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 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. 

**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.
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.

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