Development of preventative and reparative treatments for Alzheimer’s disease and other dementias, Glaucoma, Huntington’s disease, Multiple Sclerosis, Parkinson’s disease, Spinal cord injury, Stroke, Traumatic brain injury
The Brain Repair Centre was established in 1995 in a new purpose-built building funded by the Medical Research Council. It was the first Brain Repair Centre in the world, and has been a leader in its field ever since.
In the early 1990s real progress was being made in understanding how the nervous system is built during development. The founders of the Brain Repair Centre decided that it was time that our knowledge of brain development was put to work in finding out how to rebuild the nervous system after damage. Although we now know that there are significant differences between the mechanisms of development and those of repair, the basic idea was sound. Our research based on these ideas has delivered treatments that are in clinical and preclinical development for multiple sclerosis, spinal cord injury, Parkinson’s disease, Huntington’s disease and traumatic brain injury. We also have promising leads for Alzheimer’s disease and dementia, glaucoma and stroke. The faculty of the Centre have been recognised for their success through the award of many prizes and lectureships, and through the award of numerous research grants from organizations in the UK and abroad. In 2012 the Centre was named after John van Geest in recognition of continuing support over many years from the John and Lucille van Geest Foundation.
Damage to the nervous system is devastating, and at present it is permanent. Chronic nervous system disease is now the main source of disability in our population. The Brain Degeneration and Brain Repair programmes in Cambridge University are developing treatments to prevent this damage and to repair damage that has already occurred.
The target diseases of the John van Geest Centre for Brain Repair are Alzheimer’s Disease and Dementia, Glaucoma, Huntington’s Disease, Multiple Sclerosis, Parkinson’s Disease, Spinal Cord Injury, Stroke, Traumatic Brain injury. This is a long list of target diseases. However, the technologies that are needed to repair or prevent these conditions are fewer, and common between the conditions. By conquering cell protection, cell replacement, nerve fibre regeneration, plasticity and control of inflammation we can develop treatments for our target diseases.
Our target diseases: what they are what our research has achieved
Alzheimer’s disease and tauopathy
Alzheimer’s disease (AD) is a terminal age-related disease that kills neurons throughout the brain. AD affects over 20 million people worldwide and is the leading cause of dementia. There are probably several causes of AD; in some cases genetic inheritance plays a role but the vast majority of AD patients develop the disease sporadically. The brains of patients with AD exhibit certain hallmarks of the disease including plaques made of a protein called beta-amyloid and tangles within the neurons of the brain that are associated with another protein called tau. Changes in tau are seen in a variety of other neurodegenerative diseases as well. However, while the development of these plaques and tangles has been implicated in the pathology of AD, it is uncertain how they kill brain cells, or how to halt their effects. Currently, there are no approved treatments to prevent or slow the progression of AD, though medications are available which partly treat the cognitive symptoms of the disease and potential new agents are currently under clinical trial.
Research in the Brain Repair Centre focuses on both the molecular and genetic causes of AD, and on ways to alleviate the symptoms. A variety of novel mutations in the tau gene have been created in BRC laboratories in order to study how the development of tau-related tangles in the brain contributes to neurodegeneration. For example, BRC researchers have demonstrated that pathogenic forms of tau disrupt the transport of important molecules within neurons, leading to their death. Genetic studies of patients with AD have pointed towards particular genes that might increase a person’s susceptibility to the disease. BRC investigators also have been at the forefront of demonstrating abnormalities in the tau protein in other diseases including Parkinson’s disease and frontotemporal dementia. A novel treatment based on stimulating brain plasticity has been shown to restore memory in animals with Alzheimer’s pathology.
Glaucoma is an age-related neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs), the neurons which carry visual information from the retina to the brain via the optic nerve. It is one of the leading causes of vision loss in the world, affecting approximately 60 million people and resulting in permanent blindness in 8 million. The most important risk factor for the development and progression of glaucoma is an elevated intraocular pressure (IOP) and currently the only approved treatments for glaucoma include pharmacological or surgical methods aimed at reducing IOP. While these therapeutic approaches often slow the rate of disease progression, they are not effective in all patients and are incapable of reversing glaucomatous vision loss that has already occurred.
Research in the Brain Repair Centre focuses on both pathology and potential treatments for glaucoma. While high IOP is associated with glaucoma, it is not understood how it ultimately leads to the death of RGCs. Current work in the BRC investigates how impaired axonal transport or triggering of mechanisms of cell death might contribute to the disease. New methods for protecting or replacing RGCs in the context of this devastating condition also are being studied. For example, gene therapy, which directs the retina to produce neurotrophic factors, appears to protect RGCs in various models of glaucoma. Additionally, stem/progenitor cell transplantation is demonstrating potential as a neuroprotective and regenerative therapy.
Huntington’s disease (HD) is a rare genetic neurological disorder. Symptoms increase over time, and typically include random, uncontrolled movements (so-called chorea), cognitive deficits as well as psychiatric problems. HD is caused by an abnormal expansion of a trinucleotide repeat in the huntingtin gene. This mutation is inherited as an autosomal-dominant; this means that children of patients have a 50% chance of inheriting the mutant huntingtin gene. The expanded trinucleotide CAG codes for the amino acid glutamine, and HD is therefore one of several polyglutamine diseases. The result is a mutant huntingtin protein, which eventually causes neuronal cell death in certain areas of the brain, especially the frontal lobes and the striatum.
Research at the BRC into HD studies the basic molecular mechanisms, i.e. how exactly the mutant huntingtin is toxic to neurons, performs clinical studies which involve investigations into the neuropsychology of HD, and assesses the efficacy of stem cell transplants in HD patients.
Multiple Sclerosis remains one of the most devastating illnesses of young adults, and is the commonest cause of disability after trauma. It is a complex and heterogeneous disease, in which both inflammation, demyelination (removal of the insulation which enables signal transmission in nerves) and nerve fibre degeneration occur in the brain and spinal cord. Repetitive immune attack against the myelin sheaths and oligodendrocytes (the cells that produce myelin) mark the first phase of disease. These events are termed relapses and cause temporary disability followed by partial recovery. These events are usually followed by slow cumulative degeneration of nerve fibres, which leads to progressive accumulation of disability.
Work at the Brain Repair Centre has focused on prevention and repair. Compounds have been identified which speed repair of the myelin loss. New oligodendrocytes have been generated from stem cells, to be used for repair and for testing reparative drugs. Various factors that prevent remyelination have been identified and there are also several growth factors that can stimulate the process.
Further, Cambridge has developed the methods and led a trial of an inflammation reducing treatment (Campath-1H: alemtuzumab) that has now been approved for treatment of human patients. The treatment almost eliminates relapses in MS, and also allows significant recovery from disability. Cambridge has also led international genome-wide association studies to find new susceptibility genes.
More than 20 million people worldwide are affected by neurodegenerative disorders of which Parkinson’s disease (PD) is second commonest. In the United Kingdom about 10,000 people are diagnosed every year. PD is a progressive neurological condition affecting movements such as walking, writing and talking. It is caused by the loss of nerve cells in the part of the brain known as the substantia nigra. These cells are responsible for producing dopamine, a chemical that enables transmission of messages that co-ordinate movement.
At the John van Geest Centre for Brain Repair we are working to understand the various causes of PD and develop new treatments. Patients are assessed using tests for memory, eye movement recordings and brain imaging studies. Together with blood these tests are leading to better diagnostic tools for distinguishing the subtypes of the disease, for which treatments are then being optimised. Cambridge is leading a new international trial of embryonic brain grafts in Parkinson’s disease.
Spinal cord injury
Every year thousands of people are crippled due to spinal cord injuries. In Europe alone, about 10,000 individuals are paralyzed, most of them at a very young age (the commonest age of injury is 19). These injuries can happen due to a variety of causes such as vehicle accidents, sporting injuries, tumours & various other neurodegenerative diseases. Depending on the level of spinal cord injury, a patient’s symptoms can vary from quadriplegia – inability to breathe or move at all below the neck level (cervical) – to loss of lower limb control, loss of bladder/bowel control, loss of sexual dysfunction (lower-level cord injuries).
A major aim of research in Centre for Brain Repair is to stimulate regeneration of damaged nerve fibres in the spinal cord to restore function. Regeneration is being enhanced by enzyme treatments to the scar tissue surrounding cord injuries (extrinsic factors) and we are developing approaches to enhance the ability of axons to regenerate (intrinsic factors). Some parts of nervous system have the ability to rewire after an injury – a phenomenon known as “plasticity”. However Chondroitin Sulphate Proteoglycans (CSPGs) block both plasticity and nerve fibre regeneration. Research in the Brain Repair Centre is now focussed on ability of CSPG digesting enzymes to rejuvenate plasticity and regeneration. We are also focussing on methods to enhance the effectiveness of rehabilitation & physiotherapy. Two recent veterinary clinical trials have demonstrated that a transplant of olfactory cells can improve recovery after spinal cord injury in dogs, and that an electronic device can restore bladder control. Plans are underway to translate these findings into humans.
Traumatic Brain Injury and Stroke
Injury to the brain kills nerve cells and nerve fibres, leading to neurological deficits. Stroke kills areas of the brain when the blood vessel supplying that area gets blocked. In the immediate aftermath of stroke and injury there are prospects for preventing the processes that lead to the spread and worsening of the neurological deficit. One active field of research in the Brain Repair Centre is to develop treatments to preserve the brain by ensuring that the areas of injured brain receive a sufficient blood supply. The spread of injuries also involves changes in the metabolism of neurons, and various treatments are under development to counteract these changes.
After the acute injury phase of stroke and head injury there may be considerable recovery of neurological function. Thus a patient who initially is paralysed over one complete side of their body may leave hospital with just weakness in one arm. Much of this recovery is due to the ability of the brain to adjust its connections so as to make new circuits which can take over the functions of circuits that have been damaged. This process is called plasiticty. Research in the Brain Repair Centre has identified ways to enhance and direct this plasticity.
Faculty of the John van Geest Centre for Brain Repair
Roger Barker, Professor of Clinical Neuroscience
Roger Barker gained his PhD on neural grafting working with James Fawcett and Stephen Dunnett. He then trained in Neurology at Cambridge and the National Hospital Queen Square in London before returning to Cambridge and the Brain Repair Centre. He became a Lecturer in Neurology in 2000 and Professor of Clinical Neuroscience in 2011.
His research group works on clinical aspects of Parkinson’s and Huntington’s Disease as well as new therapeutic strategies to treat these disorders. Prof. Barker is heading a worldwide programme to develop brain grafting for Parkinson’s disease through the TransEuro consortium. He is an active neurologist and runs the regional Huntington’s disease clinic and also sees patients with a range of neurological disorders.
Two recent papers
A functional role for adult hippocampal neurogenesis in spatial pattern separation. Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH, Bussey TJ. Science. 2009 Jul 10;325(5937):210-3.
The distinct cognitive syndromes of Parkinson’s disease: 5 year follow-up of the CamPaIGN cohort. Williams-Gray CH, Evans JR, Goris A, Foltynie T, Ban M, Robbins TW, Brayne C, Kolachana BS, Weinberger DR, Sawcer SJ, Barker RA. Brain. 2009 Nov;132(Pt 11):2958-69.
Michael Coleman Group leader, Babraham Institute
Michael Coleman works on the mechanisms of nerve fibre degeneration, and on methods to preserve nerve fibres. All people show a progressive loss of axons with age. Metabolic, environmental or genetic factors accelerate axon loss in some individuals, and in all of us the risks of age-related disorders such as dementia increase because even if mechanisms differ the losses due to ageing and disease are additive.
Dr. Coleman has identified a protein that must be transported down axons in order for them to remain alive. Efficient axonal transport must continue for decades but in various conditions it is compromised, making axons vulnerable.
Two recent papers
Babetto E, Beirowski B, Janeckova L, Brown R, Gilley J, Thompson D, Ribchester RR, Coleman MP (2010) Targeting NMNAT1 to axons and synapses transforms its neuroprotective potency in vivo. Journal of Neuroscience 30 13291-13304
Conforti L, Wilbrey AL, Morreale G, Janeckova L, Beirowski B, Adalbert R, Mazzola F, Di Stefano M, Hartley R, Babetto E, Smith T, Gilley J, Billington RA, Genazzani AA, Ribchester RR, Magni G, Coleman MP (2009) WldS protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice. Journal of Cell Biology 184 491-500
Alastair Compston Professor of Neurology
Alastair Compston’s research interests focus on clinical and experimental demyelinating disease with an emphasis on multiple sclerosis – the commonest potentially disabling disease of young adults. The research group has a broad set of interests: we work on the aetiology with international collaborations in genetics involving large-scale whole genome screens for factors that confer susceptibility and influence disease progression; in neurobiology, we study interactions between glia and axons, and the potential role of human stem cells as ‘medicines’ for limiting and the repairing the damage; our work in therapeutic immunology has used the monoclonal antibody Campath-1H (Alemtuzimab) both to treat patients and to understand mechanisms of tissue injury that determine the clinical course of the disease.
Two recent papers
Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara MA, Compston DA; CARE-MS I investigators. Lancet. 2012 380:1819-28
Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. CAMMS223 Trial Investigators, Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK. N Engl J Med. 2008 359:1786-801
James Fawcett, Professor of Experimental Neurology
James Fawcett trained in medicine at Oxford University and St. Thomas’ Hospital London then obtained his PhD under Michael Gaze at the National Institute for Medical Research. He moved to the Salk Institute in the laboratory of Max Cowan then set up his own laboratory in the Physiology Department in Cambridge. Since 2001 he has been Chairman of the John van Geest Centre for Brain Repair.
His main interest is the repair of CNS damage, particularly the spinal cord. He has worked on modification of the extracellular matrix to relieve the inhibition of axon regeneration by glial scar tissue, and on reactivation of plasticity in the adult nervous system. He also works on the design of protocols for clinical trials in spinal cord injury.
Two recent papers
Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. G García-Alías, S Barkhuysen, M Buckle, JW Fawcett. Nature neuroscience 12 (2010), 1145-1151
Animals lacking link protein have attenuated perineuronal nets and persistent plasticity. Daniela Carulli, Tommaso Pizzorusso, Jessica CF Kwok, Elena Putignano, Andrea Poli, Serhiy Forostyak, Melissa R Andrews, Sathyaseelan S Deepa, Tibor T Glant, James W Fawcett. Brain 133 (2011), 2331-2347
Robin Franklin Professor of Neuroscience, Dept. Veterinary Medicine
The Franklin lab is interested in the mechanisms of CNS regeneration with a particular focus on remyelination, an adult stem/precursor cell-mediated process in which new myelin sheaths are restored to demyelinated axons. Remylination becomes much less efficient with age, and can fail completely in multiple sclerosis. Prof. Franklin has identified key age-related mechanisms that make remylination inefficient, and has developed treatments to restore it. He has also shown that cells derived from the olfactory epithelium can be transplanted into dog spinal cord injuries to improve recovery.
Two recent papers
Ruckh JM, Zhao JW, Shadrach JL, van Wijngaarden P, Rao TN, Wagers AJ, Franklin RJM (2012) Rejuvenation of regeneration in the central nervous system. Cell Stem Cell 10: 96-103.
Huang JK, Jarjour AA, Nait Oumesmar B, Kerninon C, Williams A, Krezel W, Kagechika H, Bauer J, Zhao C, Baron van Evercooren A, Chambon P, ffrench-Constant C, Franklin RJM (2011) Retinoid X receptor gamma signaling accelerates CNS remyelination. Nature Neuroscience 14: 45-53.
Ragnhildur Thora Karadottir Wellcome Trust RCD Fellow
Ragnhildur Karadottir works on the mechanisms of myelin formation. Oligodendrocytes produce myelin (in the CNS), which speeds the propagation of the action potential. When the myelin sheath is lost, in diseases like cerebral palsy, spinal cord injury and multiple sclerosis, it causes mental and physical disability. She studies how oligodendrocytes respond to neurotransmitters released from axons, both in the normal brain and in pathological conditions.
Two recent papers
Stacpoole S. R., Bilican B., Webber D. J., Luzhynskaya A., He X. L., Compston A., Karadottir R., Franklin R. J. and Chandran S. 2011. Efficient derivation of NPCs, spinal motor neurons and midbrain dopaminergic neurons from hESCs at 3% oxygen. Nat Protoc, 6: 1229-40
Káradóttir R, Bakiri Y, Hamilton N & Attwell D (2008). Spiking and non spiking classes of oligodendrocyte precursor glia in CNS white matter. Nature Neuroscience 11(4): 450-456
Andras Lakatos David Walker Research Fellow
Andras Lakatos investigates inflammatory events and changes in glia-neuron interactions following nerve fibre damage and demyelination. He aims to develop new neuroprotective treatments for neurological disorders, particularly multiple sclerosis.
Two recent papers
Meningeal cells enhance limited CNS remyelination by transplanted olfactory ensheathing cells.Lakatos A, Smith PM, Barnett SC, Franklin RJ. Brain. 2003 Mar;126(Pt 3):598-609.
Olfactory ensheathing cells induce less host astrocyte response and chondroitin sulphate proteoglycan expression than Schwann cells following transplantation into adult CNS white matter. Lakatos A, Barnett SC, Franklin RJ. Exp Neurol. 2003 Nov;184(1):237-46.
Keith Martin, Professor of Ophthlamology
Keith Martin aims to understand and reverse the mechanisms of retinal ganglion cell (RGC) death in glaucoma, the leading cause of irreversible blindness worldwide. The objective is to develop methods to protect RGC thus slowing the progression of glaucomatous visual loss, and ultimately to restore vision in those blind due to the disease.
He is currently exploring the pathogenesis of axonal injury in glaucoma and investigating stem cell transplantation and neurotrophic factor gene therapy as potential treatment approaches.
Two recent papers
Gene therapy with brain-derived neurotrophic factor as a protection: Retinal ganglion cells in a rat glaucoma model. Martin, K.R.G., Quigley, H.A., Zack, D.J., Levkovitch-Verbin, H., Kielczewski, J., Valenta, D., Baumrind, L., Pease, M.E., Klein, R.L., Hauswirth, W.W. Invest Ophthalmol Vis Sci. 2003 Oct;44(10):4357-65.
Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Johnson, T.V., Bull, N.D., Hunt, D.P., Marina, N., Tomarev, S.I., Martin, K.R. Investigative Ophthalmology and Visual Science 2010 51 (4) , pp. 2051-2059
David Menon Professor of Anaesthesia
Professor Menon’s main research interest is protection of the brain after traumatic damage. The research program has aimed to understand regional cerebral pathophysiology to advance the care of critically ill patients after brain injury, from initial ictus, through recovery from coma and rehabilitation, to final outcome. These aims have been realized through a series of MRC Program and Cooperative Group Grants, based in the Wolfson Brain Imaging Centre, which have formed a focus for productive collaboration with other departments in the Clinical School, and the broader neuroscience community in Cambridge.
Two recent papers
Traumatic brain injury: rethinking ideas and approaches. Maas AI, Menon DK. Lancet Neurol. 2012 11:12-3
Parcellating the neuroanatomical basis of impaired decision-making in traumatic brain injury. Newcombe VF, Outtrim JG, Chatfield DA, Manktelow A, Hutchinson PJ, Coles JP, Williams GB, Sahakian BJ, Menon DK. Brain. 2011 Mar;134(Pt 3):759-68
Stefano Pluchino John Van Geest lecturer
Stefano Pluchino aims to protect the nervous system from multiple sclerosis and traumatic damage. He has shown that systemic injection of neural stem/precursor cells (NPCs) protects the CNS from degeneration induced by inflammation in experimental multiple sclerosis, cerebral ischemic stroke, or contusion of the spinal cord. He is working out how stem cells transfer microRNAs to immune cells to change their function, and developing innovative new methods to use small RNAs in the treatment of spinal cord injury.
Two recent papers
Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Pluchino, S., Zanotti, L., Rossi, B., Brambilla, E., Ottoboni, L., Salani, G., Martinello, M., (…), Martino, G. Nature 2005 436 (7048) , pp. 266-271
Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Ziv, Y., Avidan, H., Pluchino, S., Martino, G., Schwartz, M. Proceedings of the National Academy of Sciences of the United States of America 2006 103 (35) , pp. 13174-13179
Maria Grazia Spillantini Scholl Professor of Neuroscience
Professor Spillantini has discovered some of main mechanisms by which Alzheimer’s disease, Parkinson’s disease and other dementias damage the brain. Her current interest is in the identification of the mechanisms leading to neuronal death clinical disability in these diseases. In particular she studies how aggregation of the microtubule-associated protein tau and the neuronal protein alpha-synuclein leads to pathology in tauopathies and alpha-synucleinopathies. The work extends from genetic studies in patients to disease models. The aim is to identify mechanism-based therapies for these disorders.
Two recent papers
Ubiquitination of α-Synuclein in Lewy Bodies Is a Pathological Event Not Associated with Impairment of Proteasome Function . Tofaris, G.K., Razzaq, A., Ghetti, B., Lilley, K.S., Spillantini, M.G. Journal of Biological Chemistry 2003 278 (45) , pp. 44405-44411
Interaction of tau protein with the dynactin complex. Magnani, E., Fan, J., Gasparini, L., Golding, M., Williams, M., Schiavo, G., Goedert, M., (…), Spillantini, M.G. EMBO Journal 2007 26 (21) , pp. 4546-4554
Colin Watts University lecturer in Neurosurgery
Colin Watts obtained his PhD in the Brain Repair Centre in 1999. His research is linked to his clinical practice in glioma neurosurgery. He is interested in the similarities between cancer stem cells and stem cells in the normal and injured brain. He has developed the Cambridge Protocol for the reliable derivation of self-renewing tumourigenic cells under serum-free conditions. He has characterised these cells in vitro and in vivo and to compared them to stem cells in the normal and injured brain. Within the tumour he has shown how the cells are constantly evolving new tumour properties. In this way he aims to identify markers that will enable us to further enrich and define the tumour competent population. Such populations will then be used to identify and validate biomarkers of disease and potential therapeutic targets and strategies.
Two recent papers
Astrocytes and oligodendrocytes can be generated from NG2+ progenitors after acute brain injury: Intracellular localization of oligodendrocyte transcription factor 2 is associated with their fate choice. Zhao, J.-W., Raha-Chowdhury, R., Fawcett, J.W., Watts, C. European Journal of Neuroscience 2009 29 (9), pp. 1853-1869
An efficient method for derivation and propagation of glioblastoma cell lines that conserves the molecular profile of their original tumours. Fael Al-Mayhani, T.M., Ball, S.L.R., Zhao, J.-W., Fawcett, J., Ichimura, K., Collins, P.V., Watts, C. Journal of Neuroscience Methods 2009 176 (2) , pp. 192-199