Corante

About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Nuclear Fusion, Wordsworth, German Cooking. The Usual. | Main | Ignorance Was Bliss »

March 10, 2004

A Mechanism for Thimerosal

Email This Entry

Posted by Derek

There's some fresh news in the (quite possibly endless) debate about the vaccine preservative thimerosal. The Institute of Medicine is working on another report, due in several months. Their last report, in 2001, found no evidence to support a link, but didn't dismiss the possibility, either.

I've written about this topic before. My belief, then and now, is that autism and thimerosal are very unlikely to be related. I haven't seen any data that make me lean the other way, and the evidence against a link has continued to pile up. One of my objections to the hypothesis has been that it's hard to rationalize, mechanistically. Mercury compounds are certainly neurological bad news, but autism hasn't generally been noted as a symptom of developmental mercury exposure. (There's a different set of effects, instead.) It's hard to come up with an explanation for why thimerosal's effects would be different and specific, while still partaking of the general toxicity of mercury compounds. (Why no rising epidemic of, say, cerebral palsy?) And there's the matter of the low dose, too.


But now there's a paper in Molecular Psychiatry by a team of researchers (from Northeastern and several other schools) which suggests a mechanism. They're looking at the synthase enzyme that produces the amino acid methionine, which is an important source of methyl groups for other enzymatic systems. DNA methylation is particularly important in gene expression, and many cellular growth factor pathways seem to have a methylation requirement in them as well. They've found that thimerosal is a powerful inhibitor of two particular growth-factor driven methylation reactions, with an IC50 of about 1 nanomolar.

Single-digit nanomolar is the kind of inhibitory constant that we look for in a new drug, too, so it's certainly plausible that that could have effects in vivo (if the pharmacokinetic behavior - blood and tissue levels of the compound - go along.) The paper points out that the ethylmercury blood levels produced by thimerosal-containing vaccines are in the 4 to 30 nM range, which is enough of a multiple of the IC50 to keep the hypothesis going (but see below.) So is this the proof against thimerosal, or not?

Well, on one level, this could answer some of my mechanistic objections. But I still have the same questions as before. This could be a refinement, but not enough by itself to establish a link. We're still in the same place: It's not that I can't imagine that thimerosal could be toxic, it's that I have trouble with it being toxic in just such a way as to produce only autism. Methylation pathways are ubiquitous - how does such a specific phenotype show up from this? (More such scepticism from an immunologist at McGill is here.


The authors do suggest some possible answers. Perhaps some individuals have a less robust methylation system than others, especially in specific brain development pathways, and are thus predisposed to thimerosal-induced damage. That's definitely a hypothesis worth investigating. If that looks like it's the case, I'll have to upgrade my take on the whole idea, subject to the 800-pound-gorilla in the last paragraph below.

And they suggest some limitations to their work. For one thing, they're working on cultured cell lines, which are tumor-derived and may well respond quite differently than primary cells in vivo. They also point out the potential complication that their cells have not fully differentiated into neurons. It's responsible of them to mention these factors.

I also wonder what the hit rate is in this assay - if we run a few thousand natural products or other environmental-exposure compounds through, how many are positive at nanomolar levels? I could also add that the ethylmercury blood levels they quote might not mirror the levels in the brain. That's been a battleground in the whole thimerosal debate, because we don't have definitive mercury pharmacokinetics in the brains of human children (and I sure can't think of an acceptable way to get 'em, either. The methods we use for that kind of data in rodent studies are clearly not going to apply!)

But my biggest objection to a thimerosal/autism link is epidemiological. So far, there seems to have been no change in the autism rate in response to the discontinuation of thimerosal. Data continue to be collected, of course, but there's no apparent connection, even from countries that eliminated the compound before the US did (and thus have a longer baseline.) The real-world numbers trump any amount of biochemical speculation. That goes for my own ideas as well, as my research projects demonstate to me regularly.

Comments (6) | Category: Autism | Toxicology


COMMENTS

1. Cath on May 26, 2004 1:42 AM writes...

What would the real-world numbers say about a possible link between folic acid supplements for pregnant women and the upswing in autism? I've been trying to find good stats on the internet, but without luck thus far. Given the possible methylation connnection to autism, it seems like folic acid should at least be investigated.

Permalink to Comment

2. Donna on June 3, 2004 7:00 PM writes...

I just read your comment on thimerosal and autism, You are correct! The mercury in the thimerosal affects other children other than autism. My son has been poisoned by mercury in utero from rhogam and also his vaccines...His 6 month old baby hair tested for mercury was 13.78mcg. He DOES NOT have autism...He does have progressive microcephaly, cp, seizures and is nonverbal.... His only exposure to mercury would have come from the rhogam shot I had and his vaccines. A woman I met who has a niece with retts, her hair tested for mercury was 14.8...The mother had the Flu vaccine during pregnancy(which contains mercury) I have been asking around to see if other mothers with disabled children(not autistic) Have taken a shot that contained mercury while they were pregnant...Angelman syndrome was a big one! One woman has three children with angelman syndrome and had the rhogam injection during all three pregnancies. Mercury that is injected into a pregnant woman WILL cause severe brain damage to a infant! My son is 18 years old and has the mental age of a 6 month old infant!

Donna

Permalink to Comment

3. Donna on June 3, 2004 11:19 PM writes...

It should be noted that this research study compared equal doses of
methylmercury and thimerosal. However, thimerosal is only 1/2 mercury
(ethylmercury), so the authors should have compared 1/2 dose
thimerosal
with 1 dose methylmercury. The conclusion would then be that
ethylmercury is equally potent to methylmercury in increasing Ca2++.
The
study also says that unlike methylmercury (which is usually bound to
cysteine in a cell) thimerosal's potency is unaffected by presence of
L-cysteine in the neuron, so under in vivo conditions the effects of
ethylmercury are likely greater (by a factor or 2) than methyl.
Finally,
the study shows that thimerosal is more potent than methyl in
decreasing
glutathione levels in the cell, which is what other researchers
have/are
finding as well.

wrote:
> Methyl-mercury, usually from contaminated food, is very dangerous
to
> pregnant women. Methyl-mercury causes profound mental retardation,
> cerebral
> palsy, seizures, spasticity, tremors, and incoordination, along
with
> eye and
> hearing damage in the unborn baby as a result of the mother's
> exposure.
> Organic mercury passes into the breast milk as well.
>
>
>
> The effect of thimerosal, an organomercurial preservative in
> vaccines, on cerebellar neurons dissociated from 2-week-old rats
was
> compared with those of methylmercury using a flow cytometer with
> appropriate fluorescent dyes. Thimerosal and methylmercury at
> concentrations ranging from 0.3 to 10 microM increased the
> intracellular concentration of Ca2+ ([Ca2+]i) in a concentration-
> dependent manner. The potency of 10 microM thimerosal to increase
> the [Ca2+]i was less than that of 10 microM methylmercury. Their
> effects on the [Ca2+]i were greatly attenuated, but not completely
> suppressed, under external Ca(2+)-free condition, suggesting a
> possibility that both agents increase membrane Ca2+ permeability
and
> release Ca2+ from intracellular calcium stores. The effect of 10
> microM thimerosal was not affected by simultaneous application of
30
> microM L-cysteine whereas that of 10 microM methylmercury was
> significantly suppressed. The potency of thimerosal was similar to
> that of methylmercury in the presence of L-cysteine. Both agents
at
> 1 microM or more similarly decreased the cellular content of
> glutathione in a concentration-dependent manner, suggesting an
> increase in oxidative stress. Results indicate that thimerosal
> exerts some cytotoxic actions on cerebellar granule neurons
> dissociated from 2-week-old rats and its potency is almost similar
> to that of methylmercury.

Im just a mother with a very sick child...I know that for a 17 lb baby having a level of mercury at 13.78mcg is very high... There was 30mcg of thimerosal in the shot of rhogam I had while I was pregnant then I had another one after giving birth while breastfeeding my son...He had all his vaccines on time. I can not do anything to help my son get better, But I can try my hardest to find answers to save another child from mercury. Mercury was taken out of Rhogam in 2001, But my biggest concern is that pregnant women are being encouraged to take the flu vaccine this fall which contains mercury.. People say this is good for the pharmecutical companies...The more sick kids the bigger the profits for Pharma. I dont want to believe this, But when I read about the huge profits some of these pharmecutical companies are making, It makes me wonder..

Donna

Permalink to Comment

4. Derek Lowe on June 4, 2004 11:32 AM writes...

Donna, you're right in not wanting to believe that "the more sick kids the bigger the profits for Pharma." That sort of thing drives me crazy when I hear it, as you can imagine, since I work in the industry.

And it doesn't even make sense. Even if mercury is injuring people in vaccines, which I don't think it is, and even if we were these evil sickness-mongers, which we certainly aren't, we aren't selling things to patients like your son.

As you mention, you can't do anything to help him get better. It's a terrible situation. But where's the drug company that's profiting from it?

Permalink to Comment

5. Donna on June 4, 2004 6:19 PM writes...

My son has been on so many diffrent medications over the years, I can not even tell you how many. He has Lennox Gastaut syndrome(severe seizures) We have tried every drug known to man to stop his seizures...Including shots of ACTH. At the current time he is taking 8 diffrent medications everyday...So if you add him to the list of all the other children who have been hurt by vaccines... Thats a lot of money in sales for Pharma.

I do not want you to think I am against vaccines, I am not. I am against using mercury in vaccines. I know my son was poisoned by mercury in the vaccines, and from the rhogam injection I had while I was pregnant. It was the only exposure he had to mercury. Could you think of any other way his baby hair would be so high with mercury? I dont eat fish and had 4 fillings in my mouth, I was 23 years old, very healthy, I had natural child birth so my son would not be poisoned by the anesthesia.

I know I will never change your feelings on mercury causing my son's illness..

If a person smokes and gets lung cancer, the tobacco company use to deny this was the cause of that persons lung cancer.

My son was definitely poisoned by mercury..13.78mcg is a very toxic level for a 17 lb baby.

Can you honestly tell me without a doubt, that shooting mercury into my body while I was 6 months pregnant could not have caused my son problems?

He is not a statistic, he is my son.

Donna

Permalink to Comment

6. Donna on June 6, 2004 11:30 AM writes...

U.S. Counts One in 12 Children As Disabled
Census Reflects Increase Of Handicapped Youth

by D'Vera Cohn, Washington Post Staff Writer, Friday, July 5, 2002;
Page B01

One of every dozen U.S. children and teenagers -- 5.2 million -- has
a physical or mental disability, according to new figures from the
2000 Census that reflect sharp growth in the nation's young
handicapped population over the past decade.

What really gets me is the population growth is at the lowest level
since national data have been available.


For Immediate Release
Wednesday, June 25, 2003
Contact: NCHS Press Office (301) 458-4800
CDC Office of Media Relations (404) 639-3286
E-mail: paoquery@c...

Births: Preliminary Data for 2002. NVSR Vol. 51, No. 11. 20 pp.
(PHS) 2003-1120.
View/download PDF 1.2 MB

The U.S. birth rate fell to the lowest level since national data
have been available, reports the latest Centers for Disease Control
and Prevention (CDC) birth statistics released today by HHS
Secretary Tommy G. Thompson.

Permalink to Comment


EMAIL THIS ENTRY TO A FRIEND

Email this entry to:

Your email address:

Message (optional):




RELATED ENTRIES
XKCD on Protein Folding
The 2014 Chemistry Nobel: Beating the Diffraction Limit
German Pharma, Or What's Left of It
Sunesis Fails with Vosaroxin
A New Way to Estimate a Compound's Chances?
Meinwald Honored
Molecular Biology Turns Into Chemistry
Speaking at Northeastern