MRC Autism Forward Look and Review

MRC Autism Forward Look and Review 1.0 Aim and background 1.1 The rationale for the Forward Look and Review The rationale was partly to revisit the MRC’s previous Autism Initiative (see Annex 1). However, it was also considered timely to take a forward look at research priorities and opportunities in the autism spectrum disorders (ASDs). It was hoped that by taking a realistic forward look at the tractable questions that future research might address, that this would be of value in updating the public on recent progress in autism research. A major part of the Forward Look was a workshop held on 15 January 2009 at the Melia Whitehouse Hotel in London. (more details of this workshop are at Annexes 2 and 3). The report of the Forward Look was subsequently postponed while the MRC-led a major review of mental health on behalf of all public funders of mental health research in the UK. The Autism Forward Look informed that report (and vice versa) and Autism Speaks contributed (as did many other stakeholders) to the Review of Mental Health Research which has been published on the MRC web site at www.mrc.ac.uk/mentalhealthresearch 1.2 Features of autism Whilst it is well known that autism involves impaired social communication, language impairment and repetitive, stereotyped interests, it is still unknown as to whether this constellation of impairments is inherent in a cohesive syndrome (usually called Autism Spectrum Disorder or ASD) or whether it is an artifact of diagnostic practice. There is association1 with intellectual impairment (albeit within a wide IQ range) and with epilepsy in about a quarter to a third of cases (with onset typically in late adolescence). Like many neurodevelopmental conditions, for example, ADHD and dyslexia, autism is characterized by a marked male preponderance (circa 3 or 4 to 1). While some autistic individuals achieve considerable independence and autonomy, many remained severely handicapped and have virtually no contact with the outside world. It is rare for autistics to make love relationships, to marry and have children. The worst outcomes are for those who have not gained spoken language by 5 years of age and have a low IQ. Psychologically, autism has been described as an impaired ‘theory of mind’ skills (in essence autistic subjects can not see situations from any other perspective than their own. This is preceded by earlier impairment in imitation and joint attention (the process by which one alerts another to a stimulus via nonverbal means, such as gazing or pointing). There is also a lack of central coherence (the ability to see the ‘big picture’ and the ability to plan). Unlike other mental health problems, there is usually only a very limited response to attempts at psychological and behavioural therapy. Other features of autism that have emerged from research include: 1 Association in scientific terms infers a cause but it is not proof . For example, the association could be ‘secondary’ that is that autism itself is the cause of the observed effect, not the other way round. 1 the fact that it is partly heritable and that this is at least partly due to an increased rate of Copy Number Variations2. that there is no localized brain abnormality although sophisticated brain imaging techniques combined with psychological experiments in autistic individuals do suggest that there is some impairment across ‘brain systems’. raised serum serotonin levels in about one third of cases of autism although there is no therapeutic response to attempts to regulate this 2.0 General points raised and conclusions from Forward Look 2.1 MRC strategy and portfolio (overview) Autism has been an MRC priority for research since 2001. At that time there was concern about the higher prevalence of autism than had been previously recognised and there were public concerns about a possible relationship to immunisation and bowel disorders. This led to the MRC review of Autism “Epidemiology and Causes”. Since then, autism research has focused much more on the aetiology and risk for autism and research has become more enmeshed in the neurobiology of complex brain disorders. It was agreed that was the correct approach. Except for the Autism Initiative, MRC does not ear-mark funds for autism and researchers can submit in response mode to all of MRC schemes. MRC strategy is to encourage ASD researchers to link with expertise in conjoint disciplines and work with partners such as Autism Speaks3 to encourage the development of competitive proposals. However the number of applications submitted remains low despite evident strengths in this area. With the relatively small number of active autism researchers in the UK, it is impossible for the UK to address every question in autism research. However when viewed in the context of the whole MRC portfolio of mental health research, autism research seemed to be doing well and better than other neurodevelopmental disorders. Out of a total MRC research spend of £579m in 2007/08, the financial commitment to autism research had been £2.26m. This had increased by £0.56 m on the previous year. The total value of the 18 major autism grants awarded between 2000 and 2007) was £8.9m*. Just over 1 in 5 applications submitted were awarded – which was not dissimilar to the award rate for all grant applications. The research funded by MRC naturally had mostly long-term relevance to policy and practice in that the MRC mostly supported well-designed studies to understand the biological basis of autism. It was stressed by those attending the Forward Look workshop that this remained an important goal. The reason for this is that we know already that the developing brain is altered in autism and we have some knowledge about how, but we do know what causes these changes. Given that one stimulus for the increase in autism funding by the MRC was the controversy provoked by the studies published by Andrew Wakefield, it was interesting to note that none of the current projects funded by MRC dealt with the issue of immunizations and autism. This remains a contentious issue in the UK for 2 Copy number variations are microscopic changes in the DNA sequence that can be found within genes. They can be inherited or arise spontaneously by mutation . It is thought that possessing certain CNVs in a chromosome could put the developing child at risk of being on the autism spectrum. 3 In the UK, the UK-arm of Autism Speaks has become a new charity; ‘Autistica’. 2 some parents but had become a much bigger issue in the United States where there were calls for more funding to address the parental concern that has its origin in the Wakefield publications. Academic scientific interest had waned in this area in the UK and the very few proposals submitted to MRC in this field had all been declined. MRC agreed to work with any applicants in terms of a study coming forward in this field in recognition of the remaining public concern about this issue. Delegates at the Forward Look workshop were struck by the fact that the MRC receives few grant applications for autism studies. Given the rapid developments in the field of animal models and neuroscience, it was considered worthwhile to see how the MRC could encourage more neuroscientists to study autism and apply for grants for research relevant to autism. The MRC had achieved a lot in terms of encouraging collaboration within autism researchers but there was still further work to be done in engaging those in conjoint neurobiological disciplines. Delegates agreed that there was a need to reach out and bring new scientists into the field either through studentships or perhaps junior fellowships. This could also be of value in studying other mental health conditions and learning and intellectual disabilities. It was noted that this might be an issue for the general field of mental health research that was likely to be addressed in the mental health research review. In respect of comparisons with the US and Canada, the majority of the funded projects in North America focused on animal models, immunology and gene- environment interaction. Computational biology was also a burgeoning field (e.g. pathway-based genetic studies). In the UK, distinctive strengths were apparent in population-based studies and genetics. 2.2. The need for large resources and shared infrastructure From the autism researchers' perspective, large shared resources were needed to tackle the challenges of the heterogeneity among individuals with ASD and because assembling large cohorts of autistic subjects was particularly challenging. There are a number of registries and cohorts in existence that could be explored further, for example, the IAN Project at Kennedy Krieger Institute that is funded by Autism Speaks and the US NIH’s National Database for Autism Research. Registries focused on severe mental illness were being considered in the UK4 and having a resource based on NHS contact with the general population was particularly attractive in overcoming ascertainment bias. Improving the availability of human brain tissue for research, such as through the UKCRC (MRC- led) Brain Banking Initiative should also advance research progress. Projects such as the Autism Genome Project, the Infant Sibling Network, and the Autism Tissue Bank are also potentially valuable assets in moving the field forward. An interesting suggestion was the notion of a brain image repository so that the rich wealth of information coming from such studies could be pooled. There might also be an opportunity to attract leaders in brain imaging at the most advanced 4 Since the workshop that formed the cornerstone of this Forward Look, the MRC has completed a review of mental health.

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