More of that vaccine/autism research that doesn’t exist

There are some parents who want research on vaccines and autism. I may not agree that this is the best way to spend our limited resources, but there’s no denying that this group exists and is very vocal. One thing that surprises me is that these parents appear to be unaware of vaccine/autism research that is ongoing. Not just the studies that come out that show us over and over again that autism risk is not increased by vaccines. But other projects. Biology. Studies on regression. And more. I pointed out recently that using NIH Reporter, one can find a number of projects on autism and vaccines or autism and mercury.

But NIH is not the only Federal agency funding autism research. And there are private funders as well. As I mentioned in my previous article, another place to look for funded research projects is the IACC/OARC Autism Spectrum Disorder Research Portfolio Analysis Web Tool as this includes work the various groups represented on the IACC–both Federal and Private. Unfortunately, this tool only has 2008, 2009 and 2010 projects (had the GAO not required OARC to provide a lot of information last year, perhaps this tool would be updated by now. But such is the government.) But, even with this limitation in years, let’s see what projects come up with searches for vaccines or mercury. I’ll give the titles first, and then the abstracts for these projects below.

It’s understandable that parent advocates are not aware of these projects. I’ve written about this before (“What projects are being funded in autism research? Part 1: vaccines and GI issues”) but I think it’s safe to say that parents who believe in the vaccine/autism connection do not frequent Left Brain/Right Brain. There are places on the web that carry that message (for example, the Age of Autism blog and the sites of the organizations that sponsor it). They aren’t telling their constituencies about the ongoing research efforts. As an example, as I was finishing this article, SafeMinds came out with a letter discussing how no work is being performed on vaccines and autism.

Again, this list is only for 2008, 2009 and 2010. More recent projects from NIH were discussed here.

Vulnerability phenotypes and susceptibility to environmental toxicants: From organism to mechanism (funded by Autism Speaks)

Evaluation of the immune and physiologic response in children with autism following immune challenge (funded by Autism Speaks)

Vaccination with regression study (funded by Autism Speaks)

Vaccine safety datalink thimerosol and autism study (Federally Funded)

Analysis of developmental interactions between reelin haploinsufficiency, male sex, and mercury exposure (Funded by Autism Speaks)

MeHG stimulates antiapoptotic signaling in stem cells (Federally funded: DoD)

Etiology of autism risk involving MET gene and the environment (Funded by Autism Speaks)

Epidemiological research on autism in Jamaica (Federally Funded, NIH)

investigation on the potential harmful effects of mercury in the nonhuman primate (Funded by SafeMinds)

Investigating the effect of mercury on ASD, AD and ASD regression (Funded by SafeMinds)

The effect of mercury and neuropeptide triggers on human mast cell release of neurotoxic molecules (Funded by SafeMinds)

Does mercury and neurotension induce mitochondrial DNA release from human mast cells and contribute to auto-immunity in ASD? (Funded by SafeMinds)

Toxicant-induced autism and mitochondrial modulation of nuclear gene expression (Federally Funded: DoD)

Below are the abstracts for these research projects.

Vulnerability phenotypes and susceptibility to environmental toxicants: From organism to mechanism (funded by Autism Speaks)

One hypothesis regarding the association between genetic changes, environmental factors and autism is that many mutations or polymorphisms make the organism more vulnerable to later exposure in some individuals. Called the “vulnerability phenotype”, the Noble lab hypothesizes that one potential unifying theme of the vulnerability phenotype of children with ASD is that they are more oxidized. This elevated oxidation state has been shown to be sufficient to cause dramatic changes in cellular function. In this project, Dr. Noble will test the hypotheses that genetically-based differences in oxidative status are associated with differences in vulnerability to physiological stressors in vitro and in vivo, with even greater increases in vulnerability to combinations of physiological stressors. Specifically, thimerosal and other vaccine adjuvants will be studied. The second part of the study will determine if these effects on a novel regulatory pathway called redox/Fyn/c-Cbl is a necessary mechanistic convergence for increases in vulnerability caused by a more oxidized metabolic status. These results will provide a better understanding of the biochemical effects and mechanisms of possible toxicity of vaccines and vaccine additives. What this means for people with autism: These studies will initially focus on the combination of vaccine additives, but then examine whether a background genetic vulnerability phenotype affects the response to these additives. The results would provide new targets for intervention against the adverse effects of increased oxidative status in children with autism.

Evaluation of the immune and physiologic response in children with autism following immune challenge (funded by Autism Speaks)

The overall goal of this proposal is to address immune function in children with autism, including the response to vaccine challenge, and how that relates to behavior. Evidence suggests that autism is associated in some cases with altered immune function, but the response of the immune system in children with autism to specific immune challenges, such as vaccines, has not been investigated directly. While it has been reported that some children with autism respond poorly following vaccination with symptoms ranging from rash, diarrhea, irritability, seizures, and loss of skills, no careful, thorough approach has been undertaken to fully characterize this issue, both at the biology and behavior level. We propose to use our current CHARGE (Childhood Autism Risks from Genetics and the Environment) and Autism Phenome Project (APP) study population to address this critical issue. The overall approach would include an examination of the immune response to both viral and bacterial vaccines in children with autism, as compared to typically developing age-matched controls, in real time following vaccination at 5 years of age. Vaccines have advantages for directly studying the immune response as they provide a known, scheduled immune challenge, whose dose is well characterized – making it possible to collect and interpret immune response data at the time that it occurs. Therefore, we think that exposure to an immune challenge with vaccine would result in an increase in inflammation compared to controls in a subpopulation of children with autism. However, we also anticipate that some children will respond to vaccine challenge differently, depending on form of the vaccine, i.e. viral vs. bacterial. Thus, we propose to address the issue of immune function in children with autism through a careful analysis of the immune system, medical and mitochondrial issues, and behavioral response to both viral and bacterial vaccines.

Vaccination with regression study (funded by Autism Speaks)

A major challenge to studying autism with a suspected vaccine-related regression is identifying children with acute regressive-type symptoms following MMR vaccination; there are no specific codes, tests, or procedures that identify this occurrence with a high degree of specificity. This study will explore the Kaiser Permanente electronic databases to ascertain whether we can identify children with regressive type autism and identify the timing of the regression in relation to the period directly following MMR vaccination. In order to see if identification of regressive autism from medical records is possible, the investigators will attempt to identify children vaccinated with MMR who then abruptly undergo a ‘cluster’ of visits, tests, and/or procedures in the time period directly following vaccination. The researchers feel that there may be a number of children who receive a diagnosis (such as ‘prolonged crying’) in the emergency department on the day after vaccination, followed shortly thereafter (1-2 days later) by another set of diagnoses (such as ‘fever’ & ‘irritability’) in the pediatric office or other outpatient department, and then receive either diagnostic or laboratory tests indicating (at least) a moderate degree of severity of concern, such as CT scans, metabolic testing, or referral to neurology. If this study is successful in using medical databases to identify a specific group of children with demonstrable autism-related regression that clearly follows vaccination, it may point to the feasibility of further studies concentrating on this specific population.

Vaccine safety datalink thimerosol and autism study (Federally Funded)

The Thimerosal and Autism Study is a case-control study conducted in three U.S. managed care organizations (MCOs). Data collection began in 2005 and took three years to complete. In this study, children who were diagnosed with autism were matched with control children. The autism diagnosis of the case samples was confirmed by a standardized clinical assessment protocol. Vaccination histories and information on other potential confounding factors were confirmed by reviewing the medical records for all children. In addition, the mothers of both cases and matched controls were interviewed.

Analysis of developmental interactions between reelin haploinsufficiency, male sex, and mercury exposure (Funded by Autism Speaks)

This project will investigate the role of three separate factors in an animal model of autism spectrum disorder: a) genetic susceptibility, b) hormonal environment, and c) possible environmental triggers. A mouse model with a mutation of the reelin gene, implicated in autism spectrum disorders, will be studied after exposure to methyl and ethyl mercury. Both behaviors and neuropathological endpoints will be explored. Finally, the role of endogenous sex hormones will be examined by eliminating the testosterone “surge” around the time of puberty. The individual effects of each will be examined, as well as the interaction of the three components (genetic liability, environmental exposure, hormonal influences) to determine gene x environment interactions. What this means for people with autism: This study will use a unique design to study multiple factors in the etiology of autism spectrum disorder in a mouse model, isolating and combining factors which previously have been implicated in the pathophysiology and behavioral phenotype.

MeHG stimulates antiapoptotic signaling in stem cells (Federally funded: DoD)

This project is a study of the antiapoptotic effect of low concentration of methly mercury and cadmium in cells.

Etiology of autism risk involving MET gene and the environment (Funded by Autism Speaks)

Two independent lines of evidence indicate that the maternal immune system and a functional genetic variant contribute to autism spectrum disorder (ASD) risk. Here, the Van De Water lab will partner with scientists at Vanderbilt University to examine whether these two seemingly unrelated contributions may converge to define a unique ASD susceptibility. Preliminary evidence collected by the Van De Water lab indicates an association between the Mesenchymal epithelial transition factor (MET) gene ‘C’ type, which reduces MET protein expression, and the presence of specific maternal anti-fetal brain autoantibodies. This relationship suggests that this as a pathway for production of the maternal autoantibodies, leading to a gene x environment interaction underlying ASD susceptibility. The next line of experiments will examine the relationship in an even larger sample and assess the functional effect of the MET gene polymorphism on immune cell activity as well as further examine the impact of environmental toxins (including ethyl mercury) on the gene expression-dependent function of maternal immune cells.

Epidemiological research on autism in Jamaica (Federally Funded, NIH)

The prevalence of autism spectrum disorders (ASD) appears to be on the rise in developed countries and has become a serious public health concern. In most developing countries, however, the nature and prevalence of factors associated with ASDs are unknown. The long term goal of this planning project is to develop capacity for conducting large scale population-based ASD studies in Jamaica. First, the diagnostic criteria used in Jamaica and the United States will be compared. Then, questionnaires regarding the demographic and socioeconomic position, occupation, and drinking habits of each child’s parents will be used, and information will be gathered about family history of developmental disorders, family size, birth order of the affected child, and whether the child is taking any medications. An age and sex matched case-control study, including a dietary questionnaire, will also be conducted to investigate whether environmental exposures to mercury, lead, arsenic, and cadmium play a role in autism. Blood and saliva samples will be collected to determine if any DNA polymorphisms that might affect interactions with heavy metals are present in children with ASD. New knowledge of potential environmental risk factors for ASD may arise from this research, thereby reducing physical, psychological, and economic burdens on the child, family, and society and helping parents make decisions about avoiding exposure to environmental contaminants.

An investigation on the potential harmful effects of mercury in the nonhuman primate (Funded by SafeMinds)

An investigation into the effect of mercury on neurons, astrocytes, and microglia on the central nervous system of the nonhuman primate.

Investigating the effect of mercury on ASD, AD and ASD regression (Funded by SafeMinds)

An investigation into the influences of demographics and environmental variables in the development of neurodevelopmental problems such as AD, ASD, and ASD-regression

The effect of mercury and neuropeptide triggers on human mast cell release of neurotoxic molecules (Funded by SafeMinds)

An investigation to determine the pro-inflammatory effects of mitochondrial DNA with and without mast cell triggers.

Does mercury and neurotension induce mitochondrial DNA release from human mast cells and contribute to auto-immunity in ASD? (Funded by SafeMinds)

Further investigation into preliminary data that neurotensin (NT) stimulates mast cell activation and that NT is elevated in young children with autism spectrum disorder.

Toxicant-induced autism and mitochondrial modulation of nuclear gene expression (Federally Funded: DoD)

Autism has been associated with epigenetic changes: Tiny chemical tags in the regulatory regions of genes that affect how genes express themselves by turning them on or off. One gene often decreased in expression in the brain tissue of autistic individuals is MECP2, a gene that governs the expression of genes crucial to brain development. Exposure to environmental pollutants is also thought to play a role in autism. These two phenomena both involve a small cellular organ called mitochondria. The suspect environmental pollutants are toxic to mitochondria, which play a critical role in epigenetics: Pollution exposure can lower the amount of mitochondrial DNA (mtDNA) in a cell, causing an increase in placement of epigenetic tags by DNMT1 that leads to gene silencing. We hypothesize that exposure during pregnancy to pollutants toxic to mitochondria causes a decrease in mtDNA copy number and increased placement of epigenetic tags by DNMT1 on key developmental genes, affecting pathways that have direct roles in the development of autism. We will expose mice, during pregnancy, to selected toxicants and evaluate adult behavior and associated biochemical changes in brain tissue. Valproic acid will be used as a positive control, with saline as a negative control. The environmental pollutants lead, arsenic, cadmium, manganese, mercury, and permethrin will be investigated for their potential to induce autistic behavior changes. Brain tissue will then be used for molecular studies of mtDNA copy number, expression of DNMT1, and alterations to the epigenome on both a genomewide and gene-specific level.

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By Matt Carey

Note: I serve as a public member to the IACC. My views here and elsewhere are my own, not those of the Committee.