Having a daughter who regressed into autism compels me to research medical journals because she began having health complications after vaccinations. I have an insatiable hunger for knowledge about mitochondrial dysfunction, inflammatory responses (brain and gut), oxidative stress, immune abnormalities, and hormonal dysfunction causing seizures. Cancer was really not on my radar too much but it has crept up more as Megan's estrogen levels now make her a prime candidate for it, especially breast cancer. You can read about her horrific hormone levels as a causative factor in her catamenial epilepsy HERE. Cancer can be considered a "regression" in healthy cells, most likely due to an environmental cause, yet we don't always hear that.
In a related search last year, I began to examine and write about melanin, and my thoughts about its involvement in autism. It seemed to me that there was a peculiar propensity for an autism diagnosis in those who had red hair, light eyes or just more of a fair complexion, ie - less melanin. Tyrosine, an amino acid needed to make melanin, seemed somehow tied up but I wasn't sure how. Much research backed up the idea that having less melanin did make one more vulnerable to other "neuroregressive" disorders such as ALS, Parkinson's, Alzheimer's, and Schizophrenia, but also Melanoma. Add Melanoma as another Megan health concern I have because she is just so fair, and seems to contain the recipe for these environmental attacks. What brought me closer to these concerns is that by looking at the similarities of these diseases, one can see the pattern emerge. I saw that as I began to look not only at the symptoms but also at the pharmaceutical management - ie - medications being used or contemplated. The first clue was that there seemd to be some pigmentary disorders in children who also happen to have an autism diagnosis. Is that a coincidence or is that showing a mechanism of what may be happening behind the scenes of this historically misunderstood disorder? I hope I can unfold this pattern here so that it can be looked at for further research. It seems that medicine too often develops a pill to treat a symptom while not searching for the roots to the actual diseases and illnesses. Since autism has become a disorder that is increasing at alarming numbers, and with much physical and emotional suffering, it is our duty as a moral and ethical nation to find both cause and cure.
Recently, as I was reading about each - melanin, autism and cancer - certain websites and words kept reappearing - the puzzle pieces were emerging. One of those pieces that I kept running into was medication, initially FDA approved for neurodegenerative conditions, yet interestingly, one was now being considered for use in breast cancer. Since the two seem completely unrelated as diseases, I was intrigued. Now what makes that more compelling is that the same pharmaceutical medication is now being looked at for autism. The key factor that the drugs are working on for each of these diseases are the mGluR, Metabotropic Glutamate Receptors. I wrote about them HERE as many were racing to find a cure with drugs targeting these receptors but hardly any of them seemed to care about the causation or WHY they were implicated. Now cancer is another race for the cure with these glutamate receptors but how is it related to autism? Here was a study that could answer that question:
"Methylmercury Increases N-Methyl-d-Aspartate Receptors On Human SH-SY 5Y Neuroblastoma Cells Leading To Neurotoxicity" 2008 (HERE)
"Methylmercury (MeHg) is a known neurotoxin, yet the mechanism for low dose chronic toxicity is still not clear. While N-methyl-D-aspartate receptors (NMDARs) were found to be induced after exposure to MeHg in a mink model, its role on neurotoxicity is not known. The aims of this study were to investigate the expression and the functional roles of NMDARs on the induction of cell death in the human SH-SY 5Y neuroblastoma cell line after exposure to MeHg. We found a significant increase in NMDARs followed by increased caspase-3 activity after 4 h of exposure to MeHg (0.25-1 microM). Necrotic cell death was found after 4 and 24 h of exposure to MeHg (0.25-5 microM). The NMDAR antagonists dizocilpine ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-iminemaleate [(+)-MK801]) and Memantine (1-amino-3,5-dimethyl-adamantane) (10 microM) completely attenuated MeHg-mediated cell death by blocking NMDARs, thus demonstrating the importance of NMDARs in mercury neurotoxicity.
Two things of importance from that study: 1- From Wikipedia - "Metabotropic glutamate receptors are known to act as modulators of (affect the activity of) other receptors. For example, group I mGluRs are known to increase the activity of N-Methyl-d-Aspartate Receptors (NMDARs), a type of ion channel-linked receptor that is central in a neurotoxic process called excititoxicity."---- meaning that mercury is shown here to be CAUSATIVE to the " (NMDARs) were found to be induced after exposure to MeHg" and 2- Memantine is one of these drugs being used for neurological, regressive diseases and also being investigated for Autism: OSU Medical Center
That seems pertinent on many levels. Some caveats: A significant increase in NMDAR's after exposure to mercury. Memantine weakened that effect by blocking the NMDAR's. The NMDAR's are important in mercury neurotoxicity.
From Wikipedia: Memantine is the first in a novel class of Alzheimer's Disease medications acting on the glutametergic system by blocking NMDA glutamate receptors. It was first synthesized by Eli Lilly and Company in 1968. Memantine is marketed under the brands Axura and Akatinol by Merz, Namenda by Forest, Ebixa and Abixa by Lundbeck and Memox by Unipharm.
Very interesting connections. Here too, is another study but this one describes Riluzole's effects on mercury. Remember, Riluzole was first introduced as a drug to treat ALS and according to the ALS Association , "Riluzole, the first treatment to alter the course of ALS, was approved by the FDA in late 1995. This antiglutamate drug was shown scientifically to prolong the life of persons with ALS by at least a few months. More recent studies suggest Riluzole slows the progress of ALS, allowing the patient more time in the higher functioning states when their function is less affected by ALS. Rilutek® (Riluzole) is manufactured by Sanofi-Aventis Pharmaceuticals, who sponsor a Patient Assistance Program that helps patients who qualify receive the drug." An internet search shows the price of Riluzole to be about $9 a pill.
Journal of Environmental Health, 2010 "Antagonism of Dextromethorphan and Riluzole to Neurotoxicity Induced by Methylmercury in Rats"
"Objective- To observe the adverse effect of methylmercury on the cortex and cerebellum respectively as well as to approach the antagonisms of dextromethorphan(DM) and riluzole to the mercury-induced neurotoxicity...Conclusion "Glu-Gln Cycle" can be destroyed by MMC ( methylmercuric chloride). DM and Riluzole present some antagonistic effects on MMC-induced neurotoxicity in rats."
The fact that these drugs target glutamate dysfunction and then research shows that these same drugs are shown to stop MERCURY-INDUCED NMDA NEUROTOXICITY, well, it appears that correlation and causation sure seem to fit. So how is cancer related to that? It looks like a similar pathway with similar causation. Last year, I posted research that linked mercury exposure to melanoma. Here it is again as it seems to make sense as we discuss melanin, NMDA receptors and mercury exposure:
"Skin Cancer" by Keyvan Nouri - 2007
"Metal exposure may be quite important in the development of melanoma and has been very little studied. Occupational arsenic and mercury exposure have been associated with an increased risk for cutaneous melanoma among Swedish women who were members of an occupational cohort."
"Cutaneous melanoma in Swedish women: Occupational risks by anatomic site."
"Accordingly, our aim was to identify occupations with higher risk of cutaneous melanoma, overall and by site, in Swedish female workers. RESULTS: High risks were observed among educators, bank tellers, dental nurses, librarians/archivists/curators, horticultural workers, and hatmakers/milliners. Some occupations with possible exposure to arsenic/mercury displayed increased risk."
Well, in an interesting exchange directed towards our own Jake Crosby, who wrote about Dr.David Gorski Age of Autism Financial Ties , cancer doctor and now head of a clinical investigation into Riluzole for breast cancer: "Official Title: Metabotropic Glutamate Receptor-1 (mGluR1): Validation of a Serendipitously Discovered Molecular Target for Breast Cancer Treatment" ClinicalTrials.gov
"The reason Jake mentioned Riluzole is because it’s one drug I study as a potential therapy for breast cancer. In fact, if I do say so myself, the project looking at Riluzole in breast cancer is an example of why science-based medicine is so cool compared to the fairy dust of “alternative” medicine or the pseudoscience that is the anti-vaccine movement. It all began a while back with a basic scientist at Rutgers named Suzie Chen, who wanted to make a transgenic mouse to study adipogenesis. So she used standard techniques to insert a gene she wanted to study, but after the transgenic mice were born the mice in one of the strains all developed skin lesions that looked like melanoma by the age of two to four months. Being a good and careful scientist, Dr. Chen realize that she had inadvertently created something really interesting, a mouse model of melanoma. So, teaming up with Dr. James Goydos, my surgical partner at The Cancer Institute of New Jersey (which is where I was at the time), Dr. Chen went back and looked at what had happened and figured out that the transgene had disrupted part of the regulatory region of a gene known as Grm1 (GRM1 in the human), which codes for a gene known as metabotropic glutamate receptor-1 (mGluR1), in such a manner that mGluR1 was being made at a level far higher than normal."
"A word of explanation is in order here. Glutamate is a major neurotransmitter in mammals that functions by binding to either ionotropic or metabotropic receptors (genes: GRM1-GRM8; receptors: mGluR1-mGluR8). I’m not going to talk about ionotropic glutamate receptors. mGluRs belong to a family of G-protein-coupled seven transmembrane domain receptors (GPCRs), which mediate responses to a diverse array of signaling molecules, including hormones, neurotransmitters, chemokines, and autocrine and paracrine factors. In the mammalian CNS, mGluRs, which are categorized into either group I, II, or III receptors based on sequence, what compounds they bind, and how they signal in the cell, are essential for normal neuronal function, and have been implicated in diverse neurological pathology, particularly ALS. Their existence and importance in melanoma had previously been unsuspected."
Another point made by Dr. Chen in a different interview was that "melanoma cells release a lot of a substance called glutamate." I think that is worth mentioning as it relates back to the melanin implications of these diseases.
The irony and Serendipitously Discovered realization that cancer and here, breast cancer, as also having roots with glutamate receptors is just so strange. I am eternally hopeful that breast cancer will be cured and I'm all for research but the search for medications seems more of a money-maker than a true medical breakthrough in the abolishment of disease. Dr. David Gorski, who incessantly ridicules parents for looking at both cause and cure to autism and especially concern about vaccines and mercury/thimerosal, has never discussed the issue of glutamate dysfunction in autism nor the strong correlation to mercury exposure. His glaring disdain for the topic of mercury induced illness in children vaccinated, who then develop symptoms of autism, has always been mystifying and hardly scientific. Here was Dr.Gorski just eight months ago regarding autism and mercury: "Two and a half years ago, very early in the history of this blog, I wrote one of my usual logorrheic (although I prefer the word “comprehensive”) posts entitled, "Mercury in Vaccines as a cause of autism and autism and autism spectrum disorders )ASDs): A failed hypothesis. In that post, I characterized the scientifically discredited notion that the mercury in the thimerosal preservative that used to be in several childhood vaccines was the cause of the “autism epidemic” as “one of the most pernicious medical myths of recent years.” And so it is."
In 1998, Wayne University, where David Gorski is currently doing the Riluzole Clinical Trial, did a study that seems related to this topic:
"Low levels of ionic mercury modulate protein tyrosine phosphorylation in lymphocytes"
"The ability of ionic mercury to induce protein tyrosine phosphorylation in mouse spleen cells and in the mouse WEHI-231 B-cell lymphoma was investigated. We have confirmed previous studies which showed that exposure to high levels (several hundred microM) of mercury lead to very large increases in the level of protein tyrosine phosphorylation in these cell systems. However we have also demonstrated that low levels (in the order of 0.1 to 1.0 microM) of mercury also significantly upregulate protein tyrosine phosphorylation. Mercury induced protein tyrosine phosphorylation is inhibited by the mercury chelator penicillamine and by pretreating treating target cells with the sulfhydryl blocking reagent N-hydroxymaleimide. These results suggest that exposure to low levels of mercury could potentially interfere with lymphocyte signal transduction and so offer a possible explanation as to how mercury exposure could lead to immune cellular dysfunction. On a molecular level, the results suggest that the site(s) of action with respect to mercury dependent induction of protein tyrosine phosphorylation is likely a free disulfide group or groups located on the outer leaflet of the plasma membrane."
Here is a brief description of protein tyrosine phosphorylation: Recent research shows that protein tyrosine phosphorylation (tyrosine kinases) are important mediators of the signaling cascade, determining key roles in diverse biological processes like growth, differentiation, metabolism and apoptosis in response to external and internal stimuli. Recent advances have implicated the role of tyrosine kinases in the pathophysiology of cancer. Tyrosine phosphorylation is a reversible, dynamic process controlled by the activities of the protein tyrosine kinases (PTKs) and the competing actions of the protein tyrosine phosphatases (PTPs).
Here was that word, "tyrosine" along with the word "chelator"and maybe now I could see how it may fit into this connection of mercury to NMDA receptors:
"Stimulation of protein tyrosine phosphorylation by NMDA receptor activation" 1991 HERE
"The N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors, plays a key role in synaptic plasticity in the nervous system. After NMDA receptor activation, calcium entry into the postsynaptic neuron is a critical initial event. However, the subsequent mechanisms by which the NMDA receptor signal is processed are incompletely understood......Stimulation of cultured rat hippocampal cells with glutamate resulted in the rapid and transient tyrosine phosphorylation...."
It seems there is a process here and mercury can start the signalling: HERE , 2004 "Results demonstrated that low, noncytotoxic doses of metals induce tyrosine phosphorylation"
And HERE, 2008 "Exposure to environmental heavy metals has been reported to affect the immune system. Here, we tested the hypothesis that Hg+2, acting through membrane proteins, disrupts metabolic dynamics and downstream cell functions in human neutrophils. We found that HgCl2 inhibited: (1) polarization and (2) immunoglobulin (Ig)G-mediated phagocytosis of sheep erythrocytes in a dose-dependent manner from 2.5 to 10 µm. Because these activities have been linked with pro-inflammatory signalling, we also studied the effects of HgCl2 on intracellular signalling by measuring protein tyrosine phosphorylation. HgCl2 at doses = 1 µm increased tyrosine phosphorylation."
Now here is Thimerosal, the vaccine mercury: HERE 2002 "Thimerosal stimulates focal adhesion kinase and cytoskeletal changes by redox modulation"
In the present study, we showed that HeLa S cells treated by thimerosal generated reactive oxygen species (ROS). Thimerosal-generated ROS stimulated the tyrosine phosphorylation of focal adhesion kinase (FAK) and also induced cytoskeletal changes. Pretreatment with intracellular calcium chelator, BAPTA did not block the thimerosal-mediated FAK tyrosine phosphorylation. On the other hand, either FAK inhibitor, tyrphostin or ROS scavenger, N-acetyl-L-cysteine (NAC) suppressed the tyrosine phosphorylation and cytoskeletal changes. These results suggest that thimerosal seems to induce FAK tyrosine phosphorylation and cytoskeletal changes by ROS generation but not by intracellular calcium mobilization.
That process sure seems related to this downstream signalling:
"Phosphorylation of focal adhesion kinase promotes extravasation of breast cancer cells" HERE
"Inhibition of focal adhesion kinase (FAK) delays transendothelial migration of breast cancer cells...These findings suggest that modified signaling mechanisms regulate cancer cell migration."
Dr. Gorski has mentioned " the role of glutamate receptors in promoting the growth and metastasis of breast cancer" as well as "it’s amazing that we have been able to do as well as we have with various forms of “targeted” therapy directed at specific single molecular targets or a class of molecular targets in cancer cells. Gleevec®, for instance, has been amazingly successful as a targeted agent directed against several members of a class of enzyme known as a tyrosine kinases" in a blog about, "Why haven’t we cured cancer yet?." Perplexing that no where does he mention that Thimerosal/mercury can cause phosphorylation of focal adhesion kinase and that process promotes extravasation of breast cancer cells or at the very least, that there is "a compelling case for a role for FAK in the pathology of human cancer." HERE
Ignoring cause to race for a cure?
With Sanofi and also Bayer funding him for research, it will be interesting to see what the outcome will be. Ironically, Sanofi makes flu vaccines today that contain 25 mcg of Thimerosal. In January, it was reported that "government officials are looking into reports of seizures in patients who'd been given the Sanofi-Aventis influenza vaccine Fluzone. The reports mostly involved children younger than 2--36 of the 42 cases, to be precise--and 10 of the cases were serious, Reuters reports. Thirty-eight of the febrile seizures happened within a day of the Fluzone vaccine." Sanofi's response -- "Adverse events after vaccination may be causally related to vaccine or may be coincidental." CDC's response -- "There's no proof of a causal link--as Reuters points out, just because something happens soon after a vaccine is administered doesn't necessarily mean the vaccine caused it." HERE
Bayer had a long history of using 10.5 mcg Thimerosal in each of its Rhogam injections ( 2-3 injections usually per pregnancy) , a human gamma globulin (antibodies) directed against the Rh positive factor of blood. It is given to Rh negative mothers who give birth to Rh positive babies. HERE
I knew the word "phosphorylation" was familiar from a few years back with another redhead: "Autistic spectrum disorders can be associated with mitochondrial dysfunction. We present a singleton case of developmental regression and oxidative phosphorylation disorder in a 19-month-old girl."
"Developmental Regression and Mitochondrial Dysfunction in a Child With Autism" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2536523/ I'll conclude Part 1 with that in mind:
"Identification of tyrosine-phosphorylated proteins of the mitochondrial oxidative phosphorylation machinery" 2005 http://www.ncbi.nlm.nih.gov/pubmed/15924266
"The role of some serine/threonine kinases in the regulation of mitochondrial physiology is now well established, but little is known about mitochondrial tyrosine kinases....... Our results suggest that tyrosine kinases and phosphatases are involved in the regulation of oxidative phosphorylation."