical eye towards the argument that the observations in Mitochondrial Dysfunction in Autism are insufficiently powered to reach any conclusions about an association; at this point, I think it is fair to say that what should have been surprising finding would have been a lack of mitochondrial dysfunction in autism.   We need to rethink some foundational ideas about the relationship between oxidative stress, mitochondrial function, other neurological disorders, and/or assume that a dozen studies are all incorrect in the same way before the small number of participants and other limitations of this study should cause us to cast too much doubt on the findings.  The findings in Mitochondrial Dysfunction in Autism are not due to random chance.

All that being said, there are still lots of questions; the most intriguing ones I’ve seen raised in other discussions on this paper would include, Is the mitochondrial dysfunction physiologically significant? and secondly, What has caused so many children with autism to exhibit these physiological differences? 

I’ll admit it, early on in my online/autism persona lifetime, I’d have viewed the first question as largely deserving of a healthy dose of (hilariously delivered) sarcasm.  But the reality is that this is a more difficult question to answer than it would seem on the surface.  The reasons I’ve seen posited that this might be valid sound pretty good at first glance, i.e., the brain is the most prolific user of energy in the body, and problem with energy creation there are pretty simple to equate to cognitive problems.   And this might be what is happening, I don’t believe we have enough information reach any conclusions.  I will note, however, with no small amount of amusement, that the online ‘skeptical’ community had no problem with this exact argument in discussing what happened to Hannah Poling, as long as it was exceptionally rare. 

Specifically speaking towards the problems of physiological significance, we haven’t any direct evidence one way or the other that the mitochondrial dysfunction observed in muscle biopsy or lymphocytes is present in the CNS of people with autism, and this is an important distinction; it is known that there are large differences in mitochondrial need and function between tissue type, and it is almost always dangerous to assume that because you see something outside the privileges of the blood brain barrier, that you will see the same thing within it.  Therefore, we should remember that it is possible that the brains are unaffected, while the peripheral cells are.   

However, we do have some indirect evidence to suggest that there are mitochondrial function problems in the CNS in the autism population.  Based on studies that have measured oxidative stress levels in the brain, specifically Brain Region-Specific Changes in Oxidative Stress and Neurotrophin Levels in Autism Spectrum Disorders (ASD) we have preliminary evidence that areas of the brain are affected by high levels of oxidative stress.  Furthermore, we have a multitude of studies regarding an ongoing immune response in the brain in autism, and we know that the immune response can generate oxidative stress, and indeed, interact with some of the results of oxidative stress, potentially participating in a feedback loop.  

In short, we know that inflammation, oxidative stress, and mitochondrial function are closely linked; considering the fact that we have evidence of two of these processes being altered in the CNS in autism, barring an unforeseen mechanism by which this association is not in place in the brain, an exceedingly unlikely situation given our observations in other cognitive domains, it seems probable that some degree of mitochondrial dysfunction occurs in the brain as well as the periphery.   If this is sufficient to cause autism will require more studies; some evaluations correlating behavioral severity and / or multiple evaluations over time would be good starting points. as well, of course, as direct CNS evaluation.

The second question, towards relevance of these findings, the reason such a large percentage of children with autism appear to have characteristics of mitochondrial dysfunction is even more difficult to detangle.  The potential of a feedback loop existing between oxidative stress and mitochondrial function was problematic enough, but it seems likely there could be other participants, for example, the immune system.  There are repeated observations of an exaggerated immune response, from genetic predispositions to known toll like receptor promoters, circulating levels of endogenous factors associated with a vigorous immune response, baseline levels of cytokines and chemokines, and cytokine values resulting from direct toll like receptor activation.  Is the over active inflammatory response observed in autism causing the mitochondrial dysfunction through an increase in oxidative stress?  Is the increased oxidative stress causing an ongoing inflammatory response?  Studies evaluating for a relationship between these parameters would help to answer these questions.

For a real world example of why such a relationship might be possible, we can take a look at a paper that landed in my inbox around the same time that Mitochondrial Dysfunction in Autism did, Dopaminergic neuronal injury in the adult rat brain following neonatal exposure to lipopolysaccharide and the silent neurotoxicity.  This paper is another that shows some very difficult to predict outcomes as a response to an early life immune challenge.  Here is the abstract:

Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in motor dysfunction and dopaminergic neuronal injury in the juvenile rat brain. To further examine whether neonatal LPS exposure has persisting effects in adult rats, motor behaviors were examined from postnatal day 7 (P7) to P70 and brain injury was determined in P70 rats following an intracerebral injection of LPS (1 mg/kg) in P5 Sprague–Dawley male rats. Although neonatal LPS exposure resulted in hyperactivity in locomotion and stereotyped tasks, and other disturbances of motor behaviors, the impaired motor functions were spontaneously recovered by P70. On the other hand, neonatal LPS-induced injury to the dopaminergic system such as the loss of dendrites and reduced tyrosine hydroxylase immunoreactivity in the substantia nigra persisted in P70 rats. Neonatal LPS exposure also resulted in sustained inflammatory responses in the P70 rat brain, as indicated by an increased number of activated microglia and elevation of interleukin-1b and interleukin-6 content in the rat brain. In addition, when challenged with methamphetamine (METH, 0.5 mg/kg) subcutaneously, rats with neonatal LPS exposure had significantly increased responses in METH-induced locomotion and stereotypy behaviors as compared to those without LPS exposure. These results indicate that although neonatal LPS-induced neurobehavioral impairment is spontaneously recoverable, the LPS exposure-induced persistent injury to the dopaminergic system and the chronic inflammation may represent the existence of silent neurotoxicity. Our data further suggest that the compromised dendritic mitochondrial function might contribute, at least partially, to the silent neurotoxicity.

(my emphasis)

Briefly, the researchers challenged the animals with an immune stimulator shortly after birth, and then went on to observe chronic microglial activation and inhibited mitochondrial function into adulthood.  Behavioral problems included hyperactivity and stereotyped tasks (though these behaviors appeared to reverse in adulthood.  Subsequent challenge with methamphetamine in adulthood resulted in increased locomotive and stereotyped behaviors in the treatment group. 

Check that out!  These animals never actually got sick, their immune system had only been fooled into thinking that it was under pathogen attack, and yet, still showed chronic activation of the neuroimmune system and impaired mitochondrial function in dendrites into adulthood!  ).  In a sense, it might be appropriate to say, then, that the behaviors were not a state of stasis.  Talk about an inconvenient finding.

There is also the possibility that exposure to chemicals, such as pesticides, may be able to cause mitochondrial dysfunction. 

Finally, during the time it took me to put this post together, several other reviews of Mitochondrial Dysfunction in Autism landed online in places that purport to be bound by objective and dispassionate evaluation of the science of autism; Respectful Insolencence, LBRB, and Science2.0 all had posts (probably others too).  [The masochists out there that go through the discussion threads will note that several of the thoughts in this posting were experimented with in responses to these threads, ideas which were largely, or entirely, ignored.]  If you were to read these other reviews (I would recommend that you do), you might come away with the impression that Mitochondrial Dysfunction in Autism consisted of nothing more than criteria for selecting participants and limitations of the study.  The calls for caution in running wild with these findings are there, and I largely agree with this sense of caution, as is the admission that this is an area that should be studied more intently, but nowhere was there any acknowledgement of the consistency between these findings and the repeated observations of increased oxidative stress in autism and the biological reality that oxidative stress is linked with mitochondria function, nowhere was there any mention of the fact that the findings were in alignment with deficiencies in detoxification pathways as observed multiple times in autism, nowhere was there anything regarding our voluminous evidence of impaired mitochondrial function in a veritable spectrum of cognitive disorders.  Did the online skeptical community get a different copy of the paper that I did?  Perhaps, were they unaware of the repeated reports of increased oxidative stress in autism, and the incontrovertible evidence of an association between oxidative stress and mitochondrial dysfunction?  Is there a chance that their pubmed results regarding mitochondria and disorders like schizophrenia or bi-polar disorder are different than mine? 

I am afraid that this is what the vaccine wars and wrangling over the meaning of neurodiversity have done to us; the skeptical community absolutely went “all in” on the premise that the Hannah Poling concession was founded on a very, very rare biological condition.  They have sunk one hundred and ten percent of their credibility behind the notion that thimerosal based studies and MMR based studies are sufficient to answer the question of if vaccines can cause autism, or if we must, features of autism.  And now, with converging evidence from several directions pointing towards a confluence of mitochondria impairment and oxidative stress in autism and other neurological conditions, speaking towards the meat of Mitochondrial Dysfunction in Autism is more than just eating crow, it is akin to blaspheming, for if diagnosable mitochondrial disorder affects a meaningful fraction of children with autism, and mitochondrial dysfunction a  much larger percentage, the foundations behind the meme of the vaccine question as one that needs no further evaluations begins to fall apart.  That is a legitmately scary proposition, but one that is going to have to be reckoned with sooner or later; the only difference is that the more time passes, the greater the credibility strain on the mainstream medical establishment when, eventually, it is admitted, that we need to come up with good ways to generate quality information on vaccinated and unvaccinated populations. 

Similarly there is remakarble opposition in some quarters to the idea of imparied detoxificiation pathways, or indeed, a state of increased oxidative stress in some of the same places.  I think the underlying reason for this is that some of these early findings were used by some DAN doctors to promote things like chelation, almost certainly the wrong treatment for the overwhelming majority of children on whom it was performed; and in a well intentioned zeal to discount some of these practioners, as well as the outrage over statements by some (i.e., ‘toxic children’), the reality of the situation; that our children are more likely to have increased oxidative stress, do have less glutiathione,  became acceptable facts to bypass in the rush to hurl insults or wax poetic.   We can acknowlege that children with autism have these conditions while simultaneously expressing concern, or outrage, at the notion that this makes them poisonous; but ignoring the physiological reality of our findings does nothing to help anyone.  The data is the data. 

This is all too bad.  In fact, it is worse than too bad; there is no reason, absolutely no reason that a discussion on mitochondrial impairment must focus exclusively on the vaccine question, in fact, just the opposite.  There are lots of ways to achieve an endpoint of mitochondrial dysfunction, and lots of things besides vaccines that can be problematic for people with this problem. (including, of course, actual infection!)  But we have become so polarized, so reliant on hearing the same soundbyte laden diatribes, that any sense of nuance on the question immediately labels on as ‘anti vaccine’, ‘anti science’ (even worse!), or for that matter, ‘pro-vaccine’ or shill.  The questions raised by Mitochondrial Dysfunction in Autism are important and aren’t going to go away, no matter how inconvenient the follow up findings may be.  

– pD

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

Join 34 other followers