The news and feuds of autism research

In 1998, Dr. Andrew Wakefield published a paper hypothesizing that the measles, mumps and rubella vaccine caused a leak in the gut which sent toxic substances to the brain, resulting in autism. This study sparked a widely-publicized debate about the causes of autism, which included claims of fraud that resulted in the retraction of the paper and culminated this week in Dr. Wakefield suing the British Medical Journal for defamation. While the work of that paper has been debunked, the debate over the causes of autism still rages and researchers around the world continue working to determine the causes of the disorder.

Autism spectrum disorders (ASD) are characterized by abnormalities in social and communicative behavior. While certain forms of ASD such as Timothy and Rett syndromes have been linked to specific genetic causes, the underlying basis of the majority of ASD cases remains unknown. New research investigating the cause of ASD is continually emerging with promising clues found in the neurons, gut, and immune system of ASD children.

It’s clear that the behavioral problems commonly associated with ASD have a neurological basis. Imaging studies provide general insight into functional and large-scale structural changes in autistic brains, but provide little in terms of underlying mechanisms that lead to these changes. Understanding these mechanisms could provide information as to how to prevent or treat neurological problems in ASD. Because it is not feasible to remove neuron samples from living humans, traditional mechanistic research relied on animal models and post-mortem human brains. However, animal models often fail to translate to humans and cause versus effect is hard to determine from postmortem brains.

Recently, advances in stem cell research have allowed living neurons from an individual to be investigated in a dish. Ricardo Dolmetsch at Stanford applied this technique to study Timothy syndrome, a single gene mutation that generally results in ASD. These studies demonstrate that the ultimate fate of the cortical neurons from Timothy patients differ from control children, which could contribute to altered neural connectivity patterns. While the use of cultured neurons to study neurological disease is still in its infancy, these studies are able to bridge preclinical animal model studies, postmortem brain analyses and imaging in live subjects.

In addition to neurological problems, many ASD children suffer from gastrointestinal disorders, which can exacerbate behavioral problems. Researchers have begun to look at bacteria in the gut in an attempt to understand what puts autistic children at risk for these disorders. Recently, Brent Williams at Columbia University found the presence of relatively high amounts sutterella bacteria in around 50 percent of ASD children with gastrointestinal problems, but not in control children with gastrointestinal problems. This is an interesting observational finding, but future research is needed to determine what, if anything, this bacterium contributes to ASD or ASD related gastrointestinal problems.

Recent research also delves into the role the immune system may play in ASD. Some ASD children express elevated levels of soluble amyloid precursor protein α (sAPP-α), which has been thought to play a role in the T cell immune response. This led Jun Tan at the University of Southern Florida to look at the role of sAPP-α in the T-lymphocyte immune response. Over expression of human sAPP-α in mice increased cytotoxic T-cell number and impaired secondary immune response. These findings show that sAPP-α contributes to the immune response, but do not clarify whether this is a cause or effect of ASD. Additionally, immunological dysfunction is not found in all ASD individuals, which may limit the predictive value of immune dysfunction.

Research on ASD is rapidly advancing our understanding of the mechanisms of the disorder on brain, gut and immune function. While these studies are quite promising, they remain too preliminary to provide definitive answers on preventing and treating this disease.