University of Edinburgh Proposal
Proposal for an Edinburgh Cognitive Centre for Childhood Cognitive Impairment, Including Autism and Fragile X Syndrome
1) Executive Summary
It has long been recognised that many children fail to reach their potential because of disorders affecting the nervous system. These may be evident from infancy (e.g. Fragile X syndrome and many cases of autistic spectrum disorder and childhood epilepsy) or later on in adolescence or indeed early adult life (e.g. autistic spectrum disorder, schizophrenia). Such diseases can have a profound and often adverse affect on individuals, their families and the medical and care systems. Many affected people will require constant and specialist care throughout their lives.
The University of Edinburgh is developing an exciting new centre that will bring together clinical research and new approaches to laboratory-based research to unlock some of the underlying causes of childhood cognitive impairment. Our aim is to improve diagnosis of these diseases and, critically, point the way to new curative techniques and therapies for patients and their families.
Developing brains have an enormous capacity to be modified by experience. In fact, experience is crucial for infants to learn how to walk, talk, see, hear and feel as well as develop the complex cognitive skills that are necessary for normal behaviour. A growing body of evidence indicates that many forms of childhood cognitive impairment result from disruption of the mechanisms by which experience shapes brain development. While the precise cause of many forms of cognitive impairment is not known, it is clear the vast majority have at least one of the following two common features.
1) They result from alterations in the normal development of the nervous system
2) They result from alteration of our genetic code.
With the complete sequencing of the human genome and innovation in genetic technologies, the genes underlying altered brain development that results in childhood cognitive impairments are beginning to be elucidated. Two important generalisations seem to be emerging from these genetic studies. 1) Many forms of childhood cognitive impairment have been linked to the disruption of a single gene, making them tractable for laboratory studies examining the precise neurological basis of the impairment. 2) Numerous forms of cognitive impairment share common neurodevelopmental alterations, even with conditions such as autism that often do not result from disruption of a single gene. These findings indicate that the study of single gene conditions such as Fragile X Syndrome will shed light upon the cause of and perhaps provide treatments for autism and other neurodevelopmental conditions.
What is Fragile X Syndrome and why is it an important research model for diseases of childhood cognitive impairment?
Fragile X Syndrome is the most common inherited cause of childhood cognitive impairment. It affects approximately 1:4000 boys and 1:8000 girls, equivalent to over 10,000 people in the UK. FXS belongs to a group of developmental disorders in which clinical symptoms appear during the first two years of life. It is characterised by low IQ, attention deficit disorder, increased anxiety and seizures. FXS is also the leading genetic cause of autism with 7% of sufferers exhibiting autistic like symptoms and 30% meeting the clinical criteria for autism spectrum disorder (ASD). Furthermore, it has been estimated that 2-5% of ASD sufferers have FXS.
Unlike autism, which has multiple underlying causes, Fragile X Syndrome is caused by the loss of a single protein called the Fragile X Mental Retardation Protein or FMRP. The fact that there is one underlying explanation for the complex behavioural symptoms makes it possible to gain valuable insight into the key developmental events that underlie normal cognitive development. Furthermore, since Fragile X Syndrome patients share many behavioural features with other developmental disorders, including autism, it is highly likely that research into Fragile X Syndrome can be generalised to other forms of cognitive dysfunction. For these reasons, initially research into FXS and related cognitive impairments will be the central focus of our planned new centre. The long-term plan, however, is to explore a wider-range of neurodevelopmental abnormalities looking for commonalities in aetiology as well as treatment strategies.
What are the research avenues for Fragile X and developmental disorders?
Several novel treatments have been proposed for FXS and drugs developed that are now in human trials. This is a very exiting time for research into Fragile X Syndrome and Autistic Spectrum Disorders. Numerous drug trials are underway that have arisen from basic research examining basis of Fragile X Syndrome. However given the complexities of the syndrome, it is very unlikely that any one drug therapy with fully reverse the disease process. Furthermore much research is needed to determine when any drug therapy will be most effective, both from the perspective of reversing the disease as well as how particular side-effects may be best minimized.
We are current addressing two main aims:
To determine the developmental stage(s) that emerging drug therapies are most effective in restoring normal brain development, and
To determine novel therapeutic strategies for treatment of Fragile X Syndrome, Autistic Spectrum Disorders and related developmental disorders.
What are the implications for the conditions and other neurodevelopmental disorders, X-linked/autistic spectrum/learning disability such as X-linked conditions, autistic spectrum and the generality of learning disability?
At present we are in a field where treatment and management are at best supportive and palliative and we cannot know what the implications our research will be. However, given the similarities in behaviours between different forms of cognitive impairment and the rapid rate at which theories and drug interventions based on these theories are being developed, we have good reason to be optimistic that effective treatments will be developed over the next decade. However, the work of Professor Adrian Bird’s laboratory on Rett’s Syndrome strongly suggests that an appropriate molecular intervention may not only progress of these conditions be halted but also that abnormalities can actually be reversed. In terms of FXS, there is a real belief emerging amongst parents and researchers alike, that although a “cure” may still be in the relatively distant future, the development of therapeutic drug strategies for effective treatment of many of the behavioural disorders is a real possibility in the relatively near future (within the next 5-10 years).
Why is Edinburgh one of the best places to research the causes of and treatments for learning disability?
Modern day medical research relies on two key elements: a medical team with an infrastructure to conduct patient-based research (in addition to providing effective provision of care and treatment) interacting with a strong basic research team with the desire to translate research into treatment. The University of Edinburgh has both of these key elements making it the most appropriate place to house the first UK Centre for Research into Childhood Cognitive Impairment and these are explored in more depth below?
1) Provision of care, treatment and research infrastructure at Edinburgh:
Edinburgh is home to a critical mass of work that has been done in relevant fields over the years. Furthermore, under the guidance of Professor Eve Johnstone, Edinburgh has been at the forefront of studies examining the biological basis of psychiatric disorders. Some of the early work on the defining of the effects of sex chromosome anomalies was done here decades ago, and this was re-visited using imaging in the more recent past. Some of the earliest imaging studies of adults with learning disability were done here relating the findings to the occurrence of psychiatric features and discrete genetic anomalies. More recent work has demonstrated the structural brain anomalies occurring in non syndromal, learning disabled autistic people as compared with equally learning disabled non syndromal, non autistic people.
The large cohorts of affected individuals necessary for these studies continue to receive clinical care here in Edinburgh where there are modern purpose built inpatient facilities at the Royal Edinburgh Hospital, an extensive network of appropriate supported accommodation in the community and appropriate day centre provision, including a dedicated service for adults with autistic spectrum disorder, all of this being supervised by specialist staff.
2) Existing Excellence in Basic Science and Translational Research:
The University of Edinburgh Medical School has worked hard to break down so called “silos” in medical research. It has adopted a particularly collaborative attitude by bringing together researchers who also treat patients with scientists who work on disease types in the laboratory. Modern medicine terms this “bench to bedside” approach as translational research.
A good example of this type of research into developmental cognitive disability at the University of Edinburgh is the work of Professor Peter Kind’s laboratory on neural development and most recently Fragile X Syndrome. Professor Kind has published numerous high-profile papers on the way early experience shapes brain connectivity. This work has led him to his recent studies on FXS and related diseases of the childhood cognition. Professor Adrian Bird has published a very influential paper on the rescue of Rett’s Syndrome related symptoms in mouse model even in adult animals. Professor Richard Morris and David Wyllie are world leaders in the physiological and behavioural basis of learning and memory and their input will be key to establishing a multi-disciplinary approach to understanding the precise nature of the impairments associated with FXS and its related disorders.
Our plan for the future
We will use all of the funding available to create a “virtual” Centre for the Study of Childhood Cognitive Impairment. The University of Edinburgh has excellent laboratories and staff and the Centre will build upon existing strengths including world renown research in developmental disorders of cognition (Professor Adrian Bird and Professor Peter Kind), the cellular and behavioural basis of learning and memory (Professor Richard Morris and Dr. David Wyllie) and the genetic basis of developmental disorders (Professor David Porteous and Dr. Andrew Jackson). Most importantly, we will bring together the clinical and basic researchers present at the University to create a research team that will focus on providing continuity of patient care of the highest quality as well as world-class research designed to test and develop novel therapies both experimentally as well as in human trials. We will also recruit new world-class medical and basic researchers to complement our existing strengths.
It is very timely for the University of Edinburgh to focus on research translation in learning disability and cognitive impairment. A number of opportunities will come together over the next few months
Recruitment of a new Chair: the University and the NHS are negotiating a fully-funded post that will be attractive to clinical academics interested in Autistic Spectrum, Fragile X and other learning disabilities. The possibility of a research centre focused on this area of medicine will be extremely attractive to potential candidates for this post.
Brand new facilities: Outstanding research facilities newly available by the time the new Professor arrives will include the Clinical Research Imaging Centre (which has a dummy scanner suitable for reassuring anxious young patients in “practice runs”) and outstanding facilities for gene and protein analysis.
Existing Expertise in Regenerative Medicine: Edinburgh hosts a major initiative in Regenerative Medicine, directed by Sir Ian Wilmut, who was the first to clone a mammal successfully, Dolly the Sheep. This research powerhouse provides a unique platform of support and expertise in stem cells, nerve damage and growth as well as experts in other neurological diseases such as Parkinson’s, MND, MS and Stroke.
Relocation of Royal Sick Children’s Hospital and Clinical Neurosciences to Little France by 2012: This provides an attractive and powerful critical mass in paediatrics and clinical neuroscience.
Funding required for Edinburgh’s research centre for learning disabilities
If we can commit to raising approximately £1,000,000 over 5 years, we propose that it could be deployed as follows:-
£250K for a five-year senior research fellow
£250K for a three-year medical research training fellowship
£200K for four three-year PhD studentships
£200K for high specification imaging and microscopy equipment
£100K for research expenses, consumables and laboratory running costs
However, the key to attracting an outstanding leader would be the “upfront” aspiration to raise £1M.
We have already raised over £130,000 in philanthropic gifts for this research centre and a further £1.4 million has been won by the research groupings from MRC and Wellcome Trust Grant sources.
Our immediate aim is to raise £200,000 per year over the next five years to underpin the activity of this centre and to fund this vital research which will develop therapeutic interventions for a wide range of cognitive impairments in both children and adults.
For more information or to talk about this project in greater depth, please contact:
Chloe Kippen Deputy Director
Development and Alumni
Charles Stewart House
9 Chambers Street
tel: 0131 650 2232
fax: 0131 650 2239