Genetic vs. Environmental Hypotheses of Disease Causation: The Case of Autism

1. Results Background Methods Discussion Future Directions Genetic vs. Environmental Hypotheses of Disease Causation: The Case of Autism Holly K. Tabor, Martine Lappé, Marci Pepper, Mona Mohindra, Angie Boyce and Mildred Cho Stanford Center for Biomedical Ethics, Stanford University, Palo Alto, CA 94304-5748 • Framing of Genetics • Presenters framed the role of genetics in the causation of autism in three main ways. • 1) Genetics Does Not Play a Role, Only Environment • Autism can’t be caused by genetic factors because it’s an epidemic, and epidemics can’t be genetic. • “There is no genetic disorder that increases from one in 10,000 to one in 160 in one generation. There has to be some sort of environmental trigger.” • -Clinician • 2) Gene-Environment Interaction • Genetic factors increase risk of autism by creating a “genetic susceptibility,” inhibiting the ability of people to process toxins that they are exposed to in the environment. • “This would be a specific mercury vulnerability factor. It is not an autism gene, in the sense that it doesn’t build an autistic brain, but it makes you vulnerable to the potential effects of mercury, and it makes you likely to have autoimmune disease . . .” • -Clinician • 3) Epigenetics as a Model for Gene-Environment Interaction • Autism is caused by inherited or somatic epigenetic changes. • “Vaccines and vaccine components, of course, are the charge to this committee. We know that there are a variety of epigenetic effects that can occur from wide classes of xenobiotics. We need to know which xenobiotics can have these effects, which ones are most important during development.” • -Neuropharmacologist • Our preliminary analyses suggest the following about the framing of genetics in the causation of autism in this setting: • A simplistic model of genetic causality does not resonate with any of the speakers. • Genetic factors are framed not as determinative, but as factors that predispose individuals to increased disease risk through environmental exposure. The role of genetics outside of this role of environment-mediator is largely ignored. • The appeal of this model is that it allows for intervention: screening for increased risk, monitoring of exposure, and possible agents to improve exposure processing mechanisms. • The study designs and methodologies for studying the joint roles of genes and environment are disputed and understood to be poorly developed. • Analogous Disease Comparisons • Presenters used several disease analogies to help model their understanding of causation, and the role of genetics in causation. • Genetic Disease of Toxin Metabolism: • Wilson’s Disease: an inherited metabolic disease caused by a mutation in the ATP7B gene, coding for a copper transport protein • Results in the accumulation of copper in tissues • “Wilson's disease is one of the rare treatable genetic disorders. Not very many genetic disorders can be treated.” -Toxicologist • 2) Genetic Diseases with Autism-Like Symptoms • Rett Syndrome, Fragile X • 3) Diseases Caused by Environmental Exposure with Developmental Symptoms • Micromercurialism • 4) Diseases Requiring a Paradigm Shift in Methodology • Neural Tube Defects • ‘I would implore the committee to consider . . . the best way to study this is to study it with populations at risk. That is how we found folic acid and neural tube defects. If you looked at folic acid and neural tube defects and did this epidemiology, you might not see it . . . it may not be that 100 percent of children with autism have this, so you would miss it if there is a subset of children that have it.” • -Neurosurgeon • Helicobacter Pylori and Ulcer • “I just want to close on this issue with respect to paradigm shift, just as a reminder that 10 years prior to this report of Helicobacter pylori and its role in ulcer, we were talking about stress for duodenal ulcers and which type of stress created whatever type of outcome. Then we knew about Helicobacter pylori. So it brings us to this quote: In the period that Einstein was active as a professor, one of his students came to him and said, “The questions on this year’s exams are the same as last year’s.” “True,” Einstein said, “but this year all the answers are different.” So it behooves us to keep our eyes open to the possibility of new answers.” • -Neuropharmacologist • Complete analysis of texts and final IOM report. • Conduct project interviewing 50 genetics and epidemiology researchers and leaders of disease advocacy groups about the evolution of causal explanations and the role of genetics. • Understand the way that genetics is used to cross disciplinary boundaries of explanation for complex traits. • Characterize the language and social meaning of genetics and genetic research for complex traits. Complex diseases have both genetic and environmental components, and the genetic component may be due to a large number of genes of small effect size. The proliferation of studies on the genetics of complex traits has resulted in conflict around what it means if a disease is primarily environmental or genetic in origin. We analyzed a public debate about the causation of one complex disease: autism. Autism is a neurodevelopmental disorder with markedly abnormal social interaction, communication ability, patterns of interests, and patterns of behavior. Autism is thought to have a strong genetic component, yet no single-genes have been conclusively identified that account for most of the cases. In the last ten years there has been significant public debate about the role of vaccines in causing autism, specifically vaccines containing thimerosal, a mercury-based preservative, and the Measles Mumps Rubella (MMR) vaccine. In 2004 the Institute of Medicine (IOM) convened a panel to examine the possible role of vaccines containing the mercury preservative thimerosal and MMR vaccines in causing autism. Scientists from a range of disciplines and perspectives were invited to present data in public testimony. This session was a unique snapshot of public scientific discourse on causation: expert scientists speaking to scientist panel members in a public forum. We analyzed the transcripts of the speakers using a qualitative textual analysis software (MaxQDA). The goal was not to evaluate the accuracy or strength of the evidence presented or the quality of the science on which it was based. The goal was to characterize the language used to frame the roles of genetics and environment in causation. The data set included thirteen presentations, each lasting 20 minutes with 10 minutes of question and answer time. Six presenters came from academic institutions, five from government agencies and two from private research organizations. Five of the presenters were epidemiologists. The remainder included a toxicologist, a neurosurgeon, a clinician, an immunologist, a chemist, a microbiologist, a pharmacologist and a geneticist. Research supported by NHGRI and DOE