Sunday, March 12, 2006

Armchair Science vs Real Science

In American football, there is a term for those who sit in front of the telly and pontificate on what they would have done if they had been in charge of the game. They are called "Armchair Quarterbacks". As I understand it, it is not meant to be a compliment.

In the world of pseudoscience and quackery - and especially in the world of "alternative" autism therapies - there are a group of people who sit in front of television cameras and pontificate on what "might" cause autism and what "might" treat it. I think the term "Armchair Scientist" fits these people well.

As with "Armchair Quarterback", "Armchair Scientist" is not a flattering term.

An Armchair Scientist gets to sit and speculate about what might be without ever having to do the hard work of actually doing any research to find out what is. The average Armchair Scientist doesn't even bother to review the published literature - they just make it up from what people have told them, what they've read on the Internet and what comes to them in their dreams.

However, the more pernicious of the Armchair Scientists have a pasing familiarity with the literature and cite it to their benefit. Several good examples of Armchair Scientists can be found on the FAIR Autism Media website. My personal favorites from this site are the dynamic (definitely sarcasm - see the video) duo of Geier and Geier (pere et fils).

In their video clip from the FAIR site, Geier and Geier expound at length (in a performance that can only be described as "petrified" - it's too stiff to be "wooden") about how they "discovered" that testosterone is the linchpin to explaining:

[1] How thimerosal invaccines causes autism (their bread and butter - literally).
[2] How the myriad of disparate and illogical autism treatments "work".
[3] Why more boys than girls are autistic.

It's a masterful piece of work, to be sure, and it would be a magnificent addition to the corpus of medical knowledge except for one small problem...

They don't have any data.

They begin with a stirring description of how they "found" that mercury inhibited a key enzyme in the pathway (more properly, the web of interlocking synthesis pathways) from cholesterol to testosterone and how this discovery led them to the belief (unsupported, as yet, by any data) that this was the key to the autism puzzle. Their "discovery" was from a paper by Ryan RA and Carrol J, Studies on a 3beta-hydroxysteroid sulphotransferase from rat liver (1976).

In this paper, Ryan and Carrol describe that the enzyme 3beta-hydroxysteroid sulphotransferase (EC 2.8.2.2) was, "...inhibited by p-chloromercuribenzoate and HgCl2". However, if you do a search of Medline for that enzyme, you will find that it is regulated, stimulated and inhibited by a wide variety of substances besides mercury.

So, let's look for a moment at some of the other claims they make on this video.

They cite a "study" by Boyd Haley, PhD who reportedly exposed neurons in cell culture and found that testonsterone enhanced the toxicity of mercury. This would be interesting - if not earth-shattering - news, except that it hasn't been published anywhere. Boyd Haley has a long list of publications and his name alone was able to get unadulterated twaddle published in an otherwise respectable journal, so I doubt the lack of publication is due to the infamous "conspiracy of silence".

A possible explanation for this absence of publication is that Boyd Haley doesn't feel confident enough of his results to embarrass himself in front of his peers. It's one thing to show video of neurons "unraveling" to a group of credulous parents - it's another thing entirely to show the same piece of work to people who know the "tricks".

That said, there are several studies that have looked at the role of testosterone in mercury poisoning (which should never be confused with autism - the symptoms and signs are completely different). A study by Barregard, Lindstedt, Schutz and Sallsten, Endocrine function in mercury exposed chloralkali workers (1994), showed that "Serum total testosterone, but not free testosterone, was positively correlated with cumulative Hg exposure."

Another study by Tanaka, Naganuma, Miura and Imura, Role of testosterone in gamma-glutamyltranspeptidase-dependent renal methylmercury uptake in mice (1992), showed that "Renal mercury content in 4-week-old male mice was twofold higher than that of females and increased with age, but remained constant in females." and "Seven days after castration of 4-week-old male mice, both renal mercury content and gamma-GTP activity were decreased to the levels in females."

On the other hand, a study by Mohamed, Burbacher (a familiar name) and Mottet, Effects of methyl mercury on testicular functions in Macaca fascicularis monkeys (1987), showed "The MeHg-induced increase in semen abnormalities was not accompanied by any significant changes in serum levels of testosterone."

Even more interesting is a study by Hirayama,Yasutake and Inoue, Effect of sex hormones on the fate of methylmercury and on glutathione metabolism in mice (1987), which found:


"Twenty-four hours after oral administration of MeHg, urinary Hg levels were significantly higher in males than in females. Tissue Hg levels of males were higher in the kidney, but lower in the brain, liver and plasma than those of females. The fate of injected MeHg in castrated males was similar to that in normal females except for its brain levels. This feminization of the mercurial behavior in the castrated males was restored by treating with testosterone propionate (TP). When control mice were treated with TP, urinary excretion of Hg increased in both sexes, whereas renal Hg level increased only in females. Administration of estradiol benzoate (EB) to males decreased the renal accumulation and urinary excretion of Hg, whereas its hepatic levels
increased."
In short, Hirayama et al [thanks Clone3G, for the reference!] found that testosterone protected the brain and increased mercury excretion. And that estrogen made the mice more susceptible to mercury poisoning. Quite the opposite of what Geier and Geier speculate might be happening in autistic children!

So, the connection between mercury and elevated testosterone - which seems so solid to the Geiers - is not clear at all, even at overtly toxic levels. Nor does the idea that testosterone impairs mercury excretion or increases mercury toxicity seem to be holding water.

The real laugh in the show was when the Geiers described how mercury "coordinated" the binding of testosterone into large "sheets" and "matrices" that were resistant to breakdown by enzymes. They based this - so they said - on crystallographic data. Since there is only one report of co-crystallization of testosterone and mercury [Cooper A, Gopalakrishna EM, Norton DA, The crystal structure and absolute configuration of the 2:1 complex between testosterone and mercuric chloride (1968)], it seems that is the source of this datum.

Apart from the fact that the processes used to crystallize testosterone (or most any other biological molecule) for X-ray crystallography are not happening in the body, there are some flaws in this "reasoning":

[1] If the mercury is complexed into a matrix of testosterone and mercury, it is not available to cause problems. It would seem that these "sheets" of testosterone would be an ideal way to sequester mercury away from delicate brain tissue, which would leave open the question of why the Geiers want to reduce testosterone.

[2] Mercury doesn't complex with carbon, oxygen or hydrogen very well - it "prefers" sulfur, but will complex with phosphorus or nitrogen in a pinch. below are the structures of several compounds related to testosterone (including testosterone itself). For those unfamiliar with the notation, the lines have a carbon atom at each end unless a letter is present.



Clearly, there is no high-affinity spot for mercury to attach.

[3] How is mercury - a brainless atom that cannot read structure diagrams - to know that it should attach to testosterone and not one of the several "look-alike" molecules? How many of the intelligent life-forms reading this blog can spot the testosterone molecule?

Here's the "key" for the above test:



So, we have no data to support the idea that testosterone binds preferentially to mercury, that mercury bound to testosterone (if it were possible) would be bioavailable (capable of doing harm). We also have no data that mercury causes an increase in DHEA (as proposed by Geier and Geier) or that testosterone impairs excretion of mercury. What's left?

Prometheus

21 Comments:

Blogger Flea said...

What's left?

I'm sure Fore Sam will tell us.

(Sorry to wake the troll)

Flea

12 March, 2006 10:58  
Blogger Fore Sam said...

Prometheus;
Why are you so concerned with all of this?
Do you work for Eli Lilly?

12 March, 2006 11:08  
Blogger Kev said...

Fore Sam, Prometheus ain't smart enough to get a job with Lilly. He is really Senator Frist.

12 March, 2006 13:16  
Blogger Bronze Dog said...

Why are you so concerned with all of this?

Because a lot of people are potentially inflicting harm on children by chelation, based on a fairy tale.

How about you point out the flaws in Prometheus's article, rather than performing the standard issue, baseless mud-flinging, known as "appeal to motivation" and "Obtain Disapproval"?

12 March, 2006 13:30  
Blogger clone3g said...

Thanks for the mention Prometheus. I found that study while sitting in my very worn out armchair ;-)

Another excellent blog entry!

Fore Sam,
Keep working at it buddy. I think your getting closer to your version of the truth.

"I'm trying to think but nothing happens."
- Jerome "Curley" Howard

12 March, 2006 13:48  
Blogger Prometheus said...

Fore Sam,

I'm concerned about this because there are human lives at stake.

I'm concerned because the Geier's are grossly misrepresenting the data and are pretending to have a degree of certainty that they don't have and can't have.

I'm concerned because desperate parents are being told "Just So" stories about autism that are about as factual as "Little Red Riding Hood" or "Puss in Boots".

I'm concerned because the parents of autistic children do not have infinite amounts of time, money or energy and the Geiers are asking them to spend those resources on therapies that have never been shown to work.

I'm concerned because people like you - who have no idea what you are talking about - are trying to convince people that mercury causes autism and chelation is the cure despite an utter lack of data supporting that "hypothesis". And in the face of overwhelming data refuting that "hypothesis".

If it makes you happy to think that I work for Lilly, or SKB or "the government" or whatever other conspiracy theory you believe in, then you go right to it. I'm not trying to convince you (or Kev C), I'm trying to reach the people whose minds haven't already petrified.


Prometheus

12 March, 2006 18:15  
Blogger Do'C said...

Hi Prometheus,

I so want to see you do an "Armchair Scientist of The Year" awards post - maybe every april 1st?

Highlight all the blunders and buffonery, and get as many blogger to post it on APRIL 1 as possible.

It could be called a catchy name just like they do with the Oscars.

How about the Golden Duck?

12 March, 2006 20:52  
Blogger hollywoodjaded said...

Totally stellar idea!

12 March, 2006 23:19  
Blogger notmercury said...

I like it! How about:

The La-Z-Boy award?
The Nauga-Prize
The Barca Medal of Excellence
The MacScience Foundation Awards
The Enrico Firmy Award
The Phony Awards

13 March, 2006 06:07  
Blogger Bartholomew Cubbins said...

the vulturians won't be able to sit down for a bit after this spanking. Nice work.

I'm interested to know whether the Hg was either in the mother liquor or soaked into the xtal and why - was it to solve the phase? I was under the impression that small molecule xtallography isn't prone to the phasing problems like macromolecules.

13 March, 2006 10:26  
Blogger Prometheus said...

Master Cubbins,

I've asked the University library to pull that volume out of storage, so I should be able to answer that question soon. I wonder if the Geiers even bothered to read the article - more than the abstract, that is.

My rather limited experience with doing crystallography (I love to work with the resulting structures) gives me no ready explanation for why they used mercury, which I usually associate that with protein crystallization.

Still, I can't see how mercury can be coordinating or "complexing" with testosterone in vivo with all of those juicy sulfhydryl groups around.

Or, if mercury does coordinate ("complex", "bind") with testosterone, how mercury can be specific for testosterone and not have the exact same reaction with estrogen, cortisol or even cholesterol.

More will be revealed when the trusty and over-worked librarians unearth this article.


Prometheus

13 March, 2006 16:47  
Blogger Bartholomew Cubbins said...

I'll bet a paycheck that the concentration of the molecule was no lower than millimolar.

And I do think you're right about them not reading the paper. It's too easy to look at a title that comes up via pubmed and drop it into a word file using Endnote; armchair science, indeed.

These hooligans make a great case study for an ethics and professionalism class for young grad students in the life sciences.

13 March, 2006 17:38  
Blogger Do'C said...

That's it BC, the perfect name for the Armchair Scientist of The Year awards - The Hoolie

:)

13 March, 2006 19:39  
Blogger Clark Bartram said...

I'm currently taking care of a young child with Smith-Leimli-Opitz who is unable to make cholesterol and thus testosterone. It's a shame(well not really because it is a bad thing to have that I would not wish on my worst enemy)that this illness isn't more common. A study on the incidence of autism amongst children with no testosterone might be interesting.

14 March, 2006 18:16  
Blogger notmercury said...

It's possible for many cases of mild SLOS to go undiagnosed or present as classic autism when the characteristic facial features aren't present.

It may be more common than current estimates which would mean the Geiers may end up administering Lupron to a child with autism and undiagnosed SLOS.

There are several drugs that should never be given to a person with SLOS because they can exacerbate the condition. I don't know if Lupron would be disastrous for SLOS but I can't imagine it would be helpful.

Since the Geiers don't seem too concerned with diagnostic criteria I doubt they are looking at 7-dehydrocholesterol levels in each of their patients to screen for SLOS.

15 March, 2006 06:02  
Blogger María Luján said...

Hi Prometheus

Not perhaps totally related to the proposal of the Geiers, that for me lacks of scientific basis, but to address the potential role of Hg in testosterone levels/male reproductive organs following this

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14572090&query_hl=10&itool=pubmed_docsum

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11696407&query_hl=10&itool=pubmed_docsum

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11284652&query_hl=10&itool=pubmed_docsum

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9821262&query_hl=10&itool=pubmed_docsum

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9821262&query_hl=10&itool=pubmed_docsu

I wonder if there are possibilities (in the case of Hg poisoning and depending on the particular compound) of being a catalysts of modification of testosterone in vivo? Few studies are available to answer this. Mercury has some affinity by Oxygen, more to Nitrogen but far higher to sulfur . Adsorption studies of Hg+2 on biopolymers such as chitosan demonstrated affinity to N and lower to O.
Prometheus What do you think?
Thank you in advance
María Luján

15 March, 2006 06:26  
Blogger María Luján said...

In adults, recent manuscripts say that lower levels of DHEA are present in ASD adults.
Eur Neuropsychopharmacol. 2005 May;15(3):305-9.
Lowered DHEA-S plasma levels in adult individuals with autistic disorder.
Strous RD, Golubchik P, Maayan R, Mozes T, Tuati-Werner D, Weizman A, Spivak B.
and older ones
J Autism Dev Disord. 1995 Jun;25(3):295-304.
Plasma androgens in autism.
Tordjman S, Anderson GM, McBride PA, Hertzig ME, Snow ME, Hall LM, Ferrari P, Cohen DJ.

I wonder in children what are the published results, if any, because of possible differences. If DHEA imbalances are/are not related to Hg is another topic.

MAría Luján

15 March, 2006 06:58  
Blogger Julia said...

DoC: "Hoolie" works a lot better than your first suggestion, "Golden Duck". There is already a "Golden Duck" award given for SF children's books.

15 March, 2006 07:53  
Blogger I ROCK!!!!! said...

This comment has been removed by a blog administrator.

16 March, 2006 07:03  
Anonymous HCN said...

No you don't, spammer.

16 March, 2006 08:55  
Blogger Heraldblog said...

The Mercury Monkey

22 July, 2006 09:41  

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