The Wellcome Trust, based in the United Kindom, is the world's second largest medical research charity, funding $1 billion in research annually. Its mission is to improve human and animal health. Yet, despite its wealth, the Wellcome Trust has not historically funded much autism research. In an effort to change this, Autism Speaks (AS) and its partner organization, AS United Kingdom (AS UK), conducted a joint workshop with the Wellcome Trust to highlight the many recent advances in the biology of autism.
The workshop, held in London on January 9-10, was the first time the Wellcome Trust had been directly engaged in autism discussions. Nine of the top US & Canadian researchers specializing in autism and developmental neurobiology joined with eight top European neurobiologists to present their data in a small forum that included representatives from the Wellcome Trust as well as from the United Kingdom's Medical Research Council, the Sainsbury Foundation, and the Simons Foundation, all of which are major funders of biological research.
Treating autism and designing targeted therapies will ultimately require gaining an understanding of its symptomology on a biological level. Therefore, the goals of the workshop were to 1) review the outstanding neurobiological research in order for the Wellcome Trust to gain insight into the direction of autism research, and 2) identify key scientific questions and road blocks that are amenable to experimental investigation with today's available resources and scientific methodologies.
What do we know about the neurobiology of autism?
To open the workshop, Sir Michael Rutter (Institute of Psychiatry, London and Patron of AS UK), one of the early pioneers of autism research and treatment, reviewed the clinical features of autism. He particularly stressed the heterogeneity in all aspects of the disorder, including in progression, presentation, and ultimate outcome. Dr. Rutter cautioned the audience that, from a clinical perspective, the variation in impairment ought to be re-framed instead as an appreciation for the variation in unique coping mechanisms (and special skills) individuals with autism develop over their lifetime. As Dr. Rutter pointed out, the strengths of individuals with autism absolutely deserve to be studied as well.
Dr. Rutter's overview of the clinical outcome of autism set the stage for Dr. Lonnie Zwaigenbaum (University of Alberta), who explained how he has drawn upon the clinical features of autism to study its developmental emergence and progression. Dr. Zwaigenbaum and colleagues have utilized a “baby sibling” approach to prospectively follow the development of younger siblings of individuals with autism because they are at a higher risk for having the disorder. Among other advances, this exciting research has resulted in design of a new clinical scale, the Autism Observation Scale for Infants (AOSI), which reliably detects some of the earliest signs of autism. This scale has allowed researchers to discover that even though autism may not be standardly diagnosed until age three or later, many of the first signs actually emerge around 6 months, with differences becoming more exaggerated by 12 months of age. Researchers are currently unsure whether the approximately 20-30% of children that show autistic regression truly represent a separate form of disorder, or rather an extreme in a continuum of clinical onset. Importantly, it is diagnostic breakthroughs such as these that have made it possible to begin trials of early interventions in infants and toddlers that can conceivably halt or even reverse the progression of autism.
Dr. Zwaigenbaum's discussions of the onset of the earliest behavioral signs underscored many of the major themes presented by Drs. Eric Courchesne (University of California, San Diego) and Declan Murphy (Institute of Psychiatry, London), who reviewed what is known about the brain structure and function in autism. One of the most reproducible findings appears to be an unusual spurt in brain growth, beginning late in the first year of life, perhaps paralleling the behavioral changes witnessed by diagnosticians such as Dr. Zwaigenbaum. Interestingly, it is most pronounced in the areas of the brain associated with language and social skills. The phase of accelerated growth is followed by a second pattern of atypical brain development, in which brain growth tapers off and ultimately becomes slower than that of other children, such that by adolescence the brains of individuals with autism may actually be smaller than their typically-developing peers.
These unexplained differences in brain growth trajectory potentially represent a key to understanding autism, and no doubt influence subsequent development of the intricate circuitry of the brain. They are also consistent with the well-documented alterations in brain connectivity, structure and function in adults with autism. In fact, the researchers stressed that beyond these early brain growth trajectories, almost all we currently know about the function and pathology of the autistic brain is from older individuals, well after autism has presented itself. The developmental window in which the critical behavioral changes Dr. Zwaigenbaum and colleagues have described has been virtually unstudied from a biological perspective. Researchers explained that we will never resolve the precise cellular and molecular aspects of the impact of autism on the brain if we do not focus on studying it at these earliest ages. New tools and methodologies are needed to image the brains of toddlers and infants, and a special emphasis should be put on the difficult task of collecting postmortem brain tissue from these ages.
Knowledge about genetic and environmental risk factors and how they exert their affects, are important steps in unraveling the altered neurobiological pathways and brain structures in autism. Drs. Dan Geschwind (University of California, Los Angeles), Anthony Monaco (University of Oxford), and Chris Walsh (Harvard Medical School) summarized the multitude of new genetic findings, many emerging in only the past half year. Broadly speaking, researchers are learning that there are many ways genes appear to contribute to autism susceptibility, and that these contributions may be different in different families. In some families the genetic susceptibility may take the form of multiple common genetic variants that separately contribute only a small risk, but which when combined together produce a much stronger risk for developing autism. In other families the genetic susceptibility may come from a rare mutation in a single gene. Well-known examples of these powerful but rare single gene mutations include the MECP2, TSC1/TSC2, and FRP1 genes, mutated, respectively, in Rett, Tuberous Sclerosis, and Fragile X syndromes (medical syndromes in which affected individuals also often show signs of autism). As presented at this meeting by Dr. Thomas Bourgeron (Pasteur Institute, Paris) and others, geneticists have very recently expanded the list of rare genetic mutations to include ones discovered in individuals without these other co-occurring medical syndromes, such as mutations in genes for the neuroligins, neuroexins, SHANK3, and CNTNAP2.
Finally, the speakers also emphasized that the genes involved in autism have been fairly difficult to trace, not because they don't exist, but rather because the experiments designed to identify them had not originally accounted for this unexpected variety in genetic contribution. Although the heterogeneity currently being uncovered on the genetic level may not strictly parallel the heterogeneity witnessed on the behavioral level, deriving methods to sub-group autism into individuals with similar behavioral or clinical phenotypes may provide one approach to sorting out the complicated patterns of genetic risk.
Because genetic risk likely provides susceptibility to environmental factors, one workshop session was devoted to discussing potential environmental triggers of autism. These may include immunological factors to which babies are exposed prenatally. Dr. Paul Patterson (California Institute of Technology) described a maternal immune activation model in which mouse pups born to pregnant mothers exposed to immune stimuli develop altered brain anatomy and unusual behavior in adulthood. His research has implicated one particular immune molecule, IL-6, as a mediator of the “maternal immune activation” effect. In a separate lecture, Dr. Tony Persico (University "Campus Bio-Medico" Rome) summarized his findings on a relationship between genetic risk and potential toxins such as pesticides, which he hypothesized may combine to cause an overload of oxidative stress and alter development of the nervous system. He also discussed his evidence for a subgroup of individuals with autism that includes enlarged heads, enlarged bodies and an increased tendency to have atypical food “allergies.” This may provide scientists with one specific autism subtype in which to study gene/environment interactions.
What tools do we need to expand our understanding of the neurobiology of autism as rapidly as possible?
After the introduction to autism, a large portion of the workshop was spent determining which approaches can be taken to rapidly further our biological understanding of autism. Broad avenues discussed included the use of both animal and cellular signaling models. Models of autism are a critical next step because they will provide a laboratory setting to test possible new interventions.
Several potential animal models of autism were presented by Drs. Randy Carpenter (Seaside Therapeutics), Adrian Bird (University of Edinburgh) and Luis Parada (University of Texas Southwestern Medical Center), which included mouse models of the medical syndromes mentioned above. They are currently determining whether the mice display behaviors reminiscent of autism to decide if these are valid models of the disorder. Dr. Jacki Crawley (National Institute of Mental Health), an expert in analysis of mouse behavior, explained that as more models are created, the challenge will be to design more accurate tests of each of the three behavioral domains of autism (sociability; communication; stereotyped behaviors). Therefore, another immediate area of opportunity identified at the workshop is development of standardized behavioral assays that can be adopted by the entire research community. Researchers also noted that routine testing of models for the few known biological indicators of autism (such as enlarged heads) is surprisingly not yet commonly done. Focusing on these last two points will be critical now that we have progressed to the stage where novel treatments targeting autistic behaviors are being assessed in these models.
One of the most exciting themes emerging from the meeting was the apparent ability to treat disease symptoms in mouse models of several neurodevelopmental disorders related to autism, such as Rett, Fragile X and Tuberous Sclerosis. The mice could be rescued by replacing the defective gene or using pharmacological agents. In some cases, such as Rett Syndrome, the disease progression was reversed after the animals had already begun to show signs of illness. These unsuspected findings suggest that so-called “developmental” disorders may, in fact, be capable of treatment even into adulthood. The experiments also illustrate how mouse models can be pivotal for both testing hypotheses about the roles of specific risk factors and as tools for evaluating the efficacy of novel treatments.
Experiments in adults with autism have revealed that neuronal connectivity is somehow disordered in the brains of individuals with autism. Therefore, another model approach to designing biological therapeutics for autism is to identify the biochemical signaling cascades that have been disrupted in the brain circuitry. Dr. Daniela Toniolo (Instituto Scientifico San Raffaele, Milano) described elegant data identifying the GDi1 gene product as a signaling molecule implicated in mental retardation. GDi1 is involved in signaling at the synapse, the cellular structure which is responsible for passing signals from neuron to neuron. Attendees discussed at length whether autism, too, may be a disorder of synaptic functioning, and offered insights into signaling pathways known to regulate synapse activity. Drs. Nils Brose (Max Planck Institute of Experimental Medicine Göttingen, Germany) and Michael Greenberg (Harvard University) detailed research on various signaling cascades found in the synapse, and concluded that a focus on synaptic molecules is yet another arena now open for immediate exploration by autism researchers.
Because of the introductory nature of this meeting, workshop organizers chose to focus discussions on the basic neurobiological underpinnings of autism, an area of clear interest to the Wellcome Trust, and one which is becoming more accessible with the many recent research breakthroughs highlighted at this meeting. Yet, despite the focus on the biological aspects, the meeting concluded where it began, with a reminder that the requirement for such research stems directly from our need to understand and help those impacted by autism. Cognitive scientist Dr. Uta Firth (University College, London) urged attendees not to be so reductionist that they forget to integrate the special psychological and cognitive features of autism with the biological features. From a family perspective, Jane Westley, a volunteer with AS UK and mother of an adolescent son with autism, reminded everyone of the purpose of autism research – that it should be directed and exploited to meet the needs of families living with the disorder. Basic science discoveries should be translated into something tangible and meaningful that lessens the impact of the disorder and improves quality of life for all those affected.
In the short-term, it is hoped that concrete results of the workshop will be to attract new highly-capable scientists to the field, and to increase the number of quality autism grants submitted to the Wellcome Trust for funding consideration. For these purposes, the meeting itself provided many networking opportunities and chances to discuss collaborative projects between meeting participants. In the long-term, AS hopes to continue discussions with the trustees of the Wellcome Trust and the other funding agencies in attendance in order to identify potential areas for partnerships in furthering our joint mission to improve the lives of individuals with autism. AS would like to especially thank Dr. Jenny Longmore (AS UK) and Dr. Martin Raff (University College, London) for their dedication to making this meeting happen.
A complete meeting summary can be found at here.