The exoneration of John O'Leary

5 Sep

Since the publication of the latest MMR study to refute any connection to autism, the principal believers in the idea that vaccines _simply must_ have some connection to autism have been floundering to spin some positives from the study. They have decided to concentrate on getting this study to exonerate Unigenetics (the lab of Professor John O’Leary). A little backstory is necessary here.

The idea that MMR leads to autism was first perpetuated by Andrew Wakefield. The idea goes that the MMR is injected, the measles component travels to the gut where it persists and causes severe gastric issues. It travels on to the brain and causes autism. Hence, it is – in the Wakefield scenario – the measles virus component of the MMR that causes autism.

In order to test this hypothesis, Wakefield tested for the presence of measles virus in the gut of autistic kids and lo and behold found loads. The way he found them was to send his biopsy samples off to the lab of John O’Leary, Unigenetics, in Dublin. Unigenetics ran the tests on the Wakefield samples and reported they had found measles RNA in significant percentages in Wakefield’s samples. They tested the samples using a technique called PCR.

So, later on, as study after study failed to replicate Wakefield’s – except, tellingly, for studies that went through Unigentics – investigators became suspicious of the results being generated at Unigenetics. As part of the UK litigation into MMR Professor Stephen Bustin – quite possibly _the_ world expert in PCR – went in and spent over 150 hours examining the methods used at Unigenetics to get their results. What he found was a bombshell.

Two things clearly arose from Bustin’s investigation. The first was a clear error of methodology. They forgot to perform an ‘RT Step’. What this was and what it meant is cleared up nicely here by commenter Brian:

The RT stands for “Reverse Transcriptase”, an enzyme that makes a DNA copy of an RNA molecule.

Measles virus exists as an RNA molecule. The polymerase chain reaction (PCR) assay amplifies DNA. Thus to detect an RNA molecule in a PCR assay, the RNA must first be copied (by the reverse transcriptase enzyme) into DNA, which can then be amplified.

Bustin showed that the O’Leary lab reported positive results even when they could not possibly have detected an RNA molecule because they had left out the step to copy that RNA into DNA. Thus the positive results reported for such assays were undoubtedly false positives.

Its worth noting here that Bustin found this methodological error by following Unigenetics lab manual if I recall correctly.

Here is Bustin himself:

If you detect a target that is _apparently_ measles virus in the absence of an RT step by definition it can’t be measles virus because it has to be DNA [measles virus does not exist as a DNA molecule]. It’s a very simple concept. At least it is to me. It’s not to everyone else.

So what were they reporting as measles virus? Lab contamination. That was the second error.

OK, so now back to today and the new MMR paper and the drive to make it exonerate O’Leary.

The new study used three labs to perform its detection. All three performed excellently. One of the labs was (you guessed it) John O’Learys in Dublin.

So, two new press releases have hit since then. I’ll quote from them both.

This is from Thoughtful House (Andrew Wakefield’s Texan fiefdom):

This new study confirmed that results from the laboratory of Professor John O’Leary….were correct, and identical to the results obtained by the laboratories of the Centers for Disease Control and Prevention (CDC) and Dr. Ian Lipkin of Columbia University.

In that this new study affirms the reliability of Professor O’Leary’s laboratory and therefore of his previous findings, a major impact upon the current hearings in vaccine court is likely, wherein the government’s defense relies largely on the claim that Professor O’Leary’s finding of measles in the intestinal biopsy of Michelle Cedillo (a child with severe autism and epilepsy) was unreliable. The historical reliability of the measles assay used in Professor O’Leary’s laboratory is now confirmed.

And SafeMinds:

One of the three labs involved in the Hornig study was led by John O’Leary who conducted the testing for the Wakefield study. The three Hornig study labs validated each other,
confirming the rigorousness of Dr. O’Leary’s work. Dr. O’Leary conducted the testing for one of the autism test cases now in the Federal Court for Vaccine Claims. The child, who regressed into autism
and bowel disease after receiving the MMR, tested positive for measles virus.

So, you can see that this is the spin – exonerating Unigenetics work that Stephen Bustin had demolished.

They take a rather simplistic viewpoint of things – that because the lab performed well now, it did then. I think that’s rather a large assumption.

I also think that they have forgotten the timeline of events surrounding the Cedillo case.

Michelle Cedillo’s positive measles virus finding was in 2002:

From the cross examination of Arthur Krigsman:

Q: OKay, now in support of your opinion that Michelle has persistent measles virus in the lymphoid tissue of her bowel, you cite to the positive finding in *2002* by the Unigenetics in Dublin, Ireland of measles RNA in the tissue sample tested in Michelle, correct?

A: By the published report, of their findings.

Q: But from Unigenetics, specific to Michelle?

A: Right.

(Page 531, line 9 – 18)

Stephen Bustin did not enter the lab until January 2004.

From the Direct examination of Stephen Bustin:

Q:…..Now, you were granted physical access to the Unigenetics laboratory?

A: I was, yes.

Q: When?

A: In January 2004 and then again in May 2004.

(Page 1964, line 12 – 16)

In other words, Michelle Cedillo’s test results were generated by Unigenetics, _before_ Stephen Bustin (or anyone else) had discovered the catastrophic errors that made it impossible they were detecting measles.

The question becomes – if you were John O’Leary and someone had made it perfectly clear that you had done bad work two years earlier would you then carry on missing out the RT step? Or would you not? By the time 2008 rolled around, would you hope that your lab staff could do their jobs properly? Or wouldn’t you really care?

The idea that this new MMR study somehow exonerates the work of Unigenetics prior to 2004 is a joke. Unfortunately, Michelle Cedillo’s testing was done prior to 2004. Two years prior, back to a time when Unigenetics weren’t so good at lab work.

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35 Responses to “The exoneration of John O'Leary”

  1. HolfordWatch September 5, 2008 at 13:34 #

    It would be both graceful and helpful if Prof O’Leary were to accept Prof Bustin’s criticisms of the previous lab work and to distinguish between the performance of the lab now and previously.

  2. Kev September 5, 2008 at 13:52 #

    It would. I don’t think he’ll ever cop to it though. If he does, thats it – game over for MMR. Is he capable of that?

  3. Socrates September 5, 2008 at 15:08 #

    Utterly incredible. (Btw, what ever happend to Wakefield’s 17 monkeys study? Correct me if I’m wrong, but it doesn’t even seem to have made it into the bottom-feeding journals).

  4. Kev September 5, 2008 at 15:15 #

    The Hewitson one presented at IMFAR? No idea, its probably doing the rounds. I’ll be interested to see whether it makes it past peer review.

  5. brian September 5, 2008 at 16:27 #

    I think that Dr. O’Leary deserves his excellent reputation despite the past problems in his lab, and it is to his credit that he corrected the procedural errors that Dr. Bustin reported. Nevertheless it’s nonsense to claim that that means that the earlier erroneous results were correct.

    I can appreciate the problems that O’Leary faced. I happen to have collaborated for several years with a distinguished scientist on some studies that use PCR to determine a clinical endpoint. When we unblinded the first study, it became apparent that either there were some errors made in his laboratory or that we’re on the verge of an exciting discovery. While chance favors the prepared mind, it’s perhaps more likely that one or more of his highly-trained, competent and intelligent lab workers erred than that we’ve won the lottery. I’m working with him now to determine how we can handle this situation; our first steps will be to see if we can replicate the results here, but we’re also contracting with an independent lab to provide an additional level of scrutiny.

    In situations like this, science should be and often is self-correcting. It wasn’t just Dr. Bustin’s investigation that ensured that Dr. O’Leary would reexamine his lab procedures. You can compare two papers to see just how this worked.

    Here’s the 2002 Uhlmann article (with Wakefield, O’Leary et al.):

    http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1187154&blobtype=pdf

    Notice that they found 75 of 91 children with a “developmental disorder” were considered PCR-positive for measles virus.

    Now check this follow-up article from D’Souza, Fonbonne, and Ward:

    http://pediatrics.aappublications.org/cgi/reprint/118/4/1664

    Using the PCR primers that had been used by Uhlmann, they, too, found that tests of almost all the samples were positive. As Bustin indicated in his testimony, almost all the PCR positive results could be shown to be false positives for technical reasons (melting curves or the molecular weight of the product). However, they also performed a definitive test on those samples that were not shown to be false positives by those technical checks. D’Souza, Fonbonne, and Ward did something that Uhlmann had not done: They checked the DNA sequence of the PCR products. This is the definitive test–and in every case the positive result was a false positive. (That definitive result, by the way, may explain why the PCR study discussed by Karin Hepner in the Cedillo hearing–a study that also used the Uhlmann PCR primers–apparently remains unpublished.)

  6. Patrick September 5, 2008 at 17:23 #

    Well, if they want to try and stretch it that far, where are the validated quality control records, done at regular interval, for the life of the lab, and have they also been audited?

    Where are the accreditation records, again throughout the life of the lab, by an association like in the U.S. from the College of American Pathology?

  7. Ringside Seat September 5, 2008 at 17:34 #

    With the whole vaccine/autism charade, there’s often been the problem that a lot of people who have waged the campaign have been too ignorant to be exposed as liars. Thus, the guy who has published huge “reports” on autistic enterocolitis, which have gone to antivaxxers everywhere was caught out by a reporter in London who asked him what “enterocolitis” meant. The report’s author didn’t know. He’d simply parroted Wakefield for years, without even knowing the meaning of the words.

    Thus, you’d have trouble showing that he was a liar, because to lie involves an intent to mislead.

    But with these claims that O’Leary’s earlier work – exposed in the omnibus hearing – has now been exonerated come from people who plainly must know that what they are saying is untrue. They simply must know.

  8. DT September 5, 2008 at 18:47 #

    Is O’Leary’s current lab SOP for measles PCR exactly the same as it was in 2002? Does he still make the mistake of omitting the “RT step”?

    Clearly he does not, so the answer is that laboratory procedures have changed, and are now up to scratch.

  9. isles September 5, 2008 at 23:12 #

    The response of Safeminds and the like are pathetic. Can they really still believe they are acting in the best interest of children when they find themselves having to twist reality violently in order to avoid the conclusion that they’ve been dead wrong all along?

  10. Sullivan September 5, 2008 at 23:51 #

    It is nice of Dr. Wakefield to suggest that the O’Leary laboratory was doing good work all along–since this implies that the mistakes in the 1998 and 2002 papers are on his (Dr. Wakefield’s) side. This was the suggestion made at the press conference for the Hornig et al. study. So, good for Dr. Wakefield. Probably not accurate, but if he wants to take on the blame for getting this wrong, he’s welcome to it.

  11. Schwartz September 6, 2008 at 02:09 #

    The comments here about the lab assumptions are right on the money IMO. Unless the lab certifies that the procedures are substantially the same today as before, then I would have trouble assuming the quality was the same in the past.

    The other portion of Wakefield’s comments are interesting in that they are technically correct but I’m not sure I buy them. It is true, that the methodology was different in the selection of the study group because he selected candidates with a different profile and the sample size of the group meeting his original criteria was very low.

    Calling for a study of identical design (or a bigger sample size meeting his criteria) is technically the only the way to disprove it. However, I already have my doubts given the previous study showing no leaky gut.

    The temporal argument is technically correct as well, but I am still very skeptical about the original hypothesis at this point.

    I think it much more likely that the GI issues and the Autism may both be related to something common, but I personally think it unlikely that the GI issues cause the Autism.

    It is also interesting to note, that it’s not even clear if Dr. Wakefield still believes his own original hypothesis or not.

    My biggest complaint from this latest study, is that I couldn’t find a number of explanatory details that I would have liked to see.

    It’s frustrating that after 10 years, we seem no closer to finding the cause or reasons for the seemingly extensive GI issues in these children.

  12. Loftmatt September 6, 2008 at 03:46 #

    Schwartz, I think there are some pretty obvious clues related to GI problems in autism that are being overlooked.

    It is clear that the human stress response is at the core of many or most GI problems. We all know what it is like to have a nervous stomach – it is called that for a reason. Stress does bad things to our GI tracts, from too much acid, to diarrhea, to constipation. It does this for reasons that are pretty clear and that relate to the fact that stress causes the body to react as if a threat were present. It has to do with how the stress response causes sympathetic nervous system activation which causes many results, including the colon to tend to spasm in an effort to empty (better to face a predator with an empty gut), blood flow to be redirected from the gut to more crucial muscles and organs (like the major muscles and heart), and for the gut nervous system to become sensitized.

    We know that many disorders of the gut intimately involve stress. IBS (also known as spastic colon) shows up more frequently in people who suffered traumatic stress as children, frequently sexual abuse. And, psychosocial stress is the most important factor in both triggering and worsening IBS symptoms. Leaky gut is tightly associated with stress. Candida overgrowth is dramatically impacted by stress. So is ulcerative colitic and pretty much all of the functional bowel disorders.

    While I know stress is not a sexy topic, maybe stress has something important to do with autism, and maybe it is in fact the key connection betweeen autism and GI disorders. Autoimmune conditions are also seriously elevated in autistic individuals. Guess what is the most important environmental factor in the development of autoimmunity generally? Stress, and in particular the variation in the production of cortisol seen with chronic stress.

    I have been communicating with an autism researcher on this and other topics. A letter I received a couple weeks ago from him contained this quote in response to some of my assertions: “I completely agree with the connection between stress and the GI and immune findings in autism, and we are trying to start a study to look at this”.

    Stress is not a popular topic in medicine and hasn’t been since Selye coined the term in the 1930’s. This is largely because 1) it is excruciatingly hard to separate out the different types of stress in our world (and thus prove something to statistically significant standards), and 2) the biological responses to various types of stress tend to be very similar, also confounding the establishment of causation.

    But, maybe this is the factor that is staring us in the eye that we can’t seem to see. Why can’t stress be the cause of most GI dysfunction in autistic children, like it is in neurotypical adults. Maybe we don’t need to come up with complicated and tenuous models of measles/gut/brain interactions to explain something that a simpler model could account for. Maybe our lack of connection between stress and autism it what causes you your frustration. Just for contemplation.

  13. Ms. Clark September 6, 2008 at 04:00 #

    Description of the O’Leary lab (unigenetics) from Dr. Bustin.

    ——
    Q Now, are temperature and time important?

    A I’m sure as you have gathered by now timing and temperature are crucial for PCR because you’re relying on small bits of DNA binding to other bits of DNA in a vast gamish of other molecules, and in order to find their partners or their targets they have to be at the right temperature.

    If the temperature is too low you get nonspecificity, if the temperature is too high you don’t get any binding at all, if you give them too long they will, again, be nonspecific, if you don’t give them enough time they won’t, again, bind and be less efficient.
    So it is crucial that once you have got your primers you optimize your assay and then stick by that assay in temperature in terms of 20.

    Q Now, what was happening in the Unigenetics lab with respect to time and temperature?

    A There was quite considerable variation between runs in both the temperature of the reverse transcription and the time they reversed the runs for.

    Q And just can you clarify what a run is?

    A A run. A run is a single assay which involves a 96 well state, and it typically involves 90 odd samples they have been looking at. …
    (page 1985)
    But then there are instances in accord in the lab book where the F-gene gives them a positive result and the H-gene gives them a negative result.
    They comment on this in the lab book and say the H- gene isn’t concordant. They then looked at a sensitivity and found that the H-gene was more sensitive.
    So the obvious conclusion is that there’s a problem with the F-gene assay, and we should redesign the F-gene assay because we’re looking for concordance. What they in fact did was they ignored the H-gene results and went with the F-gene results. That would give them positive results.
    Q Okay. So in the instance that you would have a positive F and a negative H Unigenetics’ practice was to?

    A There’s only a few runs where that happened because they then gave up on the H-gene, but there are instances where the H was negative, the F was positive and they went with the F-gene.

    Q So they reported the F-gene as positive?

    A Yes.

    Q They reported the test result as positive?

    A Yes.
    ….
    (page 1998)
    A well-known problem with these instruments is that they rely on a heating block that contains 96 wells. So they can do 96 assays in a heating block. In order, as we established, to get a good PCR result,
    you have to have very accurate temperature control and time controls.

    The problem with these older instruments is that heating/cooling is not uniform across the block, and, again, this is well known. So, very often, people don’t use the outside wells because they already know there’s problems with these wells.

    Now, I was able to look at the instruments that they have used, and this is not a specific criticism about Uhlmann because they could never have known about this. In fact, they had the instrument services, according to Dr. Sheils, and ABI should have picked this up, but the problem was that there was a problem with one of the instruments they were using.

    Because I was doing all of the basic looking into the innards of the instrument, I was able to finger print the results and identify which run was done on which instrument, and what I found was that the instrument that was used on most of their runs had a huge variation in the heating and cooling characteristics across the block. What this means is that there is variability of your results, depending on where you place your tube on the instrument.

    So, regardless of any problems you have with the assay, this contributed to the variability that we’re seeing in the results produced by Unigenetics.

    Q And you discussed this earlier, but is RT sensitive to temperature?

    A It is very sensitive to temperature, yes.

    Q And PCR?

    A And PCR even more so because there is an exponential amplification, yes.

    Q And was Unigenetics aware of this problem?

    A I suspect they were not, of this particular problem because, as I said, Dr. Sheils told me that ABI serviced the instrument. We had ours serviced once a year. I was surprised to see this, but certainly their first runs were in 2000 and 2001 from this machine, and the last ones, I think, were in 2003.

    So it was three years’ worth of runs that I was able to fingerprint, and the problem persisted from the very first run to the very last run, a very characteristic pattern of problems with the heating block. So if they serviced it, they didn’t do a good job.

  14. Ms. Clark September 6, 2008 at 04:55 #

    Loftmatt,

    The stress and gut thing is something I’ve been hammering on for a couple of years now. The experts seem to be more interested in listening to psycho antivax parents crying about rivers of diarrhea caused (they insist) by this or that vaccine.

    http://autismdiva.blogspot.com/2007/04/stress-causes-tummy-trouble.html

  15. Loftmatt September 6, 2008 at 05:24 #

    Ms. Clark, I enjoyed that Autism Diva piece. I had seen it before, but definitely worth reposting here.

    Glad you see the same thing related to stress and the gut. Scientists generally hate the stress response. It is inherently non-specific, meaning hundreds of different stressors, from extreme cold to loud music to scarlet fever, cause 1) their own specific symptoms such as shivering or redistribution of blood flow to the core (in the case of exposure to cold), but also 2) a constellation of non-specific effects including Selye’s original triad, adrenal gland enlargement, thymus gland shrinkage, and duodenal ulceration. Stress is exactly and precisely, under Selye’s original model, the sum of these non-specific effects.

    So, when looking into stress, science is faced with many, varied specific causes that they can’t untangle resulting a host of non-specific biological consequences that they can’t untangle. Causation becomes hopelessly muddled. Statistical significance is largely impossible in conventional studies. And, you can’t get famous if you can’t hit that milestone. Thus, they look into other areas. At least you can tie out causally a vaccine exposure with GI distress – hence, that is where the researchers go to your and my great frustration. However, there is enough research and information out there to put together a pretty complete picture of how this works.

    In my thinking, gastrointestinal dysfunction is another of the constellation of non-specific symptoms that result from chronic exposure to any number of specific stressors of the type that are multiplying in our society, from too much television, to constant exposure to vibration and noise, to the ever present automobile.

  16. Ms. Clark September 6, 2008 at 05:28 #

    I’d be happy if they’d test autistic kids’ saliva for cortisol in real world situations. They did it with a contrived stressor at the MIND and they were going to repeat that with another contrived stressor (I don’t know if they ever did). Why not take several kids, some autistic and some developmentally delayed and some typical and test their saliva during a typical school day (or pre-school day). I would bet they’d find a correlation between cortisol level and stress-related disease, like lowered immunity and gut problems…

    They can also do things like test heart rate and sweating. Autistic kids are not as likely to show their stress, so people keep piling on more stress, then the kid melts down and they blame the kid…. (sorry, ranting again).

  17. M September 6, 2008 at 08:12 #

    little off-topic.
    Loftmatt wrote: a constellation of non-specific effects including Selye’s original triad, adrenal gland enlargement, thymus gland shrinkage, and duodenal ulceration.

    yes, one must admit that there is a tendency to explain lot of things by stress.
    For example duodenal ulcer was some 20 years ago generally known as a stress-related/caused disease.
    Actually, there is nothing to do with stress, but a bug named Helicobacter pylori is the reason.
    You may have lot of stress, but if you do not have this bug in your stomach, you will never develop duodenal ulcer. There is no differences between duodenal ulcer patients and persons without duodenal ulcer in terms of stress, other than ulcer exacerbation pain may induce.

    Eradication of Helicobacter pylori cures the disease – duodenal ulcer will never again exacerbate, it does not matter, how much stress you will further have.
    H. pylori was discovered in 1982, and in 2005, the Nobel prize was awarded for this discovery.

    In my point of view, stress is a very vague and unspecific term.

    (English is not my mother language, sry, if i did lot of grammatical errors here)

  18. M September 6, 2008 at 08:26 #

    I prefer to use term “abdominal dyscomfort/pain” instead of using term “stress”.

  19. Bink September 6, 2008 at 14:29 #

    My child participated in a study a few months ago at Virginia Commonwealth University that focussed on stress hormones in saliva. There was a part with what Ms. Clark calls a contrived stressor, but I also had to gather samples on other “normal” days for comparison. Our personal results were in line with what I had long known/observed about my child, but I don’t know when the overall results will be published.

  20. Loftmatt September 6, 2008 at 17:36 #

    M, glad to be chatting on my favorite topic.

    You state that stress is a very vague and undefined term – that type of misperception is one of the reasons why stress is not a popular topic for researchers or parents. Stress is very precisely defined, but a necessarily broad topic – loosely, any exposure that tends to shift the body out of its normal homeostatic balance. People are always looking for specific exposures that alone can cause specific results (i.e. vaccines cause autism). These situations are easier to think about, and easier to test. However, rarely is that how the world works. Normally, it is the aggregration of influences (stressors) that result in tangible results. Obesity, type 2 diabetes, cancer, cardiovascular disease, and gastointestinal disease, just to name a few outcomes, all result from the complex interaction of a host of factors, both genetic and environmental.

    You mention h pylori, one of my favorite examples of how science works. For decades, everyone knew what causes ulcers – stress. Then, in 1982, two australian researchers cane up with a new theory, ulcers were really caused by a bacteria. They travelled the world talking about their theory. No one wanted to hear it. It was only a decade later that their theory starting gaining legs. In 1994, CDC recommended antibiotics as a treatment for ulcers. In the late 1990’s, the CDC was still urging doctors to accept the bacteria theory. When medicine finally accepted this, they went all the way. Stress was out, drugs were in. Now, they had a tool to cure ulcers. No need to mess around with that messy stress concept and all that non-specific doctors used to give their patients about diet and exercise and keeping their stress levels down. Medicine went all the way.

    Unfortunately, the answer is somewhere in the middle. Yes, h pylori is involved in about 80% of ulcers. However, about 50% of the global population is infected with h pylori, but only 10-20% (wikipedia) of that infected group will ever develop ulcers. What is the most important factor in determining which infected individuals develop ulcers? Stress. Not everyone with h pylori develops ulcer and those who develop ulcers don’t have them all the time. The bacteria is largely dormant most of the time, waiting for a period to thrive when stress has suppressed the immune system, decreased the viability of the rest of the intestinal flora, and made for a cozy home for expansion. Then it goes after the stomach lining.

    Medicine was right the first time (stress), and the second time (h pylori), but it has chosen to favor the specific cause over the non-specific one, which is typical for medicine, and humans generally.

  21. Schwartz September 6, 2008 at 18:31 #

    Loftmatt,

    While I agree completely that stress has an effect on the gut, I am not convinced that it is the causative factor, only an aggravator.

    I suffered from IBS for many years and although stress would exacerbate the issue, it was fully resolved through a thorough change in diet. In my case, diet has a direct effect whereas stress is just a complicating one.

    I also find it difficult (not impossible mind you) to believe that signficant numbers of children are undergoing such high stress at that young an age to be the causative factor.

    Do you have any ideas or suspicions as to the cause of the stress? Do you think it’s purely psychological, or physiological?

  22. M September 6, 2008 at 19:42 #

    Yeah, I know the prevalence data etc. Besides, in ca 95% of ulcer cases Helicobacter infection is diagnosable and lot of remaining cases are probably just false negative in regards of H. pylori infection. Gastric ulcers are also often associated with H. pylori but not so prominently, there are other reasons as well (NSAIDs etc). So, of peptic ulcers (duodenal ulcers plus gastric ulcers) 80% are associated with H. pylori.
    But still, the association between stress and duodenal ulcer is an old theory what has no solid evidence to prove it.
    Why not all H. pylori positive subjects develop ulcers – H. pylori strains are different (there are more and less virulent ones), host is different (different genetic background – ulcers run in some families and in some families do not) and environment – food, smoking etc.
    Yes, stress ulcers may also develop – in intensive care units patients, but this is a totally different story than peptic ulcer disease.
    This discussion is quite far from autism now, sorry!

  23. Ms. Clark September 6, 2008 at 20:36 #

    Schwartz,

    Maybe if you had any idea what it is like to be on the autism spectrum you wouldn’t doubt the connection between gut problems and stress in young children with autism. If people start making demands on you that you are not ready to tackle and the people continually assume that you are not trying hard enough or that you had just better do what your normal peers can do, that will cause stress, even in a toddler.

    Because you are not part of the autism community or the autistic community you are more likely to make this kind of big error. Maybe you should ask why we think stress can be a factor in the health of autistic children before you form an uninformed opinion and share it. It would be like me saying, “Well, it’s like this for men, they go hunting because they want to avoid mowing the lawn. I tried fishing one time, I didn’t like it. Therefore, I know that men only go hunting and fishing to avoid their responsibilities. They don’t even enjoy it.”

    What would make me an expert on what men think? Nothing. It appears to be the same for you and your opinions on autism.

  24. Loftmatt September 7, 2008 at 04:33 #

    Schwartz, let me start with some basic theory, as I understand it and I am certainly not an expert, before getting directly to your question.

    Basic Theory

    Some people are more sensitive to stress than others. There are genetic and environmental causes of this that likely mix in many people. The genetic side of this is still largely wrapped in mystery, but for instance there has been a lot of research indicating that variations in the 5HTT promoter polymorphism affects resiliency to stress in ways that affects vulnerability to disorders like PTSD and depression, and potentially autism. This is one of many articles on the topic.

    http://www.indianjpsychiatry.org/article.asp?issn=0019-5545;year=2008;volume=50;issue=1;spage=47;epage=50;aulast=Margoob

    I firmly believe there is an underlying genetic vulnerability to stress that exists within most on the autism spectrum. This vulnerability is part of the autism neurotype. As a result of having some of the good stuff of autism at least on the high functioning side, you get some of the bad stuff too, and vulnerability to stress, which is present in infancy, is part of it. This is wired into those on the spectrum from conception.

    From an environmental standpoint, there are various ways someone can be sensitized to stress. To a large degree, PTSD involves the nervous system being sensitized to external stressors / threats due to the impact of one particularly acute stressor, or a series thereof. If you look at PTSD symptoms that don’t involve responding to the initiating stimuli, they look a lot like aspects of autism (i.e. markedly diminished interest or participation in significant activities, restricted range of affect, difficulty falling or staying asleep, irritability, difficulty concentrating, hypervigilance, exaggerated startle response). Also, a significant minority of women with IBS were sexually molested as children, having long lasting effects.

    There is a whole psychiatric concept called kindling that involves the winding up of the nervous system through a series of interactions with external stimuli – this results in, among other things, an exaggerated responsivity to external stressors. One of the best books I have read on stress is a textbook called A Clinical Guide to the Treatment of the Human Stress Response. The authors led by a researcher named George Everly proposed a concept called Disorders of Arousal, a series of disorders that involve essentially exaggerated sensitivity to external stressors. More specifically, Everly argued that an ascending neural overload (too much information flowing up the peripheral nervous system to the processing centers of the brain) may be responsible for creating unorganized and dysfunctional discharges of neural activity that are manifested in persons with insomnia, undefined anxiety, depressive behavior, and in some cases manic behavior patterns lacking direction or apparent purpose.

    This neural wind up can be seen very clearly in certain animal models. For instance, maternal touch is a crucial part of the nurture of rat pups. Rats that are regularly touched by their mothers tend to become well adjusted, stress resilient adult rats. Same thing goes for experimental rats that are taken from their mothers but handled 15 minutes a day. However, rat pups that are denied normal physical interaction tend to develop fearful, nervous personalities and become much more reactive to the stressors in the world around them.

    Addressing Your Question

    I have actually written a brief paper on this topic that I would be happy to share if you want more detail. But, the way the paper goes is that genetic predisposition is adequate to result in severe stress responsivity and autism in some affected individuals. Others require an interaction between genetics and environment to develop the condition. For these individuals, their genetic predisposition for excessive reaction to the stressors in their world is compounded by environmental difficulties both prenatally and postnatally, from maternal smoking and drinking, to a poor maternal diet, to excessive maternal stress that releases large quantities to cortisol, to abnormal sensory environments like extreme noise in a job environment (i.e. working at the airport on the runway), to toxic chemicals consumed in food or water, to a combination of some of these and many other factors. The situation may be worsened due to sensory processing abnormalities the infant suffers from that cause them to react to even maternal touch as a threat to be avoided. All of this may mix up into a stew that interrupts normal developmental programs, such as the development of neurotransmitter patterns like you see in normally handled rats, in a way that ultimately results in the development of autistic behaviors.

    One group of researchers, who wrote the best book on autism I have seen (GABA in autism), put this same basic concept in more scientific terms:

    We hypothesize that autism and associated disorders are the result of an adverse cascade of psychoneuroimmunological events that derive from one or more gene / environmental insults or unmitigated stressors. We also hypothesize that early intervention can interrupt the adverse cascade of events, thereby compensating for such insults and averting the further on-going sequelae that lead to severe chronic developmental disorders. Environmental insults can occur in utero or postnatally. Without intervention, the infant’s stress profile will result in a failure to activate specific developmental program, such as glucocorticoid and GABA receptor compositions. The cascade leads to a disruption in the stress-regulatory system of a developing infant, impairing ability to benefit from the caregiver’s nurturing or stress-modulation. The disruption results in an interruption of key genetic developmental programs that are normally activated by peptidergic mechanisms. In the face of genetic / environmental stressors, the excess demands on the infant’s stress regulatory mechanisms make peptide modulation critical.

    The failure we further hypothesize persists until the peptide balance is restored. The earlier the silenced or arrested gene programs are activated by successful intervention, the less stress induced damage will occur. Conversely, the longer the infant is unable to receive stress modulation, the more the infant’s adaptation to environmental and emotional challenges is adversely conditioned. In such cases, in the face of unremitting emotional and environmental challenge, the infants adopt various maladaptive defense strategies that result in regressive adverse behaviors and a range of pathology. In the case of autistic children adverse behaviors include stereotypical movements, approach / avoidance behaviors, obsessiveness, compulsiveness, and tantrums.

  25. Loftmatt September 7, 2008 at 16:36 #

    Sorry if this is duplicative. Trouble posting it.

    Ms. Clark, I agree with your concerns about testing autistic kids for stress response problems. If people were paying more attention to the role of stress in autism (as is evident from the reports of parents and those who suffer from the condition), they would overcome the problems you see in measuring cortisol and other markers of stress. However, there is a fair amount of data showing cortisol abnormalities in autism other than the MIND study you mention.

    This is a study on autism. http://www.ncbi.nlm.nih.gov/pubmed/3437610?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

    Similar findings have been shown in Tourette’s syndrome, which is highly comorbid with autism.

    http://www.ncbi.nlm.nih.gov/pubmed/16005570?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed

    However, the most interesting findings I have seen in autism relate to a small variant of kids with infantile autism who tend to develop schizophrenia later in life, what is called Multiple Complex Development Disorder. Their autistic symptoms are less severe than autism, and their progression is abnormal. The researchers were surprised by the results of this study, which showed typical elevated cortisol in the typical autistic kids, but very low marginal cortisol responsivity in the MCDD kids.

    http://www.ncbi.nlm.nih.gov/pubmed/12629541?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

    However, if you go beyond cortisol levels, there are a host of other indicators that stress responsivity is a problem in autism.

    – Behaviors: many behaviors of autistic kids convey the fact they are under stress, from the stereotypies that mimic behaviors of adults under stress (pacing, rocking etc…), the eye contact avoidance (harder to do under stress), the tendency to withdraw (the flight portion of the fight or flight response), to the melt downs (capacity to absorb more stress is exhausted – neurotypical children also experience melt downs at times like the holidays).

    – Co-Morbid Conditions: autistic kids have many co-morbid conditions that indicate high stress, from the gastrointestinal disorders we have discussed, to elevated levels of autoimmunity (cortisol function is key here) along with other immune system abnormalities, to nearly universal anxiety disorders like panic disorders, phobias, and generalized anxiety disorder, to depression (most cases of major depressive disorder are triggered by stressors).

    – Blood Chemicals: autistic kids frequently show higher levels of stress system chemicals like noradrenaline and endorphins, HPA axis chemicals like ACTH, and neuropeptides associated with the stress response like Substance P, VIP, and CGRP.

    – Abnormally high levels of oxidative stress, which is intimately tied into the human stress response. This may be responsible for some of the findings in autistic children that are often tied to heavy metals, such as low levels of glutathione, high levels of homocysteine, and abnormal nitric oxide.

    – Many other indicators of overactive stress responsivity that I can go into if people are interested.

  26. Loftmatt September 7, 2008 at 16:39 #

    Ms. Clark, I agree with your thoughts on failures in measuring stress response activation in autistic kids. Even with these failings, a body of evidence is accumulating suggesting stress is a core component of autism:

    – Behaviors: many behaviors of autistic kids convey the fact they are under stress, from the stereotypies that mimic behaviors of adults under stress (pacing, rocking etc…), the eye contact avoidance (harder to do under stress), the tendency to withdraw (the flight portion of the fight or flight response), to the melt downs (capacity to absorb more stress is exhausted – neurotypical children also experience melt downs at times like the holidays).

    – Co-Morbid Conditions: autistic kids have many co-morbid conditions that indicate high stress, from the gastrointestinal disorders we have discussed, to elevated levels of autoimmunity (cortisol function is key here) along with other immune system abnormalities, to nearly universal anxiety disorders like panic disorders, phobias, and generalized anxiety disorder, to depression (most cases of major depressive disorder are triggered by stressors).

    – Blood Chemicals: autistic kids frequently show higher levels of stress system chemicals like noradrenaline and endorphins, HPA axis chemicals like ACTH, and neuropeptides associated with the stress response like Substance P, VIP, and CGRP.

    – Abnormally high levels of oxidative stress, which is intimately tied into the human stress response. This may be responsible for some of the findings in autistic children that are often tied to heavy metals, such as low levels of glutathione, high levels of homocysteine, and abnormal nitric oxide.

    – Many other indicators of overactive stress responsivity that I can go into if people are interested.

  27. Schwartz September 7, 2008 at 23:39 #

    Ms. Clark,

    You might have missed the “While I agree completely…” part. No where did I state that I doubted any stress/gut connection. I am discussing the causative factors with Loftmatt, and asked clarifying questions as to his thoughts.

    The rest of your post was a waste of screen space.

  28. Schwartz September 7, 2008 at 23:54 #

    Loftmatt,

    Thanks for the thorough response. I sent you a PM on the AS boards which still work.

  29. Ms. Clark September 8, 2008 at 02:25 #

    Schwartz, let me help you out here. You wrote
    “I also find it difficult (not impossible mind you) to believe that signficant numbers of children are undergoing such high stress at that young an age to be the causative factor.”

    There is no reason to find it difficult believe that stress is a factor in (you name it) in very young autistic children. Hence my point, if you knew what small autistic children are like and what they are expected to do, that they can’t do (sometimes), then you wouldn’t be doubting that stress was a factor for small children (babies/toddlers).

    If you just admit that you don’t know something, that’s OK. As for wasted screen space, you are constantly hammering on vaccines when vaccines have absolutely nothing to do with autism.

  30. Schwartz September 8, 2008 at 04:19 #

    Ms. Clark,

    My statement was WRT to singular initial causation (note the term “the causative factor”). That would imply strictly unique stress factors on these infants which I stated I found difficult (but not impossible) to believe as the causative factor.

    A very complex interaction between multiple factors as per mattloft’s hypothesis makes a lot more sense than just pure stress/GI interaction.

    Too bad you see past your own bias that you need to project conflict on everything other people say.

  31. Ms. Clark September 8, 2008 at 10:00 #

    Singular initial causation of **what**? Are you talking about the causation of autism or the causation of gut problems? Stress alone can cause diarrhea and constipation.

    Does stress on an infant all by itself cause autism? Good grief, no. Who would think that? So what’s your point? So far I’m guessing you are saying that vaccines caused a (non-existent) autism epidemic and that maybe it was vaccines plus stress that caused gut problems which cause then caused autism?

    Vaccines don’t cause autism. There was no autism epidemic so we don’t need to go searching for something that changed at the same time autism started to “increase”… No reason ever to have looked at vaccines in relation to autism at all (no more than we needed to look into the effect of space alien abduction or cell phones) except for those lawyers and those parents looking for someone to sue and the antivax establishment is always ready to flood the internet with their scary, scary stories, which is very helpful to the lawyers.

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