Dr David Komander, PhD
MRC Laboratory of Molecular Biology
Dr Komander received his Diploma in Biochemistry from Ruhr-University Bochum, Germany, having spent his Diploma thesis at the University of Dundee with Profs. Dario Alessi and Daan van Aalten ( Lister Prize Fellow in 2006). He subsequently became a MRC Predoctoral Fellow to continue with his PhD studies in Dundee, during which his work focussed on structural characterisation of the protein kinase PDK1, an important upstream ‘master’ kinase in growth factor signalling. Crystal structures of the kinase domain and the Pleckstrin Homology (PH) domain explained how PDK1 interacts with substrate kinases and phosphoinositides, respectively. His work was recognized with the Karl-Lohmann Prize of the German Society for Biochemistry and Molecular Biology (GBM) and the Biochemical Society Early Career Award for Signal Transduction. David then moved on to a postdoctoral position at the Institute of Cancer Research, London, to work with Prof. David Barford on deubiquitinating enzymes, where he became a Beit Memorial Fellow for Medical Research in 2006. In 2008, he started his independent research group at the MRC Laboratory of Molecular Biology in Cambridge. In 2011 David became an EMBO Young Investigator.
David’s work aims to unravel the emerging complexity in the ubiquitin system. Protein ubiquitination is a posttranslational modification of proteins that affects virtually all cellular processes, as it regulates, amongst other things, degradation, localisation and activity of its substrates. This versatility is enabled by ubiquitin’s ability to form different types of polymers, but so far only a small subset has been studied in detail. For several ‘atypical’ ubiquitin chain types, no cellular functions are known, although they exist abundantly in cells. To reveal the functions of these unstudied ubiquitin polymers, the Komander lab tries to identify proteins that specifically make, bind or cleave atypical ubiquitin chains. The lab recently showed that many enzymes of the ubiquitination cascade are highly linkage-specific, enabling a first definition of cellular roles for these new posttranslational modifications.
Protein ubiquitination is particularly important in infection and inflammatory signalling cascades. Interestingly, many pathogenic bacteria (including Salmonella, Yersinia, Escherichia and Legionella) modulate cellular ubiquitination cascades in various ways, by injecting effector proteins into human cells. These effector proteins are exciting, as they are often structurally and mechanistically distinct from human enzymes. The Komander lab currently studies bacterial effectors that assemble atypical ubiquitin chains, and bacterial deubiquitinating enzymes that may become future drug targets.
Dr David Lyons, PhD
Centre for Neuroregeneration
University of Edinburgh
David Lyons received his B.Sc. (Neuroscience, 1999) and Ph.D. (Developmental Biology, 2003) from University College London. He then undertook postdoctoral work at Stanford University in the Department of Developmental Biology with Prof. William Talbot (2004-2009), where he started his work using the zebrafish as a model organism to study myelinated axon formation. In 2009, Dr. Lyons joined the Centre for Neuroregeneration at the University of Edinburgh, as an independent group leader, supported by a BBSRC David Phillips Fellowship. The focus of the Lyons lab is currently on elucidating mechanisms that orchestrate the formation, function and repair of myelinated axons.
The majority of axons in our nervous systems are eventually myelinated. The myelin sheath is a lipid rich structure made by glial cells that is wrapped many times around axons. Myelin provides electrical insulation to axons, and facilitates rapid energy-efficient nerve conduction. Disruption to myelin contributes to the symptoms of numerous devastating conditions, including the demyelinating disease multiple sclerosis, MS. Although our nervous system has some ability to repair damaged myelin, this process of remyelination eventual fails, and this causes the axonal and neuronal degeneration associated with currently untreatable stages of MS. Although we know much about the structure and function of myelin, we have a relatively limited understanding of the interactions between axons and glial cells that specifically regulate myelination. Gaining a clearer picture of the cell-cell interactions that occur during myelination, demyelination, and remyelination will identify key events that could enhance repair. Finding new genes that control myelination will provide mechanistic insights into myelination and identify new molecules that could be targeted during repair. Identifying compounds for their ability to enhance repair in an animal model will accelerate drug discovery for the treatment of demyelinating/ neurodegenerative conditions, such as MS.
The Lyons lab uses zebrafish as a model to study myelination to try to achieve these aims. The small size, optical transparency, relative simplicity, and rapid development of zebrafish embryos are properties that allow direct observation of entire developmental (or repair) events as they occur in live animals, which is technically difficult in mammals. The Lyons lab has developed a non-invasive method to induce demyelination in zebrafish and has also generated a suite of tools to visualise myelin and myelinated axons at high-resolution in live zebrafish, which allow them to observe cellular, sub-cellular and molecular behaviours during myelination, demyelination, and remyelination as they occur in a living animal.
Zebrafish are well established as a powerful system with which to identify new genes required for biological events. In a genetic screen carried out at Stanford University Dr. Lyons and colleagues identified new roles for genes with known involvement in myelination, established zebrafish models of human disease, and identified new genes required for myelination. Further screening by the lab will identify additional genes that control myelination.
Zebrafish have also become increasingly popular for drug discovery studies. Zebrafish embryos are small, aquatic, and available in very large numbers, which means that large-scale screens can be carried out in a cost-effective manner, that is not possible using other animal models. This means that the effect of thousands of potential drug like compounds can be tested on whole animals at a very early stage of the drug development process. Importantly, zebrafish exhibit well-conserved responses to drugs approved for use in man, and new clinical trials based on work carried out in zebrafish are already in progress. The Lyons lab hopes to identify compounds that can enhance the repair of myelinated axons in zebrafish, from which new therapies for humans can be developed.
Dr Akhilesh Reddy, MA, MB BChir, PhD, MRCP
Institute of Metabolic Science
University of Cambridge
Akhilesh Reddy qualified from the MB/PhD programme at Cambridge after completing his research and clinical training. He completed the doctoral component in Dr Michael Hastings’ laboratory at the MRC Laboratory of Molecular Biology, while simultaneously pursuing studies at the University of Cambridge School of Clinical Medicine. At that time, his interests were primarily focused on the neurobiology of circadian rhythms – approx. 24 hour cycles that control our body’s physiology. In particular, he investigated the molecular basis of the clockwork by using systems-level tools, including microarrays and high-throughput proteomics. This theme continued through his postgraduate medical training, and as a post-doctoral Research Fellow at St John’s College, Cambridge, he was able to show the pervasive control that the molecular clock has on liver physiology – with 10-15% of genes and proteins undergoing daily oscillations.
After a period of full-time training in Neurology, Dr Reddy was awarded a Wellcome Trust Clinician Scientist fellowship in 2008, which allowed him to start his research group within the Institute of Metabolic Science at the University of Cambridge. The Reddy lab investigates the fundamental molecular mechanisms that bring about 24 hour oscillations, and their relationship with sleep biology, using a combination of targeted approaches, including whole animal physiology, systems biology and synthetic biology. Akhilesh now straddles between his research lab and clinical work as an Honorary Consultant Neurologist at Addenbrooke’s and Peterborough City Hospitals. In 2011, Akhilesh was selected as an EMBO Young Investigator and received the Colworth Medal for Biochemistry in 2012.
Dr Reddy’s group recently discovered a new mechanism by which cells keep time. They showed that, remarkably, even when cells do not have DNA to ‘instruct’ them what to do, they can still maintain an autonomous ticking clock. This is significant because all previous models of how the clock worked in complex multicellular organisms was based on the presumption that a genetic switching mechanism was absolutely required. This work has opened up many avenues of research into how these ‘non-transcriptional’ metabolic redox oscillations arise. In particular, the Reddy lab recently showed for the first time that oscillations of Peroxiredoxin proteins are an evolutionarily conserved ‘readout’ of clocks in all domains of life (Bacteria, Archaea and Eukaryotes), implying that redox oscillations are a fundamental unifying feature of cellular timekeeping. Akhilesh’s group continues to extend this novel area of clock biology with recent funding for his ‘MetaCLOCK’ project from the European Research Council (ERC).
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