MRC Centre for Neurodevelopmental Disorders

Neurodevelopmental disorders are a group of disorders in which the development of the brain is disturbed. This can manifest as neuropsychiatric problems or impaired motor function, learning, language or non-verbal communication. These disorders include epilepsy, intellectual disability, autism, and even other diseases with a relatively late onset, such as schizophrenia. These disorders are very difficult to treat and often cause a life-long disability.

The development of the brain is a highly orchestrated process, controlled by genetic information under very clear influence from the environment. In humans, brain development prolongs from early in life to adolescence, when many connections between neurons, the cells of the brain, are actively remodelled. Any deviation from this very protracted program can result in neurodevelopmental disorders and, depending on specific timing, might lead to distinct pathology later in life.

Neurodevelopmental disorders have a prominent genetic basis, although this does not necessarily mean that they are hereditary. For instance, many patients carry de novo mutations - an alteration in a gene that is present for the first time in one family member as a result of a mutation in a germ cell (egg or sperm) of one of the parents or in the fertilized egg itself. Recent advances in human genetics have identified specific mutations with these disorders. Unfortunately, we still do not understand how these mutations and concomitant environmental insults cause neurodevelopmental disorders.

Our vision is to build a world-class Centre at King's College London with research programmes that will transform our understanding of the origin of neurodevelopmental disorders. To this end, we will investigate the biological mechanisms underlying these disorders in human patients and animal models. We will also train and nurture the next generation of scientific leaders in the field, equipped to dissolve the boundaries that exist between basic research and clinical disciplines.

In the long term, we aim to translate the new knowledge into clinical advances that change the lives of affected individuals and their families, in collaboration with industrial partners, other research centres and patient associations.

The MRC Centre for Neurodevelopmental Disorders will bring together world-leading researchers in psychiatry, neonatology, neurology and neuroscience with the goal of identifying the biological mechanisms underlying neurodevelopmental disorders. This synergy will lead to breakthroughs in understanding which would otherwise not be possible. To reach this goal, we will combine mechanistic studies on patients and the genetic discoveries that are becoming available through the work of large sequencing consortia to guide our interrogation of specific brain circuits in both animal models and humans. In addition, we will explore how environmental factors influence the impact of disease susceptibility genes, both in humans and in animal models.

Our research will focus on epilepsy, autism spectrum disorder and schizophrenia, three disorders that are largely caused by abnormal brain development. These are high prevalence diseases which cause long-term burden, and are very difficult to treat. In addition, although these conditions represent a spectrum of diseases with broad sets of causes and clinical manifestations, they have overlapping phenotypes and genetics, which are suggestive of common deficits. The research focus of the new Centre is justified by our top clinical expertise in this field, the access to large patient populations, and our existing high-profile research programmes on neurodevelopment.

In five years, we will contribute to dissolving the boundaries that exist across clinical disciplines and that prevent an integrated understanding of common versus distinct biological mechanisms in neurodevelopmental disorders. Our unique combination of basic and clinical researchers will train and nurture the next generation of scientific leaders in the field, equipped with a translational agenda and a multidisciplinary set of skills. Finally, we also expect the Centre to develop new collaborations with Industry to identify and test new treatments for these disorders.

Beneficiaries:

The MRC Centre for Developmental Disorders will mainly carry out research on the neurobiological and environmental causes of epilepsy, autism spectrum disorders and schizophrenia. The beneficiaries from our research will be: (1) pharmaceutical companies, (2) policy-makers, and (3) patients and their families. We will valorise the entire dataset for further exploitation by the UK and/or global industry because this is in the best interest of the population of patients with neurodevelopmental disorders. Should the full potential of our scientific strategy come to fruition, the financial saving due to halting disease progression will be considerable.

Expected impacts:

Disease prevention and health promotion: More than 129 billion euros (as of 2010) are spent each year in Europe on the disorders that are the focus of this proposal. Our Centre will work towards the identification of the mechanisms causing these disorders. We will also identify how these mechanisms interact at different 'critical periods' (e.g., at birth) with environmental factors. This will help prevent neurodevelopmental disorders by defining the time at which specific pathophysiology should be targeted. More effective treatments based on the underlying pathophysiology will substantially reduce costs of health care.

Raising awareness and combating stigmatization: Our Centre will commit to raising public awareness on neurodevelopmental disorders. One of our main objectives is to educate professionals and the public about neurodevelopmental disorders to combat stigmatization and to promote a healthy life style. This is particularly important for schizophrenia, which has a long history of neglect, demonisation and concealment.

Therapy development through biologically validated targets: Selection of targets in psychiatry is driven largely by historical success. We propose working with genetic variants associated with neurodevelopmental disorders to identify common abnormal pathways, i.e., points of convergence, which could become new therapeutic targets.

Therapy development through more effective clinical trials: A fundamental problem in neurodevelopmental clinical trials is the reliance on a list of subjective criteria (as in DSM-5), which leads to the selection of a biologically heterogeneous population. We will use biomarkers to identify signatures that predict outcome, thereby providing a rational basis for patient selection and stratification in clinical trials. This should lead to more efficient and cost-effective clinical trials, thereby facilitating the development of new therapies.

Provision of specialists in neurodevelopmental disorders: We will train a new generation of scientists and clinicians with an integrated view of neurodevelopmental disorders. The provision of these specialists to the workforce will improve the competitiveness of the UK in this field, and will contribute to increase the effectiveness of public services.

Improving speed of impact: We will liaise with major stakeholders such as the EMA, patient organizations and Pharma, to help define the shortest development pathway for regulatory and market approval, making our findings available to the patients as quickly as possible.

Improving health services: Our Centre will play a major role in a nationwide effort to coordinate research and clinical practice through an MRC-funded Neurodevelopmental Disorders Network. In particular, we will contribute to redefining these disorders based on empirical evidence as opposed to classical diagnostic boundaries. This concerted effort should contribute to increasing the effectiveness of public services in the UK, and serve as a model for other European countries.