Monday, August 27, 2012

Autism, immunity, inflammation, and the New York Times

[Note: An interview that appeared 9/4/12 on Wired's Website of the writer of the op-ed piece I critique here and conducted by an associate of his seems to imply that I am not a scientist and should have "ask(ed) a scientist" before commenting on these issues. For the record: I am, in fact, a scientist, with a PhD in biological sciences and postdoctoral training, both in vertebrate developmental biology and the latter in mammalian developmental genetics (with mice!), areas associated with this discussion. In addition, I have spent 8 years deeply engaged in following, evaluating, and writing about autism-related research.]

The Preamble
On Saturday, the New York Times online ran a piece from its Sunday Review Opinion pages entitled, “An immune disorder at the root of autism.” The piece is packed with overstatements and overinterpretations and lacks much-needed modulation and qualification. More than that, it promises a "preventative" for autism that is, pardon me, off the hook(worm). 

The author is Moises Velasquez-Manoff, who has a book coming up, An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases. Although I understand that someone who has written a book may well have expertise in a specific subject area, a fund of knowledge does not give them carte blanche to bring their bias without scientific counterpoint to the editorial pages of the New York Times. Velasquez-Manoff's  book hits the stands on September 4. 
                                                                                                                    
Velasquez-Manoff's work appears to rely on the “hygiene hypothesis” to explain a host of modern-day ills that are, presumably, on the rise, in part because we’re just not toting around enough parasitic worms (more later). Among these modern-day afflictions, Velasquez-Manoff includes autism. Except that autism, you see, probably isn’t actually on the rise that much or a modern-day affliction. And the hygiene hypothesis itself is controversial** and remains a hypothesis that doesn't necessarily explain all immune dysregulation. I have a hard time taking controversial hypotheses in progress and faux epidemics as an unequivocal rationale for anything.

From the headline to the final paragraphs focused on using parasitic worms to treat or even prevent autism, the science as Velasquez-Manoff presents it is limited at best, and frequently unsourced and unreferenced. Where a source is given or traceable, the conclusions are overstated or cherry-picked. Yet to a lay reader, he writes plausibly and with confidence. The upshot is that anyone without a deeper understanding of immunology or autism could come away from reading this piece thinking that autistic children or pregnant women should immediately be exposed to parasitic worms and rolled around in dung as a cure. Lest you think I exaggerate about what people will do at the slightest hint of efficacy in autism, see here, here, here, here, and here

Squishy science, misrepresentative headlines, and hyperleaps to conclusions are not that unusual in science stories. But articles and editorials about autism require special attention to accuracy. Anyone paying attention likely is aware of the vaccine–autism controversy. Anyone paying a little more attention, particularly someone writing an article about autism, should know that using the words “inflammation” and “autism” or “immune disorder” and “autism” inflames the substantial number of people whose resistance to vaccines because of autism fears has led to outbreaks of pertussis and measles that in turn have led to fatalities. That use requires the support of an extraordinarily well-sourced, fact-based article.

Lest you think I overstate, Velasquez-Manoff’s piece has already made it onto the “mercury in vaccines causes autism” discussion boards, and someone tweetspammed me last night (with three tweets) about vaccines and autism in response to my tweet about this article. I’m sure the party has just begun. Accurate science, however, likely won't be one of the attendees.

The science
First, the headline: “An Immune Disorder at the Root of Autism.” No one knows what causes autism, but every week (or even every day), some new candidate turns up, either as a potential cause or adding to risk, from being the second born to having lungs with symmetrical branching. A big factor, according to most studies, is genetics, often in interaction with environmental factors--not “toxins” like pesticides or air pollution, necessarily, but factors like parental age. The vast majority of autism research focuses on one or other of these factors, sometimes both. Environment in the case of autism seems to primarily mean the womb, according to a good-sized twin study. Of course, the womb is a busy and complex place, so no one quite knows what happens there that might influence the development of autism or how the development of autism affects the womb. Many candidates exist, among them the hypothesis that a maternal infection during pregnancy might set the stage for inflammation that triggers autism. That’s a hypothesis, though, and even a generous interpretation of it doesn’t warrant such an unequivocal and--excuse me--inflammatory headline.

Inflammation and autism, as I noted above, are a touchy pairing. One of the core arguments of those who oppose vaccines because of autism fears--which the vast majority of scientific research has debunked--is that the vaccines trigger some kind of inflammation that brings on autism. Inflammation or dysregulated immunity may play a role in a subset of autism, but the body of research on autism and inflammation is, as yet, rather limited. Not a huge body of work to go on yet, but interesting research directions to follow.**

When a researcher or a writer becomes deeply engaged in a concept, like the idea that autism and inflammation are linked, it can be difficult to step back from that commitment to an idea and handle it with moderation and qualification. It’s also very tempting to take one’s hypotheses and create elaborate scenarios of “if that, then this, then that, then this” and then start to see them as actualities. But scientists and people who write about science should try to take one wary step at a time. One group at CalTech, led by Paul Patterson, which does work with a mouse model of autism, exercises a pretty good level of caution in reporting and interpreting their results, not failing to note that work done in mice is not necessarily an accurate reflection of how things will pan out in people.  

Velasquez-Manoff is not so cautious. First, he appears to describe autism as a “parallel epidemic” with autoimmune diseases, even though a careful review of the literature shows that there likely isn’t an “epidemic” of autism. I'm also having trouble finding any data to confirm an epidemic of autoimmune diseases (he provides no sourcing), although I find that incidence rates in general seem to go up with improvements in diagnostic tools, a scenario that is common with application of new technologies in many diseases and disorders. Without that parallel or even confirmation of either "epidemic," his carefully constructed, fragile “if that, then this” scenario suffers from that point on. 

Even if the parallel were accurate, his argument would suffer in other ways. For example, he takes the work from Patterson’s lab and states, without qualification, that in that model, “Autism results from collateral damage” of maternal infection of the mother mouse as an "unintended consequence of self defense" in pregnancy. Except that mice don’t have autism, which is a human neurobiological construct shaped in part by social and cultural perceptions of what is considered “normal.” I’m pretty sure the lives of mice don’t incorporate these features. I’ve worked with a lot of mice. I know mice. And we, sir, are not mice. The most we can justifiably say is that they may have “autistic-like” behaviors. That’s it.

This example of overstatement is just one of many that litter Velasquez-Manoff’s piece. In fact, the opening of the article is an overstatement. I’ll step over the lede’s reference to autism as an “affliction" (terminology that pains and incenses many autistic people) and go straight to graf two. There, we find what Velasquez-Manoff calls “the short of it.” He claims that a “subset of autism--perhaps one third and very likely more--looks like a type of inflammatory disease. And it begins in the womb.”

I’m guessing the headline writer didn’t make it to the second paragraph. But what has me scratching my head more is how Velasquez-Manoff can say without qualification that autism “looks like” an inflammatory disease that “begins in the womb” when actual autism researchers don’t have any firm idea of what causes autism or what the factors in the womb are. A subset of autism may be immune related, in part because of genetics. The writer doesn’t source his “one third” value, but I think it’s a generous inference from this Italian study. One third does not, however, equate to all cases of autism. Nowhere else in this piece does Velasquez-Manoff remind us of that subset distinction or qualify generalizations about autism, perhaps one of the most idiosyncratic of neurobiological conditions.

Velasquez-Manoff goes on to say that your immune system should work like an “action hero,” leaping into action accurately and without misfires before returning to a “Zen-like calm.” Your immune system is never in a state of Zen-like calm unless maybe you’re living in a sterile room at Plum Island, sanitized to the gills. In addition, your immune system is much more of an unpredictable and ungrateful harpy who will, on occasion, totally overreact to viral invasion and just kill you in the process; see, for example, the Spanish flu or the recent outbreak of H1N1. An action hero, this is not. Your immune system is not your buddy. It’s a cellular gang that follows instructions, even if those instructions result in collateral damage.

After this heroification of your immune system, Velasquez-Manoff goes on to say, without ambiguity, that the immune system fails in its presumed balancing act in “autistic individuals.” Not some autistic people. Not “might fail” or “some researchers hypothesize that it might fail.” No memory of that “one third” notation. Just… it fails in autistic people. Period.

And that’s where he lost me completely, not because I wasn’t following him but because that phrasing alone breaks the promise any science writer owes a reader to be as honest and warts-and-all as needed to ensure accuracy. It is simply indefensible to have written that sentence as though it were scientific gospel. Even the words of his second paragraph (subset, one third) don’t support it. It is not his last instance of this transgression.

No doubt much to your relief if you’ve read this far, I’m not going to parse this opinion piece sentence by sentence. Sourcing and citation are limited throughout. As he did with the Patterson work, the author overstates and leaps to conclusions that are not warranted. I’m just going to hit some points where the scientific leaping outdoes a show jumper on her best day.

Velasquez-Manoff gives a list of some of the factors that have been linked by correlation to autism, including a “mother’s diagnosis of asthma or allergies” in pregnancy. The list could consist of hundreds of factors, genetic and environmental, but he gives us only the handful arguably linked to immunity. He spends time on infection, particularly the finding from a Danish study that a viral infection resulting in hospitalization in the first trimester of pregnancy is linked to increased autism risk in the child. 

Although he says that blaming the autism "epidemic" on infections is "folly," it forms the backdrop of the piece. Infections and other stuff like maternal (of course) autoimmune gene variants, obesity, and metabolic syndrome, he says, lead to inflammation that causes “maternal immune dysregulation.” He calls these "paths" to autism, even though in all cases, they are correlations associated with increased risk, not causes. Indeed, no one has resolved the chicken-egg question of the relationship between the womb and autism: Does the development of autism influence the womb environment or does the womb environment influence the development of autism? 

Then Velasquez-Manoff references another Danish study from last year that he calls “direct evidence of this prenatal imbalance,” saying that amniotic fluid samples from newborns in Denmark who later were diagnosed with autism “looked mildly inflamed.” The thing is, that Danish study largely found very little evidence at all of elevated inflammatory markers investigated in the amniotic fluid in the 331 samples from children later identified as autistic. The one marker they identified as increased was  MCP-1, which, they concluded, “may decipher an etiologic immunologic dysfunction or play rather an indirect role in the pathophysiology of (autism spectrum disorder).” What Velasquez-Manoff doesn’t note is that the Danish researchers did not find elevated levels of any of the markers of inflammation when comparing the entire autism and control cohorts but found these MCP-1 correlations only after breaking down the cohort into groups based on specific autism diagnoses.

The molecule in question is known for its involvement in neurodegenerative diseases. Autism is not neurodegenerative. MCP-1 was identified in one study as elevated in a study of post-mortem autistic brains, but much of that cohort of 11 also had epilepsy. In other words, a correlation and a confounded finding in a small group of post-mortem brains isn’t enough to warrant using the words “direct evidence” of a hypothesized prenatal imbalance as causative in autism. It’s interesting stuff and worth following up, particularly as it relates to a potential subset of autistic people with immune dysregulation. In the interests of intellectual honesty and absence of follow-up as yet, however, we have to leave it at that. 

Velasquez-Manoff then asks, “What has happened to the modern immune system?” and goes on to assert that the concepts underlying the “hygiene hypothesis” also underlie autism and correlations between autism and maternal autoimmune disorders or asthma. An “evolutionary answer,” he says, is that we are no longer sufficiently riddled with parasites and microbes (we actually still have our microbes), so our immune system, twiddling its presumably heroic thumbs, casts its roving eye elsewhere--i.e., on ourselves. See, people who still live with parasites, he says, “don’t suffer from inflammatory diseases as much as we do” (italics mine). “We,” I assume, being the clean people of the western world. No sources given, and that assertion does not dovetail with, for example, what we know about asthma rates in Latin America (really high) versus Western Europe (not so high), although in places where things like leprosy, parasitic worm infections that include river blindness, and nasty bacterial eye infections are high, type 1 diabetes is low. Raise your hand if you're willing to make that tradeoff. And then he says, “Autism also follows this pattern” and “seems to be less prevalent in the developing world.”

After I cleaned up the pieces of my cranium, I suffered through his eliding of the fact that when you’re dealing with intestinal parasites and their friends, you and your government may not really have the time to go around carefully diagnosing developmental disorders. I suffered through his unsourced dismissal of epidemiologists who say as much, and I just about had a coronary when he cited “at least one (unnamed) Western doctor” (the best kind, you know) who had found autism was “nearly nonexistent” in a Cambodian population “rife with parasites and acute infections.” Um… if, as Velasquez-Manoff seems to argue, maternal infection sets the stage for maternal immune dysfunction and presumably autism, how is it that a population rife with acute infections evades autism? He doesn’t ever name the “Western doctor,” but autism does exist in Cambodia [ETA: link references an autism population in that nation--"an additional unserved population in Cambodia was children with disabilities. Children with Down Syndrome, autism, or other disabilities typically led isolated lives"--and describes a specific case; see also PDF linked below, which describes data from an evaluation study in Cambodia. I try to avoid paywalls, but here and here are studies addressing developmental disabilities/mental health in the developing world, including Cambodia, and factors influencing the lack of previous diagnosis], and while we’re at it, here are a few other things Cambodian children must endure because they’ve got this great “evolutionary”-based existence that 'protects' them against autism.

[FYI: Here is a great summary [PDF of PowerPoint] of work going on in “developing” countries to better establish what the rates of autism are. I’m not sure what the rate of parasitic worm infections is in each of these places, but I imagine there’s some overlap.]

Whether he means to or not, Velasquez-Manoff then echoes one of the favorite refrains of the anti-vaccine movement, that back when the world was a beautiful place of dirty, worm-infested children, clean water, 100% breastfeeding, and no television, it was a place where the immune system could do its work peacefully and with presumably Zen-like calm, weeding out the weak among us and leaving behind the strong. Of course, infant mortality was sky high, primarily as a result of diseases against which we vaccinate. And I don’t know about you, but I’d prefer to avoid shitting out worms and parasite eggs on a regular basis. But Velasquez-Manoff references those good old days wistfully as the “world of yore” and claims that scientists “working on autism” just aren’t “generally” aware of this evidence linking our modern-world lack of worm parasites, subsequent inflammatory condition, and autism. Poor, stupid clueless autism researchers. He then goes on to cite two people who are not autism researchers.

One of these scientists not working in the field of autism, William Parker of Duke University, compares sewer rats and clean rats in his work (fun!). The sewer rats have a lot of parasites and the lab rats don’t. The sewer rats have “tightly controlled” inflammation; the clean rats don’t.  This researcher and “many others” (unnamed others) think that we should still be sewer rats. [NB: Just as we are not mice, we also are not rats]. Then Velasquez-Manoff quotes Parker noting that it was all cool when we just had some allergies and autoimmune disease because we were too clean, but then adding, “but autism? That’s it! You’ve got to stop this insanity.” If I’m inferring correctly, we have to stop the insanity that is autism--not my phrasing--by picking up some worms and acute infections. Autoimmune diseases? OK! But autism? Insane.

And then the kicker. Velasquez-Manoff actually says that we can stop the insanity: “Fix the maternal dysregulation,” he writes, “and you’ve most likely prevented autism” (italics and jaw-dropped boldface mine). This unequivocal statement is a core untruth of this article. And possibly without meaning to, Velsaquez-Manoff now echoes an even more dangerous refrain from the history of autism research: refrigerator mothers. Except here, the mothers are “dysregulated,” with dangerous wombs and frantic immune systems that have not achieved the appropriate Zen-like state during her pregnancy. I'm expecting Freud to pop in at any moment and start lecturing us about hysteria.

This article no doubt will have many mothers of autistic children scanning their memories of whether they had infections during pregnancy. It no doubt will have pregnant women feeling at least a little paranoid every time they develop an upper respiratory illness or sneeze. No doubt, women with autoimmune disorders, which have a severe female bias whether you're western or not (and generally aren't linked with behaviors associated with autism, even when the nervous system is involved), will worryworryworry, given this specter of the autism "insanity" and their own genetics. And again, I don’t see how desiring to prevent autism with a return to days when everyone had “acute infections” jibes with the implication that maternal infections during pregnancy are linked by subsequently induced inflammation to autism.  

How do we fix this non-Zen-like maternal dysregulation? Worms. Parker proposes “pre-emptive restoration” of what he calls “domesticated” parasites into all people, everywhere, as though parasitic worms were like docile farm animals grazing away in our intestines. [NB: the definition of parasite is an organism that lives in or on a host and harms the host.] In case you think that’s what is insane, there was a clinical trial planned at the Mt. Sinai School of Medicine to try the eggs of these worms to treat adults with autism. The recruiting status of this trial has not been updated in awhile. Velasquez-Manoff writes that a trial is "under way" at Montefiore Medical Center and the Albert Einstein College of Medicine, but I find no hits at clinical trials.gov reflecting that. At the Albert Einstein website, I find such a trial described with a note that says, “This study is still pending.” Perhaps potential candidates have seen pictures of the worm in question and found themselves declining. Regardless, “pending” is not the same thing as “under way.”

The worm in question is a whipworm that typically parasitizes pigs, and there doesn’t seem to be a disease or disorder it or its wormy brethren are not claimed to help. Some of it may be valid and looks quite interesting, but the successful trials have been in autoimmune disorders. No data exist to support using them to treat or prevent autism, much less to claim that they would be preventative. Lest we handle this too lightly, I’ll add that infections with parasitic worms afflict an estimated 740 million people and can cause anemia and malnutrition. Having a bunch of worms growing in your intestines generally isn’t preferable to not having them there.

As he closes with two paragraphs in which he uses, without preamble, the word “superorganism” twice, Velasquez-Manoff then violates science yet again by calling this plan to colonize all people with worms an “ecosystem restoration project.” Never mind the plain fact that you simply can’t go home again when it comes to ecosystems and that colonizing our guts with pig parasites isn’t exactly replaying our evolutionary history. Either way, we are not the organisms we were 10,000 years ago or even 1000 years ago, not even counting the worms, and we won’t be again. Talking about “days of yore” and “time immemorial” doesn’t backtrack the collective changes our species has accumulated since the good old days of rampant parasitic infestations and high infant mortality. And my hope is that articles like this one won’t backtrack us to viewing all of autism as rooted in immune dysfunction and find ourselves once again staring into the abyss of vaccine panic.

What we have here is an argument that relies on shaky and shifting hypotheses of autism and autoimmune epidemics and hygiene, built using sparse data and scientific hints, a poor understanding of basic evolution and ecology, and a paradox of calling for a return to a more infectious past to “cure” autism while blaming immune-dysregulated, occasionally infected mothers of the present for …  autism. In his closing, Velasquez-Manoff argues that evolution provided us with a roadmap of the original microbial and parasitic ecosystems we once were, one that, presumably, if we follow it, will guide us out of the “insanity” and “affliction” that is autism. If it’s possible, that’s where he’s most wrong. Evolution isn’t something that happens with a plan. To describe it in those terms is to have a profound failure of understanding of what evolution is. Where we’re going, evolutionarily speaking, there are no roads.  And it would be better for most of us if there weren’t any parasitic worms, either. 

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**By "rather limited," I mean by comparison to other autism-related studies, such as gene variant studies, although some of those involve immune-related genes, and that most of the studies available are correlational, thus sketching only a relationship without a cause-effect established. For a comparative, search PubMed for combinations of autism, genetics, genes, immune, immunity, inflammation, etc., with particular attention to mechanistic and functional studies available.
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Update: The writer of the original op-ed has posted an annotated source list on his personal Website. I have analyzed the list and the annotations in the context of the "cause" argument here.

100 comments:

  1. Thanks for confirming my initial suspicions about that article when I saw it yesterday. As you point out, the problem is not merely that he knows little about autism, but he seems to know little about biological science, too. "Ecosystem restoration project", indeed! I hope you will submit a condensed version of your critique as a Letter to the Editor, or possibly for consideration as a follow-up op-ed. You need a larger audience for your important critique.

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  2. Excellent assessment of the piece and the state of the work. And there's that whole other thread of research that suggests that the burden of infection in kids in the developing world stunts their brain development. That work (also not something I'd draw firm conclusions on just yet) could have implications for this proposed strategy too. A good piece summarizing that was here: http://www.economist.com/node/16479286?story_id=16479286

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  3. This is a great article debunking the claim about autism, autoimmunity, and inflammation. However, I think you are a little unfair to the "hygiene hypothesis". This idea is one that has a fair amount of support, including a reasonable mechanism based on the known role of IgE in type I autoimmunity (anaphylaxis) and also in mediating responses to parasitic infection. I also think you should know that your asthma citation (about Latin America) doesn't support your point - the abstract clearly states that the asthma seen in Latin America is mostly non-atopic, and thus unrelated to autoimmunity. I have no expertise in autism, and no wish to wade into the autism wars, but the idea that parasitic worm infections in the developing world are related to the much lower rates of allergy and autoimmunity is not a bad one.

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    1. I certainly didn't mean to be unfair about it but to point at that there was controversy surrounding it and that it might not apply broadly to all inflammation-related disorders (e.g., asthma). My observation wasn't supposed to relate to autoimmunity per se, but to *inflammatory* disorders in general (the previous quote references "inflammatory diseases"). I don't think the idea that worm infections might be related to lower rates of allergy, etc., is utter nonsense (and I don't say that, either) but ... I don't buy the leap from that to "preventive for autism," either.

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  4. Great job! You've said what I was thinking - but articulate and organized. I can now point friends and family to this piece :)

    Loved this phrase: when you’re dealing with intestinal parasites and their friends, you and your government may not really have the time to go around carefully diagnosing developmental disorders.

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  5. Brilliant! I'm counting on this being widely read and shared!

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  6. Great critique and commentary. I'll be posting this to friends who posted the NYT article and to The Institute for Public Health Genetics Facebook page.

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  7. The incidence of the autoimmune disease type 1 diabetes has been increasing since the 1950s in industrialized countries around the world. It's not because of better diagnosis; type 1 is a fatal disease if untreated, has been diagnosed since ancient times, and has been treated with insulin since the 1920s. See: http://www.ncbi.nlm.nih.gov/pubmed/19481249, http://www.ncbi.nlm.nih.gov/pubmed/12453886.
    It's not genes either: http://www.ncbi.nlm.nih.gov/pubmed/15530631.

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    1. Thanks for the links; I believe it is also increasing in other areas, as well?

      I understand that it is fatal, etc.

      Don't you just love PubMed?

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  8. What an amazing post. Thank you for the play by play take down full of well sourced links and engaging writing!

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  9. Slow clap...

    Thanks for doing all the legwork needed to rebut this article. So well laid out. I just wish it had enough of an audience. Have you thought about submitting a shorter version as a letter to the editor?

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  10. I loved reading this! Sharing this to everyone!

    This Moises Velasquez-Manoff guy seriously needs to re-do his homework! As a person with Autism I was completely offended and appalled with his 'findings' and 'facts'.

    I'm not a rat, I'm not a mouse, I'm not some sort of BRICK WALL in the way of the 'proper' evolution tack that needs to be cured and gotten rid of.

    I am a person who doesn't want to be infested with worms that can harm me and for all you know, Autistic and Aspergers people ARE the "PLAN" for evolution in humans and Nero Typical s are the ones who are lacking.

    Moises Velasquez-Manoff needs to go live in a 3rd world country where he can jump around in all the parasite infested dirt and water he wants, where they often don't have the proper resources to help people with physical sickness and disorders let alone diagnose people with behavioral alignments like Autism, OCD, ADD, ADHD, and many, many others.

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  11. Thanks for the clarification and the critic of the ill constructed argument. I love your witty text ! I'm also a bit fed up with the "invention of tradition" (Hobsbawm & Ranger) in regard to immunity ...

    Kind regards Patricia (in Switzerland)

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  12. Hello friends -

    I figured this article would stir up some trouble; but I find myself on the outside looking in, largely in agreement with the OP@NYT on many big points.

    If anyone thinks that there isn't an change in the number of autoimmune disorders, try sending your child to school with a peanut butter sandwich and see what happens. How many children in your child's grade school have an epipen on them? Did any of us know what an epipen were when we were in middle school?

    If you want to know if asthma rates are rising or not, why not follow the scientific american link on this thread, the title of which is Why Are Asthma Rates Soaring?

    Type 1 diabetes is also on the rise:The Rise of Childhood Type 1 Diabetes in the 20th Century [link culled / character restriction]

    Then Velasquez-Manoff references another Danish study from last year that he calls “direct evidence of this prenatal imbalance,” saying that amniotic fluid samples from newborns in Denmark who later were diagnosed with autism “looked mildly inflamed.”

    Though the OP@NYT did a poor job of referencing all of their links, I believe that you have mis-identified the Danish study regarding amniotic fluid and further autism risk regarding a state of increased inflammation. They likely were referring to: Amniotic fluid inflammatory cytokines: Potential markers of immunologic dysfunction in autism spectrum disorders.

    And then the kicker. Velasquez-Manoff actually says that we can stop the insanity: “Fix the maternal dysregulation,” he writes, “and you’ve most likely prevented autism” (italics and jaw-dropped boldface mine). This unequivocal statement is a core untruth of this article.

    This might be a stretch, but it isn't a jaw dropping stretch. This post mentioned Paul Patterson, who has done a ton of the animal studies on autism. Here is a quote from one of his papers, Effects of maternal immune activation on gene expression patterns in the fetal brain [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337077/]

    Maternal infection is a risk factor for schizophrenia and autism. In the case of schizophrenia, a wide variety of infections during pregnancy (viral, bacterial, parasitic) are associated with increased risk for this disorder in the offspring. Summing these risks, Brown and Derkits1 estimate that >30% of schizophrenia cases would be prevented if infection could be averted in pregnant women.

    He also goes on to speculate on affecting the innate immune response in order to attenuate the effect of a maternal immune activation.

    Finally, what is the critical time window for modulating the IL-6/crystallin pathway during which we can reverse the detrimental behavioral effects of MIA?

    That's the quote from a Paul Patterson paper published in Translational Psychiatry (impact factor 16). This study was funded, in part, by NIH grants. None of the peer reviewers, or editors of the paper felt it was inappropriate to question if altering IL-6 pathways could "reverse the detrimental behavioral effects of MIA". While the OP@NYT is overly simplistic, the core idea of modulating the immune response to affect outcome is being considered as a valid avenue to evaluate by real autism researchers.

    The animal literature is absolutely littered with examples of immune challenges having 'black swan' style effects if they occur during developmentally critical timeframes, and most importantly, this data does not need a phantom force to explain the correlation. There you don't need anything else except an immune response to generate altered neuroanatomy, neuroimmune profiles, seizure susceptibility, and behavioral patterns in the treatment group.

    (409 chars == stinky)

    - pD

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    1. pD, thanks as always for commenting. As the author did not specify the Danish study referenced, it is hard to know which one was meant,mans I thank you for calling attention to this one, in which the authors found elevated levels of cytokines for autism and for "other psychiatric disorders," which again raises the chicken-egg question and is not specific only to autism.

      I did not dismiss the potential role of immune dysfunction/inflammation in a subset of people with autism; my major issue with that op-ed was the confident generalization and lack of qualification. Indeed, it seems entirely plausible to me for a specific subset, but my impression of that is largely anecdotal and based on studies like those you cite from Patterson et al.

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    2. I had a peanut allergy in grade school (1970s). My siblings all had other terrible allergies (1950s-60s). We didn't have epi-pens but could have carried them had they existed.

      What we didn't have was a megaphone about our family of allergies and extensive social media to talk about our allergies at excruciating length. Nor was diagnosis and reporting as good. Nor did we feel it was the rest of the culture's fault and that others should be prevented from having foods because we were allergic.

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    3. pD, I'm wondering which study *is* the referenced study now. V-M wrote, "Earlier this year, scientists presented direct evidence of this prenatal imbalance. Amniotic fluid collected from Danish newborns who later developed autism looked mildly inflamed." The one I cited fits the description and is from "earlier this year." The other is from late 2011. Regardless, thanks for pointing it out.

      Another thing that seems open to me, although I am not at all an expert in amniotic fluid, is the source and meaning of elevated cytokines in amniotic fluid. For example, in some cases, they're viewed as being correlated with protection ... e.g., http://www.ncbi.nlm.nih.gov/pubmed/22699404

      Finally, because I am (was) a developmental biologist, I am acutely aware of the importance of developmental time points/windows in determining outcomes. I by no means dismiss any of the literature; I simply am very uncomfortable with anyone's being unequivocal or stating these things without qualification when so much remains unknown.

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    4. Regarding anecdotes about allergies: In my sons' collective dozens of classroom experiences, we had only one in which peanuts were verboten specifically for the class. I have never personally known anyone with a peanut allergy (that I can recall or know of), although I have a nephew who had a genuine dairy allergy as a very young child, but he's now outgrown that.

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    5. Thinking more about amniotic fluid ... from what I infer is the same set of Danish samples, Simon Baron-Cohen found elevated levels of androgens across the hormone metabolic pathway (obviously looking into this as part of his androgen hypothesis of autism); I wrote about that a little here: http://www.thinkingautismguide.com/2012/06/imfar-2012-androgens-and-autism.html. Androgens affect cytokine levels, but which ones, when, and where varies. Curious to see if anyone looks into that connection.

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    6. Mary - in further "allergies not all new" news, I tend to avoid eating bread, because it makes me bloated and feel generally horrible. Call it an early 21st century wheat intolerance...

      ... except that my grandma died in January, two weeks off her 97th birthday, having spent the past fifty years letting bread go stale for a day or two before she ate it, because fresh bread upset her stomach. Exactly the same symptoms, except that I generally describe it as a very mild wheat intolerance and she called it "gives me a bit of a dicky tummy". And the fact that I have enough alternatives that it's fairly easy for me to avoid bread if I want to. Pasta, rice, couscous, bulgar wheat, quinoa and so on weren't much of an option in 1950s Grimsby, when it was bread or potatoes or pastry or nothing.

      She also avoided red wine, oranges and chocolate as migraine triggers. But for some reason, that's totally different from modern day allergies.

      And then there's Mr Woodhouse and his gruel...

      --- Another Mary!

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    7. @Mary II It's odd you mention that because I asked in another venue a few weeks ago what people must have done generations ago when they had celiac, etc., and one responded that her (great?) grandmother and other relatives basically just about died of malnutrition because ultimately, their intestines began to self shed (!). No one knew why.

      Mr. Woodhouse also thought eggs should be very perfectly soft boiled. I wonder what effect that was supposed to have.

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  13. This takedown was fun to experience. I was getting very involved, "Oh, he did NOT just write that! You go, Emily! Bam!" (science writing as a full-contact sport).

    I'm glad you hit on the longing for the fantasy of the perfect "natural" world that underlies so much of alternative medicine and alternative theorizing about anything that seems unusually wrong with the modern condition. It's such a tragedy that Autistic bodies are being used as fodder and scaffolding for these destructive fantasies. Thank you for your advocacy, and for making sense out of all the nonsense.

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  14. Looking forward to your responses after his book hits the racks (or the e-devices) Sept. 4.

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  15. Immune Balance, Homeostasis, and Autism Spectrum Disorders (ASDs). Perhaps you prefer my post on this subject? http://drhellengreenblatt.info/2011/08/immune-balance-homeostasis-and-autism-spectrum-disorders-asds/ Thank you.

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  16. I'm surprised that you characterize the Hygiene Hypothesis as "controversial" -- there are strong indications that there is a correlation between some auto-immune diseases, iNKT vs Type II NKT populations, and early exposure to antigens. I have no opinion on the "autism-is-an-autoimmune-disorder" position, but I thought I should raise a flag for the HH.

    "Early exposure to germs and the Hygiene Hypothesis", Dale T Umetsu, Cell Research (2012) 22:1210–1211.
    http://www.nature.com/cr/journal/v22/n8/full/cr201265a.html

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    1. I characterized it that way because I found that term frequently in the literature about it, e.g., http://www.ncbi.nlm.nih.gov/pubmed/20415858. That doesn't mean it's invalid, just that it's not unchallenged or as potentially sweeping in application as some think.

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  17. I am a pediatrician with a developmental fellowship. I practice on long island and have 2 nephews with autism ( 17 and 21 years old. There are a number of doctors, chiropractors etc. who "treat" autism on the basis that they know it's an inflammatory condition. A couple of them have give Actos at double the adult dose, as a trial and claim that out of 25 children all were doing better. We all know the chelation, special diets, special ( in that it costs hundreds of dollars a year ) Vit B12, Secretin, and now the boom in hyperbaric oxygen centers. These doctors main training is in pediatrics, podiatry, and obgyn. They appear on local TV and tout their knowledge. What can't be argued is that their bank accounts have risen exponentially. They are the most capable parasites of all. There is no oversight and other than Paul Offit, no real response from the health systems or politicians who are supposed to be protecting people and children from these charlatans. Years ago when secretin was the new cure in town my sister in law had 20 people lined up for the drug. It was $1500 a dose. I refused to do it for my nephews or anyone else. They ended up seeing a neurologist at Albert Einstein who said she wanted to study it anyway and only charged $1000. The irony is that my younger nephew was sick and couldn't go. The day after he said his first word Needless to say how much money that coincidence saved my brother. What you fail to mention in your wonderful article is there is another collaborator here, and that is the New York Times. That paper on Sunday could have been sold next to the National Enquirer at the supermarket. Not the first time they have shown such utter irresponsible and Sarah Palinesk reporting. ( I would cancel the subscription but I love the sports and science times, and most importantly, it lays out to perfectly to read when I am on the toilet. ) Anyway, I appreciate that people like you are around. At least I know that most of my patients will not have taken the time to read such a massive "opinion" piece.

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    1. Thanks for your comments. When it comes to autism, I don't think that we can, in good conscience, partition public reaction to public commentary from a sober focus on the chugchugchug of scientific progress. When we write about autism, whether as scientists or science writers, I think it's important to stick as much as possible to the most limited interpretations. Your experience is one reason I argue for that.

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  18. Awfully snarky response that comes very close and actually crosses the line into some of the very territory it's complaining the original NYT piece strayed into. It's important to note that it was an Op-Ed piece, not a research article being published in a scientific journal; the expectation that every fact be sourced and qualified is unrealistic. Had this response been submitted to the editor at The Times, I suspect it would have been returned with instructions to cut the length by half and then some. Beyond that, the sense of indignation is overblown. I don't necessarily accept the author's assertions (I'm very dubious about some of them), but I'm not willing to reject them out of hand, either, or nit pick every comma and semi-colon looking for some angle from which to discredit the ideas or the form in which they were presented.

    The idea that this article shouldn't have been published because it doesn't meet some hyperbolic level of qualification or because of of some unintended reaction among the anti-vaccine crowd is just plain nuts. People should always be free to express ideas. You can disagree, you can publicly refute, you can offer alternative ideas, but once you start criticizing a legitimate news source for publishing in the first place, you've crossed into censorship. That does no one any good.

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    1. I noted in the opening sentence that it was an opinion piece. Obviously, we disagree on the rest, except that part about commas and semi-colons.

      Delete
    2. Would the Times have printed an opinion piece by Congressman Akin? The whole presentation looked like a scientific article. Sorry, they choose to print what they want so they have ultimate censorship. The piece was a belief system that is dangerous, expensive to those who are desperate, feeds junk science and causes needless angst, particularly to any mother who may get sick during pregnancy. Mother's feel guilty enough about any issues their child may have they do not have to be exposed to a belief system that is given credibility by a " well respected newspaper. " Those of us who have to deal with the fallout can ask for responsible journalism.

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    3. Anonymous--not to be argumentative, but The Times doesn't exercise censorship; as a news publication they have a choice. I've never heard anyone, even their most vociferous critics, accuse them of censoring anyone. Clearly, they can't print everything, so they have to choose. Your riff about junk science and guilty pregnant mothers seems pumped up to an emotional level that's not appropriate for the circumstance. This guy is *not* Andrew Wakefield. We're all a little gun shy after years of having the loudest voices in the room be the Jennys of the world, but we need to be careful to not suppress legitimate discourse simply because we disagree with someone's opinion. That's a very bad idea.

      To answer your question, I am absolutely 100% positive that if Congressman Aikin offered to write an Op-Ed piece for them, they would print it in a heartbeat; they print opinions contrary to their official editorial position all the time. I kind of think the congressman's people would advise against it, though.

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    4. Oh, and for the record, I'm the father of an 11 year old non-verbal autistic boy. I know all about dealing with the fall out.

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    5. Do you remember David Kirby, writer for times, and whose book " Evidence of Harm" was touted all over including Imus's wife. Read Paul Offit's books if you would like to learn about junk science, vindictiveness, and autism. No, the author is not Andrew Wakefield, but he is one of the enablers for the Wakefields and profiteers of the treating autism industry. As you are sadly aware, the money that goes to these people out of understandable desperation ( if there is no answer follow the money ) is going to be needed when the children become adults. Can the people who offer the cures and take your money pass lie detector tests, probably. Just like Madoff could have. As far as pumped up emotional level, I deal not just with my family, but 100's of others so my experiences are everyday and numerous. I only see these charlatans growing in number. People who have unlimited funds can survive it, but those who take our mortgages on their houses, or strip their bank accounts cannot. This blog exists because of a person who is emotional about trying to bring some understanding to an easily manipulated subject. So go to your son and enjoy every positive glance, smile, and interaction. Hug him, kiss him, tell him you love him as he loves you and let's not waste anymore time on defending those that that look at your son in dollar signs or those that enable them.

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    6. "This blog exists because of a person who is emotional about trying to bring some understanding to an easily manipulated subject."
      No, it doesn't. It exists because I am a writer.


      "So go to your son and enjoy every positive glance, smile, and interaction. Hug him, kiss him, tell him you love him as he loves you."
      I spend all day, every day with my son, but thanks for the advice. My work and my ability to love, interact with, and hug my son are not mutually exclusive.

      "and let's not waste anymore time on defending those that that look at your son in dollar signs or those that enable them."
      We have different ideas about what constitutes a waste of time.

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    7. My remarks were a reply to Gomer Kierkergard not you. I have nothing but admiration for your blog. I did not know you had an autistic child until this reply. This reference was to Gomer as was the waste of time arguing between the two of us. It was actually a defense of your wonderful response to the NYT article. Certainly emotion and life experiences does have a lot to do with our interests and responses to various topics. I certainly responded to this blog because of mine and your cogent piece was because of yours. This hits home to a lot of us. I don't see emotion as negative if it causes a rational interest and in your case rational analysis. Again I refer to Paul Offit. Perhaps passion would be a better word but that is also emotion. Please do not take offense at remarks that were not at all directed toward you and was just trying to defend what you do and try to end a dialogue with a person who is suffering. Friendly fire?

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    8. One of the drawbacks of Blogger's not threading comment replies to more than one level. Having been told on more than one occasion in such situations to just "go hug my child," I assumed you were talking to me. Apologies.

      Delete
  19. Emily, what do you think of this Sutter stem cell clinical trial that just started that is based on the immunity hypothesis?

    As a stem cell scientist, this trial worries me..

    http://www.sacbee.com/2012/08/21/4743150/sutter-neuroscience-institute.html

    Paul

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    1. Hi, Paul-- I actually wrote about that a couple of days ago, here: http://www.emilywillinghamphd.com/2012/08/stem-cell-clinical-trial-for-autism.html

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    2. Also, your critique and comments on that are welcome.

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  20. I also find it frustrating when the NYT publishes articles like these and then allows no comments on them.
    Paul

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  21. Wow. Not to be overly simplistic, but- SMACK.DOWN. Love it!

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  22. There actually IS a pretty extensive peer reviewed literature correlating abnormal levels of immune molecules (such as cytokines) and various neurodevelopmental disorders, such as autism and schizophrenia. However, the link between these two is unclear although various mechanistic explanations exist, for example several cytokines are known to modulate neural processes necessary for normal brain development. Yet there is no clinical evidence, that I know of, that shows that treating inflammation results in improved outcomes in treating neurodevelopmental disorders. Unfortunately all the anti-vaccine quackery and other bogus alternative treatments to autism based on this idea, Ithink put a serious hindrance on proper research into the links between autism and immune dysfunction.

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    1. My reference to 'relatively' there was that in comparison to, say, genetics and autism or other environmental factors and autism, the literature for either of which numbers in the thousands, whereas a search on autism/inflammation (if I recall correctly) or autism/neuroinflammation turns up a couple of hundred and a couple of dozen hits, respectively. Not sufficient for the lack of qualifiers in this op-ed. I am aware of the literature showing that cytokines modulate normal brain development. Again, if I infer correctly, one of the issues with the correlations is that it's difficult to tease out which came first. What I've written isn't a denial of the potential role of these factors in autism--a subset of autism. And for the reason you cite in your last sentence, I think it's particularly important to be as cautious as possible in interpretations and to avoid generalizations and hyperbole in characterizing them.

      Regarding the clinical evidence question, I looked into that, too, for a previous post I wrote about autism and inflammation and an upcoming stem cell trial, and yes, there is very little suggesting that inflammation treatment is efficacious.

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  23. @Namenzia -

    Yet there is no clinical evidence, that I know of, that shows that treating inflammation results in improved outcomes in treating neurodevelopmental disorders.

    There have been some primitive animal experiments to test the effect of attenuating the effect of immune challenge on subsequent outcomes (more of a prevention approach, as opposed to a treatment approach). Take these with all necessary caveats of an animal model, and an animal model of autism at that:

    Multiple pathways in prevention of immune-mediated brain disorders: implications for the prevention of autism [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788108/]

    Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism. [http://www.ncbi.nlm.nih.gov/pubmed/19766327]

    Postnatal inflammation increases seizure susceptibility in adult rats [http://www.ncbi.nlm.nih.gov/pubmed/18596165]

    IIRC, there is a minocycline paper in progress that had mixed or negative results. There is an open fragile X paper with minocycline that reported benefits. [http://www.ncbi.nlm.nih.gov/pubmed/20937127]

    - pD



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    1. @pdrone: Thanks for the refs. I am familiar with some of these animal studies since one of our projects is related. What is never clear is whether the immune dysfunction is environmental or genetic, I'd bet on the latter, but that's just a guess. But it makes sense that for most neurodevelopmental disorders it makes sense to treat these early in development while circuits in the brain are being formed, rather than "reversing" the symptoms.

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    2. @Namnezia Why would you bet on the latter? I know of variants (I carry some myself, allegedly) associated with immune dysfunction. Is that what you mean? Or something different? It was my understanding that even with a pretty elevated risk associated with a variant, environment fills in the rest (in many disorders, anyway).

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    3. Hi Namnezia -

      What is never clear is whether the immune dysfunction is environmental or genetic, I'd bet on the latter, but that's just a guess.

      I think it is probably "both" most of the time, but we do have evidence that persistent immune dysfunction, and behavioral manifestations, can be caused solely by immune challenge alone. Again, the often publishing Paul Patterson had a pretty neat one a month or two ago,

      Modeling an autism risk factor in mice leads to permanent immune dysregulation [http://www.pnas.org/content/early/2012/07/10/1202556109] wherein the treatment group (MIA challenge animals) showed persistent "altered immune profiles and function" and behavioral abnormalities. Even cooler, bone marrow transplants from naeive mice rescued the altered immune profile and behavioral patterns. So, in a sense, that is sort of like a model of reversing course (of mouse autism. . . ). But it's still pretty cool.

      To me (?), this is largely in line with other animal studies that seem to be telling us that there are critical windows during which our immune systems, and the systems it interacts with, are malleable to persistent change, i.e.,

      Neonatal programming of innate immune function [http://ajpendo.physiology.org/content/300/1/E11.full]

      Microglia and memory: modulation by early-life infection [http://www.ncbi.nlm.nih.gov/pubmed/22031897]

      and the startlingly named

      Early Life Activation of Toll-Like Receptor 4 Reprograms Neural Anti-Inflammatory Pathways [http://www.jneurosci.org/content/30/23/7975.full.pdf]

      In all of these cases, the data indicates that early life immune activation resulted in persistent alterations in memory formation, innate immune response, and the neuroimmune environment of the CNS. (there are many others with broadly similar results)

      My best guess is that if there are some situations wherein immune activity is a participatory agent in some cases of autism, it's probably a mix of environmental and genetic shuffling. I'm not sure we are really clever enough to understand at this point. For a very clever paper that may have found some insight onto this question, you might take a look at Transcriptomic analysis of autistic brain reveals convergent molecular pathology [http://www.ncbi.nlm.nih.gov/pubmed/21614001] (published in Nature), which reported enriched suites of genes in the CNS involving cortical patterning and immune function; but curiously found that the immune gene expression set did not appear to be due to an underlying genetic cause.

      Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder.

      Neat.

      - pD

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    4. @Emily - yes by genetic I mean some sort of genetic variant which confers some susceptibility which could be triggered by environment.

      @pD - that is a cool study. What's cool is that two different signaling systems seem to converge onto a common outcome.

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    5. Which is in line with the many roads lead to Rome/autism concept.

      pD ... if not due to an underlying genetic cause, how would the role of a mother's autoimmune disorder fit in, I wonder?

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    6. Hi Emily -

      if not due to an underlying genetic cause, how would the role of a mother's autoimmune disorder fit in, I wonder?

      I'm not arguing against a genetic participation, but was simply noting that we do have evidence that the operational mechanism of the OP@NYT, an inflammatory event, and such an event alone, seems capable of producing widespread changes in animal models. If we look at Paul Patterson's paper above, the bone marrow paper, the treatment group offspring showed altered immune profiles; it was as if their immune systems were "programmed" by early life events. From an evolutionary standpoint, I think this could make some sense, the fetus 'detects' that the world is a pathogen filled place, and puts an emphasis on invoking a robust immune response. A lot of the animal literature regarding early life immune events targets early life as a critical timeframe for this programming; Postnatal inflammation increases seizure susceptibility in adult rats makes this case gracefully.

      This (to me) has strong parallels to the fetal programming model of metabolic syndrome that has some crazy robust findings in the human realm.

      As to why a mothers autoimmune condition would fit in, my best answer would be that the end product of said condition, a state of increased inflammation, would have a broadly similar functional end product as an acute infection; increased levels of proinflammatory cytokines/chemokines.

      If increases in IL-6 and associated pathways are associated with altered behavioral profiles, it seems likely that the mechanism by which those pathways are upregulated is unimportant. As an example of this, in the Postnatal . . . study I posted here and above, the researchers used LPS, and direct TNF-alpha administration and observed alterations in the treatment group. When they co-administered minocycline (LPS group), or anti-tnf antibodies (tnf alpha group), they observed an attenuation of effect. Stating up front the big problems with animal models, this still gives us evidence that the trigger of the inflammation isn't the problem; it is the result of invoking the innate immune system. This would seem be consistent with what our observations of humans tell us; being obese as a mother is a risk factor, getting an infection during pregnancy is a risk factor, having asthma as a mother is a risk factor.

      I was absolutely not surprised when the autism / obesity study came out. It made perfect sense to me. Check out this (totally great) paper: Enduring consequences of maternal obesity for brain inflammation and behavior of offspring which found that obese dams gave birth offspring characterized by Microglial activation markers were increased in the hippocampus of SFD/TFD pups at birth. At weaning and in adulthood, proinflammatory cytokine expression was strikingly increased in the periphery and hippocampus following a bacterial challenge [lipopolysaccharide (LPS)] in the SFD/TFD groups compared to controls. Microglial activation within the hippocampus was also increased basally in SFD rats, suggesting a chronic priming of the cells. (!!!!)

      So, take a fetus that inherited the MET-C allele from mommy, a variant that has been replicated repeatedly in the autism population. One of the functions of MET-C is regulation of the immune response; that isn't to say that MET-C makes your immune system 'go crazy', but it's a tweak; and a tweak that speaks towards OP@NYT's proposal. For example,

      Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309488/]

      found the 'expected' MET-C association in the autism mom cohort; but also saw that when stimulated, the mothers immune response was pro-inflammatory, and produced less IL-10, a key regulator of the immune response. In a sense, they're burning the candles at both end.

      - pD

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    7. Very thorough, as always. I guess what I meant was, if there's not a genetic cause in the offspring but the mother has an autoimmune disorder, which typically has some genetic contribution, I was wondering how the two get separated in the offspring. Your answer about the "end product" is what I was thinking, too.

      What do you think about the fact that Simon Baron-Cohen has used the Danish cohort amnio fluid samples and found elevated levels of androgens, which also happen to influence the cytokines mentioned above and also ID'd as altered in those samples?

      Delete
  24. Emily, thanks so much for such a clear, facts-based critique. It's hard to believe that such sensationalism was published in the NYT!

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  25. I think your critiques are well founded but want to add a personal experience in which a whipworm infestation was a serious problem and that eliminating the whipworm resulted in a much healthier and higher functioning child who went from the first percentile to the 17th in height and weight. There is lots more to tell but I know that personal stories can be as tedious as they are compelling. We look at the kid we have, we try what we can, we weigh the evidence and we move on. I think we are still in the dark ages of what we know about the autism diagnosis spike and we should do no harm and not rule anything out until all the research is in (and keep doing the research!!). Thank you for your thoughtful and thorough critique.

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    1. I understand completely, but telling your story here as you do is very different from overstating it in a NYT op-ed.

      We are not completely in the dark ages about the spike, at least not as far as a lot of experts I asked or what the data seem to say. Any heterogeneous condition with an ever-changing diagnostic landscape is going to exhibit fluctuations. As I noted in the piece I linked about the "epidemic," the diagnosis of Asperger's, for example, may suddenly sink to zero if that diagnostic category is eradicated in the DSM V, but that doesn't mean that no people with Asperger's exist. That's a sledgehammer example, but it's illustrative.

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  26. Regarding the sentence "There’s a good evolutionary answer to that query."
    Actually there is an e alternative to the the "answer" Velasquez-Manoff's propose. And it is based directly on the most important contribution of Darwin to the theory of evolution, natural selection.
    According natural selection, organisms with challenged immune system (due to genetic variation) will undergo negative selection (i.e die). But modern medicine introduced hygene, antibiotics and vaccines and the selective powers acting on humans in developed countries are very different than those that were present in the past (or are present in developing countries). Therefore, children that would die in the past now survive. As a result we see more genetic variation in the immune system, and since some genes of the immune system has a role in development, including neurodevelopment we also see more variation in neurodevelopment. Autism, or better say ASD is part of this increased genetic variation. So it is expected there will be some overlap between immune disorders and neurodevelopment disorders, but it is less probable that infecting children with parasites will balance either their immune system or their neurodevelopment (though it might be the case in some less frequent situations).

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  27. Emily, thank you for this detailed, intelligent, and incredibly elucidating analysis of Moises Velasquez-Manoff's piece. When I read it yesterday, I knew the whole thing seemed off, and while it didn't point at vaccines, it felt like it was pointing at vaccines. He dredging up of the same old tired autism fears made me uneasy, but they were so subtle that they needed a light shined on them. No one could have done it better.

    The New York Times should publish this.

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    1. Thanks, Karen. I didn't really get the vibe that he was pointing to vaccines, per se, although the hygiene hypothesis--or people talking about it in layperson's terms, anyway--seems to roll vaccines in with everything else that keeps us too clean in the modern era. What concerned me was that people who think vaccines cause some kind of inflammation that causes all autism or link the two in some way would find his piece supportive of that. He made a wave at denying the possibility, but it requires more than that.

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  28. Here is my answer to the recent news about autism. Parents need a translator to define what is important and which study has promise. Enough!
    http://www.examiner.com/article/parents-of-autistic-children-need-a-translator-to-define-recent-news?cid=db_articles

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  29. Loved the post -well done. Unfortunately it is not often that a voice of reason is seen or heard in the autism/ASD field. One thing that gets me is cause and effect. It may be that cytokine levels in blood are altered in those with ASD, and their mothers (which may be explained if they are asymptomatic female carriers of the causal genes), but this has nothing to do with the autism symptoms. For exampoe, it may affect susceptibility to infection (e.g. ear infections), but actually not impact on the diagnostic ASD phenotype. Conversely, it also may be that the cytokine profiles detected in those with ASD may be at some kind of "optimal homeostasis" for each individual, and while these levels may be considered 'abnormal', they may actually be minimizing the overall impact of the genetic deficits. We just don't know...

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  30. I am a parent of a child with autism, not a scientist.

    I'm a little bewildered at your reaction, since you don't seem to be new to the Times or the wild world of medicine. Since my child was diagnosed in 1994, I've come to expect a steady stream of pronouncements, nearly always unqualified, from doctors and researchers about the causes of autism, the prognosis, the efficacy of various treatments. I remember the Times printing an article quoting a researcher who asserted that autism was caused by small amounts of alcohol consumed during pregnancy - no qualifiers there. I remember a leading neurologist telling me that no treatment at all would make any difference in my son's prognosis, that I should let the school decide how he should be educated. I've read articles about how the increase in autism in an illusion, when I saw the pre-school population of autistic children in my town go from one to 30 in a year, at a time when doctors were still conservative in diagnosing. I remember being lectured angrily by a pediatrician when I confessed to letting my infant sleep on his back - this was a few months before it became clear that American pediatricians had taken conjecture (maybe babies on their backs will spit up and choke) as established fact, leading to how many crib deaths. I read unqualified statements that vaccines and autism are proven to have nothing to do with each other, while watching increase of children with mitochondrial disorders - which looks like autism.

    Maybe I'm just cynical. Is there a grain of truth to the piece? Who knows? Who cares? I did have a chronic illness when my son was conceived and my husband and I were both under 30, so today, this theory looks more interesting than the "older fathers cause autism" theory, but really, if you think parents are going to go out and buy hookworms based on something from the NYT, you insult us.

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    1. I don't just think that parents take that piece as warranting such a course, it's already making the rounds on the Web with exactly that effect. And I am you, as I am a parent of an autistic child.

      We react differently to different things. As a science writer, a scientist, and someone with a deep interest in autism and autism-related research, I have a particular focus on what I've written about here.

      Anecdotes are not data. I also have a particular interest in not using anecdotes to support my points, even though it can be extremely tempting.

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  31. I think it sort of says it all that the Times had to print this in the Op-Ed section and not the Science or Health sections.

    I'm planning on canceling my online subscription this week; I'm just too tired of paying money I can't really afford for the privilege of reading bad science and outright bigotry about autism.

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  32. Emily, I love this response of yours. On the other hand, despite the Times claim that it's all that's "fit to print", and possibly-junk science arguably should not be fit to print, the inflammation hypothesis is interesting and deserves to be looked at more. There's a chicken and egg problem here. To get the funding to study a hypothesis more, one may need to stoke popular interest in the hypothesis, or grant and government money won't flow to investigate it further. It's a chronic problem of journalism that it tends to easy answers which contradict the received opinions. But the money to work on problems comes from: rich nabobs, and politicians with uneducated electorates, who both read journalists from prestigious media such as the New York Times. If the nabobs and politicians approve granting money, they can cover their butts with articles such as this. The alternative would be to have all funding come from organizations such as the National Science Foundation (NSF) which are led by respected scientists. But even the NSF will get its money from those politicians too. THe bottom line has always been and always will be that science depends either on scientists with their own inherited money, or on uneducated grant deciders. In the latter case, the grant deciders can either be beholden to less educated broader populations, or to elite advisors (an example would be: the French Academies). The elite advisors could be bought and paid for too. I wish the choices were clear but in this real world they're not so clear.

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    1. Thank you for your comment, I am not arguing that inflammation is not worth pursuing, and some pretty well-funded groups at doing exactly that. I just have a problem with the presentation of hints as facts and of carefully constructed fragile houses of cards as solid, evidence-based edifices.

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  33. Great Blog - really really great blog. Glad that you posted on The Conversations so I can follow it!

    Grendelus Malleolus

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    1. Thanks for commenting. Not quite sure what "The Conversations" is, but glad you stopped by.

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  34. I agree with the message of the article - if not the style. Please see my blog at: infectiousdisease.wordpress.com

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    1. I think the link you mean is here: http://infectiousbehavior.wordpress.com/2012/08/28/huge-interest-in-nyt-article-an-immune-disorder-at-the-root-of-autism/

      You mean in your comment that you agree with the message of the NYT article, yes (?), which agrees with the rationale you lay out in your book, correct? I don't disagree with the hygiene hypothesis--altered immunity link, and I also haven't dismissed an autism-immunity link for a subset, but my post is not about that, it's about overstating the science and overpromising (worms likely will *prevent* autism ?!). As you point out--and as I did, as well--for example, he seems to place a very generous interpretation on the values from the cluster analysis study. That's just the start.

      Yes, it was an opinion piece, but even opinion pieces should target accuracy and try to avoid hyperbole, especially when the topic is one as fraught as this one is. You say the the message of immune involvement in autism needs to be out there in the "public eye," but the thing is, it is out there. The problem is, it's out there in the wrong guise, in an overblown and misleading representation that threatens public health, and unless the science is presented clearly and with appropriate qualifications, that misrepresentation of this link will continue to take on outsized and hyperbolic proportions, with repercussions well beyond autism.

      You say in your post, "I sincerely hope, however, that the patients to be entered into this study belong to the subset of autism cases that are 'immune-related', otherwise this treatment will likely not correct anything." I made that point in the previous post about the stem cell trial in autism, and unless the discussions modulate so that there is an understanding of the "subset" aspect here, work in this area will suffer.

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    2. Oops - thx for correcting my typing of my own URL!
      RE the point about immune involvement in autism already being widely recognized: Many, many women tell me that they have never heard about maternal infection being a risk factor for autism and schizophrenia in the offspring. If he has brought this to wider attention, he has done a great public service.

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    3. I was referencing the general belief among people who oppose vaccines because of the "autism link" that the immune response triggers autism.

      I'm not sure what you mean by doing a public service by letting women know that a maternal infection is associated with an increased risk of these two conditions in their offspring. How? Unless something is available to prevent their receiving the infection--and he doesn't argue that women, should, for example, get flu shots (they should--all it does is leave women rather ineffectively worried or, based on the NYT piece, self infecting with helminths.

      If we are talking about the same study, there was no increased risk for the overall period of pregnancy, and bacterial infection+hospitalization in the second trimester was associated with an increase of 42%. Viral infection in trimester 1 *associated with hospitalization*, which must mean a pretty raging viral infection, was associated with a 3x risk. For a woman with no other child with autism, the average risk is about 1%, so the viral infection-with hospitalization risk ups that to 3%.

      Paradoxically, the best way for a pregnant woman to avoid hospitalization for the most common viral infection that might do that--influenza--is for her to get vaccinated, yet articles like the NYT op-ed tend to be taken up as banners by people opposed to vaccines for reasons I've already mentioned and used to argue against that very effective, available preventative. So this kind of awareness may not have the consequences that might be expected.

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  35. My error - someone linked to your blog from the Australian site "The Conversation". I initially assumed it was you but on checking, it was not.

    https://theconversation.edu.au/abcs-four-corners-and-the-messy-truth-of-autism-9050

    Grendelus Malleolus

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  36. I have a 16 year old son with autism. He received a heart transplant as an infant and again when he was 9 years old. His immune system seems to be quite healthy and difficult to suppress. He was not able to receive an MMR shot because of the live virus. He had a couple episodes of pinworm infection when he was young. He is very seldom sick. He had numerous rejection episodes prior to his 2nd transplant, but has had no acute rejection since then. In recent years, he has been diagnosed with humeral rejection and is not considered eligible for a 3rd transplant due to a very high antibody count.

    I really never noticed any variation in his autism throughout all of the immune reactions, immunosuppression, parasitic infection, vaccinations, or lack thereof, nor do I remember having any type of infection during pregnancy. I hope they continue to research and find some real answers, but I am tired of the constant suggestions of a cure or prevention with no real evidence to back it up. I appreciate your reaction to an article that seems so ignorant and irresponsible. Most parents of autistic children do their best to be well informed, but there are a few just desperate enough to try anything, no matter how difficult, costly, or potentially harmful it may be.

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  37. My take on the original NY Times piece is that the author is over-emphasising one etiological possibility over a heap of others. Autistic brains are probably a final common pathway of many original setting conditions, and most autistic people have other unusual behavioural or cognitive patterns which may be the result of different developmental conditions than the core autism. It seems plausible to me that an inflammatory condition in a mother might make a metabolic difference to the conditions surrounding her fetus and thus contribute to a difference in brain development. However, it's just an interesting possibility and hardly something that could be controlled before the fact. Otherwise why aren't ALL the children of mothers with autoimmune conditions autistic or damaged in some other way? Apologies to all the people who like to say autistic people are different not damaged- that's the way I write & think. As for worms- who knows? My friends & I all had them at various times when we were kids, even adults- so they're still around doing whatever job they do. Our internal flora are the same or we'd die- millions of years of evolution didn't put them in us and on us if they weren't helpful, so we certainly haven't killed them off with modern medicines.

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    1. Thanks for commenting.

      "My take on the original NY Times piece is that the author is over-emphasising one etiological possibility over a heap of others." Yes, that is my take, as well. As I wrote, it's easy to lapse into a focus on one's specific area of research or writing and the "if then, then that" string of possible links and start to exclude other avenues.

      Very much dislike the "damaged" terminology, so apology accepted.

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  38. Emily,

    This is an honest question and I am really curious to know if there are any non-pharmaceutical non-conventional treatments you use for your child. No matter what your answer is my next question is how and why?

    Thanks in advance!

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    1. No, not unless you consider the probiotics, vitamin supplements, and fish oil my husband doles out to all of our children every day a non-pharmaceutical, non-conventional 'treatment' for just being a child. We gave our autistic son flaxseed oil for a specific, anxiety-related GI issue when he was young, and it was, as it is known to be, quite effective in that regard. How? With a spoon. :)

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  39. Your post was so snarky it invalidated the points you were trying to make. And, based on the way you've engaged the comments, it seems like you're primarily engaged in warfare. It's especially odd that you approach this way, given one of the criticisms you levy against the Times OpEd is sensationalism. I imagine your blog stats have lit up in a Fox News-worthy way since you wrote.

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    1. I don't think snark qualifies as an invalidator, and sensationalism and snark are not the same thing, so I don't see how a snarky approach would be odd in the context of critiquing something for being sensationalistic.

      Everyone has different thresholds of tolerance, and what you perceive as "warfare" has, in my mind, been a pretty interesting discussion with commenters providing some good insights, links, and other information.

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  40. This sort of thing happens increasingly as science stories are treated by news outlets as "lifestyle" reporting - marketing-driven and all about the tie-in. Nothing seems to count as news anymore unless it can spur consumption, either now (buy the book) or in the future (when we market the cure).

    ~argillic

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  41. "hygiene hypothesis itself is controversial"

    There is a great deal of published peer reviewed evidence from multiple countries and multiple populations that supports the hygiene hypothesis. In addition, there is a large amount of data from germ free and non-germ free mouse studies that support this hypothesis. Just do a little research in PubMed.

    "and remains a hypothesis that doesn't necessarily explain all immune dysregulation."
    Who ever said this hypothesis has to explain all of immune dysregulation? There are all kinds of immune dysregulation.

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    1. I did, which is where I found a number of papers talking about the hypothesis as controversial, e.g., as discussed here: http://www.ncbi.nlm.nih.gov/pubmed/20415858. That doesn't mean there isn't support for it; otherwise, it wouldn't be worth mentioning at all.

      The article itself relies on this broad interpretation, suggesting that in addition to explaining "allergic disease," it would also explain the "immune dysregulation" the author claims leads to autism. My point was that just because the hypothesis stands up as an explanation for one form of immune dysregulation, it's not necessarily going to translate for all other alleged forms of it (asthma, autism)--which seems to be exactly what you are saying, too.

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  42. Thank you for time for sharing your opinion as well. Austism Speaks posted this article from the NY Times as as well and linked your blog post. I think it is important for people also see a different side. Although, I don't understand all of the research presented, I appreciate the time you took to counter some of the other author's evidence.

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    1. Thanks for commenting. I don't see a link to this post at the Autism Speaks site (found their unequivocally positive commentary about the NYT Op-Ed here: http://www.autismspeaks.org/science/science-news/new-york-times-opinion-piece-highlights-immune-research). There is a live chat today they are having today with Paul Patterson that you can access here: https://www.facebook.com/autismspeaks/app_226961267321617

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    2. It was linked up on Austim Speaks FB Fan site.

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    3. Now I see that I made an error in my first post. They posted the link the NY Times article and then I posted in the comments your article so that other parents . I'm sure Autism Speaks will be all over this like "white on rice." I'm a new parent with a son who has autism. I'm still trying to navigate through all the literature and still trying to gauge where I need to stand on issues related to Autism.

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    4. This is totally a boost, but I'm part of the editorial team for the Thinking Person's Guide to Autism (we are all volunteers), and we have a blog site here: http://www.thinkingautismguide.com/ We've got a lot of information for the "at diagnosis" stage of things there, and please feel free to ask me any questions; you can email me at ejwillingham at the mail o' G. Our mission statement is here: http://www.thinkingautismguide.com/p/mission-statement.html

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  43. I think you should read the response to your criticism of the article here and let us know what you think:

    http://infectiousbehavior.wordpress.com/2012/08/28/huge-interest-in-nyt-article-an-immune-disorder-at-the-root-of-autism/

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    1. I provided that link above in the comments (http://www.emilywillinghamphd.com/2012/08/autism-immunity-inflammation-and-new.html?showComment=1346132286153#c8228242817920992766) and have already commented on it, even though the post itself does not cite me or this post specifically. Patterson notes that the article is not well sourced and that the author overinterpreted. On that much, we agree. We had an exchange in the comments above about some of it. He seems to have added some text since that link to say that the Cambodia/doctor reference is from one doctor in Cambodia who has a clinic there and that the author of the NYT piece is putting together an "annotated" version that will be placed online to show the sources of his information. That would correct at least one of the drawbacks of the piece.

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  44. Here are the sources for the Op-Ed article: http://www.moisesvm.com/2012/08/30/source-list-for-nyt-op-ed/

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  45. I enjoyed your critique of the NYT article. I am a scientist, public health worker, helminth user, former participant in clinical trials, and parent of a child with both ASD and autoimmune disease. I do agree that there is a tone of snark.

    "I’d prefer to avoid shitting out worms and parasite eggs on a regular basis."
    Helminth replacement such as hookworm and TSO doesn't result in pooping out worms, and the eggs are microscopic, the same as the bacteria we poop out daily. I'm sure many people would be appalled to hear they are pooping out billions of infectious bacteria daily. Most of the helminth users I know are actually members of the science community, these are people who can look beyond the natural aversions.

    "Anyone paying a little more attention, particularly someone writing an article about autism, should know that using the words “inflammation” and “autism” or “immune disorder” and “autism” inflames the substantial number of people whose resistance to vaccines because of autism fears has led to outbreaks of pertussis and measles that in turn have led to fatalities. And my hope is that articles like this one won’t backtrack us to viewing all of autism as rooted in immune dysfunction and find ourselves once again staring into the abyss of vaccine panic."
    This is an ad hominem attack.

    "The upshot is that anyone without a deeper understanding of immunology or autism could come away from reading this piece thinking that autistic children or pregnant women should immediately be exposed to parasitic worms and rolled around in dung as a cure."
    Evolution has gifted us with a natural aversion to feces and parasites. Due to this and the expense of helminth therapy, I doubt many parents will jump on helminthic therapy.

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    1. Thanks for commenting. This is my first encounter with the phrase "helminth user," so that's especially appreciated.

      I describe myself as "sometimes snarky" in the profile you see in the rightnavbar of this blog. I don't deny it. As for your notation about "helminth replacement," I was referencing more our blessed ecological past mentioned with such nostalgia as a somehow preferable tradeoff, one in which, presumably, we weren't infected with amenable "domestic" worms and thus were likely shitting worms or eggs, depending on species and so forth. And as as scientist, you are surely aware of the difference between bacteria and parasite eggs. Also, thank you for introducing the phrase, "Many of the helminth users I know."

      I don't see how a comment on an article and articles like it is an "ad hominem attack." Weird.

      As far as the last comment--well, you're not hanging around in the right places because yes, parents do jump on that therapy and others that lack an evidence base in autism. That said, thank you for highlighting the evolutionary basis for our natural aversion to feces and parasites; it certainly is a reasonable counterpoint to the argument that we should all be carrying a parasitic worm burden.

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    2. Attacking Velasquez-Manoff's ideas based on the fact that they MIGHT inflame the anti-vaccine crowd is an ad hominem/guilt by association attack on Velasquez-Manoff. Velasquez-Manoff himself does not say vaccines are responsible for the autism or autoimmune disease increase.

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    3. "Attacking ideas" is distinctly not an ad hominem. In the paragraph you reference, I did not "attack" ideas, though, I said that context matters and has public health repercussions when one is writing about immunity, inflammation, and autism and that because of that context, it's important to write in a way that is well sourced, accurate, and fact based. This article was not that. I'm not simply making a prediction; history shows the powerful role of how the news media presented, for example, the Andrew Wakefield story and the ripple effects of that dog-and-pony show on public health.

      An ad hominem would be, for example, my saying that the only reason Velasquez-Manoff so carefully builds this thread of narrative is because of his own health issues or personal experience, rather than because of the science. I did not write that in this post and don't think it would have been-or is--a valid point to make. The focus here is the ideas, their interpretation, their sourcing, and their generalization.

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  46. This is an amusing comic about this phenomenon: http://www.phdcomics.com/comics/archive.php?comicid=1174.

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    1. Yes, that one's funny. It does leave out "researcher overstates conclusions."

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