Dr David Komander, PhD
MRC
Laboratory of Molecular Biology
Cambridge
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).
