Monday, August 27, 2012
Autism, immunity, inflammation, and the New York Times
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, 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.
Posted by Emily Willingham at 5:30 AM
About Me
Emily Willingham
I am a biologist, writer, and editor. Sometimes cranky, sometimes
snarky, usually cheerful, always interested.
All material on these pages is copyrighted and the property of Emily
Jane Willingham. (c) 2012. Travel template. Powered by Blogger.
--
Jim Devine / "Patriotism is the conviction that your country is
superior to all others because you were born in it." -- George Bernard
Shaw
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