Waly M, Olteanu H, Banerjee R, Choi SW, Mason JB, Parker BS, Sukumar S, Shim S, Sharma A, Benzecry JM, Power-Charnitsky VA, Deth RC, Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal. Mol Psychiatry. 2004 Apr;9(4):358-70.
The 2010 Dwyer decision:
[Deth's] own research, most of which was unpublished, unduplicated, or mentioned for the first time during the Theory 2 general causation hearing, was poorly performed and scientifically implausible. Based on in vitro effects of mercury on “neuronal cells,” he claimed that mercury had the same effects on human brain cells.
Kathleen Seidel's correspondence with Deth March 22, 2006, Deth to Seidel:
I would like to make a virtual wager that within the next 18-24 months scientific evidence will make the thimerosal-autism link a near certainty.
January 12, 2006 Bartholomew Cubbins on Autism: Waly et al.
February 22, 2007 Kev or Sullivan at Leftbrain/Rightbrain
Deth’s paper, if I may quote myself, can be summed up thusly:The basic gist of the Deth paper is that various toxins, including thimerosal, affect methionine synthase activity (a process that helps in building proteins) and that this can adversely affect children. In short, the Deth paper alleges that thimerosal causes methionine synthase dysfunction (MSD).
There are several issues with this as they relate to autism. Firstly, MSD and autism do not resemble each other. Symptoms of MSD are: Anemia, moderate to severe developmental delay, lethargy, anorexia, and homocystinuria (mental retardation, dislocation of the crystalline lens of the eye, sparse blond hair, and cardiovascular and skeletal deformities).
1) There is no active transport mechanism into the central nervous system currently known for ethylmercury (thimerosal) whereas there is an known and active transport mechanism for methylmercury.
2) Because its half-life is much longer, methylmercury is more likely to accumulate than ethylmercury, causing higher levels of mercury in the blood.
3) Exposing cells in vitro to ethylmercury eliminates the most important difference between those two forms of mercury, and ignores the fact that ethylmercury is unlikely to enter the central nervous system at concentrations likely to be harmful.
4) The authors chose to use a cell line derived from a metastatic peripheral nervous system tumor to make predictions about developing healthy cells of the central nervous system. If the authors were interested in making claims about the developing central nervous system they should use cells derived from there.
5) The authors make statements in their introduction about developmental disorders such as fetal alcohol syndrome, Rhett’s syndrome, or Fragile-X syndrome, they fail to consider the fact that all of these diseases have their origins in the developing embryo and fetus, not postnatally.
6) The authors’ reference a study that evaluated the causal association between thimerosal and vaccines using the Vaccine Adverse Events Reporting System (VAERS). Remember how good VAERS is?
On December 30, 2007, Kathleen Seidel published the full text of a lengthy Memorandum Opinion issued on December 21, 2007, in Blackwell v. Sigma Aldrich, Inc. et al. (Circuit Court for Baltimore City, Case No. 24-C-04-004829). In that hearing, Judge Stuart Berger excluded Deth's testimony on the following grounds:
Dr. Richard Deth teaches pharmacology at Northeastern University. He was offered by the plaintiffs as an expert in the areas of physiology, neuropharmacology and the effects of thimerosal in the human brain. Dr. Deth is clearly qualified to testify as an expert witness in the areas of physiology and neuropharmacology. However, there is no recognized field of science in the third proposed area of expertise, namely "the effects of thimerosal in the human brain."
Dr. Deth offered the opinion that exposure to mercury for thimerosal-containing vaccines causes autism, based on a molecular theory that he developed through his in vitro studies. Questions about the effect mercury has in the human brain necessarily come within the ambit of the field of toxicology. These questions, including any opinions about the absorption, distribution, metabolism, and the excretion of thimerosal or mercury all involve issues of toxicology.
Further, Dr. Deth is neither an epidemiologist, a neurologist nor a geneticist. That — vel non — would not operate to preclude his testimony. However, he has never taken any courses in epidemiology, has published no papers in any epidemiological journal, and is not a member of any epidemiological societies. He relies on an epidemiology paper published by Dr. Geier as support for his opinions. (20) Further, he relies on several papers about the neurology of autism. He is not a medical doctor and is not an expert in the field of pediatric neurology. Lastly, although he relies on various studies in the field of genetics, he does not have a degree in genetics nor is he a member of any professional genetics organizations or societies. Accordingly, in light of his expressed reliance on Dr. Geier's studies (that the Court has addressed at pp. 24-38 of this Opinion), this Court finds that he lacks a sufficient factual basis to support his testimony.
On March 15, 2010, Kathleen Seidel published lengthy extracts of the Dwyer decision
The following excerpts are drawn from Special Master Denise Vowell’s 310-page decision in Dwyer v. Secretary of HHS (Case No. 03-1202V), one of the three “thimerosal theory” test cases presented in the Omnibus Autism Proceeding. The claim was dismissed on March 12, 2010, for failure to prove that thimerosal-containing vaccines can cause autism, or that they did so in this instance.
Deth's research and the resulting paper was deeply flawed. Does this paper "demonstrate that vaccines can cause autism"? No, for all the reasons given abouve.
On Dr. Richard Deth’s testimony regarding mercury, oxidative stress and sulfur metabolism (pp. 176, 185, 192, 208, 224)
Summarizing Dr. Deth’s opinions on the causal role of mercury in autism is difficult. Not only were the biochemical processes allegedly affected very complex, his explanations of those processes lacked coherence. He opined that very small amounts of mercury had a scattershot effect on a number of biochemical processes, inducing systemic metabolic abnormalities and oxidative stress. He also opined that these metabolic abnormalities resulted in interference with neuronal functioning in attention and cognition, causing the major symptoms of autism. His entire hypothesis rested on a speculative “genetic susceptibility” to environmental toxins, such as heavy metals in general, and mercury in particular. He asserted that children with autism have polymorphisms – variations in genes that are not considered mutations—that render them more sensitive to mercury’s effects by impairing their ability to eliminate ethylmercury, maintain normal oxidative and methylation balance, and maintain synchronization in neuronal signaling. The scientific studies upon which he relied provided, at best, only tangential support for his hypothesis. His own research, most of which was unpublished, unduplicated, or mentioned for the first time during the Theory 2 general causation hearing, was poorly performed and scientifically implausible. Based on in vitro effects of mercury on “neuronal cells,” he claimed that mercury had the same effects on human brain cells.
In addition to his own unpublished research, Dr. Deth relied heavily on his one article on mercury, the Waly study. He relied on two studies conducted by Dr. S. Jill James, calling them the strongest evidence in support of his hypothesis. He also claimed that the “strongest evidence” in favor of his hypothesis derived from his own unpublished work on post-mortem brain samples from individuals with ASD.
Perhaps his most extravagant claim involved the quantity of mercury required to induce the claimed effects. He claimed the ability to detect the effects of mercury on cells at levels 100-1000 times lower than levels used by other researchers. He testified that mercury, in amounts at or well below the amounts contained in TCVs, could induce some individuals to enter into and remain in a state of oxidative stress.
n the course of the hearing, nearly every premise of his causation theory, other than that of the ubiquity of mercury exposure in children (with or without autism), was seriously undermined, where not completely demolished. Mercury, and a number of other heavy metals, can affect cellular metabolism, but Dr. Deth’s assertions that mercury does so in the manner and at the levels of exposure postulated and with the effects claimed were not scientifically supported. His assertion that oxidative stress in children with autism is causal of their autism was pure speculation.
…Although Dr. Deth’s testimony was superficially coherent, the defects pointed out by true experts revealed the critical flaws in Dr. Deth’s presentation, and, ultimately established that his hypothesis of causation was not reliable.
…The discovery of an extracellular methylation cycle, when all other methylation cycles take place inside cells, is so highly unusual that it warrants independent confirmation. That confirmation is lacking. The assertion in the Waly study that the D4 receptor was the site of the methylation activity was based on gel electrophoresis, but a critical failure in that process was noted by Dr. [Richard] Mailman. In view of Dr. Mailman’s many publications on dopamine receptors, his testimony regarding them carries exceptional weight.
As Dr. Deth had not conducted studies on human brain cells, other than his unpublished work discussed below, his testimony that human neurons lack the ability to use SAM to reactivate methionine synthase lacks scientific support. He based his findings on experiments conducted on cells with a known methionine synthase mutation. In summary, Dr. Deth and his colleagues designed an experiment around two faulty premises: the existence of the only extracellular methylation cycle, and a purported defect in human neuronal cells. In view of these problems, and the other issues noted by Drs. Jones and Mailman, any conclusions drawn from the first part of the Waly study are so unreliable as to render its evidentiary value virtually nil.
…Dr. Deth’s late-in-the-game switch from mercury’s impact on glutathione to its binding to otherwise unidentified “regulatory proteins” was unpersuasive. After considerable testimony about mercury’s effects on transsulfuration and the methionine methylation cycle and his many experiments that purported to measure these effects, Dr. Deth’s new focus on “regulatory proteins” was disingenuous at best. Given the ubiquity of thiols and sulfur in the brain and elsewhere in the body, the tiny amounts of mercury administered through TCVs, and the even smaller amounts that will reach and remain in the brain, are unlikely to deplete the thiols available. Most mercury in the brain is already bound, and only the small amount not already bound to thiols would be available to react with these “regulatory proteins.”
…Initially, to someone unacquainted with mercury’s toxicology, ASD, or biochemistry, Dr. Deth’s opinions on mercury, oxidative stress, and sulfur metabolism might appear to be solidly based and plausible. After all, mercury can be toxic to cells and is known to produce neurological injuries. Mercury does bind to glutathione, the body’s primary antioxidant molecule, and thus might be expected to affect adversely the body’s oxidative status. Mercury is known to bind to cysteine transporters, and thus might be expected to affect cysteine levels in cells, and thus adversely affect cells that cannot manufacture their own cysteine, such as neurons. There is evidence to indicate that mercury can cause proliferation of microglia and reductions in astrocyte numbers in at least some areas of the brain, which Dr. Deth equated to the neuroinflammation found in the brains of individuals with ASD. There is some evidence that children with ASD display biomarkers of oxidative stress in peripheral blood, and may even have some polymorphisms associated with higher levels of oxidative stress.
However, when critically examined, Dr. Deth’s causal assertions fall apart. Mercury, at sufficient doses, is toxic to cells, but humans are born with mercury in their brains, blood, and hair as a result of maternal exposures. Humans continue to be exposed to mercury throughout their lives, and methods for detoxifying and eliminating mercury have evolved to account for this exposure. In populations with high mercury exposure, there is no increased incidence of ASD, and thus the low levels once found in vaccines are unlikely to be a cause or a substantial contributor to the condition. Mercury, at sufficient doses, can produce neurological injuries, but not at the levels of mercury found in vaccines. The neurological injuries it produces are well established and do not resemble ASD. A comparison of autopsy findings in mercury’s victims and autopsy findings from individuals with ASD do not show the same patterns of damage or injury.
Dr. Deth attempted to demonstrate that vaccine levels of mercury could adversely affect sulfur metabolism and produce oxidative injury in the human brain through a series of experiments on cells in culture. He represented the cells as “neuronal,” although they were not neurons and had defects affecting the processes he attempted to measure. His laboratory experiments, funded largely by contributions from groups associated with the belief that vaccines cause ASD (ARI [Autism Research Institute] and SafeMinds), found adverse effects from doses of mercury between 100-10,000 times lower than those used by other researchers. Assuming, arguendo, that these experiments were properly performed and produced correct results (both points about which I am unconvinced), the experiments contribute little to nothing to the causation hypothesis. In vitro experiments on cells in culture may suggest likely avenues for further research, but the complexity of sulfur metabolism presented in Dr. Deth’s testimony and report demonstrates the robust systems in place in human beings to handle oxidative stress and produce the methylated products needed for cellular functioning, including DNA expression. I note that Dr. Deth heavily relied on mercury’s effects on glutathione, but the evidence overwhelmingly illustrated that glutathione levels in the body would be unaffected by vaccine level doses.
Dr. Deth also relied heavily on evidence indicating that children with ASD display peripheral markers of oxidative stress, and that brains of those with ASD have evidence of neuroinflammation, which he equated to oxidative damage. He failed to mention that oxidative stress in the periphery is associated with many different diseases, but that peripheral levels do not represent brain redox status. He likewise failed to point out that neuroinflammation is found in many brain disorders and injuries, including those produced by trauma. Thus, a finding of oxidative stress or even oxidative injury says little about mercury as a probable cause of the stress or injury because there are so many other possible causes, including neuroinflammation as a response to the other pathophysiological findings in the brains of those with ASD. Since ASD is a highly genetic disorder, it is unsurprising that preliminary studies have found some polymorphisms exist in children with ASD in higher numbers than in neurotypical individuals. It is equally unsurprising that some of these polymorphisms are associated with problems in oxidation or sulfur metabolism. Children with Down syndrome, an entirely genetic disorder involving mental retardation, also have oxidative stress levels higher than neurotypical children. Children with Rett’s disorder, another entirely genetic condition, have impairments in DNA methylation, a sulfur metabolism problem. The preliminary findings in children with ASD say nothing about a genetic susceptibility to mercury or even that the oxidative stress levels found actually affect mercury detoxification.
Dr. Deth’s own experiments were based on faulty premises regarding methylation of the D4 receptor and defects in methionine synthase activity in human neurons. His experiments detecting effects of nanomolar levels of mercury on glutathione, cysteine, methylcobalamin, and methionine synthase had so many flaws that they cannot be considered reliable as evidence. Respondent’s experts in oxidative stress, sulfur metabolism, neurodegenerative disorders, and mercury pointed out the serious deficiencies in Dr. Deth’s hypothesis, experiments, and conclusions. Their criticisms, coupled with the flaws in Dr. Deth’s logic, his own acknowledgment that eliminating TCVs has not produced any decline in ASD rates, and the conflicts between his testimony and what is well established about mercury’s toxicology, all convince me that Dr. Deth’s hypothesis is not reliable, and cause me to accord his testimony and report little weight.