Saturday, April 21, 2007

Theories of Everything

Physics, that most pure of pure sciences, has been pursuing the "Theory of Everything" - a theory that will explain the four fundamental forces and their interactions - for some time now. Nobel Prize aspirants hope to connect the electromagnetic, strong nuclear and weak nuclear forces with gravity in a Grand Unified Theory. They've managed to connect the electromagnetic and weak forces into the "electroweak" force, but the other two forces obstinately refuse to join the game. For now.

Chemistry, which is sometimes referred to as "applied physics" (usually by physicists), has quantum chemistry, which is a close approach to a "theory of everything" in that field.

Biology (which snide chemists refer to as "applied rudimentary chemistry") has yet to develop anything even remotely resembling a "theory of everything". This is due to the immense complexity of the systems involved (so say the biologists) or the immense simplicity of the biologists involved (so say the chemists and physicists), take your pick.

However, I have noticed that at least one small segment of the biological sciences seems to be developing a "theory of everything". In fact, it seems to have developed several.


I refer, of course, to the field of autism "alternative" research.

The Grandmother of Grand Unified Theories of Autism

The first truly successful (in the sense of "popular" rather than "accurate") candidate for the "Grand Unified Theory of Autism" has to be the "mercury-causes-autism" hypothesis, first published (in Medical Hypotheses) by Bernard et al in April 2001. This hypothesis asserted that autism and mercury poisoning were one and the same, based on the use of similar words (in English) to describe certain features of both disorders.

Despite the fact that none of the authors had actually seen, let alone diagnosed a person with actual mercury poisoning, this hypothesis resonated with the zeitgeist of the community of parents with autistic children and resulted in massive popular support. Its scientific support has been less massive, unfortunately, and it stands in peril of fading to a mere cult phenomenon.

As a "theory of everything" in autism, the mercury hypothesis has met most of the requisite criteria. It is flexible enough to "explain" the features of autism, even as the definition of autism continues to change. In part, this is due to the protean nature of mercury poisoning, which has a wide variety of symptoms and signs.

However, a large part of the credit goes to the flexibility of the people applying the mercury-causes-autism hypothesis, who are willing to overlook significant ways in which autism differs from mercury poisoning. It is this willingness to suspend critical thinking, more than any inherent validity of the hypothesis, that accounts for its continued survival despite its lack of supporting data and the vast amounts of direct and indirect data refuting it.

With only a vague and easily disputed connection between signs and symptoms of autism and mercury poisoning and a few unrelated (and some might say also trivial and obvious) studies to support it, the mercury-causes-autism hypothesis is in trouble. The few studies that have been held up in support of the hypothesis, on closer examination, do not support it.

Some of these studies merely confirm what is already known (trivial), e.g. that mercury is neurotoxic. Others have shown that mercury can cause other types of disorders, e.g. autoimmunity, without connecting that to autism. In the end, most of the studies used to support the hypothesis are of three basic types:

[1] The study fails to show a connection to autism - i.e. mercury causes X, X is a bad thing, but no indication that either X causes autism or that X is part of autism, with X being a sign or symptom.

Example: Hornig, et al, "Neurotoxic effects of postnatal thimerosal are mouse strain dependent". This study demonstrated that mouse strains that were known to be prone to develop autoimmune disorders were more likely than other strains (which were not prone to develop autoimmune disorders) to develop autoimmune disorders after exposure to thimerosal. This is the trivial part of the study.

They then go on to posit that a variety of behavioral responses of the mice - decreased movement and decreased reaction to novelty - were signs of mouse autism. This is more than a bit of a stretch, as there are several alternative explanations, including the simple explanation that the mice were not feeling well, having developed autoimmune disorders.

[2] The study shows association without data supporting causation - i.e. the sudy shows that X is found in children with autism, but fails to show that X might cause autism. X might be caused by autism or simply be a co-traveler.

Example: James, et al, "Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism", which demonstrates signs of increased oxidative stress in autistic children without showing that the oxidative stress led to autism or what the cause might be. Significantly, when they corrected the signs of oxidative stress with betaine and folinic acid, the children remained autistic.

[3] The study proposes mechanisms that are either unsupported by the data and/or are contrary to known physiology

Examples: Kern, et al, "Sulfhydryl-reactive metals in autism", and Holmes, et al, "Reduced levels of mercury in first baby haircuts of autistic children". Both of these studies found reduced levels of mercury in the hair of autistic children and both propose - without providing a single citation or shred of data to support the proposal - that autistic children excrete less mercury into their hair.

This is contrary to decades of research into hair physiology, and so should have been accompanied by at least a paragraph of explanation. However, neither group of authors have found it necessary to provide support for their astounding claim that hair excretes mercury. Until they can, both studies are merely sources for scientific amusement.


The mercury-causes-autism hypothesis also has no explanation for the continued rise in autism numbers (from data sources that its proponents used to establish the "autism epidemic" in the first place) despite falling mercury exposure (both in vaccines and from the environment) and so its supporters have resorted to circular reasoning.

Despite having failed to establish that mercury causes autism, the proponents have boldly claimed that trace amounts of mercury remaining in vaccines, along with environmental mercury (which has been dropping since the 1960's), are sustaining the rise in autism.

This, of course, completely negates their earlier assertions that it was the rise in vaccination - and exposure to thimerosal - that caused the rise in autism, since the mercury exposure to children born after 2000 has been less than that of children born before 1980 (before the onset of the "autism epidemic").

What they have done - or tried to do - is say that the continued rise of autism (in USDE and California CDDS numbers) supports the mercury-causes-autism hypothesis because of the continued exposure to mercury - this continued exposure being proven by the continued rise in autism. And so, even though it took mercury exposures far in excess of what children are presently receiving to start the "autism epidemic", it takes only trace amounts to sustain it. Anyone want to go around again?


Another tactic used in support of the mercury-causes-autism hypothesis is to claim that chelation "cures" (or treats, if you like) autism. This supposedly establishes that mercury is the cause of autism, although it conveniently overlooks the fact that the chelating agents - if they do work - have effects beyond removing mercury.

Even more fundamentally, the proponents of the modified mercury-causes-autism-because-chelation-cures-autism have failed to support their claim that chelation has an effect on autism that is greater than placebo. Until this is established, they have no argument. They are trying to "prove" one unproven statement with another unproven statement.


Other "Theories of Everything" in Autism

Other "theories of everything" have arisen in the field of "alternative" autism research since the rise of the mercury-causes-autism hypothesis, although none have generated as much press or excitement. What these lesser hypotheses share with the mercury-causes-autism hypothesis is an emphasis on anecdote, unrelated (to autism) studies and hype.

Some of the current contenders for the "theory of everything" are:

[1] Nitric Oxide - since this is a widespread inter- and intra-cellular signalling molecule, it is not surpising that it is found in association with a variety of disease states. It is also not surprising that it is affected in a variety of conditions, both normal and pathological. This is roughly equivalent to saying that calcium is associated with autism, since calcium fluxes are critical in release of many neurotransmitters, including those thought to be important in autism.

Unless nitric oxide can be shown to either cause or treat autism, it remains just an interesting footnote. Considering the amount of hype that nitric oxide has in the "alternative" medicine and "nutraceutical" fields, it is no surprise that it has found its way into "alternative" autism therapy.

[2] Allergens (especially latex) - what could be more ubiquitous than latex? It's in car tyres, surgical gloves and a myriad of medical, industrial and household products. Latex allergies are on the rise - probably due to increased exposure, although this can be debated - and so is autism. Coincidence? Almost certainly, but this hasn't stopped some people from seeing a connection. It's not their fault - finding connections is what our brains are "hardwired" to do - even when there isn't a connection.

[3] RF energy (from cellphones, of course) - this seems to be a revival of the old "cellphones cause brain tumors" urban legend and should be as readily dismissed. Yes, the use of cellphones has paralleled the rise in autism. So has use of the Internet, popularity of Britney Spears and numbers of hybrid automobiles.

Doubtless, there are many others that I have overlooked. Feel free to e-mail me your favorite "theory of everything" for autism.



Prometheus

12 Comments:

Anonymous Anonymous said...

"Even more fundamentally, the proponents of the modified mercury-causes-autism-because-chelation-cures-autism have failed to support their claim that chelation has an effect on autism that is greater than placebo. Until this is established, they have no argument. They are trying to "prove" one unproven statement with another unproven statement."

If treatment can take years, and people like yourself are doing everything they can to dismiss chelation as a treatment for autism - how does one go about doing a placebo study? Seriously, this is not a pill, one would have to find a parent willing to put their child through years of placebo-iv treatment while not using any other methods of intervention (otherwise, individuals like youself would call the study bogus because the child was receiving some other form of treatment such as behavioural therapy).

Do you have any thoughts on what type of studies need to be done to convince skeptics like yourself that chelation does have efficacy in treating autism?

21 April, 2007 12:16  
Blogger daedalus2u said...

Prometheus, Thank you for shining a little light on the low NO hypothesis of ASDs. However so far as I know, there are only two serious proponants of it, me, and Lennart Gustafsson
. I have spoken with him, and he comes about the hypothesis from how NO would affect minicolumn geometry during production of those structures in utero. He is looking at it more as a "feedback" problem, rather than as a controlled normal feature of neurodevelopment. His paper is available here


NO is very different than calcium in that it is an uncharged molecule, and so can diffuse through every lipid membrane with no resistance. Calcium as an ion, cannot penetrate lipid membranes except through ion channels. The signling done by NO is thus quite different.

Most of the "hype" surrounding NO is based on a wrong understanding of NO physiology. Similar to the hype surrounding antioxidants, which has now been quite clearly shown to be wrong in that many antioxidants actually increase mortality.

I hope to dispell at least some of the wrong understanding of NO physiology, but as we all know, displacing "conventional" wisdom is difficult, even when it is wrong.

21 April, 2007 13:59  
Blogger daedalus2u said...

Prometheus, The rise in allergies is due to the fall in NO levels. NO inhibits NFkB, which is the "master switch" of inflammation and the immune system. I am quite sure that the bacteria I am working with are the causal agent in the "hygiene hypothesis", and are the reason why allergies are virtually unknown in the rural undeveloped world.
The association of allergies with ASDs isn't because allergies "cause" ASDs, or ASDs cause allergies, but rather that low NO causes both.

21 April, 2007 14:14  
Blogger notmercury said...

One of my favorite "theory of everything" autism hypotheses, is the autism-fries hypothesis.

Really, I think many of these hypotheses are so similar they must rely on the same boiler plate DIY autism hypothesis form.

21 April, 2007 14:49  
Blogger Prometheus said...

Anonymous,

In your comment about testing chelation, you stated, "If treatment can take years..."

Years?

Who said that?

Every study on chelation for mercury describes treatment as lasting - at most - months, not years. Even chelation for lead, which becomes incorporated into the bone, only takes months.

You go on to say, "...this is not a pill, one would have to find a parent willing to put their child through years of placebo-iv treatment..."

IV? The best chelation treatment - both the best chelation efficacy and the best safety - is DMSA, which is given by mouth. It isn't even available as an IV preparation. Of course, you can always get a compounding pharmacy to make it up as an IV, but why? It works just as well by mouth.

Even DMPS, which has a higher toxicity than DMSA with only marginal (if any) improvement in efficacy, can be given by mouth.

Only EDTA - which is at best marginally effective at chelating mercury - needs to be given IV. And even EDTA can completely chelate mercury in less than a year, let alone years. And need I remind you that it is the only one of the three that has killed an autistic child?

You asked for my advice on studies. My advice is to start by ignoring people who are using inappropriate chelating agents.

Secondly, I would ask to see the data that makes the practitioner think that years of chelation are needed.

Finally, I would suggest that anyone who claims that mercury needs years of IV chelation is someone I wouldn't allow within a country mile of my child.

Seriously, the people who are claiming that their "therapy" needs years of treatment to show effect are hedging their bets. Any autistic child will be better after years of any therapy, even if it doesn't work. That's because autism is a syndrome of developmental delay, not developmental stasis.

And before the inevitable comments arrive, let me emphasize that I don't necessarily believe that you or your practitioner are lying - just mistaken.


Prometheus

21 April, 2007 15:23  
Blogger Club 166 said...

Excellent post!

Nice summary of much that is wrong with those who would chelate/suck the dollars from unsuspecting and desparate parents.

21 April, 2007 19:34  
Blogger Bartholomew Cubbins said...

Has anyone address the poor excretor hypothesis and its implication that an adult autistic ought to be shedding moles of Hg daily from his/her skin?

GUTs are always good for a laugh. I wonder why parents of those who failed out of physics classes haven't banded together and rallied against the scientific establishment to form their own GUT opposing string theory? After all, these well-read moms and dads have access to the titles and some of the abstracts of the leading papers in the field so they must be able to go head to head with the likes of Hawking.

21 April, 2007 20:01  
Blogger Prometheus said...

Master Cubbins,

I've addressed the so-called "poor excretor" hypothesis in a few of my previous posts - the most recent being "A Tale of Two Studies".

http://photoninthedarkness.blogspot.com/2007/03/tale-of-two-studies.html

Although I haven't tried to quantify the amount of mecury that the Holmes et al and now Kern et al papers claim should be "excreted" by hair, I have addressed the fact that all physiological work on hair has shown - repeatedly - that mercury is passively incorporated into hair as it grows, in proportion to the mercury concentration of the blood at the time.

There are no "poor excretors" when it comes to hair mercury, since none of us mammals excrete mercury in our hair. If the mercury isn't in the hair, it is because it wasn't in the blood. And if it wasn't in the blood, it can't get into the brain - unless you inject it directly into the brain tissue.



Prometheus

23 April, 2007 13:24  
Blogger daedalus2u said...

Master Cubbins, I have also addressed the "poor excreters" idea (not a hypothesis), a hypothesis has to be consistent with what is well known. If an idea isn't consistent with what is well known it isn't an "hypothesis".

http://daedalus2u.blogspot.com/2007/03/discussion-of-false-mercury-causes.html

Prometheus is quite correct. Mercury simply tags along with other thiols in the body. A disruption of thiol physiology sufficient to cause several orders of magnitude difference in partition ratios between brain/hair/blood has never been observed in any organism, and would likely be incompatable with life in utero.

I also address the quantity of mercury excreted in the chelation provoked tests of Bradstreet et al. Over 3 days, there was an increased excretion of 3 micrograms, the average amount in an ounce of tuna. Perhaps "significant" in a statistical sense (but I would like to see the actual data, not just a mean and a standard deviation) but not in any clinical sense.

23 April, 2007 15:33  
Anonymous Michael J. Dochniak said...

Hi Prometheus,

I've proposed that exposure to the Hev-b proteins from natural rubber latex may have caused an increased incidence of ASD globally. I'm currently having baby bottle nipples and pacifiers that are made from Hevea Brasiliensis tested at Pace Analytical for total organic nitrogen content (kjeldahl nitrogen test EPA 351.3)to determine the protein content. Thereafter, further analytical testing will be pursued to determine the antigenic characteristics of such articles.

Q. Why should we have NT and/or autistic neonates sucking the known allergens out of natural rubber latex based bottle-nipples and pacifiers.

If the theory "Exogenous protein insult - Hev-b" is determined not to be involved in the etiology of allergy induced autism I'll...

28 April, 2007 06:34  
Anonymous Michael J. Dochniak said...

Prometheus,

I noticed on your home page that the Quackwatch link has a page about 'The Latex Allergy Epidemic' http://www.quackwatch.org/03HealthPromotion/latex.html

Q. If Quackwatch is concerned about latex allergies in adults shouldn't we also be concerned about what latex allergies may do to prenates/neonates.

Saying, "there isn't a connection" when talking about the latex/ASD theory is, in my opinion, a Semmelweis reflex especially when embedded in an editorial of about 20 words. Although I'm sure some blogger's like to see such bold statements in that it reinforces a sense of defeatism.

02 May, 2007 15:07  
Blogger Prometheus said...

Michael,

I would suggest that you take your concerns about the Quackwatch site to the editor of the site, not to me. I link to the site - I don't run it.

As far as latex allergy, I believe that people are already concerned about latex allergy in children and infants. However, latex allergy is a well-described phenomenon that does not include the neurological disorders you attribute to latex-derived antigens.

I would suggest the following:

[1] Contact Dr. Stephen Barrett with your concerns about Quackwatch.

[2] Develop some data that supports your hypothesis that latex-derived antigens cause neurological disorders (i.e. are not simply associated with them).

Best of luck


Prometheus

03 May, 2007 08:56  

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