To make this groundbreaking volume, Dr. James Lyons-Weiler combed through the past fifty years of published research on autism, exploring subjects such as genetic variation, mechanisms of neurotoxicity of metals and pesticides, and the central and combined roles of each in causing autism.
Lyons-Weiler provides a major overview of all aspects of the condition of autism, reviews changes in diagnoses and treatments, and explains how genetic information can be used to tailor effective treatments, and sometimes reversals, of the symptoms. He also presents practical forward-looking suggestions on how to design future studies to facilitate the discovery of biomarkers for autism risk and how to classify the full range of autism spectrum disorders.
Autism is considered one of the most mystifying conditions of our day, and alarmed scientists, doctors, politicians, and parents are desperately trying to understand why the condition is escalating. According to the CDC, rates in the United States have risen from an estimated one in two thousand children in 1980, to one in sixty-eight in 2012, and a new National Health Interview Survey shows a rate of one in forty-five. By the time you read this book, that number may have changed yet again.
While most autism researchers focus on either environmental or genetic causes of autism, Lyons-Weiler’s opus demonstrates that to fully understand the condition and to finally put its rate on the decrease, it is essential to pay attention to the science showing how the two classes of factors interact.
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BACKGROUND AND CONCEPTS
What causes autism?
Genetic factors or environmental factors? Nature versus nurture?
Three things are certain. First, these questions pose a false and grossly misleading dichotomy given the breadth of published knowledge available. Second, false dichotomies can misdirect research funding priorities away from understanding the true causes of autism and can even warp public health policy and reduce priorities for the care of autistics. Third, the existence of mutations that confer risk does not automatically exonerate environmental factors in autism any more than mutations that confer cancer risk exonerate carcinogens. In developmental toxicology, risk due to exposure is cumulative.
If only autism were so simple as to give those questions significant meaning. Given the weight of the available evidence in objective scientific studies, no fruitful discussion about the causes of autism can rule out genetics as an important factor in autism. The same is true for environmental factors. Focus on one to the exclusion of the other reveals bias toward a particular agenda, ignorance of the massive published literature available on the genetics of autism, or both. In short, there is ample room for the discussion of both genetic and environmental factors.
In 2008, a survey of physicians found that many thought genetics played a weak and limited role as a causal factor in autism (Hoop et al., 2008). In a way, they were correct: no single gene can be found that, by itself, contributes to more than 1 to 2 percent of autism cases. Thus far, specific mutations can account for only perhaps 10 percent of individual autism cases. Throwing percentages around without a firm reference point can be confusing, however, because at the same time, genes and environment each share approximately one-half of the liability for autism in twins (Hallmayer et al., 2011; Sandin, 2014).
At the beginning of this century, all known identified Mendelian genetic factors — the sense of genes with mutations that were found to be associated with autism — were rare. This was in part due to a lack of research. Now that a great amount of research has been conducted, we know that in the sense of frequencies in the population and in the sense of frequencies in the ASD population, genes with mutations that are found to be associated with autism are rare. This was initially puzzling, because autism was also observed to have a very high heritability — at least a high concordance, which suggested high overall heritability. An awakening of sorts has occurred that involves three important observations:
1. Identical, monozygotic (MZ) twins show a significantly higher concordance of autism diagnosis than fraternal, dizygotic twins for autism, even though siblings grew up together, sharing many environmental influences.
2. No single gene has been found to have a large effect, and studies have resulted in the discovery of numerous genes, clustered in specific pathways, each explaining a minor percentage of cases of autism ASD.
3. First-degree relatives of affected individuals are often found with subthreshold autism or ASD symptoms, indicating that autism and ASD is a heterogeneous, variegated set of conditions, as opposed to a discrete (all/none) genetic disease.
In the terminology of genetics, these observations led to the conclusion that a simple autosomal or X-linked dominant model, or even a recessive mode of monogenic inheritance, was insufficient to describe the patterns of inheritance of risk of autism. They pointed to autism risk as a complex trait, involving many loci and many genes, with likely interactions among genes (epistasis). However, although the number was not known, an early estimate by modeling suggested approximately 15 loci (Newschaffer et al., 2002).
As complex as ASD appears, it is also common for pedigrees to appear "bottom heavy" for ASD diagnosis (see Figure 1). This is inconsistent with poor diagnostic accuracy in past generations. However, it is consistent with the appearance of new factors in the latest generation. Brandler et al. (2016) found that ASD diagnosis was associated with increased rates of copy number variations (CNVs), but not increases in large chromosomal rearrangements. In contrast, Chen et al. (2016) found idiosyncratic structural mutations to be important in autism. The finding of increased number of de novo CNVs in ASD would seem to indicate that something, or things, are in fact different in the environment.
Compared with what was known in 2002, the number of suspected genetic factors is now much larger, and there is even more evidence for heritability of numerous genetic factors, each weakly contributing to risk at the population level. The Simons Foundation's SFARI Autism Database Human Gene Module contains, as of July 2016, over 790 genes potentially related to autism in some way, based on data from 1,266 curated references and 1,268 noncurated references. While many of the reported findings are individual reports of single individuals with mutations that may be clinically related to ASD, the resource is incredibly valuable for quickly determining the level of and type of support indicated by the literature variations involving any specific gene. In spite of systematic analyses of the literature to find "common variants" (e.g., Warrier et al., 2015), no gene contributes more than 1 percent to overall ASD prevalence.
A variety of common (inherited) variants account for 17 percent of the liability in ASD and up to 29 percent among other psychiatric conditions (Cross-Disorder Group, 2013). The large amount of overlap in the causal role of genetic variation across psychiatric conditions means that many genetic markers and even specific variations are not disease specific. The high frequency of common variants compared to the low frequency of autism indicates significant environmental liability: parents with these variants did not develop autism.
A large study by Matsunami et al. (2013) identified twenty-four regions with CNVs, and while some of the genes in the regions affected are involved in interesting parts of neurobiology, the most common variations were found in areas with genes involved in basic cellular functions. For example, the ANKRD9 (RAGE) variation is involved in ionic transport and signaling and OTUD7A variation, which is in turn involved in deubiquination signaling. Even housekeeping genes have to work properly for the CNS to function and develop well.
There is a big lesson here for understanding how genetics and environmental factors can induce autism as well as for picking targets for general and individualized treatments. This informs projects targeting development as well as those for evaluating the role of non-CNS specific genes in autism.
The risk of a newborn being autistic is higher in families that already have an autistic child, and the intensity of autistic symptoms is more pronounced in families with more than one autistic child. These facts would seem to further indicate a genetic risk. Not all of this risk can be considered genetic, however. Families share environmental factors. Numerous additional familial risk factors have been identified, such as parental age and birth order. Mutations new to a population, which occur during gamete formation (de novo mutations), are extremely rare but are more likely in gametes from older parents; and the incidence of autism is higher for babies born to older mothers and fathers, with the age of both genders contributing independent increased risk (Shelton et al., 2010). Note that Shelton et al. removed 324 parents because the variable "education level" was missing.
Some shifts associated with age of parents may reflect shifts in the methylation programming during sperm and oocyte formation. If this is increasing due to the environment, it spells increasing trouble. It could, however, also be due to overall cohort effect reflecting vaccination trends: autism has been steadily increasing since the 1980s; the CDC began expanding the pediatric schedule in 1983. We are now up to seventy-two injections before age 16 — sixty of these before the age of twenty-four months. Knowing that methylation differences are involved in parental age does not tell us why methylation changes in parents, nor does it tell us if those changes are due to factors increasing in our environment.
The contributed risk from each additional familial factor is small. For example, advanced maternal age contributed to only 4.6 of the 600 percent rise in reported cases of autism in the 1990s. Demographic and socioeconomic factors are assumed to be additive but are notoriously correlated with one or more other, more ultimate causes. Birth order, for example, is a risk factor. Later-born children have a higher risk, but then they also tend to have older parents. The birth order factor seems to suggest biological causes such as aberrant methylation patterns during the formation of gametes in aging parents, and this hypothesis has been tested and is at least partly supported by data.
But increased risk due to birth order during the past fifteen to twenty years could also be a cohort effect — younger children in families receive an ever-increasing number of vaccines, or ever-increasing exposure in an increasingly toxic environment, or both. Despite the official CDC "party line" of no association between vaccines and autism, the studies conducted outside of the CDC point squarely at metal adjuvants in vaccines, which activate the immune system, as likely causal factors and not only for autism.
Data from the Vaccine Safety Datalink of the CDC found association between vaccine exposure (thimerosal + aluminum) and any neurodevelopmental disorder (National Academy of Science, Institute of Medicine [NAS/IOM], 2001). The many other neurological disorders and other health conditions are now increasing in frequency. Of course, familial factors can also include other shared environmental factors. And a more recent study (Frazier et al., 2014) demonstrated that the levels of social and repetitive behavioral symptoms were strongly influenced by common genetic factors, whereas the heritability of categorically defined ASD diagnosis criteria was comparatively low. Similarly, most emotional issues within ASD are explained by genetics (Tick et al., 2016).
As with genetic factors, numerous shared environmental factors are likely. A common statement made in popular writings is that "no one knows the cause of autism." Year after year, study after study, the body of scientific evidence mounts, and yet this myth is perpetuated by an increasingly willful ignorance on the part of the CDC. Each year, US taxpayers foot the bill for $30 billion worth of medical research. Nearly all of the peer-reviewed research is captured in scientific journals and by a branch of the government called the National Center for Biotechnology Information. One resource in particular, PubMed, is available for all researchers and the public to search the abstracts and full research articles published by thousands of scientists. PubMed is a product of the US National Library of Medicine and the National Institutes of Health, and it contains abstracts of more than 25 million scientific studies, many available as full-text versions of the published study.
Much of this research is not new. But it is richly varied in focus and form.
For example, a parent survey study conducted in 2008 (Schultz et al., 2008) reported that
Acetaminophen use after measles-mumps-rubella vaccination was significantly associated with autistic disorder when considering children 5 years of age or less.
There is no warning on the CDC website to not give your child acetaminophen after vaccination. Instead, the CDC reports "Vaccines do not cause autism" and "Ingredients in vaccines do not cause autism" (CDC, 2016).
Granted, the Schultz study is just one study. However, given some research conducted since 2008, there is little to no doubt that vaccines can contribute to autism. Given the rest of that same body of research, there can also now be no doubt how.
Rossignol and Frye (2012) conducted an extensive analysis of the biomedical research and found the following:
416/437 (95 percent) of studies on immune dysregulation or inflammation in ASD found a positive result;
115/115 (100 percent) of studies on the role of oxidative stress in ASD found a positive result;
145/153 studies that examined mitochondrial dysfunction in ASD found a positive result;
170/190 studies on environmental toxicant exposures in ASD found a positive result.
They also found 95 publications that discussed possible association between vaccination and ASD in the immune dysregulation and inflammation group of studies; most of these were editorials and added no new data (Rossignol and Frye, 2012).
The CDC has failed consistently to utilize any of this valuable resource in the formulation of their policy. Instead, they rely on their own deeply flawed internal and contracted external studies. They cite "dozens" of studies that exonerate vaccines. Rather than allow the full body of scientific evidence to inform public health policy, they "cherry-pick" the studies that support their chosen policy.
The primary focus of this book is not those studies, nor what is wrong with them. Most of them (17/22) were determined to be flawed in 2012 by the Institute of Medicine (National Academy of Sciences, 2012), and they are currently the subject of inquiry for malfeasance and scientific fraud (see "Vaccine Whistleblower: Exposing Autism Research Fraud in the CDC," Barr, 2015).
Instead, the focus of this book is the rest of the science: what the CDC has so egregiously ignored. We cannot expect to understand and therefore prevent or treat autism unless we ask old questions with new data, and refuse the fast-and-loose practices used in the vaccine safety research studies in the 2000s. We need to pay attention to the rest of science, not just the corrupted bits of science the CDC wants us to accept as valid and as the whole story. As a result, it has prevented the public from knowing the truth about neurotoxicity of vaccine additives.
This book is about the rest of the science. It includes more than 900 key references on both the genetic and environmental causes of autism. It includes perspective peppered throughout the discussions of genes, regulatory pathways, and neurobiology. It is a call for attention to all of the science that US taxpayers have paid for and a call for reform.
VACCINE SAFETY RESEARCH REFORM
For starters, I believe that the CDC should no longer be in the business of conducting vaccine research science. I believe five independent trials are needed for each vaccine, three chosen for funding by lottery and two by competitive grants. All five should conduct their own studies and analyze their data independently, and the results should be communicated to the US Food and Drug Administration (FDA).
Similarly, no one with financial conflicts of interest — or even a hint of a possibility of a conflict of interest — should be allowed to weigh on the vaccine schedule.
The Vaccine Board should be disbanded and replaced by a Congress of Patient Representatives from each state that votes on each change to the schedule. The first Congress should be composed of people who either have themselves been injured by vaccines, or have loved ones who have been injured. The Congress could elect a panel of pediatricians to provide guidance and advice on the medical matters, but they should also have panel of research scientists who work independently from the pharmaceutical industry in vaccine safety research, to provide guidance and advice as well.
I also believe the CDC should change its tune. The sooner, the better. Let the people know that vaccines can cause autism in some people. Rather than propagating the myth that "no one knows what causes autism," by far, a much more accurate statement would be that some environmental causes of autism are known, that many more are suspected, and that additives in vaccines, especially mercury and aluminum, are likely to cause autism in some people. The CDC is woefully negligent in their activities and concerns over other environmental factors as well. For instance, autism is known to be induced by gestational exposure to certain environmental factors such as valproic acid (Christensen et al., 2013; Williams et al., 2001), a histone deacetylase inhibitor used to treat seizures and bipolar disorder (Christianson et al., 1994; Rodier et al., 1997; Williams and Hersh, 1997; Ingram et al., 2000). Intraperitoneal injection of valproic acid induces morphological changes in microglial cells in the hippocampus and amygdala within 24 hours (Wang et al., 2015). They seem to not be aware or to care about the science showing other compounds and exposures that might lead to autism via microglial activation, such as the science showing that glyphosate may be a causal factor and acetaminophen/ASD links.(Continues…)
Excerpted from "The Environmental and Genetic Causes of Autism"
Copyright © 2016 James Lyons-Weiler.
Excerpted by permission of Skyhorse Publishing.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.
Table of Contents
Foreword Richard E. Frye, MD, PhD xiii
Chapter 1 Background and Concepts 5
Chapter 2 Symptoms and Diagnosis of Autism 69
Chapter 3 Evidence of Genetic and Epigenetic Risk Components of Autism and Autism Spectrum Disorder 87
Chapter 4 Speech, Language, and Communication Phenotypes in ASD 116
Chapter 5 Genetic and Environmental Factors that Influence Social Cognitive Skills in ASD 134
Chapter 6 Cognitive Phenotypes in ASD 153
Chapter 7 Repetitive Motor Behaviors and Seizure Phenotypes 159
Chapter 8 Sensory Phenotypes and Sensory Processing Disorder 165
Chapter 9 Immunological Factors in Autism and ASD 169
Chapter 10 Gastrointestinal and Renal Phenotypes in ASD 192
Chapter 11 Neurotoxin-Induced Autoimmune-Mediated Neurological Damage in Autism 200
Chapter 12 Vaccine-Autism Studies Ignored by the CDC 217
Chapter 13 Concepts of Comorbidity in Autism and Autism Research 230
Chapter 14 Study Designs for Meaningful Future Causal Research in Autism 243
Chapter 15 Biological Pathways and Networks Views of Autism 255
Chapter 16 Toward a Multidimensional Matrix Risk Model for Autism 262
Chapter 17 The Logic of Prevention in Autism and Gene-Informed Treatment 273
Chapter 18 Injecting Objective Association and Causal Inference into Clinical Trials, Prevention, Diagnosis, and Treatment of ASD 294