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Image of hands, bodies, and instruments around a face: Autism is a complex developmental disability.
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SYMPOSIA - 2007

Gut Microflora and Autism-December 2007
The Nancy Lurie Marks Family Foundation, Wellesley, MA


Autism is believed to be brought about by a combination of genetic and environmental factors affecting neurodevelopment, signal processing on multiple levels in the nervous system, with behavioral consequences for social interaction and communication. Human physiology is profoundly influenced by resident microorganisms in the gut, having their own genomes and the capability of producing highly damaging neurotoxins, mostly held in check by physical barriers and systems of detoxifying enzymes. Increasingly, it is being recognized that damage to these defensive systems can bring about disease conditions. For example, ulcers, traditionally thought to be caused by internalized stress, are now treated with antibiotics against the bacterium H. pylori. In Crohn's disease, the complex beneficial role of bacteria in the early instructional phase of the innate immune system is somehow undermined, leading to a compromised bowel lining. Many persons with autism have gastrointestinal issues, such as difficulty in early bowel training, bloating, food allergies, and pain. A Boston Club held on December 13, 2007 brought together experts in the clinical presentation of autism, including those with experience in treating autistic individuals, with experts on the biology of the gut microflora and on sequencing bacterial genomes.

The human gut is populated by over 500 species of microbes having a total mass of around two kilograms. Physiologically, these organisms play crucial roles in breaking down food products and guiding the development of immunological surveillance early in life. Many of these organisms have not yet been identified. New genomic tools are needed to discover all of the strains of bacterial populations in normal populations, and to measure the differences between normal and autistic populations. The biochemical consequences of these differences, against the genetic background of autism -- so-called host-pathogen epigenetic relationships -- need to be worked out. What neurotoxins are produced by bacteria and what are their targets in the nervous system? These are crucial questions deserving much more attention.


Matthew Anderson, MD, Ph.D., Beth Israel Deaconess Medical Center

Susan Birren, Ph.D., Brandeis University

Timothy Buie, MD, Massachusetts General Hospital

Karolinska Institute Microflora Consortium. Novel Molecular Approach to Screen Human Microflora Comparing Individuals and Groups
Ingemar Ernberg, Karolinska Institute

Albert Galaburda, MD, Beth Israel Deaconess Medical Center

Recent Studies and Perspectives on Gut Microbiology, Probiotics and Autism
Glenn Gibson, Ph.D., The University of Reading

Perinatal Factors Influencing Brain Development: Implications for Autism
Rochellys Diaz Heijtz, Ph.D., Karolinska Institute

Martha Herbert, M.D., Ph.D., Massachusetts General Hospital

Tal Kenet, Ph.D., Massachusetts General Hospital

Microflora interactions with mammalian host metabolism
Jeremy Nicholson, Ph.D., Imperial College London

Possible Role of Neuropeptides and Neuroimmune Interactions in Intestinal Symptoms in Children with Autism
Harry Pothoulakis, MD, University of California Los Angeles

Harland Winter, MD, Harvard Medical School





Cancer Biology and Autism-December 2007
The Nancy Lurie Marks Family Foundation, Wellesley, MA


An important new paradigm in autism research is that better understanding of its causes might be found by studying the biochemical circuits that control synaptic plasticity. Knowledge about the intracellular pathways that govern the response of a cell to external stimuli has come from efforts to understand how cancer develops, since many oncogenes code for proteins that participate in these signaling cascades. Mutations that give rise to cancer are often found in genes that code for kinases, phosphatases, and tumor suppressors. It is a remarkable development of twentieth century science that all eukaryotic cells, from all species and from all organs and physiological systems within a species, share a common set of signaling elements.  The signals ultimately control the metabolism (energy), transcriptional status (demand for more proteins), or the motility (growth) of the cells.

Neurons are highly specialized and differentiated cells with unusual electrical and chemical mechanisms for communicating information across incredibly complex networks. The dominant theme in neuroscience is that learning and memory are intimately connected with changes in points of contact between neurons, the synapses, which undergo up and down variations in 'synaptic strength' depending on what use is made of a particular synapse in a neuronal net. Dendritic spines, micron-sized compartments, that constitute the receiving end of a synaptic transmission are dynamic structures that change their shapes and biochemical composition in response to neurotransmitter release into the synaptic cleft. The resulting flows of calcium into the spine, and a cascade of phosphorylation, bring about polymerization of actin which underlies the changes in size and shape necessary for an increase in synaptic strength.

This suggests an important connection between cancer biology and autism: genetic 'hits' to biochemical circuits controlling metabolism, transcription, and motility may be a fundamental cause. Recent experiments (conducted at MIT) on genetically altered mice confirm this insight. If confirmed in humans, this hypothesis would imply that some forms of autism are chronic and potentially treatable by drugs now under development for cancer, diabetes and other disorders.  A Boston Club held on December 6, 2007 on 'Cancer Biology & Autism' focused on exploring this exciting theme.


Matthew Anderson, MD, Ph.D., Beth Israel Deaconess Medical Center

Molecular Windows into Brain Size and Language Development
Ma tthias Groszer, MD, University of Oxford

Dirk Iglehart, MD, Brigham and Women's Hospital

Tal Kenet, Ph.D., Massachusetts General Hospital

A Possible Role for the p53-IGF-1-mTOR Pathways in the Origins of Autism
Arnold Levine, Ph.D., Institute for Advanced Study

The Microfilament System in Health and Disease
Uno Lindberg, Ph.D., Karolinska Institute

Damon Page, Ph.D., Massachusetts Institute of Technology

Richard Sidman, MD, Beth Israel Deaconess Medical Center

Role of IGF1 Signaling in Brain Development, Plasticity and Autism
Mriganka Sur, Ph.D., Massachusetts Institute of Technology

Marc Vidal, Ph.D., Dana Farber Cancer Institute

Noncoding RNAs: Possible Involvement in Fragile X Syndrome and Autism
Claes Wahlestedt, MD, Ph.D., Scripps Research Institute





Systems Biology of Autism: Metabolomics-March 2007
The Nancy Lurie Marks Family Foundation, Wellesley, MA


We know that autism is a complex and heterogeneous condition affecting the normal functioning of human physiology in a number of different ways that manifest themselves as movement difficulties, gastrointestinal dysfunction, and problems in communication. The condition originates in the course of development and is known to involve genetic factors. If the incidence of autism is on the rise, there is a strong likelihood that environmental (toxins) or other epigenetic (immunological) factors may play a role. A major hurdle in understanding the genetics of autism, and how combinations of genes expressed in different organs at different times could lead to autism, is that the standard definition of phenotype used in genetic studies is based on observed social and cognitive behaviors, rather than in terms of neurological or biochemical circuits.

Recent advances in mass spectroscopy and nuclear magnetic resonance have resulted in
commercially available instruments capable of measuring hundreds of metabolites simultaneously in bodily fluids (blood, urine, and CSF). The classical concept of ‘biomarker', such as glucose levels in diabetes, or cholesterol levels in coronary heart disease, is being replaced by the idea of a ‘signature', a combination of signals from many metabolites. Combined with sophisticated computer algorithms it is now becoming possible to interpret these signatures in terms of biochemical pathways, providing a powerful means of bridging phenotype and genotype. This new combination of tools and concepts has been termed ‘metabolomics' and was the focus of a Boston Club held in March 2007.


The Autism Phenome Project
David Amaral, Ph.D., University of California Davis and The M.I.N.D. Institute

Matthew Anderson, MD, Ph.D., Beth Israel Deaconess Medical Center

A Combined Multi-Omics and Exploratory Bioinformatics Approach to Investigate Disease Mechanisms in Complex Neuropsychiatric Disorders.
Sabine Bahn, MD, Ph.D., University of Cambridge

Susan Birren, Ph.D., Brandeis University

Challenges of Heterogeneity, Co-Morbidity and Non-Specificity in Autism Research and Treatment
Martha Herbert, M.D., Ph.D., Massachusetts General Hospital

Tal Kenet, Ph.D., Massachusetts General Hospital

Putting Genes in their Place
Stuart Newman, Ph.D., New York Medical College

Metabolomics and Top-Down Systems Biology: Practical 21st Century Approaches Attacking Real Human Disease Problems
Jeremy Nicholson, Ph.D., Imperial College London

Istvan Pelczer, Ph.D., Princeton University

Cellular Metabolomics
Josh Rabinowitz, MD, Ph.D., Princeton University




 
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