pdfMRC NIMR Annual Report - The Francis Crick Institute

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2013/2014 Annual Report and Prospectus
MRC National Institute
for Medical Research
Science for health
Edited by: Victor Tybulewicz
Designed by: Joe Brock and Hayley Wood
Photography by: Neal Cramphorn & James Brock
Production: Alana Price & Frank Norman
Editorial Assistant: Eileen Clark
© MRC National Institute for Medical Research
Enquiries about this report should be addressed to:
Director’s Office
+44 (0)20 8816 2281
[email protected]
Further information is available on our website at:
http://www.nimr.mrc.ac.uk
Copies obtainable from the Librarian at NIMR
ISBN-13: 978-0-9572625-3-9
MRC National Institute for
Medical Research
2013/2014 Annual Report and
Prospectus
Contents
Director’s foreword
The Francis Crick Institute
Science overview
Scientific Highlights
NIMR history and milestones
Careers :
Translational research
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6
8
10
14
PhD students
Sandwich students and work experience
Postdoctoral scientists
Programme Leaders
Research support
Animal Technicians
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19
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Support for translation
Clinical translation
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28
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Public outreach
Research groups
Infections and Immunity
Kate Bishop
Retroviral infection and replication
Mike Blackman
Malaria parasite egress and invasion
Luiz Pedro de Carvalho
Mtb systems and chemical biology
John Doorbar
Human papillomavirus
Eva Frickel
Anti-Toxoplasma gondii immunity
Max Gutierrez
Cell biology of Mtb infection
Tony Holder
Malaria parasites & red blood cells
George Kassiotis
Antiviral immunity
Jean Langhorne
Immunity in malaria infections
Steve Ley
Regulation of immune responses
John McCauley
Host specificity of influenza viruses
Anne O’Garra
Regulation of the immune response
Venizelos Papayannopoulos Neutrophil-mediated immune defense
Benedict Seddon
Regulation of T cell homeostasis
Gitta Stockinger
T cell compartments
Jonathan Stoye
Retrovirus-host interactions
Pavel Tolar
Activation of immune receptors
Victor Tybulewicz
Lymphocyte signal transduction
Andreas Wack
Immune response to influenza
Robert Wilkinson
HIV-associated tuberculosis
Mark Wilson
Regulation of type-2 immuninty
Douglas Young
Mycobacterial pathogenesis
WHO Collaborating Centre for Reference and Research on Influenza (WIC)
Structural Biology
Tom Carter
Secretory organelles
Paul Driscoll
Analysis of signalling proteins
Steve Gamblin
Structural biology
Richard Goldstein
Evolution of molecular components
Ian Holt
Mitochondrial DNA Replication
Justin Molloy
Cell motility and cell signaling
John Offer
Synthetic protein laboratory
Annalisa Pastore
Structural biology in neurodegeneration
Andres Ramos
Post-transcriptional regulation
Katrin Rittinger
Immune signalling networks
Peter Rosenthal
Cryomicroscopy
Steve Smerdon
Phosphorylation-dependent signalling
Antonella Spinazzola
Mitochondrial biogenesis and disease
Ian Taylor
Protein structure analysis and design
Willie Taylor
Macromolecular assemblies
Martin Webb
Mechanisms of motor proteins
Neurosciences
Dimitrios Anastasiou
Cancer metabolism
Siew-Lan Ang
Control of dopaminergic neuron development
Denis Burdakov Brain control of sleep and appetite
Alex Gould
Regulation of growth and metabolism
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MRC National Institute for Medical Research
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François Guillemot
Analysis of neurogenesis
Troy Margrie
Typology of neuronal networks
Vassilis Pachnis
Development of the nervous system
Markus Ralser
Evolution and structure of metabolic networks
Iris Salecker
Drosophila visual circuit assembly
Andreas Schaefer
Information processing in the olfactory system
Sila Ultanir
Kinase signaling pathways in neuronal development
David Wilkinson
Boundary formation and neurogenesis
Mariia Yuneva
Oncogenes and tumour metabolism
Genetics and Development
James Briscoe
Pattern formation in the CNS
Greg Elgar
Regulation of early development
Mike Gilchrist
Gene regulatory networks
Vivian Li
Intestinal stem cell and Wnt signalling
Malcolm Logan
Limb development
Robin Lovell-Badge
Sex, stem cells and cell fate
Tim Mohun
Heart development in vertebrates
Kathy Niakan
Mechanisms of lineage specification
Andrew Oates
Embryo patterning
Jim Smith
Mesoderm formation
Peter Thorpe
Systems microscopy of cell fate
James Turner
Sex chromosomes
Jean-Paul Vincent
Patterning and homeostasis
Research facilities
Biological and Procedural Services
MRC Biomedical NMR Centre
X-ray crystallography
Mass spectrometry
Protein sequence analysis and structure modeling
Biological computing
Confocal imaging and analysis
Histology
Electron microscopy
OPT and HREM imaging
Single molecule techniques
Electron cryomicroscopy
Genomics
Laboratory infrastructure and logistics (Bioresources)
Human embryonic stem cell facility
Insectary
Flow cytometry
Level 4 high-containment virus laboratory
Scientific instrument research & development
Mechanical Engineering
Estates and Engineering
Photographics
Computing and Telecommunications
Library, information & communications
Web Team
Laboratory infrastructure and logistics (Central Services)
General services
Institute management
Nobel Laureates
Six famous alumni
In memoriam
Scientific seminars
Staff honours
PhD theses awarded
Current funding sources
Bibliography
NIMROD social club
Research themes index
Index
Map, location and travel
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inside back cover
3
Director’s foreword
It has been another very busy year at NIMR, during which we have again done some great science (see Science Highlights on pages
10-13) and recruited some great young scientists, all the while preparing for our move to the Francis Crick Institute (see pages 6-7).
New staff
Kathy Niakan started her career with Edward McCabe at UCLA and Kevin Eggan at Harvard, and then moved to Cambridge to
investigate the molecular basis of early cell fate decisions in humans and mice. At NIMR she is exploring the regulation of embryonic
stem cell pluripotency. Vivian Li did her PhD at the University of Hong Kong and then moved to the Hubrecht Institute in Utrecht
to work with Hans Clevers on Wnt signalling in intestinal stem cells. She continues this line of research at NIMR by studying Wnt
pathway regulation in the intestine and in mouse models of human colorectal cancer. Mariia Yuneva was awarded her PhD in
Alexander Boldyrev’s lab at Moscow State University and then moved to the Cold Spring Harbor Laboratory to study the nutrient
dependence of oncogene-transformed cells with Yuri Lazebnik. Having worked with J. Michael Bishop at UCSF, studying mouse
models of cancer, she moved to Mill Hill to study the relationship between oncogenes and tumour metabolism. Markus Ralser
worked in Salzburg, Amsterdam, and the Max Planck Institute for Molecular Genetics in Berlin before establishing his own group at
the MPI-MG working on the molecular biology of metabolism. Before coming to NIMR he worked at the University of Cambridge,
where he developed his interests in the regulatory and dynamic functions of the metabolic network. Sila Ultanir worked on neuronal
development and synaptogenesis in Rafael Yuste’s lab at Columbia University before moving to Anirvan Ghosh’s lab at UCSD.
Moving to Yuh-Nung Jan’s lab at UCSF she studied signalling mechanisms and dendrite development using chemical genetics, and
at NIMR she will look at pathways that regulate the formation and plasticity of dendrite arbors and dendritic spines. Finally, Andreas
Schaefer worked with Bert Sakmann and Hermann Bujard at the Max Planck Institute for Medical Research in Heidelberg, and then
moved to UCL to work with Troy Margrie. He moved back to MPI-MR as a group leader, before coming to NIMR to explore, using
the mouse olfactory system, how complex behaviour emerges from the properties of molecules, cells and ensembles of cells.
(top row) Kathy
Niakan, Vivian Li,
Mariia Yuneva
(bottom row) Markus
Ralser, Sila Ultanir and
Andreas Schaefer
New facilities
Since our quinquennial review we have established several new areas of research at NIMR, and we have set up a number of
Institute-wide technology platforms to make the associated methodologies available to as many of our researchers as possible. The
human embryonic stem cell facility will allow researchers from many disciplines to exploit this exciting and versatile technology; the
new metabolomics platform will support researchers such as Alex Gould, Dimitris Anastasiou, Mariia Yuneva and Markus Ralser, and
it will open the door for many others to contribute to this burgeoning field; and our Biological Computing technology platform will
allow all NIMR researchers to make the most of our excellent high-throughput sequencing facility. Together, these facilities will make
a huge difference to the science done at the Institute, and they will go a long way to encouraging further multi-disciplinary research.
4
Recognition and grants awarded
We were very pleased that Gitta Stockinger and Jean-Paul Vincent were both elected to the Fellowship of the Royal Society this
year. More good news followed as we heard that Iris Salecker was elected as an EMBO member and Alex Gould was elected to the
Academy of Medical Sciences. Pavel Tolar is now an EMBO Young Investigator and Annalisa Pastore was elected to the Academia
Europaea. Tim Bliss, formerly head of the Division of Neurophysiology, was one of the recipients of the 2013 Fondation Ipsen Prize
for Neuronal Plasticity, and earlier in the year Gitta Stockinger was named as the recipient of the 2014 Feldberg Foundation Prize. I
was pleased to be awarded the Waddington Medal of the British Society for Developmental Biology.
Major new funding awards this year included a Wellcome Trust Senior Investigator award for Gitta Stockinger, and a large share of a
Wellcome Trust Strategic Award awarded to Tim Mohun and me, to identify genes essential for mouse development and the origins
of developmental diseases and birth defects in humans. A European training grant for Developmental and Computational Biology is
shared between Mike Gilchrist’s and my own research group.
Anne O’Garra and Iris Salecker led a team that put together an application for an Athena SWAN award, participating in a pilot scheme
in which research institutes such as NIMR could apply for the first time. The award helps ensure that women are properly represented
at all levels in the Institute’s work, and we were very pleased to hear, at the end of last year, that we achieved the equivalent of a
bronze award.
Throughout the year the Medical Research Council has celebrated its centenary. We were pleased to welcome Sir John Savill, MRC
Chief Executive, who talked to staff about the history of the MRC and the part that NIMR, the first MRC institute, has played in that
history. Another talk was given by Harriet Tuckey, about her father Griff Pugh. He was the NIMR physiologist who advised the 1953
Everest expedition and Harriet’s biography of him was published this year. You can read more about the ways that NIMR celebrated
the MRC centenary on pages 32-34.
.
Several members of staff left during 2013. They include Tom Carter, John Doorbar, Richard Goldstein, Malcolm Logan, Elke Ober,
Annalisa Pastore, Andres Ramos and Ben Seddon. I thank them all for their wonderful contributions to NIMR over many years, and
wish them well in their new positions.
Another leaver was Paul Burgoyne, who retired after more than 20 years
at NIMR. A symposium was held in January to mark his contribution to our
knowledge of sex chromosomes, infertility and germ line development. Several
long-serving research support staff also left. These include John Wills (45 years),
Bill Jarra (43 years), Surendra Kotecha (38 years), John McCormick (36 years),
Malcolm Strath (30 years), Barry Ely (32 years) and Treena Carter (26 years).
And finally we were very sorry to learn of the deaths of three former NIMR
group leaders: James Lightbown, John Cornforth and Michael Sargent. Tributes
to them have appeared on our web site and are reprinted on pages 136-138.
Ita Askonas died on 9 Jan 2013 and a tribute to her appeared in last year’s
Annual Report. A symposium in her memory will take place in April 2014. All
three scientists made very important contributions to NIMR and will be greatly
missed. We were also sad to hear of the deaths of Arthur Rogers (Mechanical
Engineering) Gordon Bissett (Neurophysiology), Alan Brownstone (Chemistry),
Betty Higginson (Biochemistry) and Derek Rumley (Engineering).
5
The Francis Crick Institute
This year has seen the Francis Crick Institute really start to take
shape, both with respect to people and with respect to our new
building.
The Crick’s offices at the Wellcome Trust’s Gibbs Building are
becoming ever more crowded as new staff join the project. Alison
Davis has been appointed as head of IT; Nick Carter as Director of
Building Services; Michael Schuitevoerder as Transition Director;
and John Macey as Head of Human Resources. Their teams
have been augmented by many people from the two founding
Institutes, including Ben Kesel and Clive Lunny in IT, Darren
Warrington in Building Services, Neesha Rana and Marna Roos
in HR, and Anna Gibson in Finance and Purchasing. In addition,
Donna Brown works on the PhD programme, and Clare Davy
acts as Education Officer, while Michele Marron contributes her
financial skills.
Meanwhile, Steve Gamblin has taken on the role of Science
Operations Director, and his team includes Simon Caidan and
Jo Payne from NIMR and David Hudson and Nigel Peat from
CRUK’s London Research Institute. These secondments and other
placements offer great opportunities for our colleagues to play
their part in the development of their new Institute.
Photograph of the Francis Crick Institute, January 2014
Image courtesy of Wellcome Images
From the outside, the building now looks like the architects’
computer renditions. The cladding, glazing and roof are almost
complete, and it won’t be long until the Institute is completely
watertight and we can start fitting out the labs. The Crick’s
‘Topping Out’ ceremony, to mark the completion of the shell of
the building, was held on a beautiful day last summer. Paul Nurse
and Chancellor George Osborne were joined by 600 guests from
our partner organisations and the local community, and the
occasion also saw the launch of the Crick’s Scientific Strategy
‘Discovery without Boundaries’.
The Topping Out ceremony held during the summer of 2013
Image courtesy of Wellcome Images
6
One of the important aspects of the Crick’s strategy concerns the
multidisciplinary and collaborative nature of the work to be carried
out, and the Institute is going to great lengths to promote this.
Not only is the building itself designed to encourage interactions
between its scientists, but last year saw a great deal of effort
go into deciding which researcher goes where, maximising
opportunities for interdisciplinary collaborations while ensuring
that scientists are close to the equipment they use most often.
The Institute’s interdisciplinary ethos was encouraged by retreats and awaydays for group leaders and heads of technology
platforms, for postdocs, and for students. These have been very successful in introducing members of the founding institutes to
each other and for making important links with our partners from King’s College London, Imperial College London and UCL. Next
year will see awaydays for other members of staff, organised by NIMR’s Jo Payne and LRI’s Nigel Peat.
To complement these, the Crick has hosted symposia and seminars, again designed to introduce the Crick partners to each other
and to encourage interdisciplinary collaboration.
When I write next year our new building will be all but finished and we’ll be preparing to move in — these are exciting times.
www.crick.ac.uk
The second Crick Symposium
Images courtesy of the Francis Crick Institute
7
Science overview
Research Programmes at NIMR
NIMR is one of the world’s leading medical research institutes. It is dedicated to studying important questions about the life
processes that are relevant to all aspects of health. NIMR is the largest of the Medical Research Council’s institutes and its mission is:
•
•
•
•
to carry out innovative, high-quality, biomedical research
to be a major contributor to the MRC’s commitments in the training of scientists
technology transfer
the presentation of its science to the public
Research at NIMR covers a broad spectrum of basic biomedical science, including infectious diseases, immunology, cell and
developmental biology, neuroscience and structural biology. The world-class facilities for research include biological imaging
resources, the MRC Biomedical NMR Centre and the UK’s largest academic facility for small animal research. There is a major
emphasis on cross-disciplinary interactions, stemming from the pervasive culture of collaboration and strategic recruitment to
complement and bridge scientific areas. There are research collaborations with many other academic and clinical centres in the UK
and internationally, including strong links with University College London.
Scientists at NIMR study normal biological processes and diseases at the molecular, cellular and whole organism level. Research
is focused on four scientific areas: Infections and Immunity, Genetics and Development, Neurosciences and Structural Biology.
Collaborations underpin progress in these areas, e.g. on the structure and function of molecules involved in infectious diseases,
common mechanisms of nervous system and immune system development, and how the functioning of the brain arises during
embryonic development.
The immune system is a key part of the body’s defence against infections. Its importance is illustrated by the effects of a defective
immune system, as seen in people with AIDS, which results in overwhelming infections leading to death. While an effective immune
system is vital for health, an over-exuberant immune system can start to attack the body itself, a process known as autoimmunity.
Autoimmunity is the cause of allergies such as hay fever and more serious conditions such as asthma, rheumatoid arthritis, and
multiple sclerosis. We are analysing how the cells of the immune system are triggered to mount an immune response when faced
with an infectious agent, how the process can go awry in autoimmunity, and how complex checks and balances in the system
ensure activation of the immune system only when needed.
Infectious diseases result from the transmission of pathogenic micro-organisms. Examples studied at NIMR include malaria,
tuberculosis, AIDS and influenza which are responsible for the deaths of millions of people every year. This death toll is exerted
mainly in the poorer countries of the world, and is also a significant and increasing burden for the National Health Service. Our
research seeks to understand the fundamental biology of the causative micro-organisms and their interaction with hosts. We use
this understanding to promote the development of new drugs, vaccines and diagnostic reagents. The study of pathogenic agents is
also a rich source of important information on basic mechanisms of cell and molecular biology.
Structural Biology
In order to increase our basic understanding of human health we need to study the structure and function of biological molecules.
Structural biologists at NIMR use a combination of experimental and theoretical approaches to determine the structure and
dynamics of macromolecules such as proteins and DNA and also small molecules that act as chemical messengers or as fuel
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for cellular processes. Atomic-resolution information is obtained by X-ray crystallography, electron cryo-microscopy and NMR
spectroscopy and this work is complemented by a range of dynamic biophysical and biochemical approaches. Our work cuts across
the vastly different length and time scales that are important in biology. We study the arrangement of individual atoms at protein
binding sites and their behaviour on timescales of picoseconds to nanoseconds; the dynamics of individual molecules and chemical
reactions catalysed by molecular complexes which occur over microseconds to milliseconds; the assembly of viruses and dynamics
of organelles within intact living cells which take many seconds or more. Our work addresses a wide variety of fundamental
scientific questions with applications to human health and it is highly collaborative with other research teams at NIMR and across
the national and international scientific community.
Understanding how a fertilised egg generates a functional organism is an important area of biology that has many implications
for medicine. We are studying the fundamental mechanisms that underlie embryo development, including how cells proliferate,
migrate and communicate, how stem cells form and are maintained, and how diverse cell types are generated, each at the correct
location in the forming organism. A major focus is on identifying the underlying genes, how they function and are regulated, and
their role in networks of molecular and cellular interactions that control developmental processes. These studies include the use
of powerful genome-wide techniques and systems biology approaches in order to uncover gene regulatory networks. As many key
genes that control specific processes are conserved between species, our studies are carried out in a range of model organisms that
have distinct strengths for uncovering mechanisms of normal development and how defects can arise. Since similar processes and
underlying molecular pathways are utilised in the adult, studies of development also reveal the basis of disorders such as cancer in
which the proliferation and migration of cells is abnormal. In addition, elucidation of the normal mechanisms that maintain stem
cells and that direct them to form specific cell types is essential for potential therapeutic use of these cells.
Neurosciences
The nervous system carries out many crucial physiological processes, including the perception of the external environment,
control of movement of the organism, formation of memories, and the hormonal regulation of tissue growth and homeostasis.
Understanding how the nervous system forms and functions is an important challenge in biology with significant implications for
the pathogenesis and diagnosis of neurological diseases and development of therapies. We are studying how neural stem cells are
maintained and differentiate to generate the multitude of neuronal subtypes found in the central and peripheral nervous system.
An important aspect of our work is understanding how neurons migrate to their appropriate destination and how they find their
targets to form functional neuronal circuits during development. We are analysing how the wiring, differentiation, specification and
activity patterns of neurons underlie the processing of sensory information and integrate it to achieve appropriate outputs. Our
work also examines the role of the nervous system and other tissues in energy balance and metabolism. These studies take place
in close collaboration with developmental biologists who are exploring the molecular and cellular basis of organogenesis and body
patterning. We also have fruitful collaborations with clinical colleagues to understand the genetic and developmental processes that
lead to defects in the central and the peripheral nervous system.
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Scientific highlights
Key discoveries made at the Institute during 2013 include examples from each of our four broad areas of research.
Immunology and infectious disease
Pavel Tolar and Justin Molloy have used atomic force
microscopy to show that when B cells encounter a potentially
dangerous particle they give it a tug to test the strength of
binding of the particle to their immune receptors. Particles
that bind strongly are acquired by the B cells and go on
to trigger antibody production. These studies reveal an
unexpected link between mechanical activity and immune
responses, and it is possible that these might be exploited for
vaccine design and for the development of more efficient
antibodies.
Sideview reconstruction of B cell synapses with the PMS or PLB substrates. The
substrates were stained with lipid dye, DiI (red), and loaded with antigen (antiIgκ, green). B220 staining (blue) labels the B cells.
Gitta Stockinger has developed a reporter mouse to identify intestinal Th17 cells even if they have switched off their characteristic
production of IL-17. She has used this to show that Th17 cells in the vicinity of Peyer’s patches induce the development of IgAproducing germinal centre B cells. These play an important role in mucosal host defence in the gut and in maintaining homeostasis.
This work provides evidence that Th17 cells are the crucial subset required for high affinity T cell-dependent IgA production and
reveals a wider range of functions for Th17 cells.
Jean Langhorne, collaborating with the Sanger Institute, has shown that transmission of the malaria parasite Plasmodium via
mosquito bite rather than by injection of infected cells affects disease severity. Comparison of parasites before and after
transmission through the mosquito vector showed that vector transmission regulates the expression of probable variant antigens
in the erythrocytic cycle, modifies the host immune response, and regulates parasite virulence. These findings have profound
implications for malaria research and provide novel targets for the development of vaccines.
Mosquito transmission of P.c. chabaudi AS modifies parasite gene expression in the erythrocytic cycle.
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Structural biology
Steve Gamblin and John McCauley have shown how
structural changes mediate the transmissibility of flu
viruses in humans. Haemagglutinin from a mutated
version of the H5N1 virus subtype that acquired the
ability to be transmissible in ferrets showed a small
increase in affinity for human receptor and a marked
decrease in affinity for avian receptor. The crystal
structure shows that this mutant binds human receptor
like other known human pandemic viruses. An algorithm
was derived that predicts virus avidity without the need
for working with infectious material.
The SAMHD1-CtD/Vpxsm/DCAF1-CtD complex. DCAF1-CtD, is shown in grey surface,
β-propeller blades are numbered. SAMHD1-CtD is red, Vpxsm is blue and a zinc ion
shown as grey sphere.
Comparison of H5 and H2 HA complexes with human receptor.
Ian Taylor, Jonathan Stoye and Kate Bishop have
described how a lentiviral accessory protein uses a normal
cellular process to inactivate the viral defence system.
They showed that the viral accessory protein Vpx wraps
tightly around the DCAF1 molecule, a component of
the cellular degradation machinery, to present a new
molecular surface. These observations have implications
for a new type of HIV-1 therapy using drug molecules to
target the unique molecular interface between the viral
accessory protein and the cellular factor.
Katrin Rittinger, with researchers from Germany, has
discovered how the linear ubiquitin chains that play
an important role in the regulation of immune and
inflammatory responses are synthesized. She solved
the structure of a complex between the LUBAC subunit
HOIP and ubiquitin, and identified a key catalytic residue
within the active site. The study provides important
mechanistic insights into how LUBAC synthesizes
linear polyubiquitin chains, providing an important step
towards a better understanding of this class of enzymes.
The catalytic domain of HOIP (surface representation) is show in
complex with the acceptor (orange) and donor (yellow) ubiquitin.
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Scientific highlights
Neuroscience
Vassilis Pachnis has shown that two planar
cell polarity genes control the growth and
guidance of enteric neuron projections relative
to the main axes of the gut. Genetic ablation
of these genes leads to profound abnormalities
of gastrointestinal motility. This shows that
developmental deficits of the enteric nervous
system contribute to the pathogenesis of
idiopathic intestinal motility disorders.
Distension-evoked motor patterns of control and Celsr3-deficient (Celsr3|Wnt1) colons analysed by
spatiotemporal maps.
Developmental biology
Karine Rizzoti and Robin Lovell Badge have characterised a population of pituitary stem cells in mice, and shown that these cells display
regenerative potential. They used genetic lineage tracing tools to demonstrate that both SOX2 and SOX9-expressing progenitors can
self-renew and give rise to endocrine cells in vivo, in the embryo and in the adult, showing that these cells represent tissue stem cells. This
represents a first step toward the use of pituitary stem cells to modulate endocrine output and treat deficits.
SOX2- and SOX9-Positive progenitors give rise to endocrine cells in the embryo and to SOX2;SOX9-doublepositive putative progenitors in the adult.
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In collaboration with scientists at the Gurdon Institute in Cambridge, Jim Smith and Clara Collart have identified four factors that
become limiting for DNA replication during cleavage stages in the frog embryo. Over-expression of these four DNA replication
factors prolongs the rapid synchronous cell cycles that occur during early embryogenesis. These experiments provide the
mechanistic basis for a hypothesis put forward over thirty years ago.
Top row: normal embryos undergoing cell division. Cells become smaller as development proceeds. Bottom row:
embryos over-expressing the four factors. Cell size at 450 min is smaller in these embryos, indicating that cells
are still undergoing rapid cell divisions.
Jean-Paul Vincent and his colleagues have replaced the
endogenous Drosophila Wnt protein, Wingless, with a version
that is membrane-tethered and cannot spread from cell
to cell. Remarkably, the resulting flies are viable, forming
appendages of nearly the right size, albeit with a delay. This
result might be explained by the ability of cells to ‘remember’
an earlier exposure to Wingless, and it also suggests that cell
proliferation is increased by the spread of Wingless.
References
•
Stieglitz et al Nature 503:422-6 [Rittinger]
•
Rizotti et al Cell Stem Cell 13, 419-423[RLB]
•
Collart et al Science 341:893-6 [Smith]
•
Spence et al Nature 498:228-31 [Langhorne]
•
Natkantski et al, Science 340:1587-90 [Tolar]
•
Xiong et al, Nature, 497:392-6 [Gamblin]
•
Sasselli et al, J Clin Invest 123:1763-72 [Pachnis]
•
Hirota et al, Nature Immunology, 14:372-9 [Stockinger]
•
Schwefel et al, Nature, 505:234-8. [Taylor]
•
Alexandre et al, Nature 505:180-5 [Vincent]
A stable reporter gene system (brown) shows that all the cells of the
wing primordium or their ancestors express Wingless.
13
NIMR history and milestones
1933 Discovery of flu virus
Christopher Andrewes, Patrick
Laidlaw and Wilson Smith first
isolated the human influenza
virus.
Alick Isaacs discovered
interferon, a factor that can
transfer a virus-resistant state
to cells that had not been
infected, and is now used to
treat many infections and
cancers.
1952 Gas
chromatography
1940
1950
completed the first total
synthesis of the
non-aromatic steroids
and identified the
chemical structure of
cholesterol. He received
the Nobel Prize in 1975.
1936 The role of
acetylcholine as a
neurotransmitter
Henry Dale established the
chemical basis of
neurotransmission and the
role of acetylcholine as a
neurotransmitter, receiving
the Nobel Prize for this work
in 1936.
14
1986 Globin locus
control region
Audrey Smith
discovered how to
store biological
material at low
temperature,
pioneering techniques
for the freezing of
sperm, blood, bone
marrow, corneas and
many other tissues.
1960
1951 Steroid
biosynthesis
John Cornforth
John Skehel revealed the structure of
influenza virus proteins involved in the
infection of cells, for which he was
awarded the Louis-Jeantet Prize for
Medicine in 1988. This work opened
new perspectives for the design of
antiviral drugs.
1960s Cryobiology
After receiving the Nobel
Prize in 1950 for his earlier
discovery of partition
chromatography, Archer
Martin joined NIMR and with
A.T James he developed gas
chromatography, a technique
now widely used in
laboratories and the chemical
industry.
1930
1981 Structure of influenza
haemagglutinin
1957 Interferon
1970
1958 Immunoglobulin structure
Rodney Porter was given
the Nobel Prize in 1972
for the discovery of the
structure of immunoglobulins. The work
increased understanding
of the immune system
and led to novel
approaches to diagnosis
and therapy.
1957 Electron capture
detector
James Lovelock developed
the electron capture
detector, which was able to
detect minute amounts of
chemicals. It led to the
detection of key
atmospheric pollutants and
is widely used in gas
chromatography.
Frank Grosveld discovered
regulatory sequences that
govern expression of the
globin gene cluster, and that
confer a copy number
dependent level of
transgenic gene expression.
He was awarded the
Louis-Jeantet Prize for
Medicine in 1991.
1980
1975 DNA methylation
Robin Holliday proposed that DNA
methylation affected gene
expression, and that changes in DNA
methylation might therefore explain
the switching on and off of genes
during development.
1973 Long-term potentiation
Tim Bliss and Terje Lømo
discovered the phenomenon of
synaptic long-term potentiation,
one of the main mechanisms by
which the brain learns and
remembers.
1991 The sex determining
gene
2005 Mouse model of
Down syndrome
Robin Lovell-Badge showed that
the presence of the Sry gene on
the Y chromosome is sufficient to
cause the embryonic gonad to
develop as testis rather than ovary.
He received the Louis-Jeantet
Prize for Medicine in 1995.
Victor Tybulewicz created a
genetically manipulated mouse
that carries almost all of
human chromosome 21. The
resulting strain of mice has
become a valuable tool in
research on Down syndrome.
1993 Mesoderm-inducing
factor
Anne O’Garra discovered a
novel transcriptomic signature
that provides insights into
fundamental pathogenesis of
tuberculosis and has
application to the
development of improved
diagnostic tools.
2006 Discovery of Th17
subset
Jim Smith discovered that
activin is a mesoderm-inducing
factor, opening up
understanding of how signalling
factors control the formation
of tissues during embryo
development.
1990
2010 Transcriptome
signature in human
tuberculosis
Gitta Stockinger defined the
developmental steps that lead
to the Th17 immune response.
Th17 cells are important in the
pathogenesis of many
autoimmune diseases.
2010
2000
1989 Hox gene
colinearity
1999 Eph receptors mediate
cell segregation
Robb Krumlauf showed
that the linear relationship
between the organisation
of Hox genes along the
chromosome and their
expression along the
head-to-tail axis is
conserved in vertebrates.
David Wilkinson uncovered a new
mechanism that maintains the
correct organisation of tissues,
mediated by signalling through Eph
receptors and ephrins.
1996 Discovery of the
anterior organising
centre
Rosa Beddington discovered
a novel signalling centre in the
mouse embryo required for
correct formation of the
head-to-tail axis during
embryonic development.
2007 AMP-activated
protein kinase (AMPK)
structure
Steve Gamblin determined
the structure of the
enzyme that regulates
cellular energy levels, AMPK.
The discovery paves the
way for better treatments
of Type 2 diabetes.
2007 Malaria release
mechanism
Mike Blackman identified an
enzyme that triggers release of the
malaria parasite from infected red
blood cells thereby enabling it to
invade new cells. The enzyme is a
new target for improved
anti-malarial drug design.
15
CAREERS
PhD students
The training of students, at all levels, is integral to NIMR and through the programmes we offer we strive to train biomedical leaders
of the future.
PhD Programme
The NIMR four-year PhD programme has been designed to equip our students
with the scientific and transferable skills required to make them competitive at the
highest level, both nationally and internationally. Fully integrated into the NIMR
PhD programme are medical undergraduate (MB BS) students who join us each
year via the UCL MB PhD programme. All of our students benefit from access to the
state-of-the art facilities and extensive expertise available across the Institute. We
encourage innovation, interdisciplinarity and collaboration and indeed, many of our
PhD students have projects which span multiple research themes, providing them
with an excellent opportunity to broaden their general understanding of science and
practical expertise. As a result of this, our 100 or so students significantly contribute
to the research output of NIMR.
On arrival at NIMR students work closely with their supervisors to develop their
project proposal; they also choose a thesis committee, members of which have
expertise in a range of scientific areas who will advise the student for the duration
of the PhD. To support the development of our students we offer a wide range of
internal training courses ranging from bioinformatics, statistics and microscopy to
ethics, report preparation and presentation skills. We also run a series of careers
seminars and an annual careers round table event, which reflect the broad range of
careers available to PhDs.
Donna Brown
Director of Studies
We encourage a good work-life balance and you’ll find a range of social activities
here including football, fitness classes, squash and badminton, a book club, quizzes and a licensed bar. Our student representatives
(see page 17) organise a number of social events including a Christmas dinner and summer barbecue attended by PhD, Sandwich,
Summer and work experience students. Social activities at NIMR contribute to the spirit of collaboration which pervades science at
the Institute. For those looking for a short commute, we offer onsite accommodation for 12 students.
Exciting times lie ahead. In September 2014 we will launch the new Crick-NIMR PhD Programme, alongside the new Crick-LRI PhD
Programme. Students starting these programmes in 2014 will register at one of the Crick partner universities: Imperial College
London, King’s College London, or University College London; and transfer into the Crick with their research group in 2015 or 2016.
Crick-NIMR students can take advantage of the extensive academic, training and social facilities that the Crick partner universities
provide.
.
16
CAREERS
Student representatives
The 2013 intake of PhD students
The student representatives form integral links between the
student body and various parts of the Institute and the wider
community. They primarily serve the students by making student
opinions heard on a number of key committees within the Institute
including the Ethical, Trade Union and Communication committees
to name but a few. Additionally, representatives aim to inspire a
sense of community amongst the students by organising regular
meetings and social activities. Weekly student seminars expose
students to topics outside of their primary field of interest, and
allow students to receive informal feedback on their presentations,
to ask questions, and to establish potential collaborations with
other Divisions. One of the chief aims of this year’s committee will
be to ease integration of students from other constituent institutes
of the Crick by co-organising social events and importantly, an all
student symposium, which will allow students the opportunity to
present their work in a formal peer environment.
The 2013 student representatives:
Teresa McCabe, Tom Flower and Sophia Davidson
2013 Upgrade Report Prize
Each year the NIMR awards a £1000 Travel Prize for the best
upgrade report and a runner-up prize of a £100 Amazon voucher:
The 2013 prizes were presented by the Director Jim Smith to the
joint winners: Sophia Davidson (Immunoregulation) and Manuela
Hess (Molecular Structure) and the runner up, Jimena Andersen
(Molecular Neurobiology).
Jimena Andersen, Manuela Hess and Sophia Davidson
17
CAREERS
PhD students – in their own words
Ashleigh Johnston
“I’ve just finished the first year of my PhD working in Eva Frickel’s lab. My
project focuses on determining the role of human Guanylate Binding
Proteins (hGBPs) during Toxoplasma gondii infection. NIMR always
appealed to my inner research scientist. It is a renowned institute that
is the birthplace of many breakthroughs - to work here cannot fail to
inspire. When I was offered a position in the Frickel lab, working on such
an interesting topic, I couldn’t be more excited. hGBPs are a family of large
GTPases that are highly upregulated during infection with the intracellular
parasite Toxoplasma gondii. I aim to verify the characteristics of these
proteins during infection, thereby figuring out what role they may be
playing. Over the last year I have been exposed to countless resources,
techniques and experiences - we even climbed Ben Nevis as a lab! I can’t
wait to see what the next three years have in store for me.”
Daniel Snell
“Going into the second year of my PhD with James Turner, I’m looking at
the role of the X-chromosome in embryonic and postnatal growth, using
the mouse as a model organism. This project gives me the opportunity to
work in the exciting field of epigenetics, whilst at the same time having
the potential to translate my findings into increased understanding of
human disease: Turner syndrome affects about 1 in 2000 women, most
of whom have a single X-chromosome (as opposed to the normal two)
and as a result are of short stature and almost invariably infertile. The
translational aspect is of particular relevance as concurrent with being a
PhD student, I’m also a medical student on the UCL MBPhD programme.
Upon completion, I intend both to see patients and at the same time carry
out basic research relevant to those I treat.”
18
CAREERS
Sandwich students and work experience
Sandwich placements
Now, more than ever before, having practical research
experience is essential for a scientific career at any level.
Our sandwich placements provide students with the
opportunity to fully immerse themselves in a research
laboratory for 12 months and work on an independent
research project. Sandwich students also have access to
a wide range of lectures, seminar and training, and thus
fully benefit from all that NIMR has to offer. Many of our
sandwich students go on to do a PhD at NIMR or other
leading research institutions.
Work experience
The 2013 intake of Sandwich students
We encourage students from an early age to take an interest in science. Each year local school students work alongside our
researchers, quite often supervised by PhD students, for periods of up to six weeks (also see Work Experience and Mentoring on
page 33). Many of these students come back as undergraduate, Summer or Sandwich students.
Sarah Caswell
“I chose to do a Sandwich placement in order to get an idea of what working in
biomedical research might be like. NIMR seemed like a perfect place to apply,
due to its fantastic reputation and interesting project proposal. Working as a part
of Molecular Structure has given me invaluable experience and skills, not only
transferable techniques, but an idea of all aspects of how scientific research works.
From NIMR other opportunities have arisen, including experience in Science
Communication through volunteering at The Royal Society Family Fun days and
contributing to Schools Days at the Institute. I enjoyed my year in the lab so
much that I stayed on to do a summer placement project in Ian Taylor’s lab! NIMR
has a very sociable environment with a large student community and fun events
organised regularly. Overall I have gained a great deal whilst at NIMR, it has given
me the understanding of further study that has confirmed my desire to undertake
a PhD.”
19
CAREERS
In addition to its role in the training of PhD students, NIMR is a major centre for further research training and career development.
It attracts researchers from the UK and across the world due to the breadth and quality of the research, and the emphasis on
interactions and cross-disciplinary collaborations. Researchers at all stages of their career benefit from the very active programme
of seminars and internal research meetings, and the availability of courses to acquire key scientific and complementary managerial
skills.
NIMR hosts approximately 220 postdoctoral researchers supported either by MRC core funding or externally funded fellowships.
The core funding promotes careers at the postdoctoral level through three-year positions. In addition to the training and support
offered to postdoctoral researchers by NIMR, the Postdoc Committee is very active arranging seminars, retreats and careers sessions
as well as several social events throughout the year. In 2010 The Scientist ranked NIMR third in the UK among “Best Places to Work
for Postdocs”.
NIMR also has a vital role in providing research training for clinical scientists, and this is an important facilitator of translational
projects and national and international collaborations. NIMR hosts many visiting postdoctoral clinical scientists from the UK and
abroad carrying out research on, for example, infectious diseases and genetic disorders.
The Postdoc Committee
The Postdoc Committee is composed of NIMR postdocs from different divisions. It was created to inform, support and encourage
communication within the postdoc community at NIMR. Importantly, the committee represents the voice of the postdoc
community on a number of institute panels including the Heads of Divisions and the Postdoc Mentoring panels. This enables the
postdoc community to be involved in creating an enjoyable and stimulating working environment. The committee additionally
runs the postdoc website, and organises the postdoc seminar series as well as social events. Together with postdocs from LRI,
the Committee is also responsible for organising the annual Crick postdoc retreat. This year’s retreat will be the third and will aim
to encourage networking and collaboration between postdocs at both institutes in preparation for the move to the Francis Crick
Institute in 2015. In the coming year the Committee aims to continue with current activities and increase communications between
postdocs at NIMR and those at institutions that will also move into the Crick.
The 2013 Postdoc committee: Luigi Martino, Melissa Burke, Robert Moon, Hania Khouri and Hakem Ben Addi.
20
CAREERS
Postdoctoral scientists – in their own words
Melissa Burke, Division of Mycobacterial Research
“Given my PhD is in the host response to parasite infection you won’t be surprised to
know that I have strong interests in the ‘how’ of infectious diseases. I am especially
interested in the host-microbe interactions that influence the outcome of infection.
My postdoc position in Douglas Young’s group allows me to investigate both the
microbe and host side of this equation in the context of tuberculosis. My project forms
part of a collaboration with the University of Pittsburgh, and uses a systems biology
approach to determine how mycobacteria behave at the gene level at different stages
of infection. By improving our understanding of the mycobacteria biology we should
ultimately be able to design new drugs that simultaneously target all stages of the
disease. This would be a huge step forward in the field of tuberculosis research as it
would simplify the current treatment regimes.
Before arriving in the UK a year ago, I knew very little about NIMR. Since then I have
been impressed by the strength, variety and calibre of the science being done here
and the availability of cutting edge technology that will be instrumental in my project.
The collaborative nature and friendliness of the people that work here is outstanding
and has made me feel at home. From spontaneous scientific discussions, to hiking with
the Hill-walking club and socialising in the bar, I am discovering that NIMR is a great
place to work.”
Luigi Martino, Division of Molecular Structure
“In January 2013, I joined Katrin Rittinger’s lab at NIMR as a Career Development
Fellow. My project is centred on the structural characterisation and study of the
interactions of a specific class of Pattern Recognition Receptors, the NOD-like
receptors (NLRs). These macromolecules play important roles in innate immunity,
functioning as danger sensors and initiating inflammatory responses that lead to the
production of specific cytokines.
NLRs activate a number of signalling pathways and their malfunction can result in
chronic inflammation and autoimmune disease. For that reason, it is important to shed
light on their mechanism of function.
The project is very interesting and challenging, but thanks to the vast number of
experts, the friendly environment and the many excellent facilities that NIMR offers,
I am convinced that I will obtain exciting results. The large postdoc community also
represents another key element that makes NIMR a great place. I am very proud to
be part of this research institute and I truly believe that the experience gained here
will help me to step forward in my career.”
21
CAREERS
Programme Leaders
Most Programme Leaders at NIMR are initially recruited on Programme Leader Track positions. This provides core support for a
five-year period, which, following external review, can lead to promotion to an open-ended MRC Programme Leader appointment.
This latter position provides long-term core support, subject to regular scientific review, that enables ambitious research to be
carried out. A number of scientists who have established their reputation at NIMR have gone on to head institutes or university
departments around the world.
Pavel Tolar – Division of Immune Cell Biology – joined NIMR in 2009
“I obtained my medical degree in Prague, Czech Republic and then got interested
in signalling in immune cells and did a PhD in immunology. I then decided to pursue
scientific fame and went to the US for a postdoc at the NIH. I continued working in
immunology and was most enthused by watching signaling processes in live cells. It was
exciting to harness new imaging technology that was emerging at that time to address
biological questions. Certainly for me, this was a very intuitive way of doing experiments.
So when I started to look for a place to start building my own lab, I knew I would benefit
from an environment where there would be enough interdisciplinary collaborations that
would allow me to keep pace with emerging imaging technology.
NIMR seemed like a great choice. I already knew that NIMR had the best group of
immunologists on the continent. I also found out that the Institute had many great
experts in other areas, all within a very collaborative environment. Of the highest interest
to me, here were people that knew how to image things from developing organisms to single molecules. Setting up my own group here
was a revealing experience. I felt welcome and well supported. Administrative and other burdens were almost non-existent. The NIMR
structure gave me complete scientific freedom, yet I was surrounded by excellence that gave my research the inspiration needed to
tackle difficult questions. I hope to make best use of the positive energy here.“
Kathy Niakan - Division of Stem Cell Biology and Developmental Genetics – joined NIMR in 2013
“I was drawn to research as an undergraduate. I always enjoyed developing and testing
my own hypotheses and the possibility of discovering something new. I offered to wash
dishes in a research laboratory and measured the concentration of DNA samples
before being offered my own project. During this work I discovered the gene that
caused a rare blood disorder and became completely hooked on research. During my
PhD at UCLA I first heard of NIMR when I read Rosa Beddington’s seminal papers
on mammalian embryo fate-mapping and the morphogenetic role of extra-embryonic
tissues in embryo patterning, which inspired me to pursue developmental biology. Since
then I have continued to investigate mechanisms of lineage specification in human
embryos and stem cells as a postdoc at Harvard University and a research fellow at
the University of Cambridge.
The outstanding research reputation of NIMR attracted me to apply for a position.
Colleagues throughout NIMR have been extremely supportive and collaborative as I have set up my laboratory. The things I value most
at NIMR are the challenging and creative research atmosphere and access to cutting-edge facilities, which are expertly managed by our
research support staff. Before I arrived I had extremely high expectations of NIMR, which I am pleased to say have been exceeded. I am
very much looking forward to my group continuing to work in the vibrant research environment here.”
22
CAREERS
Anne O’Garra – Division of Immunoregulation – joined NIMR in 2001
“Having obtained my PhD in microbiology at NIMR, I changed fields for
my postdoc to study the role of cytokines on immune function, with
Gerry Klaus, in the Division of Immunology, headed by Ita Askonas. NIMR
turned out to be a great place to do and discuss research. Collaborations
arose easily through discussions, including at the bus-stop, in the
cafeteria or in the bar. In that, NIMR has not changed. To expand my
immunology training I joined the DNAX Research Institute in California, a
hub for cytokine research. I stayed there for 15 years and developed an
independent research programme on cytokine research.
After investigating many positions in Europe, despite the fact that my
long-term partner is a researcher in Paris, I decided to return to the
UK, and to join NIMR. UK provides a fair arena for young researchers
to develop their research career, with funding based on excellence
and not politics. As compared to other institutions around the world,
NIMR presented the most accessible cross-disciplinary institute, where collaborations are recognised positively, allowing paradigmchanging discoveries to be made, in a most collegial environment. Moreover support for scientists at NIMR is immense; animal
research is perfectly supported by the excellent Biological Services Division and all other support staff work hard and proactively to
help our research go forward. It is with all this support and collaboration that I have now successfully extended my programme to
researching the immune response in tuberculosis.”
Andy Oates – Division of Developmental Biology – joined NIMR in 2012
“After being spoilt by nearly ten years as a group leader at the Max
Planck Institute of Molecular Cell Biology and Genetics in Dresden,
I wanted to continue to work in an Institute environment that
offered longer-term funding. I knew of NIMR’s great reputation for
developmental biology and was familiar with the work of James Briscoe
and Jean-Paul Vincent. Their approach to developmental biology – using
quantitative and modeling techniques – is similar to my own way of
working. I was pleased to discover later that other labs here also use
these approaches and we have had some interesting discussions.
NIMR has an established aquatics facility – a big advantage for my
research – and a Confocal Image Analysis Lab (CIAL) that provides
excellent advice and ongoing support. CIAL also has an optics workshop
creating microscopes (e.g. SPIM) tailored to the scientific questions that
I want to answer and enabling me to carry out unique experiments.
At NIMR there is a friendly, village-like atmosphere that encourages
sharing and interactions between people. I also have strong links with
UCL’s engineering and physics departments and look forward to the strengthened interdisciplinary opportunities that the Francis
Crick Institute will offer.”
23
CAREERS
Research support
NIMR offers career opportunities that can be broadly termed research support, covering many different types of jobs. Research
Technicians are located within specific programmes and are directly involved in research. Laboratory Managers look after all the
labs and equipment of one or more Divisions, ensuring that the science runs smoothly. Many individuals are involved in the running
of NIMR’s extensive facilities. The biggest of these, Biological Services, provides a fully integrated laboratory animal and technical
resource to the Institute. Finally, the Institute employs individuals in a range of non-scientific activities, including Divisional
Administrators, Personal Assistants, Human Resources, Accounts, Procurement, Stores and Security.
Neesha Rana – Human Resources Business Partner
“I am currently employed as an HR Business Partner at NIMR.
I have been working in HR for over six years with the last five
years here at NIMR. I started my career as an HR Administrator
working for Skanska, a Swedish construction company that work
on behalf of the National Grid. Within eight months I became
an HR Assistant. I then joined NIMR as an HR Advisor in October
2008. What attracted me to work here is the training and
development opportunity I received. While I was working as an HR
Advisor, I was able to complete my Masters in Human Resource
Management, which helped with my promotion to my current
position (HR Business Partner). I came to work at NIMR because
it gave me the opportunity to work with such a variety of people
and always learning something new which keeps me engaged
and motivated. I love the social activities here at NIMR and the
working environment as it brings the staff together in the true
definition of an Institute.”
Nikolay Nikolov – Head of Biological Computing
“I did my first degree in international economics in Bulgaria
but towards the end of my studies I started a part-time job as a
programmer and stayed in computing ever since. Upon graduation
I worked for a few years as a software engineer in Vienna before
starting a PhD study focusing on database performance - making
queries run faster on large databases. This led me naturally to
a post-doc at the European Bioinformatics Institute (EBI) in
Cambridge where I started as a Marie Curie Fellow in 2005. It
changed my career in an unexpected way. Initially I had the
idea to continue my previous research and work on making EBI’s
massive databases more responsive. Gradually I moved towards
bioinformatics and doing analysis of biological data. EBI generously
co-sponsored me undertaking a masters in Computational Biology
at Cambridge. After EBI I had post-docs at the Department
of Chemistry, University of Cambridge and at the Wellcome
Trust Sanger Institute. I joined NIMR in April 2013 as Head of
Biocomputing. It is a challenging but rewarding opportunity and I
am enjoying it immensely.”
24
CAREERS
Dorota Abucewicz – Research Technician, Division of Immune Cell Biology
“After graduating in Poland I came to England to pursue
my ambitions of working in one of the most prestigious UK
organizations in the field of scientific research. In 2008 I started
at NIMR as an Animal Technician. My main duties were: breeding,
control and maintenance of mouse colonies as well as animal
welfare. During four and a half years of being in this position I
obtained a Home Office Personal Licence, which allowed me
to perform experimental procedures on animals. I was given
the opportunity to gain some experience in sperm and embryo
cryopreservation within the Procedural Services Section and was
promoted to Senior Animal Technician.
Over a year ago I was fortunate to get a position as a Research
Technician where my primary role is to contribute towards our
Down Syndrome project. I share responsibilities of breeding and maintaining our various Down Syndrome mouse colonies with
my colleagues. I provide support for experiments and make sure the lab runs smoothly on a daily basis. I feel that NIMR is a great
place to work because of the wealth of knowledge and experience the staff possess, and it is somewhere I can continually develop
and improve my skills.”
Aomar Ayad – Computing
“After studying Electronics Technology and microcomputing I
worked for five years in telecommunications, in the hotel industry. I
moved to NIMR in 1999 to work as an Animal Technician, pursuing
my interest in working with animals. Two years later I transferred
to the NIMR Computing department, working on the helpdesk
and fielding technical support calls. Because of my background
in telecoms I started to help with some network and telecoms
installation, and later on undertook some troubleshooting and
maintenance work. I was also able to attend a number of IT
Engineering courses to assist my professional development in
telecoms and Networking.
In 2006 I took over responsibility for managing telecoms at the
Institute, including telephones, voicemail plus call Logger systems,
pagers and teleconferencing. I also work closely with a colleague on
managing the NIMR network data centre switches, including Wi-Fi Aerohive, a backup and disaster recovery facility. We cover all
buildings on the NIMR site, including labs, offices and student accommodation. Working as a team we maintain the network and
telecoms infrastructure, including hardware and software, troubleshoot congestion, and gather data to inform future requirements.
NIMR is like a second home for me and I enjoy the multinational environment and the wide range of people and ideas here.”
25
CAREERS
Animal Technicians
NIMR is committed to ensuring a high standard of training and education for Animal Technicians and support staff at all stages of
their careers. Continuous Professional Development (CPD) for Animal Technicians at NIMR includes formal and informal learning,
training and experiences. Competency-based qualifications allow training specific to the individual and their work while Open
University and Institute of Animal Technology qualifications deliver a wide knowledge of laboratory animal science, the 3Rs and a
good background in biological sciences. Technicians are encouraged to spend time in NIMR research labs in order to gain handson experience of experimental procedures, and attend workshops and seminars held on a regular basis on subjects related to
laboratory animal science. Visits to other scientific establishments, symposia and international meetings are also organised which
enable technicians to gain experience in more varied aspects of laboratory animal husbandry and science, ensuring the 3Rs are
embedded in all work involving animals at the Institute.
Daniel Strawbridge - Animal Technician
I have been an Animal Technician for just over a year now. In the past year, I have been
learning on the job, gaining new practical skills and knowledge. Being an Animal Technician
is very hands on, so it is important to have access to Continuing Professional Development
(CPD) and training courses to further enhance my knowledge for the role. The CPD
comes under a variety of formats and the training allows me the chance to become more
competent and refined in the practical tasks. The assignments and workshops provide
invaluable learning so that I can contribute a more professional and motivated approach.
The seminars are useful as well to understand how other departments function and
integrate at NIMR. I am currently working on the Level 2 Animal Technology course and I
know it has made me more confident in the manner that my job is performed. Thus the
animals under my care receive the best level of care and welfare.
Jake Murphy - Animal Technician
I started at NIMR in 2009 as a summer cover animal technician in Laidlaw Green on a zero
hours contract. I trained alongside established techs in basic animal husbandry so that I
could cover the daily practical routine when others were on leave. I was lucky in that at the
end of my 12 week original summer cover period there was an opening for me to remain
for longer. Around Nov 2009 I was successful in my application for a permanent position. I
then embarked upon the probationary training programme as an animal technician which
resulted in me becoming an established member of the Biological Services team in Laidlaw
Green.
Being an animal technician in Laidlaw Green, a genetically altered rodent breeding and
experimental unit, requires an understanding of The Animals (Scientific Procedures)
Act 1986 and mouse breeding along with the more general animal husbandry practical
skills. In 2012 I acquired a Home Office PIL after completing the Home Office Module
1-3 course at the RVC. This has enabled me to continue developing and now I regularly
perform regulated procedures to support the science. In 2012 I also started the MRC
Level 2 award in animal technology which is a work-based qualification involving written
and practical assignments. The assignments are all relevant to what I do daily at work with
some additional research required which has given me a fuller understanding of the role I
carry out. Currently my level 2 qualification is going through a mapping process at the end
of which I hope to also gain an Institute of Animal Technology qualification.
26
TRANSLATIONAL RESEARCH
Support for translation
Eileen Clark
The Medical Research Council (MRC) supports research across
the whole spectrum of medical sciences, with the aim of
improving human health. The MRC’s translational research
strategy aims to increase the scale and speed of progress
from scientific discovery to clinical benefit. Laboratory-based
studies at NIMR underpin this. Discoveries of how molecules,
cells and organs are formed, regulated and function provide
the knowledge that can lead to new therapies and diagnostics.
This ‘intellectual property’ and its translation into products
such as useful novel drugs or vaccines feeds into commercial
projects that can build on this ‘know-how’, and Technology
Transfer facilitates this exploitation.
Some studies are closely aligned to specific human diseases
and this research benefits from close interactions with
clinicians. Productive exchange between basic scientists and
clinicians allows model systems to be used to their greatest
advantage in scientific discovery, and provides insights into
the disease process in patients as well as potential treatments and improved clinical care.
Technology Transfer
NIMR scientists are supported by a local Research Governance and Contracts Office, which provides mechanisms and structure
to allow basic technology transfer activities such as material transfer agreements, collaboration agreements and confidentiality
agreements to be dealt with locally and speedily. The Office is also responsible for raising awareness of intellectual property issues
and encouraging scientists to be alert to potential exploitation opportunities.
MRC Technology (MRCT) is the exclusive technology transfer agent for the Medical Research Council and is responsible for
translating cutting edge scientific discoveries into commercial products. In addition they have small molecule drug discovery
and therapeutic antibody facilities, providing lead stage therapeutic assets to pharmaceutical and biotechnology companies.
MRC Technology adds value to cutting-edge scientific discoveries through strategic patent protection and creative licensing of
intellectual property (IP) or through partnered research with industry. Examples of licensed technology include transgenic mice and
crystal structures. NIMR scientists have a variety of industrial collaborations and also act as consultants to a range of companies.
Since May 2013 NIMR has welcomed Dr Howard Marriage as Translator/Entrepreneur in Residence. Howard has 30 years of bench
to boardroom experience in biotech, pharma and academia. His role is to aid the identification of initial possibilities for translating
discovery research at the Institute into products and services for preventing and treating disease. His role also involves looking
for ways to use research findings to develop commercially viable health solutions which will generate income and benefit the UK
economy.
27
Laboratory research and animal models for human diseases provide insights that can translate into clinical benefit. Pathogens
continue to blight human health and our research on infectious diseases such as HIV, tuberculosis (TB) and malaria benefits from
and informs clinical practice worldwide.
Psoriasis
Environmental stimuli contribute to
immune-mediated skin inflammatory
diseases including psoriasis, but the
mechanisms are largely unknown.
Gitta Stockinger’s lab studies the aryl
hydrocarbon receptor (AhR), a transcription
factor that senses these stimuli, to
investigate its involvement in psoriasis.
Studies on skin biopsies show AhRactivating ligands reduce inflammation in
the lesions of psoriasis patients, whereas
AhR antagonists increase inflammation.
Similarly, AhR signalling via the FICZ ligand
reduced the inflammatory response in
a) AhR deficiency exacerbates mouse model of psoriasis. Histological sections of skin from Ahr +/- and AhR
the imiquimod-induced mouse model of
-/- mice treated with imiquimod (IMQ) for 5 days. The plots show epidermis and scale (stratum corneum)
psoriasis and AhR-deficient mice exhibited
thickness during the course of IMQ treatment. b) Assessment of AhR involvement in human psoriasis.
Biopsies were quartered, subjected overnight to the treatments listed, or left untreated, and then used for
substantial exacerbation of the disease,
RNA deep-sequencing.
compared to AhR sufficient controls.
Non-haematopoietic cells, in particular keratinocytes, are responsible for the hyper-inflammatory response, which involves increased
reactivity to IL-1β and upregulation of AP-1 family transcription factors. The data suggest a critical role for AhR in the regulation of
inflammatory responses and raise the possibility of novel therapeutic strategies in chronic inflammatory disorders.
Irreversible intestinal failure
Irreversible intestinal failure (IF) due
to anatomical or functional loss is a
devastating condition associated with
significant morbidity and mortality.
Although parenteral nutrition (PN)
services have improved IF over the
last decade, patients can suffer
complications of PN. Such patients may
be referred for intestinal transplantation,
but many die before transplantation is
Intestinal tissue engineering model. Decellularisation of rat small intestine with detergent-enzymatic
treatment: macroscopic images prior (A) and following (B) one cycle of decellularisation. (C) “Mini-gut”
available. Recent advances in stem cell
intestinal organoid culture in vitro.
biology have opened up intestinal tissue
engineering (ITE) to provide alternatives to current treatments; the goal is to engineer intestinal constructs for use in regenerative
medicine such as orthotopic transplantation and drug testing. Vivian Li’s lab in collaboration with Paolo de Coppi at UCL aims to
develop a novel ITE technique, combining a decellularised intestinal scaffold with an organoid culture protocol to create a robust
intestinal graft with structural and functional competence.
28
New drugs for TB and malaria
How an antibiotic works and can we improve it?
D-cycloserine (DCS) is an antibiotic used solely to treat human tuberculosis, and a cornerstone drug to treat multi-drug resistant
strains. Due to the importance of DCS and its potential as a starting point for future drug discovery programs, its mechanism-ofaction against Mycobacterium tuberculosis was studied for the first time in detail in Luiz de Carvalho’s lab.The results establish that
DCS inhibition of D-Ala:D-Ala ligase (Ddl) is the most important site of action in M. tuberculosis. DCS only binds to one of the two
putative D-Ala binding sites in Ddl and its inhibition is time-dependent. These results provide a blueprint of how DCS works and
indicate a rational path for the design of improved analogues for the treatment of TB, currently underway in the laboratory.
A, the structure of the antibiotic DCS. B, the newly discovered inhibitory mechanism for DCS against Mt Ddl. C, slow-onset (time-dependent)
inhibition kinetics caused by DCS.
A new target to inhibit multiplication of the malaria parasite
N-myristoylation allows proteins to interact with membranes and inhibition of N-myristoyl transferase (NMT) can interfere with
many biological processes. As part of a consortium with colleagues at Imperial College and the Universities of York and Nottingham,
Tony Holder’s group has shown that NMT inhibitors block parasite replication in the red blood cell, providing the basis for
development of antimalarial drugs against this new target.
in the absence of NMT inhibitor 20-30 nuclei (blue) are formed and the reporter protein
is in the membrane (M) fraction; in the presence of drug parasite development is
stopped at ~6 nuclei and the reporter protein is largely in the soluble (S) fraction.
29
Tuberculosis and HIV-TB interactions
HIV-1 tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) is an immune complication of antiretroviral therapy.
It has greatly increased in prevalence in the last decade, resulting from high tuberculosis rates and widespread availability of
antiretroviral therapy. Mortality from this iatrogenic condition is estimated at 3%, but prior to work in Rob Wilkinson’s group the
syndrome was poorly defined and management guidelines anecdotal. They have produced the widely accepted and implemented
case definition and conducted the only randomised controlled trial to date to treat this condition. The results are incorporated in
international guidelines.
Translation of disease biomarkers of active TB into a robust and affordable point-of-care format is important for recognition,
treatment monitoring, and control. Anne O’Garra and collaborators described a transcriptional signature in the blood of active
TB patients that correlates with the extent of lung disease. With collaborators from South Africa (the Wilkinson group), London
(Imperial College and Royal Free Hospital, UCL), Oxford and France, she has shown that this signature is distinct from that of
patients with other lung diseases such as pneumonias and lung cancer and sarcoidosis. Distinguishing TB from these other diseases
will accelerate treatment, allow effective early treatment monitoring to prevent worsening disease, and reduce further transmission
and development of drug resistance.
The Head nurse at the antiretroviral clinic where Rob Wilkinson’s work is carried out, on the occasion
of the 10th anniversary of the availability of antiretroviral therapy. This therapy has had a massive
impact on the lives of HIV-infected persons with tuberculosis but a medical complication that can
arise is excessive inflammation due paradoxically to the improving immune response.
30
PUBLIC OUTREACH
Public engagement
It has been an eventful year for outreach at NIMR. The celebration of the MRC centenary presented an ideal opportunity to expand
and develop the scope of our public engagement, with thousands of people now benefiting from the chance to take part in NIMR
events.
NIMR Essay and Poster competitions
Now in its eleventh year, our essay competition for secondary
school students received 74 entries from 22 schools. The winning
essayists wrote on the topics of ‘cell reprogramming’ and ‘bird
flu mutations’. The winners spent a day at NIMR, chatting with
some of the scientists involved in research related to their essays,
and seeing how modern medical research is carried out. This year
saw the introduction of a competition aimed at primary schools,
in which we asked children aged 7 to 11 to design a poster
highlighting the contributions of women to science.
NIMR online and in the media
Women in science was also the theme of a Wikipedia edit-a-thon held at NIMR in July. Staff received training in editing pages of
Wikipedia and successfully created and enhanced the profile of women scientists in Wikipedia.
Frequently our scientists have been on hand to provide expert comment to the media, and the Institute’s flu research featured in a
special short report for BBC News. News highlights about NIMR research feature on the institute’s external website.
31
PUBLIC OUTREACH
Public engagement
Visitors get a chance to experience the science at NIMR
NIMR Open Day
This year NIMR opened its doors to give local residents and community groups a real behind the scenes experience. The 300
visitors enjoyed a series of talks, a chance to do hands-on science experiments and a tour of some of the Institute’s labs and the
library. The event concluded with the cutting of a birthday cake to mark the MRC’s 100th year.
Highlights from NIMR’s Open Day event
celebrating the MRC centenary.
32
PUBLIC OUTREACH
Schools’ Days
The annual NIMR schools’ days in February were as popular as ever, with 357 students from over twenty local schools visiting the
Institute to listen to lectures and interact with demonstrations of NIMR science. The students asked insightful questions, and were
also able to discuss career opportunities in medical research.
Work experience and mentoring
NIMR provides a wide range of work experience opportunities, and our staff are also involved in social mobility mentoring schemes
run by external organizations. From research placements in the labs, to time spent with our engineering or graphics departments,
NIMR is keen to support the career development of local young people. The prestigious Nuffield awards went to four Year 12
students, who were selected this year to spend a month working on research projects in our labs. The students gained an insight
into modern research, and produced reports and posters to demonstrate what they had achieved. A further thirteen young
people did work experience placements in our Biological & Procedural Services department, learning about the production and
maintenance of genetically altered animals, and helping out with husbandry.
2013 saw the unexpected death of Dr Michael Sargent, who had been such a driving force behind outreach at NIMR. Many
of the projects above were initiated by him, including the essay competition, for which we will in future be awarding the
‘Michael Sargent Prize”.
33
PUBLIC OUTREACH
Public engagement
Lectures
This year marked the 60th anniversary of Edmund Hillary’s ascent on Everest. We were lucky to host a lecture by Harriet Tuckey, on
her father, former NIMR scientist Dr Griffith Pugh, and his role in the expedition.
NIMR scientists get out and about
As always our scientists have been busy out in the community.
MRC centenary events
As well as our popular open day, we marked the MRC centenary with a number of other occasions and projects. We have been keen
to encourage our staff to take part in these events and we have been able to provide them with training opportunities to develop
their outreach skills. Some of the scientists who took up this offer were to be found entertaining the shoppers of North Finchley in
June, using their “science busking” skills to engage people with NIMR science. Another of our scientists featured in the MRC’s “Strictly
Science” exhibition at Imperial College, where visitors were invited to explore past and current medical research, and speculate on
the future of science.
Science Busking (Left). The 100 Years, 100 Scientists, 100 Schools project (left to right) Observing yeast cells on a microscope; Dressing up as water molecules;
Experimenting with DNA gels.
100 Years, 100 Scientists, 100 Schools
One of our largest projects to celebrate 100 years of the MRC aimed to have 100 of our NIMR scientists taking part in science
activities with young people from 100 different schools in 2013. From a short walk across the road to St Vincents Primary in Mill Hill,
to visiting the Linz International School in Austria, we have been taking exciting, hands-on experiments and demonstrations out to
inspire the next generation. For older classes we have provided lectures on a range of topics, including flu and ‘the use of animals in
research’.
Looking forward to the Crick
In anticipation of joining the Francis Crick Institute in 2015, we have been busy with some of the other Crick partners to assist
in establishing the education and outreach programmes at the Crick. Several of our staff are collaborating with local teachers to
develop workshops aimed at secondary school children, and a fantastic ‘scientific research’ comic booklet aimed at 7-11 year olds,
was produced with the guidance of one of our scientists.
34
PUBLIC OUTREACH
NIMRart
a
NIMRart is an experimental and innovative arts programme creating opportunities for artists to make and think about art in a
non-art context. A series of residencies set up in collaboration with the Arts Council and coupled with short visits, talks, exhibitions
and publications has produced an ever-changing platform for ideas and creativity. By actively encouraging artists to engage with
scientists and other staff at the Institute an increased consideration and comprehension of the work of both the artists and
scientists involved has been achieved.
NIMR also subscribes to the Arts Council Collection’s Long Loan Scheme, allowing opportunities to exhibit works by famous and
established artists in our common public areas. This complements the examples obtained from the NIMRart programme and our
own rolling exhibition displayed in the corridors and stairwells of images taken from current scientific projects.
Loans from the Arts Council Collection include Eduardo Paolozzi, Caprese, bronze 1975. We also hosted an art project based on visual research material by
Carolien Stikker and Thomas Elshuis entitled (E)MERGE.
Mill Hill Essays
Since 1995, NIMR has produced an annual booklet of essays to increase public awareness of topical scientific issues. Written by
members of staff, each booklet includes a range of topics, ranging from emerging infections, to stem cells and cloning. They are
given to visitors and distributed to local schools and other organisations.
PDF versions of all the published Mill Hill Essays can be accessed at: http://www.nimr.mrc.ac.uk/mill-hill-essays
35
Immune Cell Biology
Immunoregulation
Molecular Immunology
Mycobacterial Research
Parasitology
Victor Tybulewicz (Head of Division)
Steve Ley
Benedict Seddon
Pavel Tolar
Anne O’Garra (Head of Division)
George Kassiotis
Andreas Wack
Gitta Stockinger (Head of Division)
Venizelos Papayannopoulos
Mark Wilson
Douglas Young (Head of Division)
Maximiliano Gutierrez
Robert Wilkinson
Tony Holder (Head of Division)
Michael Blackman
Eva Frickel
Jean Langhorne
Virology
36
Jonathan Stoye (Head of Division)
Kate Bishop
John Doorbar
John McCauley
WHO Collaborating Centre for Reference and Research on Influenza (WIC)
INFECTIONS AND IMMUNITY
Virology
Kate Bishop
Infection and replication of retroviruses
Lab members: Virginie Boucherit, Ophelie Cosnefroy, Harriet Groom, Darren Wight
Retroviruses cause severe diseases, including immunodeficiency
and cancer. The human immunodeficiency virus (HIV) is the
most widely known retrovirus due to its impact on human
health. The latest figures report that 33 million people globally
are living with HIV/AIDS. A better understanding of the
poorly defined early stages of retroviral infection would aid
development of novel antiviral therapies for retroviral diseases,
enhance the design of retroviral gene therapy vectors and help
to improve models of disease. The three main projects in my
laboratory investigate various aspects of these early steps.
The p12 protein of murine leukaemia virus (MLV) has an
unknown but essential function early in retroviral replication.
Viruses carrying mutations in p12 can reverse transcribe
their genomes but cannot integrate this nascent DNA. Using
mutagenesis studies, we have mapped two domains in p12 that
act in concert and can behave in a dominant negative manner.
We have purified p12 and shown that it does not self associate
in solution. We are now using a variety of biochemical and
virological techniques to identify p12-interacting factors and
characterise the mechanism of p12 function. In addition, we
are using microscopy to visualise p12 localisation during viral
replication.
Publications
Wight DJ, Boucherit VC, Nader M, Allen DJ, Taylor IA and Bishop KN (2012)
The gammaretroviral p12 protein has multiple domains that function during the early stages of
replication.
Retrovirology 9:83
Groom HCT and Bishop KN (2012)
The tale of xenotropic murine leukemia virus-related virus.
Journal of General Virology 93:915-924
Groom HCT, Yap MW, Galão RP, Neil SJD and Bishop KN (2010)
Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral restriction factors.
Proceedings of the National Academy of Sciences, USA 107:5166-5171
Model for the function of p12 during the early stages of MLV replication.
(A) Normally, infection results in integration of viral DNA into host chromatin.
(B) Defects in the N-terminal domain of p12, E-A, affect the stability of the viral
core and abort infection very early in the replication pathway. (C) Alterations
to the C-terminal domain of p12, E-B, prevent p12 from tethering the preintegration complex to host chromatin, inhibiting integration.
37
Parasitology
Mike Blackman
Proteases in host cell exit and invasion by the malaria parasite
Lab members: Fiona Hackett, Chrislaine Withers-Martinez, Christine Collins, Catherine Suarez, Ser Ying Tan, Maria Penzo, Sujaan
Das, James Thomas, Robert Moon, Christiaan van Ooij, Ross Hill.
Malaria causes immense suffering, killing at least one million people each year. There
is no malaria vaccine, and resistance against mainstay antimalarial drugs is widespread.
We need to find new ways to treat and control this devastating disease. Malaria is
caused by several species of a single-celled parasite, which divides within red blood
cells. These then rupture, releasing a fresh wave of parasites to invade new red cells.
Our work focuses on how the parasite invades and escapes from its host cell, in
anticipation that an understanding of this will aid the development of new antimalarial
drugs and a vaccine.
We have a particular interest in a family of enzymes that regulate parasite release
from the red blood cell. We recently discovered that the activity of one of these
parasite enzymes, called SUB1, is triggered by a cyclic GMP-dependent protein kinase
called PKG, raising the possibility of targeting this kinase to block parasite escape. We
are investigating the function and regulation of these enzymes, and searching for
inhibitory compounds with potential to be developed as antimalarial drugs. We are
also studying a recently identified new malarial pathogen called Plasmodium knowlesi,
which causes severe malaria in parts of SE Asia.
Publications
Collins CR, Hackett F, Strath M, Penzo M, Withers-Martinez
C, Baker DA and Blackman MJ (2013)
Malaria parasite cGMP-dependent protein kinase regulates
blood stage merozoite secretory organelle discharge and
egress.
PLOS Pathogens 9:e1003344
Moon RW, Hall J, Rangkuti F, Ho YS, Almond N, Mitchell GH,
Pain A, Holder AA and Blackman MJ (2012)
Adaptation of the genetically tractable malaria pathogen
Plasmodium knowlesi to continuous culture in human
erythrocytes.
Proceedings of the National Academy of Sciences, USA
110:531-536
Ruecker A, Shea M, Hackett F, Suarez C, Hirst EMA,
Milutinovic K, Withers-Martinez C and Blackman MJ (2012)
Proteolytic activation of the essential parasitophorous
vacuole cysteine protease SERA6 accompanies malaria
parasite egress from its host erythrocyte.
Journal of Biological Chemistry 287:37949-37963
See references 23, 51, 55, 56, 73, 89, 231, 248 in the
bibliography at the back for publications from this group in
2013.
38
X-ray crystal structure of Plasmodium falciparum SUB1 (grey) with its bound prodomain (brown).
Disulphide bonds are shown in yellow, whilst bound calcium ions are in blue.
Mycobacterium tuberculosis systems and chemical biology
Lab members: Peter Craggs, Cesira De Chiara, Debbie M. Hunt, Hania Khoury, Gérald Larrouy-Maumus, João Pedro S. Pisco, Gareth
A. Prosser
The recent dissemination of strains of Mycobacterium
tuberculosis (Mtb) resistant to multiple drugs constitutes
a major health threat. Mankind might soon face the first
epidemic of untreatable tuberculosis. Multidrug resistance
arises and is selected for due to the unique biology of
Mtb, its extreme adaptation to the host, and because
existing therapies are inadequate. Past mycobacterial and
anti-mycobacterial research programmes have clearly not
been sufficiently effective at providing novel effective
therapies that could reverse this trend. Innovative
approaches and technologies are urgently needed to
avoid a global health catastrophe.
Our work has demonstrated that biochemistry and bioanalytical chemistry can lead to better understanding of
phenotypes and targets, and can assist the rational design
and study of novel antibacterial agents. We discovered
a previously unknown glycerol phosphate phosphatase,
which participates in a previously unmapped lipid polar
head catabolic pathway in M. tuberculosis. Genetic and
metabolomic studies led to the discovery of a previously
unknown aspartate transporter, which is important for
nitrogen uptake during infection. We studied in detail
the mechanism-of-action of the antibiotic D-cycloserine
at the molecular and cellular levels, paving the way for
development of improved antibiotics.
Publications
Gouzy A, Larrouy-Maumus G, Wu T-D, Peixoto A, Levillain F, Lugo-Villarino G, Gerquin-Kern J-L, de
Carvalho LPS, Poquet Y and Neyrolles O (2013)
Mycobacterium tuberculosis nitrogen assimilation and host colonization require aspartate.
Nature Chemical Biology 9:674-676
Larrouy-Maumus G, Biswas T, Hunt DM, Kelly G, Tsodikov OV and de Carvalho LPS (2013)
Discovery of a glycerol 3-phosphate phosphatase reveals glycerophospholipid polar head recycling
in Mycobacterium tuberculosis.
Prosser GA and de Carvalho LPS (2013)
Reinterpreting the mechanism of inhibition of Mycobacterium tuberculosis D-alanine:D-alanine
ligase by D-cycloserine.
Biochemistry 52:7145-7149
See reference 102, 139, 140, 149, 195, 196, 197 in the bibliography at the back for publications
from this group in 2013.
Metabolomic approaches to functional genomics. (A) Selection of an orphan enzyme. (B) Metabolomic profiling identifies potential
substrates and products. (C) Enzymatic and crystallographic confirmation of the reaction identified.
39
Virology
John Doorbar
Human papillomavirus biology and disease
Lab members: Heather Griffin, Nagayasu Egawa, Zhonglin Wu, Emilio Pagliarulo
Human papillomaviruses (HPV) cause a range of significant
human diseases, including laryngeal papillomatosis, genital
warts and cervical neoplasia. Certain HPV types, known as highrisk types, cause cervical lesions that can progress to cancer.
Cervical cancer is a major female cancer worldwide and is
almost always caused by HPV. These viruses can also cause a
significant proportion of head and neck tumours and have been
implicated in the development of some non-melanoma skin
cancers. How the body controls infection is poorly understood
and currently there is no antiviral therapy that can reliably clear
infection.
Publications
Maglennon GA, McIntosh PB and Doorbar J (2014)
Immunosuppression facilitates the reactivation of latent
papillomavirus infections.
Journal of Virology 88:710-716
Doorbar J (2013)
The E4 protein; structure, function and patterns of
expression.
Virology 445:80-98
Our research aims to understand how the cellular environment
regulates the papillomavirus life cycle during lesion formation,
neoplastic progression and lesion regression, and is focusing
in particular on the nature of the initially infected cell and
subsequent disease outcome. We are particularly interested in
why HPV-associated cancers are largely restricted to certain
body sites, such as the cervical and anal transformation zone
and the oropharynx. An important offshoot of understanding
disease at this level is the development of diagnostic
methodologies and an understanding of viral latency and
reactivation. We are also looking at transmission and infectivity
and the role of E4 amyloid fibres in optimising this process.
Griffin H, Wu Z, Marnane R, Dewar V, Molijn A, Quint W, Van
Hoof C, Struyf F, Colau B, Jenkins D and Doorbar J (2012)
E4 antibodies facilitate detection and type-assignment of
active HPV infection in cervical disease.
PLOS ONE 7:e49974
See references 28, 78, 79, 116 in the bibliography at the back for
publications from this group in 2013.
40
There are >200 human papillomaviruses, with the most
studied coming from the high-risk Alpha genera that
cause cervical cancer (pink). Many Beta and Gamma
types have only recently been identified.
E4 inclusion granule (large arrow) stained with
a gold-conjugated antibody (small arrows) in
an infected skin cell. The E4 inclusion granule
is surrounded by HPV particles, which form
regular arrays.
Parasitology
Eva Frickel
A new perspective on anti-Toxoplasma gondii immunity
Lab members: Barbara Clough, Clémence Foltz, Ashleigh Johnston, Anna Napolitano, Anna Sanecka-Duin, Nagisa Yoshida
The protozoan parasite Toxoplasma gondii infects a broad range of hosts, with a
seroprevalence in man of 30%. Toxoplasma maintains an intricate balance between its
own survival and host defence to achieve chronicity. IFNγ, the main cytokine responsible
for its control, activates cells to restrict or kill intracellular parasites. Cell-mediated
immunity, driven mostly by CD8 T cells, confers resistance to the chronic phase of
infection. The outcome of an infection with Toxoplasma is determined by the host’s
immune status and by the genotype of the infecting strain. Pathogenesis results from
parasite burden and an over-stimulation of the immune system.
Our long-term goal is to identify novel pathways and mechanisms of host resistance
to Toxoplasma. We are studying how the parasitophorous vacuole (PV) is remodelled
within host cells to limit parasite replication, as well as how Toxoplasma manipulates
the immune system to mount an efficient, but not detrimental CD8 T cell response.
We are specifically interested in the functional consequences of vacuolar recognition
by IFNγ-upregulated p65 GTPases (GBPs), a yet understudied class of regulatory
proteins. Additionally, we are defining the requirements for recognition and functional
consequences of Toxoplasma antigen-specific CD8 T cells in the chronic phase of
infection.
Adoptive transfer of transnuclear (TN) CD8 T cells specific for Toxoplasma
peptide Gra6 can protect mice from parasite burden. Gra6 TN CD8 mice can
control Toxoplasma infection.
Publications
Niedelman W, Sprokholt JK, Clough B, Frickel E-M and Saeij JPJ (2013)
Cell death of interferon-gamma stimulated human fibroblasts upon Toxoplasma gondii infection
induces early parasite egress and limits parasite replication.
Infection and Immunity 81: 4341-4349
A) GBP1 and an E3 Ubiquitin Ligase at a Toxoplasma vacuole in a mouse cell. B)
Virulent (top) and avirulent (bottom) Toxoplasma can escape IFNγ-stimulated
human cells followed by cell death.
Winter SV, Niedelman W, Jensen KD, Rosowski EE, Julien L, Spooner E, Caradonna K, Burleigh BA, Saeij
JPJ, Ploegh HL and Frickel E-M (2011)
Determinants of GBP recruitment to Toxoplasma gondii vacuoles and the parasitic factors that
control it.
PLOS ONE 6:e24434
Kirak O, Frickel E-M, Grotenbreg GM, Suh H, Jaenisch R and Ploegh HL (2010)
Transnuclear mice with predefined T cell receptor specificities against Toxoplasma gondii obtained
via SCNT.
Science 328:243-248
See reference 106, 170 in the bibliography at the back for publications from this group in 2013.
41
Cell biology of Mycobacterium tuberculosis infection
Lab members : Sophie Borel, Steve Coade, Thomas Lerner, Laura Schnettger, Elliott Bernard
To live within eukaryotic cells, M. tuberculosis has developed
through evolution an impressive set of molecular tools. Many
clinical manifestations and problems during treatment of
tuberculosis are a direct consequence of a population of
intracellular bacilli. Although in vitro and in vivo studies have
shed light on some aspects of tuberculosis pathogenesis, we still
do not completely understand how M. tuberculosis manages
to survive in eukaryotic cells. We believe that a detailed
understanding of host-mycobacteria interactions will provide
insights not only into the mechanisms usurped by mycobacteria
to survive, but also into basic aspects of cellular functions and in
the innate immune system.
Endothelial cells
infected with
Mycobacterium
tuberculosis expressing
GFP. Actin cytoskeleton
is shown in red and
nucleus in blue. (Photo:
Tom Lerner)
Research in our group focuses on the mechanisms whereby M.
tuberculosis manipulates phagosome maturation and avoids
killing by macrophages and non-phagocytic cells. Towards this
goal, we study the intracellular transport of M. tuberculosis
in macrophages, epithelial and endothelial cells using live cell
imaging combined with single cell analysis. We have identified
novel factors involved in vesicular trafficking and protein sorting,
particularly phago-lysosome fusion, during infection. These
proteins are promising candidates for being involved in the
lysosomal-mediated killing of M. tuberculosis, as well as in the
molecular events linking innate and adaptive immune responses.
Publications
Gutierrez MG (2013)
Functional role(s) of phagosomal Rab GTPases.
Small GTPases 4: 148-158
Kasmapour B, Cai L and Gutierrez MG (2013)
Spatial distribution of phagolysosomes is independent of the regulation of lysosome position by
Rab34.
International Journal of Biochemistry & Cell Biology 45:2057-2065
Kasmapour B, Gronow A, Bleck CKE, Hong W and Gutierrez MG (2012)
Size-dependent mechanism of cargo sorting during lysosome-phagosome fusion is controlled by
Rab34.
42
M. tuberculosis in phagosomes positive for the late endosomal glycoprotein
LAMP-2 (shown in red). Bacteria are shown in green and nucleus in blue
(Photo Tom Lerner)
See references 104, 127 in the bibliography at the back for publications from this group in 2013.
Parasitology
Tony Holder
Malaria parasites and red blood cells
Lab members: Samuel Abah, Muni Grainger, Judith Green, Ellen Knuepfer, Robert Moon, Sola Ogun, Kaveri Rangachari, Shigeharu
Sato
Malaria is caused by a parasitic protozoan that invades red
blood cells, where it develops and multiplies before bursting
out and invading fresh red cells. This cycle is responsible
for the disease. Understanding the interaction between the
parasite and the host immune system contributes to the
development of a malaria vaccine. The identification of new
targets for drugs to kill the parasite and interrupt the cycle
of multiplication offers the potential of new therapeutic
interventions.
In one area of research, we have focused on N-myristoyl
transferase (NMT), an enzyme that adds a C14-fatty acid to
the N-terminal glycine of its protein substrates. Myristoylation
allows these proteins to interact with membranes. In addition
to substrates that are ubiquitous in eukaryotic cells, there are
many that are unique to the biology of Apicomplexa, protists
that include malaria parasites. These organisms have a surface
pellicle comprised of the plasma membrane and flattened
vesicles that form the inner membrane complex. Several
proteins that are essential for formation and function of the
pellicle are N-myristoylated. We study NMT as a potential drug
target in malaria and to understand its importance in parasite
cell biology.
Publications
Wright MH, Clough B, Rackham MD, Rangachari K, Brannigan JA, Grainger M, Moss DK, Bottrill AR,
Heal WP, Broncel M, Serwa RA, Brady D, Mann DJ, Leatherbarrow RJ, Tewari R, Wilkinson AJ, Holder
AA and Tate EW (2014)
Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical
biology approach.
Nature Chemistry 6:112-21
Knuepfer E, Suleyman O, Dluzewski AR, Straschil U, O’Keeffe AH, Ogun SA, Green JL, Grainger M,
Tewari R and Holder AA (2013)
RON12, a novel Plasmodium-specific rhoptry neck protein important for parasite proliferation.
Cellular Microbiology Epub ahead of print. doi: 10.1111/cmi.12181.
Moon RW, Hall J, Rangkuti F, Ho YS, Almond N, Mitchell GH, Pain A, Holder AA and Blackman MJ
(2012)
Adaptation of the genetically tractable malaria pathogen Plasmodium knowlesi to continuous
culture in human erythrocytes.
Tracking the formation of the inner membrane complex (IMC, in green), a
cytoskeletal structure that delineates individual developing merozoites ~42
hours after erythrocyte invasion. [Nuclei are blue.]
See references 122, 49, 65, 82, 84, 111, 121, 132, 134, 138, 144, 188, 192, 194, 198, 216 in the
bibliography at the back for publications from this group in 2013.
43
Immunoregulation
George Kassiotis
Antiviral immunity
Lab members: Urszula Eksmond, Micol Ferro, Bettina Mavrommatis, Julia Merkenschlager, Georgina Thorborn,
George Young (jointly with Jonathan Stoye)
Infectious diseases cause a quarter of all deaths worldwide and 1 in 5 cancers.
Certain viruses cause acute infections in humans, which can be rapidly fatal within
days, for example influenza A and smallpox viruses. In contrast, other viruses are able
to persist chronically in infected individuals, despite induction of an immune reaction
(e.g. HIV, hepatitis and herpes viruses). Almost all humans are chronically infected by
one or more persistent viruses. Our understanding of the pathogenic processes of
viral infection remains incomplete.
In addition to facing a multiplicity of infection with exogenous viruses, all mammals,
including humans, have a long-standing symbiotic relationship with a considerable
number of microbial species, such as the microbiota, and endogenous retroviruses
(ERVs). Recent evidence suggests that ERVs and other transposable elements actively
shape gene transcriptional networks, responsible for cell identity. These networks
can be responsive to environmental factors, exemplified by the response of immune
cells to infection. Correspondingly, ERV activity is also responsive to external factors,
providing a potential link with disease development.
Publications
Duley AK, Ploquin MJ-Y, Eksmond U, Ammann CG, Messer RJ,
Myers L, Hasenkrug KJ and Kassiotis G (2012)
Negative impact of IFN-γ on early host immune responses to
retroviral infection.
Journal of Immunology 189:2521-2529
Young GR, Eksmond U, Salcedo R, Alexopoulou L, Stoye JP and
Kassiotis G (2012)
Resurrection of endogenous retroviruses in antibody-deficient
mice.
Nature 491:774–778
Young GR, Ploquin MJ, Eksmond U, Wadwa M, Stoye JP and
Kassiotis G (2012)
Negative selection by an endogenous retrovirus promotes a
higher-avidity CD4+ T cell response to retroviral infection.
Heatmap of ERV expression induced by either the nucleoside analogue BrdU or the bacterial constituent
LPS in murine dendritic cells. Columns are independent samples and rows ERV-specific probes.
44
See references 154, 163, 269 in the bibliography at the back for
Parasitology
Jean Langhorne
Immunity and immunopathogenesis in malaria infections
Lab members: Thibaut Brugat , Barbara Cappucini, Deirdre Cunningham, Victor Kouassi, Garikai Kushinga, Sarah McLaughlin, Jingwen
Lin, Wiebke Nahrendorf, Damian Perez Mazliah, Sophie Roetynck, Philip Spence, Jan Sodenkamp, Irene Tumwine
We study the immune response to the malaria parasite and
the role it plays in the development of severe malaria disease.
This involves identification of the key components of innate
and adaptive immunity that control and eliminate parasites,
and regulate immunopathology. A second aspect of our work
is to identify parasite molecules on the surface of the infected
erythrocytes that may be responsible for antigenic variation
and for binding of the parasite to host endothelium, and in this
way contribute to pathology.
We compared blood-stage malaria (Plasmodium chabaudi
chabaudi) initiated by direct injection of infected erythrocytes
(usual laboratory practice) and after mosquito transmission
(natural mode of infection) to determine whether immune
responses and virulence are affected. Our data show that vector
transmission modifies the asexual blood-stage parasite, which
then modifies the mammalian immune response, resulting in
attenuated parasite growth and less pathology. Attenuated
parasite virulence associates with modified expression of the pir
multi-gene family. Vector transmission of Plasmodium therefore
regulates gene expression of probable variant antigens in the
erythrocytic cycle, modifies the elicited mammalian immune
response, and thus regulates parasite virulence.
Publications
Spence PJ, Jarra W, Levy P, Reid AJ, Chappell L, Brugat T,
Sanders M, Berriman M and Langhorne J (2013)
Vector transmission regulates immune control of
Plasmodium virulence.
Nature 498:228–231
Freitas do Rosário AP, Lamb T, Spence P, Stephens R, Lang A,
Roers A, Muller W, O’Garra A and Langhorne J (2012)
IL-27 promotes IL-10 production by effector Th1 CD4+
T cells: a critical mechanism for protection from severe
immunopathology during malaria infection.
Stephens R and Langhorne J (2010)
Effector memory Th1 CD4 T cells are maintained in a
mouse model of chronic malaria.
(Nature 2013, 498, 228). Differential expression
of genes in blood-stage P. chabaudi following
mosquito transmission versus serial blood
passage. Each segment represents one gene,
categorised according to the function and
ranked based on fold-change.
See references 18, 37, 120, 206, 226 in the bibliography at the
back for publications from this group in 2013.
45
Immune Cell Biology
Steve Ley
Regulation of immune responses by NF-κB and MAP kinases
Lab members: Abduelhakem Ben-Addi, Chao-Sheng Chen, Thorsten Gantke, Eva Gückel, Emilie Jacque, Julia Janzen, Agnes
Mambole-Dema, Olivia Mitchell, Matoula Papoutsopoulou, Sonia Ventura
The innate immune response of mammals is the first line of
defence to infection by pathogenic micro-organisms, and
is triggered by pathogen interaction with receptors on the
surface and in the cytoplasm of neutrophils and macrophages.
This induces the production of proteins called chemokines
and cytokines, which attract other immune cells to the site
of infection to stimulate the adaptive immune response.
Subsequently, invading pathogens are eliminated by the
resulting generation of antibodies and cytotoxic cells.
We study a key signalling pathway activated during innate
immune responses that is regulated by the protein kinase TPL2. Our current experiments are investigating the mechanism
of TPL-2 activation by pathogen infection, and how TPL-2
regulation of cytokine and chemokine production in innate
immune cells regulates inflammatory responses.
Schematic diagram of the recombinant TPL-2/NF-κB1 p105/ABIN-2
complex, and associated epitope tags used for the sequential affinity
purification.
Publications
Arthur JSC and Ley SC (2013)
Mitogen-activated protein kinases in innate immunity.
Nature Reviews Immunology 13:679-92
Gantke T, Boussouf S, Janzen J, Morrice NA, Howell S, Mühlberger E and Ley
SC (2013)
Ebola virus VP35 induces high-level production of recombinant TPL-2—
ABIN-2—NF-κB1 p105 complex in co-transfected HEK-293 cells.
Biochemical Journal 452:359-365
Roget K, Ben-Addi A, Mambole-Dema A, Gantke T, Yang H-T, Janzen J, Morrice
N, Abbott D and Ley SC (2012)
IKK2 regulates TPL-2 activation of ERK-1/2 MAP kinases by direct
phosphorylation of TPL-2 serine 400.
Molecular and Cellular Biology 32:4684-4690
46
Ebola virus VP35 blocks DNA plasmid activation of Protein Kinase R, increasing protein
translation, substantially boosting recombinant protein production by transiently transfected
HEK293 cells (LH). This allows the isolation of milligram amounts of TPL-2/NF-κB1 p105/ABIN2 complex at high purity for biochemical analyses (RH).
Virology
John McCauley
Host specificity of influenza viruses
Lab members: Steve Wharton, Lauren Parker, Kerstin Beer, Michael Bennett, Donald Benton.
Influenza A viruses infect a variety of species, with humans,
horses and pigs representing the main mammalian hosts of the
virus in which infection is sustained. Avian species, particularly
water-fowl and gulls, harbour a wide variety of influenza A viruses
defined by their haemagglutinin (H1-16) and neuraminidase (N19) glycoprotein subtypes in a variety of H/N combinations. New
pandemic strains of human influenza virus arise from an animal
reservoir either directly, as for the 2009 pandemic A(H1N1) virus,
or as a result of gene reassortment between a human and an
animal influenza virus, as in the 1957 and 1968 pandemics.
We are investigating the determinants of host range restriction of
avian and swine influenza viruses that limit their ability to infect
and propagate in human cells. The interaction between a virus
particle and its receptor on a host cell is a key feature that limits the host range of influenza viruses. Recent human H3N2 viruses
show unexpected receptor-binding activities. The characteristics of this binding and that of other human and animal influenza
viruses are being examined in collaboration with colleagues in the Divisions of Physical Biochemistry and Molecular Structure, and
with Professor Ten Feizi, Imperial College London.
Publications
Reis AL and McCauley JW (2013)
The influenza virus protein PB1-F2 interacts with IKKβ and
modulates NF-κB signalling.
PLOS ONE 8:e63852
Iqbal M, Essen SC, Xiao H, Brookes SM, Brown IH and McCauley
JW (2012)
Selection of variant viruses during replication and transmission
of H7N1 viruses in chickens and turkeys.
Virology 433:282–295
Structure of the haemagglutinin from a 2005 influenza
H3N2 virus showing its interaction with the sialic acid
sugar residue of a human influenza virus receptor
analogue.
Virus plaques from a preparation of a recent
H3N2 virus. The viruses have a polymorphism
in the neuraminidase gene enabling some
to bind to turkey erythrocytes via this
glycoprotein.
Lin YP, Xiong X, Wharton SA, Martin SR, Coombs PJ, Vachieri SG,
Christodoulou E, Walker PA, Liu J, Skehel JJ, Gamblin SJ, Hay AJ,
Daniels RS and McCauley JW (2012)
Evolution of the receptor binding properties of the influenza
A(H3N2) hemagglutinin.
109:21474–21479
See references 3, 122, 151, 202, 259, 262, 263, 270 in the bibliography at the back for publications from this group in 2013.
47
Immunoregulation
Anne O’Garra FRS, AAAS Fellow, EMBO member, FMedSci
Regulation of the immune response in infectious disease
Lab members: Leona Gabrysova, Ashleigh Howes, Xuemei Wu, Damian Carragher, Lúcia Moreira-Teixeira, Finlay McNab, Vangelis
Stavropoulos, Charlotte Whicher, Christina Taubert, Philippa Stimpson, Christine Graham, Simon Blankley, Krzysztof Potempa.
The immune system has developed multiple mechanisms to protect against infection.
Immune cells can produce different soluble factors called cytokines to control
infection, but these factors can mediate host damage if uncontrolled. Mechanisms
are in place to regulate the immune response, such as the cytokine IL-10, which on
the one hand can inhibit autoimmune or inflammatory diseases, however, if overproduced can contribute to chronic infection. We are building on our past results, to
elucidate the molecular mechanisms for the induction and function of the regulatory
cytokine IL-10 in different immune cell types and during diverse immune responses.
We continue to examine mechanisms of IL-10 production and function in contributing
to chronic bacterial infection with a major emphasis on tuberculosis (TB), a disease
that still results in significant death world-wide. Using a systems approach we identified
a blood transcriptional interferon-inducible signature in patients with active TB, which
highlighted a potentially detrimental role for type I interferons during infection, and
raised important implications for vaccine and therapeutic development. We continue,
funded by an ERC grant, using systems approaches, molecular methods and improved
mouse models of TB, to identify immune mechanisms of protection or pathogenesis
important for disease control in tuberculosis and other bacterial infections.
Publications
Berry MPR, Blankley S, Graham CM, Bloom CI and O’Garra
A (2013)
Systems approaches to studying the immune response in
tuberculosis.
Current Opinion in Immunology 25:570-587
McNab FW, Ewbank J, Rajsbaum R, Stavropoulos E,
Martirosyan A, Redford PS, Wu X, Graham CM, Saraiva M,
Tsichlis P, Chaussabel D, Ley SC and O’Garra A (2013)
TPL-2-ERK1/2 signaling promotes host resistance against
intracellular bacterial infection by negative regulation of
type I IFN production.
O’Garra A, Redford PS, McNab FW, Bloom CI, Wilkinson RJ
and Berry MPR (2013)
The immune response in tuberculosis.
Annual Review of Immunology 31:475-527
See references 19, 27, 155, 175, 176, 178, 190 in the bibliography
at the back for publications from this group in 2013.
48
Figure based on Berry et al., 2013, Curr Opin Immunol.
Mechanisms of neutrophil-mediated immune defense
Lab members: Nora Branzk, Marianna Ioannou, Qiang Wang, Annika Warnatsch
Multicellular organisms evolved sophisticated immune systems to
protect themselves against infection. Neutrophils are recruited to sites
of infection and play central microbicidal roles. They engulf and kill
microbes intracellularly and release neutrophil extracellular traps (NETs).
NETs are web-like structures composed of decondensed chromatin
and antimicrobial proteins that trap and kill bacteria, fungi, viruses and
parasites. Human patients lacking NETs are susceptible to infection
with opportunistic pathogens. However, NET overabundance has also
been implicated in inflammatory and autoimmune disease. We are
studying how neutrophils regulate NET release to generate an efficient
antimicrobial response while restricting NET-mediated damage to the
host.
Neutrophils release NETs through a novel cell death mechanism
involving some fascinating cell biology: reactive oxygen species (ROS)
trigger the selective translocation of a neutrophil-specific protease,
neutrophil elastase, to the nucleus, where it cleaves histones to promote
chromatin decondensation. Over the last year, we have uncovered the
mechanism of selective protease release. In addition we have made
significant progress in showing that neutrophils produce well-defined
antimicrobial responses depending on instructions from other immune
cells and environmental cues. Finally, we are exploring other novel
functions of NETs in infection and inflammatory disease.
3D reconstruction depicting Candida albicans fungi (red) next to a
neutrophil which has just released NETs (blue/green)
Publications
Metzler KD, Fuchs TA, Nauseef WM, Reumaux D, Roesler J, Schulze I, Wahn V,
Papayannopoulos V and Zychlinsky A (2011)
Myeloperoxidase is required for neutrophil extracellular trap formation: implications
for innate immunity.
Blood 117:953-9
Papayannopoulos V, Staab D and Zychlinsky A (2011)
Neutrophil elastase enhances sputum solubilization in cystic fibrosis patients
receiving DNase therapy.
PLOS ONE 6:e28526
Papayannopoulos V, Metzler KD, Hakkim A and Zychlinsky A (2010)
Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil
extracellular traps.
Journal of Cell Biology 191:677-691
Neutrophils (green) releasing NETs (red, arrows) in the lung of an
infected mouse.
See reference 31 in the bibliography at the back for publications from this group in 2013.
49
Immune Cell Biology
Benedict Seddon
Regulation of T cell homeostasis by antigen receptor signals and cytokines
Lab members: Thea Hogan, Louise Webb, Jie Yang
T lymphocytes are immune cells that play a central role in regulating immune
responses. There are several T cell types, all with different functions, so having the right
number and composition of these cells is essential for a normal immunity to infection.
The maintenance of T cells is strictly controlled by mechanisms regulating production,
cell survival and division. There are two main T cell types made in the thymus; killer
CD8 and helper CD4 T cells. The thymus makes four times as many CD4 T cells as CD8
T cell for reasons that are not understood.
Using an interdisciplinary approach combining mouse genetics and mathematical
modeling, we asked why the thymus makes more CD4 than CD8 T cells. This showed
that whilst there were equal numbers of CD4 and CD8 progenitor cells, only 1 in 14
potential killer T cells were successful in completing development, in contrast to more
than half of potential helper CD4 T cells. Modelling revealed that the combination
of an unexpectedly high death rate amongst all developing T cells, with a slower
development time for CD8 T cells specifically resulted in a greatly reduced efficiency of
CD8 T cell generation.
A model of thymocyte development based on known thymic
developmental pathways. Specific parameters capture exponential
rates of differentiation and death that define selection efficiency.
Publications
Bains I, van Santen HM, Seddon B and Yates AJ (2013)
Models of self-peptide sampling by developing T cells identify candidate
mechanisms of thymic selection.
PLOS Computational Biology 9:e1003102
Hogan T, Shuvaev A, Commenges D, Yates A, Callard R, Thiebaut R and Seddon B
(2013)
Clonally diverse T cell homeostasis is maintained by a common program of cellcycle control.
The thymus generates more CD4 than CD8 T cells. Helper CD4 (red) and killer
CD8 (green) T cells develop in the thymus from a common progenitor cell
population (yellow). CD4 T cells are generated in greater numbers.
See references 12, 109, 114, 223 in the bibliography at the back for publications from this group in 2013.
50
Sinclair C, Bains I, Yates AJ and Seddon B (2013)
Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive
immune system.
Proceedings of the National Academy of Sciences, USA 110:E2905-E2914
Gitta Stockinger FRS, EMBO member, FMedSci
Development, maintenance and regulation of peripheral T cell compartments
and immune responses
Lab members: Paola DiMeglio, Ying Li, Matteo Villa, Chris Schiering, Pete Morrison, Manolis Gialitakis, Joao Duarte, Helena Ahlfors, Judit Biro
Our focus is on the development and function of innate
and adaptive cytokine-producing T cells and innate
lymphoid cells (Th17 cells and IL-9 producing ILC2),
and modulation of effector functions by exogenous
and endogenous environmental factors. Th17 cells are
important for host defence against fungal pathogens and
are causally involved in autoimmune diseases, whereas ILC2
play important roles in lung inflammation.
We developed fate reporter models for the cytokines
IL-17, IL-9 and more recently IL-22 to study development
of cytokine producing cells and their behaviour during
infection in vivo. Fate reporters make detection
independent of current cytokine production and reveal
extensive plasticity in the immune system. Furthermore,
in the context of an ERC-funded programme we study the
role of the aryl hydrocarbon receptor (AhR) in the immune
system, trying to unravel its impact on the function of
different immune cells in the defence against pathogens
and in inflammatory diseases such as psoriasis that are
influenced by genetic as well as environmental factors.
Publications
Hirota K, Turner J-E, Villa M, Duarte JH, Demengeot J, Steinmetz
OM and Stockinger B (2013)
Plasticity of TH17 cells in Peyer’s patches is responsible for
the induction of T cell-dependent IgA responses.
Nature Immunology 14:372-379
Turner J-E, Morrison PJ, Wilhelm C, Wilson M, Ahlfors H,
Renauld J-C, Panzer U, Helmby H and Stockinger B (2013)
IL-9–mediated survival of type 2 innate lymphoid cells
promotes damage control in helminth-induced lung
inflammation.
Journal of Experimental Medicine 210: 2951-2965
Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L,
Renauld J-C and Stockinger B (2008)
The aryl hydrocarbon receptor links TH17-cell-mediated
autoimmunity to environmental toxins.
Nature 453:106-9
See references 38, 80, 113, 161, 206, 229, 242, 243 in the
Lung (A,B) and small intestine (D,E) from reporter mouse untreated (A,D) or treated with 25mg/kg
3-methylcholanthrene (B,E). Controls are shown in C,F. eYFP reporter (green), CD45 (blue) and DAPI (red).
51
Virology
Jonathan Stoye
Retrovirus-host interactions
Lab members: Sam Fraser, Paula Ordonez Suarez, Wilson Li, Sadayuki Okura, Martha Sanz-Ramos, Melvyn Yap, George Young
Comparative genome analysis suggests that vertebrates
and retroviruses have been in conflict for tens of millions
of years. It is thus unsurprising that a degree of coevolution has taken place resulting in the development of
specific defence mechanisms by the host and of means
to overcome such defences by the virus. Understanding
such natural anti-viral genes might suggest novel means
of combating retroviral infection. We anticipate that these
studies will shed new light on the early stages of retrovirus
replication and the control of cross-species infection.
Restriction factors from different species are capable of
recognising different retroviruses in a specific manner
apparently involving multiple low-affinity interactions.
However factors controlling specificity are poorly
understood. We are using a combination of structural,
genetic and biochemical approaches in our attempts to
understand the process of virus restriction by factors such
as Fv1 and Trim5α. Recent studies include an analysis
of Fv1 evolution and reveal an extraordinary degree of
plasticity in this gene. Subspecies of mice from different
geographic locations have developed resistance to multiple
genera of retroviruses suggesting on-going exposure to,
and selection by, such viruses.
Publications
Ohkura S and Stoye JP (2013)
A comparison of murine leukemia viruses that escape from
human and rhesus macaque TRIM5αs.
Stoye JP (2012)
Studies of endogenous retroviruses reveal a continuing
evolutionary saga.
Nature Reviews Microbiology 10:395-406
Hilditch L, Matadeen R, Goldstone DC, Rosenthal PB, Taylor
IA and Stoye JP (2011)
Ordered assembly of murine leukemia virus capsid
protein on lipid nanotubes directs specific binding by the
restriction factor, Fv1.
108:5771–5776
See references 98, 179, 214, 258, 268, 269 in the bibliography at
the back for publications from this group in 2013.
52
A cluster of restricted foamy virus virions arrested outside the cell nucleus detected by (a) in situ
hybridization or (b) immunofluorescence
Immune Cell Biology
Pavel Tolar
Activation of immune receptors
Lab members: Antonio Casal, Carla Nowosad, Robbert Hoogeboom, Katelyn Spillane
Antibodies are critical for human immunity and their induction
has been instrumental for the success of many vaccines. However,
some of the most dangerous pathogens of today’s world, such as
HIV, influenza or malaria, evade antibody responses, both natural
and vaccine-induced. A better understanding of the mechanisms
by which these pathogens trigger antibody responses will be
necessary for the development of more effective vaccines.
We are interested in activation of B cells that detect pathogens
by their B cell antigen receptor (BCR). We are developing new
techniques to image live B cells as they recognise antigen on
antigen-presenting cells. Our studies focus on mechanisms
that regulate antigen binding and the organisation of signalling
complexes in the plasma membrane. One unique aspect of B
cell recognition of antigen is that B cells actively interrogate the
antigen-presenting surface using myosin-generated forces. These forces are ultimately required to extract and endocytose the
antigen. We are investigating the molecular assembly and activation of the contractile elements.
Publications
Lee W-Y and Tolar P (2013)
Activation of the B cell receptor leads to increased
membrane proximity of the Igα cytoplasmic domain.
PLOS ONE 8:e79148
Natkanski E, Lee W-Y, Mistry B, Casal A, Molloy JE and Tolar
P (2013)
B cells use mechanical energy to discriminate antigen
affinities.
Science 340:1587-1590
Tolar P (2011)
Inside the microcluster: antigen receptor signalling viewed
with molecular imaging tools.
Immunology 133:271-277
Myosin IIa-GFP fibres (open arrowheads) in time-lapse imaging of a B cell pulling on antigenpresenting membranes (labelled with DiD, closed arrowheads). Scale bars 1μm.
See references 142, 165 in the bibliography at the back for
53
Immune Cell Biology
Victor Tybulewicz EMBO member, FMedSci
Signal transduction in B and T cells
Lab members: Dorota Abucewicz, Jochen Ackermann, Tiago Brazao, Natalia Dinischiotu, Charlotte Douglas, Kathryn Fountain,
Harald Hartweger, Robert Köchl, Eva Lana Elola, Edina Schweighoffer, Lesley Vanes, Sheona Watson-Scales, Matt Williamson
B and T lymphocytes are white blood cells that are critical mediators of the immune
response against a variety of pathogens. Inappropriate activation of these cells can
result in autoimmune diseases such as rheumatoid arthritis. We are interested in
understanding the biochemical signalling pathways within lymphocytes that control
the activation, survival and migration of the cells, and we study this using genetic,
biochemical and cell biological approaches. Recently we have shown that the Syk
tyrosine kinase is critical for B cell homeostasis, transducing signals from both the BAFF
receptor and B cell antigen receptor.
Mouse models of Down Syndrome
Trisomy of human chromosome 21 (Hsa21) occurs in around 1 in 750 live births and
the resulting gene dosage imbalance gives rise to Down syndrome, the most common
form of mental retardation. In collaboration with Prof E. Fisher (UCL), we are interested
in identifying genes on this chromosome, which, when present in three copies,
cause the many different phenotypes of Down syndrome. We have created a novel
mouse strain carrying a freely segregating copy of Hsa21, which displays many of the
features of Down syndrome, including learning difficulties and cardiac abnormalities.
We are mapping the location of dosage-sensitive genes that cause Down syndrome
phenotypes using chromosome engineering techniques.
Publications
Schweighoffer E, Vanes L, Nys J, Cantrell D, McCleary S,
Smithers N and Tybulewicz Victor LJ (2013)
The BAFF receptor transduces survival signals by coopting the B cell receptor signaling pathway.
Immunity 38:475-488
The
Syk
tyrosine
kinase is required to
transduce
survival
signals from BAFFR and
activation signals from
BCR and TLRs, but not
CD40.
Ksionda O, Saveliev A, Kochl R, Rapley J, Faroudi M, SmithGarvin JE, Wulfing C, Rittinger K, Carter T and Tybulewicz
VLJ (2012)
Mechanism and function of Vav1 localization in TCR
signaling.
Journal of Cell Science 125:5302-5314
Reynolds LE, Watson AR, Baker M, Jones TA, D’Amico
G, Robinson SD, Joffre C, Garrido-Urbani S, RodriguezManzaneque JC, Martino-Echarri E, Aurrand-Lions M, Sheer
D, Dagna-Bricarelli F, Nizetic D, McCabe CJ, Turnell AS,
Kermorgant S, Imhof BA, Adams R, Fisher EMC, Tybulewicz
VLJ, Hart IR and Hodivala-Dilke KM (2010)
Tumour angiogenesis is reduced in the Tc1 mouse model
of Down’s syndrome.
Nature 465:813-7
See references 2, 103, 105, 107, 219 in the bibliography at
the back for publications from this group in 2013.
54
4-chamber view of hearts from e14.5 mouse embryos. The developing heart from the Ts1Tyb
mouse model of Down Syndrome shows a ventricular septal defect. Images generated using
high-resolution episcopic microscopy.
Immunoregulation
Andreas Wack
Immune response to influenza
Lab members: Helena Aegerter, Stefania Crotta, Sophia Davidson, Greg Ellis, Teresa McCabe
Seasonal influenza represents a constant burden to public health, and
influenza pandemics due to new virus strains pose a serious global threat.
The influenza virus causes damage to the infected lung tissue and induces
an immune response that is necessary to eliminate the virus but at the
same time contributes to lung pathology. Influenza infection also increases
dramatically the susceptibility to bacterial coinfections. Both in single
infections and coinfections, it is unclear which host and viral factors tip the
balance between pathology and successful pathogen clearance. A better
knowledge of these processes will allow intervention to enhance, attenuate
or focus the immune response to infection.
Our work aims to identify determinants of disease outcome. We focus on
early events after infection, in particular on the interface between infected
epithelium and the innate immune system. We have used primary airway
epithelial cells to show that two parallel, redundant interferon-driven
feedback systems act in infected epithelia. Host-dependent differences
in the interferon response to influenza and their impact on the outcome
of infection are also studied. Furthermore, we investigate the roles of
natural killer cells and granulocytes in influenza infection and co-infection.
These studies allow us to link early events in infection
to subsequent immune-mediated pathology or
protection.
Publications
Stefania Crotta, Annita Gkioka, Victoria Male, João H. Duarte,
Sophia Davidson, Ilaria Nisoli, Hugh J.M. Brady, Andreas Wack
(2014)
The transcription factor E4BP4 is not required for
extramedullary pathways of NK cell development
Journal of Immunology, 192: 2677-88
Crotta S, Davidson S, Mahlakoiv T, Desmet CJ, Buckwalter MR,
Albert ML, Staeheli P and Wack A (2013)
Type I and type III interferons drive redundant amplification
loops to induce a transcriptional signature in influenzainfected airway epithelia.
PLOS Pathogens, 9:e1003773
Redford PS, Mayer-Barber KD, McNab FW, Stavropoulos E,
Wack A, Sher A and O’Garra A (2014)
Influenza A virus impairs control of Mycobacterium
tuberculosis co-infection through a type I interferon
receptor dependent pathway.
Journal of Infectious Diseases 209:270-274
Lack of type I and III interferon systems blocks
transcriptional response in infected airway epithelia.
Transcriptional response of epithelia to infection with
influenza strain PR8. Epithelia are deficient in the
interferon type I receptor (IFNAR1-/-), the interferon
type III receptor (IL-28Rα-/-) or both. Only the absence
of both interferon systems prevents upregulation of a
large subset of infection-induced genes (lateral blue bars).
Type I and type III interferons drive redundant
amplification loops in infected airway epithelia. Upon
infection, epithelia both produce and respond to IFN
I and IFN III to induce an antiviral state. These two
systems are independent of each other but induce an
identical gene set.
55
Robert Wilkinson FRCP
Understanding and intervening in HIV-associated tuberculosis
Lab members: Rachel Lai, Adrian Martineau, Katalin Wilkinson, Anna Coussens
The programme derives its research questions from the clinical care of
tuberculosis (TB) and HIV-TB co-infected persons in South Africa and
London. Through clinically-based studies we aim to improve knowledge
of pathogenesis and thereby improve prevention and treatment.
We contributed to the description of a distinct transcriptomic signature
of active TB and are conducting further studies extending to the
study of tuberculosis treatment monitoring. We have determined that
vitamin D deficiency is highly prevalent in Cape Town, associating with
susceptibility to tuberculosis both in both HIV-infected and uninfected
persons. When used as an adjunct to the treatment of tuberculosis,
vitamin D suppresses proinflammatory cytokine responses, and
attenuates the suppressive effect of antimicrobial therapy on secretion
of IL-4, CCL5, and IFN-α. This demonstrates a previously unappreciated
role for vitamin D supplementation in accelerating resolution of
inflammatory responses.
Publications
Principal component analysis (PCA) plots generated using immunological parameters which contribute
to variation in baseline inflammatory profile between PTB patients of African and Eurasian ancestry.
Coussens AK, Wilkinson RJ, Nikolayevskyy V, Elkington PT, Hanifa
Y, Islam K, Timms PM, Bothamley GH, Claxton AP, Packe GE,
Darmalingam M, Davidson RN, Milburn HJ, Baker LV, Barker RD,
Drobniewski FA, Mein CA, Bhaw-Rosun L, Nuamah RA, Griffiths CJ
and Martineau AR (2013)
Ethnic variation in inflammatory profile in tuberculosis.
Martineau AR, Nhamoyebonde S, Oni T, Rangaka MX, Marais S,
Bangani N, Tsekela R, Bashe L, de Azevedo V, Caldwell J, Venton
TR, Timms PM, Wilkinson KA and Wilkinson RJ (2011)
Reciprocal seasonal variation in vitamin D status and
tuberculosis notifications in Cape Town, South Africa.
108:19013-19017
Berry MPR, Graham CM, McNab FW, Xu Z, Bloch SAA, Oni T,
Wilkinson KA, Banchereau R, Skinner J, Wilkinson RJ, Quinn C,
Blankenship D, Dhawan R, Cush JJ, Mejias A, Ramilo O, Kon OM,
Pascual V, Banchereau J, Chaussabel D and O’Garra A (2010)
An interferon-inducible neutrophil-driven blood transcriptional
signature in human tuberculosis.
Nature 466:973-977
Circulating immunological correlates of slow sputum culture conversion differ between patients of
African and Eurasian ancestry. Upward arrows indicate parameters whose concentration was higher in
patients who converted slowly.
56
See references 11, 27, 61, 71, 72, 76, 95, 124, 126, 135, 143, 146,
150, 173, 180, 200, 220, 234, 246, 253 in the bibliography at the
Mark Wilson
Molecular regulation of type-2 immunity during allergy and helminth infection
Lab members: Stephanie Coomes, Yashaswini Kannan, Isobel Okoye, Victoria Pelly, Lewis Entwistle, Jimena Perez-Lloret, Fiona Li
A quarter of the global population is infected with one of four major
parasitic helminths, making them some of the most common infectious
pathogens. Immunity to intestinal helminths requires a coordinated
immunological and physiological response. CD4+ T helper 2 (Th2)
lymphocytes coordinate a collective type-2 immune responses essential
for expulsion mechanisms, placing Th2 cells front and centre of antihelminth immunity. However, inadvertent Th2-mediated type-2 responses
in the absence of infection can give rise to allergic diseases, which have
increased dramatically within the past 50 years. We aim to identify the
molecular mechanism underlying Th2 cell differentiation, regulation and
effector function to enhance anti-helminth immunity or prevent allergies.
miRNA-mediated regulation: Using murine models of infection and allergy
combined with next-generation sequencing and gene manipulation
technologies we have identified several molecular pathways that regulate
type-2 immunity. In particular, RNA manipulation techniques have
identified a network of small non-protein coding miRNAs that regulate
various aspects of type-2 immunity. We are also interrogating several
miRNA-regulated pathways that influence anti-inflammatory (Regulatory T
cell) responses.
Functional plasticity: De novo immune responses develop alongside ongoing immune responses. In collaboration with other NIMR
investigators, we have identified that Th2 cells contribute to secondary
immunity through re-programming mechanisms. Collectively, these studies
will help facilitate helminth elimination strategies and identify novel
interventions for allergic disease.
Immunity is costly.
Immunologically resistant mice develop significant
immunopathology following expulsion of the intestinal
helminth Heligmosomoides polygyrus.
Publications
Coomes SM, Pelly VS and Wilson MS (2013)
Plasticity within the αβ+CD4+ T-cell lineage: when, how and what for?
Open Biology 3:120157
Kelada S, Sethupathy P, Okoye IS, Kistasis E, Czieso S, White SD, Chou D, Martens
C, Ricklefs SM, Virtaneva K, Sturdevant DE, Porcella SF, Belkaid Y, Wynn TA and
Wilson MS (2013)
miR-182 and miR-10a are key regulators of Treg specialisation and stability
during Schistosome and Leishmania-associated Inflammation.
Okoye IS and Wilson MS (2011)
CD4+ T helper 2 cells - microbial triggers, differentiation requirements and
effector functions.
Immunology 134:368-77
miRNA-mediated
regulation. Using
genome-wide analysis
at the tissue (A) and
cellular level (B, Th2
cell differentiation
pathways, and C,
Th2 cell), we are
investigating the
molecular mechanisms
of Th2 immunity and
immunopathology
following infection.
See references 15, 59, 130 in
the bibliography at the back for
publications from this group in
2013.
57
Douglas Young FMedSci
Mycobacterial pathogenesis: gene expression and innate immune response
Lab members: Teresa Cortes, Melissa Burke,Yi Wang, Arun Mishra, Angela Rodgers, Jo Dillury
One third of the global population is exposed to infection with
Mycobacterium tuberculosis but only ten percent of individuals
will develop tuberculosis. The outcome of infection depends
on a complex series of interactions with the immune system,
which can result in disease or in a persistent asymptomatic, latent
infection. We are studying the way that M. tuberculosis evades
host immunity by misdirecting innate immune recognition and by
adapting to a form that resists killing by phagocytes. Ultimately, we
aim to develop drugs that rapidly eliminate persisting bacteria and
vaccines that elicit more effective immunity.
We are using high-throughput sequencing technologies to
define the genetic diversity of M. tuberculosis and to study gene
regulation at transcriptional and post-transcriptional levels. We
have discovered an extensive repertoire of non-coding RNAs
and are exploring their function, in part through participation
in SysteMTb, a European consortium using a systems biology
approach to characterise the fundamental biology of TB. Our work
demonstrates that genetic variation amongst clinical isolates of M.
tuberculosis results in phenotypic differences in their interaction
with the host innate immune system. We propose that differences
in innate immune recognition drive the epidemiology of this
complex disease.
Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, Parkhill J, Malla B, Berg S, Thwaites G,
Yeboah-Manu D, Bothamley G, Mei J, Wei LH, Bentley S, Harris SR, Niemann S, Diel R, Aseffa A, Gao
Q, Young D and Gagneux S (2013)
Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern
humans.
Nature Genetics 45:1176-1182
Rose G, Cortes T, Comas I, Coscolla M, Gagneux S and Young DB (2013)
Mapping of genotype-phenotype diversity among clinical isolates of Mycobacterium tuberculosis by
sequence-based transcriptional profiling.
Genome Biology and Evolution 5:1849-1862
Arnvig KB, Comas I, Thomson NR, Houghton J, Boshoff HI, Croucher NJ, Rose G, Perkins TT, Parkhill J,
Dougan G and Young DB (2011)
Sequence-based analysis uncovers an abundance of non-coding RNA in the total transcriptome of
Mycobacterium tuberculosis.
See references 57, 60, 81, 86, 96, 115, 136, 153, 181, 191, 207, 217, 227, 241, 250 in the
58
A single nucleotide polymorphism that generated a new
transcription start site emerged in the M. tuberculosis Beijing
strain family alongside Neolithic expansion of Chinese
Immune Cell Biology
Virology
WHO Collaborating Centre for
Tybulewicz
Reference and ResearchVictor
on Influenza
(WIC)
Director: John McCauley
Lab members: Rodney Daniels, Yipu Lin, Zheng Xiang, Karen Cross, Vicki Gregory, Lynne Whittaker, Chandi Halai, Nick Cross, Åine
Rattigan.
The WHO Collaborating Centre for Influenza is one of six Collaborating Centres that along with 141 WHO National Influenza
Centres (NICs) in 111 UN member states form the WHO Global Influenza Surveillance and Response System to track influenza
viruses as they circulate around the world. Viruses are characterised antigenically and genetically, and their resistance to antiviral
drugs is determined. Results of these and other analyses from each collaborating centre are used to develop recommendations
for the most appropriate strains for use in seasonal influenza vaccines and provide advice to national authorities on the global and
regional circulation of influenza.
Recent research has focused on the ability of animal influenza viruses infecting humans to bind to sialic acid receptors. These
studies contribute to the assessment of the pandemic potential of these viruses. Our studies on the detailed characterisation of
human seasonal influenza viruses are carried out with the NICs from around the world, with other WHO Collaborating Centres,
Public Health England, the National Institute for Biological Standards and Control, members of the European Reference Laboratory
Network for Human Influenza (ERLI-Net), the European Centre for Disease Prevention and Control and the Wellcome Trust Sanger
Institute.
Publications
World Health Organization (2013)
Recommended composition of influenza virus vaccines for use in
the 2013-2014 northern hemisphere influenza season.
Weekly Epidemiological Record 88:101-14
Xiong X, Martin SR, Haire LF, Wharton SA, Daniels RS, Bennett MS,
McCauley JW, Collins PJ, Walker PA, Skehel JJ and Gamblin SJ (2013)
Receptor binding by an H7N9 influenza virus from humans.
Nature 499:496-499
Lin YP, Xiong X, Wharton SA, Martin SR, Coombs PJ, Vachieri SG,
Christodoulou E, Walker PA, Liu J, Skehel JJ, Gamblin SJ, Hay AJ,
Daniels RS and McCauley JW (2012)
Evolution of the receptor binding properties of the influenza
A(H3N2) hemagglutinin.
109:21474–21479
See references 3, 4, 64, 88, 110, 193, 224, 244, 259, 260, 262, 263
in the bibliography at the back for publications from this group
in 2013.
Locations of amino acid substitutions on the
haemagglutinin of influenza A(H3N2) viruses
belonging to genetic group 3C.3, a group of viruses
that emerged over the 2012/2013 northern
hemisphere influenza season.
Phylogenetic analysis of the HA gene of recently
collected influenza A(H3N2) viruses showing amino
acid substitutions associated with each genetic
sub-group.
59
Structural Biology
Mathematical Biology
Willie Taylor (Head of Division)
Richard Goldstein
Molecular Structure
Steve Gamblin (Joint Head of Division)
Steve Smerdon (Joint Head of Division)
Paul Driscoll
Annalisa Pastore
Andres Ramos
Katrin Rittinger
Ian Holt
Ian Taylor
Physical Biochemistry
Justin Molloy (Head of Division)
Tom Carter
John Offer
Peter Rosenthal
Martin Webb
60
STRUCTURAL BIOLOGY
Tom Carter
Secretory organelle formation, trafficking and exocytosis
Lab members: Nikolai Kiskin, Ana Violeta Fonseca, Ianina Conte, Emma Cookson, Laura Knipe, Jennifer Frampton.
Vascular endothelial cells are highly specialised secretory cells that line the lumen
of blood vessels, the network of tubes that carry blood to the tissues and organs
of the body. Endothelial cells help regulate vital physiological processes within the
vascular network, such as blood flow, blood clotting, inflammation, vessel growth
and repair. They do this through the secretion a variety of molecules with vasoactive,
adhesive, anti-adhesive, coagulant, angiogenic, mitogenic and inflammatory functions.
Endothelial cell damage or dysfunction alters the composition or balance of the
secreted molecules, and this can predispose to an increased risk of vascular disease,
infection and cancer.
Our goal is to understand the molecular mechanisms controlling the intracellular
trafficking and regulated secretion of proteins and peptides from vascular endothelial
cells. Endothelial cells store proteins and peptides for regulated secretion in special
secretory granules called Weibel-Palade bodies (WPBs) . Our recent work has shown
that WPBs acquire a complex mixture of Rab proteins that recruit soluble binding
partners to orchestrate the delivery and secretion of a wide range of coagulant,
angiogenic, mitogenic and inflammatory mediators.
Publications
Bierings R, Hellen N, Kiskin N, Knipe L, Fonseca A-V, Patel B,
Meli A, Rose M, Hannah MJ and Carter T (2012)
The interplay between the Rab27A effectors Slp4 a and
MyRIP controls hormone-evoked Weibel-Palade body
exocytosis.
Blood 120:2757-2767
Knipe L, Meli A, Hewlett L, Bierings R, Dempster J, Skehel P,
Hannah MJ and Carter T (2010)
A revised model for the secretion of tPA and cytokines
from cultured endothelial cells.
Blood 116:2183-2191
Babich V, Meli A, Knipe L, Dempster JE, Skehel P, Hannah MJ
and Carter T (2008)
Selective release of molecules from Weibel Palade bodies
during a lingering kiss.
Blood 111:5282-5290
See reference 58 in the bibliography at the back for
publication from this group in 2013
Weibel-Palade bodies (WPBs) are secretory organelles that store von Willebrand
factor (VWF, blue). WPBs recruit Rab proteins and Rab-effectors (green and red)
that help orchestrate the delivery and exocytosis of WPBs
MRCNational
NationalInstitute
Institute for
for Medical
Medical Research
Research
MRC
61
STRUCTURAL BIOLOGY
Molecular Structure
Paul Driscoll
Structural and functional analysis of signalling proteins
Lab members: Diego Esposito, Tharindu Fernando, Acely Garza-Garcia, Hans Koss, Timothy Ragan, Christine Richter, Gemma Wildsmith
Nuclear magnetic resonance (NMR) spectroscopy provides a valuable means
to probe the three-dimensional structure, dynamics and binding proper ties
of biological molecules, large and small. Our group employs state-of-theart NMR alongside biophysical, biochemical and cell biology techniques
to investigate the nature of interactions between proteins implicated in
fundamental cellular and organismal processes. These include the activation
of death receptor signalling, limb regeneration in the adult newt, the
regulation of phospholipase C isozymes, and the role of β2-glycoprotein I
in anti-phospholipid syndrome. We also contribute to research to investigate
the impact of interventions into the development of the model organism
Drosophila melanogaster.
We have been investigating the death-inducing signalling complex (DISC)
that forms when so-called death receptors are activated by ligand binding,
a process crucial for maintaining appropriate levels of immune cells within
the body. DISC formation leads to the activation of the ‘executioner’ cysteine
proteinase caspase-8. We have developed an experimentally tractable form
of full-length caspase-8 that provides a basis for detailed investigation of
its structure and the regulation of its activity by binding to DISC proteins.
Separately we have refined methods to use NMR to characterise the molecular
components of Drosophila hemolymph, useful for the investigation of the
effect of defined diets on physiology and metabolism.
Publications
Dioletis E, Dingley AJ and Driscoll PC (2013)
Structural and functional characterization of
the recombinant death domain from deathassociated protein kinase.
PLOS ONE 8:e70095
Bunney TD, Esposito D, Mas-Droux C, Lamber
E, Baxendale RW, Martins M, Cole A, Svergun
D, Driscoll PC and Katan M (2012)
Structural and functional integration of
the PLCγ interaction domains critical for
regulatory mechanisms and signaling
deregulation.
Structure 20:2062–2075
Schematic representation of the components
of the DISC formed upon activation of the
membrane-bound CD95 death receptor (DD,
death domain; DED, death effector domain;
cat., catalytic domain; FADD, Fas-associated
protein with DD)
62
Colour-coded decomposition of a small region of the 1H
NMR spectrum of Drosophila larval hemolymph into multiplet
signals from component metabolites
See reference 74, 75, 199 in the bibliography at the back for publication from this
group in 2013.
Cheng LY, Bailey AP, Leevers SJ, Ragan TJ,
Driscoll PC and Gould AP (2011)
Anaplastic lymphoma kinase spares organ
growth during nutrient restriction in
Drosophila.
Cell 146:435-47
STRUCTURAL BIOLOGY
Molecular Structure
Steve Gamblin FRS, EMBO member, FMedSci
Structural biology of influenza, energy metabolism and cancer
Lab members: Patrick Collins, Valeria De Marco, Neil Justin, Ursula Neu, Matthew Sanders, John Skehel, Aldo Tarricone, Jon Wilson,
Bing Xiao, Alex Xiong, Ying Zhang
We study the structure and function of molecules involved in disease processes such
as influenza, diabetes and cancer. We use X-ray crystallography and NMR to determine
the three dimensional structures and dynamics of these molecules. In combination with
other biophysical, biochemical and biological techniques, the data help us elucidate the
function of the proteins of interest and provide information that may be useful for the
development of therapeutic approaches.
Our research includes a long-standing collaboration with John Skehel (Virology) and John
McCauley’s group in NIMR’s WIC. We are investigating how changes to the structural
properties of the major surface glycoproteins (hemagglutinin and neuraminidase) influence
the infectivity of different strains of the influenza virus. Recently we have shown how
mutations to the sialic acid binding site of the avian H5N1 virus, have allowed it to acquire
a strong binding preference for the human receptor over the avian equivalent. This altered
binding mode now resembles that previously observed in historically significant pandemic
viruses. Conversely although the recently emerged H7N9 influenza virus hemagglutinin
has also acquired higher affinity for the human receptor sialic acid, it has retained high
affinity binding of the avian receptor. The retention of avian receptor binding contributes
to its low transmissibility due to sequestration by avian-like receptors in human mucins.
Our biophysical and structural approach enables us to better understand the significance
of mutations in this rapidly evolving virus.
Ribbons
representations of the
receptor binding sites
in the hemagglutinin
of influenza viruses.
Mutation of the Gln226 residue in avian
H5N1 hemagglutinin
(upper panel) changes
it’s preference
to high affinity
binding of human
receptors. Mutations
of the avian H7N9
hemagglutinin (lower
panel) enable it to
bind the human
receptor with high
affinity, but unlike
H7N3 it still retains
the ability to bind to
the avian receptor
and is therefore
less transmissible in
humans.
Publications
Xiong X, Coombs PJ, Martin SR, Liu J, Xiao H,
McCauley JW, Locher K, Walker PA, Collins PJ,
Kawaoka Y, Skehel JJ and Gamblin SJ (2013)
Receptor binding by a ferret-transmissible H5
avian influenza virus.
Nature 497:392–396
Xiong X, Martin SR, Haire LF, Wharton SA, Daniels
RS, Bennett MS, McCauley JW, Collins PJ, Walker
PA, Skehel JJ and Gamblin SJ (2013)
Receptor binding by an H7N9 influenza virus
from humans.
Nature 499:496-499
Xiao B, Sanders MJ, Underwood E, Heath R, Mayer
FV, Carmena D, Jing C, Walker PA, Eccleston JF,
Haire LF, Saiu P, Howell SA, Aasland R, Martin SR,
Carling D and Gamblin SJ (2011)
Structure of mammalian AMPK and its regulation
by ADP.
Nature 472:230-233
See reference 64, 261, 262, 263, 264 in the
bibliography at the back for publication from this
group in 2013.
63
STRUCTURAL BIOLOGY
Richard Goldstein
Modelling the evolution of molecular components, systems, and behaviours
Lab members: Martin Godany, Kyriakos Kentzoglanakis, Bhavin Khatri, Christopher Monit, Grant Thiltgen
All biology is the result of evolution. In order to understand life, we need to
investigate the evolutionary process that determines its form and function.
Because living things encode this evolutionary heritage, studies of their properties
can provide insights into the evolutionary process. Following the evolutionary
path of specific components can provide important information about the
characteristics of living organisms. Combining insights from physical chemistry,
condensed matter physics, artificial intelligence, complexity theory, and
mathematical biology, we are developing computational and theoretical methods
to explore these areas.
We are investigating protein evolution, exploring what the evolutionary record
can tell us about the effect of mutations, and to understand how the evolution
of proteins determined their observed properties. We study the evolution of
HIV and endogenous retroviruses to understand the way they act now, how
they might change in the future, and how they are able to shift from one host to
another. We are also studying how horizontal gene transfer affects the evolution
of bacteria, focusing on when the interests of the genes and the organisms
conflict, as well as how behaviours such as chemotaxis evolve.
Structure of Butyrylcholinesterase (PDB 2WSL) coloured
by selective pressure for hydrophobicity (red: prefers
hydrophilic residues; blue: prefers hydrophobic residues),
determined through site-specific evolutionary analysis.
Publications
Kentzoglanakis K, García López D, Brown SP and Goldstein RA (2013)
The evolution of collective restraint: policing and obedience among
non-conjugative plasmids.
Pollock DD, Thiltgen G and Goldstein RA (2012)
Amino acid coevolution induces an evolutionary Stokes shift.
Proceedings of the National Academy of
Sciences,USA109:E1352-E1359
Tamuri AU, dos Reis M and Goldstein RA (2012)
Estimating the distribution of selection coefficients from phylogenetic
data using sitewise mutation-selection models.
Genetics 190:1101-1115
Estimated fitness of two different theoretical models of bacterial chemotaxis, (top curve: adaptive
response; lower curve: inverted response) depending upon the correlation time and correlation length
of the food distribution.
See reference 97, 131 in the bibliography at the back for publication from this group in 2013.
64
STRUCTURAL BIOLOGY
Molecular Structure
Ian Holt
Mitochondrial DNA replication and expression
Lab members: Gokhan Akman, Mark Bowmaker, Daniel Ives, Chloe Moss
Small circles of DNA are maintained in mitochondria (mitochondrial
DNA), the major energy producing compartment of the cell. Mutations
in the mitochondrial DNA can cause severe metabolic disease and
are implicated in ageing, cancer, and neurodegeneration. Our studies
aim to elucidate the processes of DNA replication and expression
in mitochondria to better understand and treat mitochondrial
dysfunction in all its myriad forms.
In the past year we have developed a new approach to studying the
process of replication in mitochondria, by incubating the organelles
with radiochemical precursors of DNA (or RNA) synthesis (Figure 1).
The new procedure has already proved its worth by revealing that
mitochondrial transcripts are used as a means of protecting the
lagging-strand template during the long delay between initiation of
first and second strand DNA synthesis. In another approach, we aim
to exploit the capacity of some cells to rid themselves of pathological
mitochondrial DNA molecules. By mining microarray datasets we
have identified the genesets that distinguish cells that favour wildtype mitochondrial DNAs over those that favour pathological variants
(Figure 2). This information was used to devise a pharmaceutical
intervention that increased the frequency of selection of wild-type
mitochondrial DNA in human cells.
Figure 2. Gene Set Enrichment Analysis identifies Endoplasmic
Reticulum Stress as a factor that prevents the propagation of mutant
mitochondrial DNA
Publications
Kazak L, Reyes A, Duncan AL, Rorbach J, Wood SR, Brea-Calvo G, Gammage PA,
Robinson AJ, Minczuk M and Holt IJ (2013)
Alternative translation initiation augments the human mitochondrial proteome.
Nucleic Acids Research 41:2354-2369
Reyes A, Kazak L, Wood SR, Yasukawa T, Jacobs HT and Holt IJ (2013)
Mitochondrial DNA replication proceeds via a ‘bootlace’ mechanism involving the
incorporation of processed transcripts.
Figure 1. In organello labelling of replicating mitochondrial DNA.
He J, Cooper HM, Reyes A, Di Re M, Sembongi H, Litwin TR, Gao J, Neuman KC, Fearnley
IM, Spinazzola A, Walker JE and Holt IJ (2012)
Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis.
65
STRUCTURAL BIOLOGY
Justin Molloy
Single molecule studies of cell motility and cell signalling
Lab members: Suleman Bawumia, Andrew Howe, Laura Knipe, Gregory Mashanov, Paul Moody, Martyn Stopps, Algirdas Toleikis
Shahid Khan, Nigel Birdsall, Tatiana Nenasheva
The principal goal of the group is to understand the mechanism
of force production by molecular motors both in vitro and
within living cells. Laser-based optical methods like optical
tweezers, Atomic Force Microscopy (AFM) and total internal
reflection fluorescence microscopy (TIRFM) allow us to observe,
track and manipulate individual molecules either in isolated
preparations or within living cells. We are interested in diverse
aspects of human health, including how muscles generate force
and movement, how acetylcholine receptors transduce signals
in the heart, and how the two strands of DNA are separated and
copied.
In collaboration with Martin Webb’s group, we have been
studying DNA unwinding at the single molecule level using AFM,
TIRFM and magnetic tweezers. With Pavel Tolar’s group we
have used AFM to help understand how B cells use mechanical
force to discriminate between strong and weak binding of their
receptors to antigens. With Ross Breckenridge and Nigel Birdsall
my team have developed methods to study M2 acetylcholine
receptors in model cell lines, primary cell culture and freshly
dissected, cardiac tissue slices. This opens the possibility to
study receptor physiology and pharmacology under defined
conditions right through to their native context.
We have developed methods to
visualise individual G-protein coupled
receptors in model cell lines, primary
cell culture and freshly dissected
cardiac tissue (see Nenasheva et al.
2013).
Publications
Hussain S, Molloy JE and Khan SM (2013)
Spatiotemporal dynamics of actomyosin networks.
Biophysical Journal 105:1456-65
Natkanski E, Lee W-Y, Mistry B, Casal A, Molloy JE and Tolar P (2013)
B cells use mechanical energy to discriminate antigen affinities.
Science 340:1587-1590
Nenasheva TA, Neary M, Mashanov GI, Birdsall NJM, Breckenridge RA and Molloy JE (2013)
Abundance, distribution, mobility and oligomeric state of M2 muscarinic acetylcholine receptors in
live cardiac muscle.
Journal of Molecular and Cellular Cardiology 57:129-136
See reference 52, 119, 159, 165, 168, 218 in the bibliography at the back for publication from this
group in 2013.
66
STRUCTURAL BIOLOGY
John Offer
Synthetic protein laboratory: acyl transfer for chemical biology and synthesis
Lab members: George Papageorgiou, Caroline Morris, Abu Baker El Sayed, Richard Raz
Proteins are now within the synthetic reach of organic chemistry. A combination
of ligation and optimised solid phase peptide synthesis can give access to many
difficult to express proteins or proteins with post-translational modifications
such as methylation, ubiquitinylation or phosphorylation. The demand for site–
specifically modified proteins or fluorescent labelling of proteins in cells is driving
the development of these emerging techniques. With the growing importance of
peptides as therapeutics, ligation chemistry is also being used to synthesise privileged
cyclic peptides and peptidomimetics. The research area of ligation has important
applications beyond protein synthesis, both in drug discovery and chemical biology.
Synthesis of proteins with post-translational modifications requires novel ligation
techniques that are fully compatible with these modifications. Methods developed
for preparation of these building blocks and novel ways of connecting them have
expanded the synthetic flexibility of the ligation approach so that we can easily
reassemble proteins from their component peptides using a straightforward
procedure. The biocompatibility of amide ligation has potential for application to
modify proteins in their native settings with minimal genetic manipulation and is part
of an expanding effort for the application of organic chemistry to the cell. We are
synthesising several self-assembling protein systems including virus-like particles.
The application
of a twisted
amide bond
to generate a
thioester by acyl
rearrangement.
Publications
Burlina F, Morris C, Behrendt R, White P and Offer J (2012)
Simplifying native chemical ligation with an N-acylsulfonamide linker.
Chemical Communications 48:2579-2581
Holm L, Ackland GL, Edwards MR, Breckenridge RA, Sim RB and Offer J (2012)
Chemical labelling of active serum thioester proteins for quantification.
Immunobiology 217:256-264
Offer J (2010)
Native chemical ligation with Nα acyl transfer auxiliaries.
Biopolymers 94:530-54
Time-course of the synthesis of murine KC from
its two component peptides
67
STRUCTURAL BIOLOGY
STRUCTURAL BIOLOGY
Molecular Structure
Molecular Structure
Annalisa Pastore EMBO member
Understanding the molecular bases of neurodegeneration
Lab members: Robert Yan, Salvatore Adinolfi, Domenico Sanfelice, John McCormick, Serena Faggiano, Cesira de Chiara,
Tommaso Vannocci, Matjia Popovic, Chiara Morelli, Rita Puglisi, Raj Menon
We are interested in understanding the molecular basis of
neurodegenerative diseases. We study the connection between
normal function and disease to eventually develop therapeutic
interventions. In our work, we use different biophysical,
biochemical, bioinformatics and cell biology tools. We focus
on neurodegenerative processes caused by misfolding and
mitochondrial dysfunction.
During the last year we have further advanced our understanding
of the cellular function of frataxin, the protein responsible for
Friedreich’s ataxia and put this research in the framework of ironsulphur biogenesis. This is an essential machine that is highly
conserved from bacteria to primates. We have specifically looked
into the role of a specialised Ferredoxin and its relationship with
frataxin. We have characterised the interaction between Ferredoxin
and the desulphurase IscS/Nfs1 that is also a frataxin partner.
By modelling the molecular complex of Ferredoxin with IscS/
Nfs1 based on experimental restraints we show that Ferredoxin
competes for the binding site of frataxin and interferes with the
role of Ferredoxin as an electron donor. Our data provide the first
structural insights into the role of Fdx in cluster assembly.
We have also further advanced our studies on ataxin-1, the protein
responsible for spinocerebellar ataxia type 1. We solved the
structure of a complex of the AXH domain of ataxin-1 and the 143-3 protein which suggests an important role of this interaction in
the normal and pathologic function of the protein. We hope that
this interaction can be used for developing new and specific drugs
which could rescue protein misfolding and aggregation in disease.
Publications
Schematic representation of the role of Ferredoxin in Iron-Sulphur
Cluster Biogenesis
de Chiara C, Rees M, Menon RP, Pauwels K, Lawrence C, Konarev PV, Svergun DI, Martin SR, Chen YW and
Pastore A (2013)
Self-assembly and conformational heterogeneity of the AXH domain of ataxin-1: an unusual example of
a chameleon fold.
Menon RP, Nethisinghe S, Faggiano S, Vannocci T, Rezaei H, Pemble S, Sweeney MG, Wood NW, Davis MB,
Pastore A and Giunti P (2013)
The role of interruptions in polyQ in the pathology of SCA1.
PLOS Genetics 9:e1003648
See reference 47, 67, 68, 69, 70, 83, 87, 157, 186, 187, 212, 213, 266, 267 in the bibliography at the
back for publication from this group in 2013.
68
Yan R, Konarev PV, Iannuzzi C, Adinolfi S, Roche B, Kelly G, Simon L, Martin SR, Py B, Barras F, Svergun DI
and Pastore A (2013)
Ferredoxin competes with bacterial frataxin in binding to the desulfurase IscS.
STRUCTURAL BIOLOGY
Molecular Structure
Andres Ramos
Molecular recognition in post-transcriptional regulation
Lab members: Zainab Ahdash, Virginia Castilla-Llorente, Katherine Collins, Andre Dallmann, David Hollingworth, Giuseppe Nicastro,
Nessim Kichik, Christopher Gallagher
Post-transcriptional control plays a key role in expanding
genomic diversity in complex organisms, and deregulation of
the metabolism of specific mRNAs lies at the basis of common
genetic diseases, cancer, autoimmune pathologies and viral
infection. Our goal is to explain how RNA-binding proteins
achieve and regulate target selectivity and how they control
the expression of subsets of genes. We combine information
obtained from NMR experiments with that obtained by other
biophysical/structural techniques and by in cell/in vivo assays.
ZBP1 is an oncofetal protein that controls cellular migration and,
in cancer, its expression is strongly correlated with the capability
of a tumour to produce metastasis. ZBP1 mediates transport and
translational control of selected mRNAs (Figure 1). However, it is
unclear how target recognition takes place, and we do not have
at present a mechanistic model of regulation. Our work reveals
how ZBP1 makes use of two domains with very different affinities
and specificities to select the b-actin mRNA target (Figure 2),
and fold the RNA chain. ZBP1 binding leads to the architectural
rearrangement of the RNA target, and ZBP1 phosphorylation by
Src may release the RNA structure imposed by the protein.
Figure 2. Structure of ZBP1 KH3/KH4 di-domain in complex with the
RNA target
Publications
Nicastro G, Garcia-Mayoral MF, Hollingworth D, Kelly G, Martin SR, Briata P, Gherzi R and Ramos
A (2012)
Noncanonical G recognition mediates KSRP regulation of let-7 biogenesis.
Nature Structural & Molecular Biology 19:1282–1286
Figure 1. ZBP1 regulation of b-actin mRNA localised translation
Cukier CD, Hollingworth D, Martin SR, Kelly G, Díaz-Moreno I and Ramos A (2010)
Molecular basis of FIR-mediated c-myc transcriptional control.
Nature Structural & Molecular Biology 17:1058-64
Trabucchi M, Briata P, Garcia-Mayoral M, Haase AD, Filipowicz W, Ramos A, Gherzi R and
Rosenfeld MG (2009)
The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs.
Nature 459:1010-1014
69
STRUCTURAL BIOLOGY
Molecular Structure
Katrin Rittinger
Structural biology of signalling networks that regulate innate and adaptive immunity
Lab members: Nicholas Brown, Diego Esposito, Manuela Hess, Louise Holland, Marios Koliopoulos, Luigi Martino, Rohini Rana, Ben
Stieglitz
The innate immune system is crucial for the rapid detection of
pathogens and the induction of a pro-inflammatory immune
response. Pattern recognition receptors (PRRs) are the sensors
of infection and activate multiple signalling pathways that lead
to the production of pro-inflammatory cytokines. However,
excessive activation of these pathways can also induce
autoimmune disease and chronic inflammation highlighting the
importance of a tight control of these processes. Members of the
NOD like receptor (NLR) family act as intracellular PRRs and we are
interested in providing a molecular description of their activity
and elucidate how they recognise their targets and relay this
information to induce a specific cellular response.
A key mechanism to regulate immune and inflammatory signalling
pathways is the reversible modification of proteins with ubiquitin
chains, a process called ubiquitination. Chains linked via K63 and
M1 (“linear chains”) are particularly important for the regulation
of immune and inflammatory responses. We aim to elucidate the
molecular mechanism by which specific types of ubiquitin chains
are synthesised and attached to a target by E3 ubiquitin ligases.
LUBAC is an E3 that specifically synthesises linear ubiquitin chains
and we have been able to explain the molecular determinants
underlying its chain linkage specificity using a combination of
structural and biochemical approaches.
The structure of the active HOIP-ubiquitin transfer complex showing how
the LUBAC subunit HOIP recognises the donor and acceptor ubiquitin and
determines chain linkage specificity
Publications
Stieglitz B, Rana RR, Koliopoulos MG, Morris-Davies AC, Schaeffer V, Christodoulou E, Howell S,
Brown NR, Dikic I and Rittinger K (2013)
Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP.
Nature 503: 422-426
Fridh V and Rittinger K (2012)
The tandem CARDs of NOD2: intramolecular interactions and recognition of RIP2.
PLOS ONE 7:e34375
Stieglitz B, Morris-Davies AC, Koliopoulos MG, Christodoulou E and Rittinger K (2012)
LUBAC synthesizes linear ubiquitin chains via a thioester intermediate.
EMBO Reports 13:840-846
See reference 228 in the bibliography at the back for publication from this group in 2013.
70
Topology diagram of the minimal catalytic core of the LUBAC subunit HOIP
STRUCTURAL BIOLOGY
Peter Rosenthal
Cryomicroscopy of proteins, viruses and cells
Lab members: Lesley Calder, Tim Grant, Andy Howe, James Streetley, Pauline McIntosh, Sebastian Wasilewski
Our group studies the architecture of large protein assemblies in
order to understand basic molecular mechanisms that control
protein and membrane traffic in the cell and in virus infection.
We apply electron cryomicroscopy and image analysis to
study the structure of purified protein complexes in frozen
solution, and electron cryotomography to directly image cells
in a frozen-hydrated state providing high-resolution images of
cell architecture as well as structural information on protein
complexes in vivo. We are also working to improve experimental
methods for high-resolution imaging of proteins and to develop
new computational procedures for image analysis.
We build structural models for Weibel-Palade bodies, storage
granules for von Willebrand factor, using cryotomography
and study their structural changes during exocytosis. We are
interested in how viruses enter cells by membrane fusion and how
new particles are assembled and released by budding through
the host membrane. High-resolution cryomicroscopy of influenza
virus reveals the structure of the virus envelope and the internal
architecture of the virus. Our website makes available software
for validating 3D structures obtained by single particle electron
cryomicroscopy. (https://cryoem.nimr.mrc.ac.uk/software/).
Tilt-pair analysis shows the consistency of different views of a 3D
structure with single particle images.
Publications
Sader K, Stopps M, Calder LJ and Rosenthal PB (2013)
Cryomicroscopy of radiation sensitive specimens on unmodified graphene sheets: reduction of
electron-optical effects of charging.
Journal of Structural Biology 183:531-536
Wasilewski S, Calder LJ, Grant T and Rosenthal PB (2012)
Distribution of surface glycoproteins on influenza A virus determined by electron cryotomography.
Vaccine 30:7368-7373
Image of influenza virus by electron cryomicroscopy.
See reference 210 in the bibliography at the back for publication from this group in 2013.
Berriman JA, Li S, Hewlett LJ, Wasilewski S, Kiskin FN, Carter T, Hannah MJ and Rosenthal PB (2009)
Structural organization of Weibel-Palade bodies revealed by cryo-EM of vitrified endothelial cells.
71
STRUCTURAL BIOLOGY
Molecular Structure
Steve Smerdon EMBO member
Structural biology of phosphorylation-dependent signalling in the cell cycle and DNA
Lab members: Julie Clapperton, Oliver de Peyer, Mohamed Ismail, Otto Kyrieleis, Richard Li, Jan Lloyd, Sapir Ofer, Simon Pennell, Lasse
Stach, Grace Yu, Tom Flower
The dynamic nature of cellular signalling processes requires them to be
rapidly reversible, a characteristic that is generally achieved through protein
phosphorylation. The response to DNA damage is mediated by a cascade of
phosphorylation that originates at the lesion and is transduced to effector
molecules and complexes. Defects in the precision of phosphorylation are
a primary cause of many cancers and other diseases. By understanding the
molecular basis of specificity within a web of regulatory interactions, we can
determine why these processes run amok, and may be able to design drugs
to combat these effects. To this end, we focus on an emerging group of
proteins and modules such as 14-3-3, Forkhead-associated (FHA), BRCA1C-terminus (BRCT) and Polo-box domains that function as phosphorylationdependent adaptors or scaffolding molecules in Ser/Thr kinase pathways.
Large-scale proteomics approaches are now revealing extraordinary levels
of protein phosphorylation activity in response to DNA-damage and other
cellular stimuli. Although we are continuing our studies of the ‘classical’
pSer/pThr binding modules, it is clear that many other protein domains are
capable of this functionality. Most recently we have been able to structurally characterise such a novel phospho-interactor called
Mob1which acts to localise its partner kinase Dbf2 to the mitotic spindle apparatus through binding to phosphosites created by the
Cdc15 kinase. Here, Dbf2 becomes activated by Cdc15 itself permitting robust initiation of mitotic exit network signalling through a
two-step scaffolding mechanism.
Publications
Rock JM, Lim D, Stach L, Ogrodowicz RW, Keck JM, Jones MH,
Wong CCL, Yates JR, Winey M, Smerdon SJ, Yaffe MB and
Amon A (2013)
Activation of the yeast hippo pathway by phosphorylationdependent assembly of signaling complexes.
Science 340:871-875
Jungmichel S, Clapperton JA, Lloyd J, Hari FJ, Spycher C,
Pavic L, Li J, Haire LF, Bonalli M, Larsen DH, Lukas C, Lukas J,
Macmillan D, Nielsen ML, Stucki M and Smerdon SJ (2012)
The molecular basis of ATM-dependent dimerization of the
Mdc1 DNA damage checkpoint mediator.
Lloyd J, Chapman JR, Clapperton JA, Haire LF, Hartsuiker E, Li
J, Carr AM, Jackson SP and Smerdon SJ (2009)
A supramodular FHA/BRCT-repeat architecture mediates
Nbs1 adaptor function in response to DNA damage.
Cell 139:100-11
See reference 205, 227 in the bibliography at the back for
publication from this group in 2013.
The expanding family of phospho-binding domains.
72
STRUCTURAL BIOLOGY
Molecular Structure
Mitochondrial biogenesis and diseases
Lab members: Ilaria Dalla Rosa, Romina Durigon, Alice Louisa Mitchell, Mara Mennuni
The biogenesis of mitochondria requires the import, targeting and
assembly of over 1,500 nuclear encoded proteins, to create doublemembrane bound organelles. Hundreds of these proteins are involved
in the maintenance and expression of small circles of DNA inside
the mitochondrion that yield a mere 13 proteins needed for energy
production. Mutations in a burgeoning set of nuclear genes have been
shown to cause defects in mtDNA that result in loss of mitochondrial
function. Hence, the characterisation of these gene products is critical
to a full understanding of the disease and the design of rational
therapeutic strategies.
We aim to define the molecular basis of mtDNA loss. To this end we are
studying the MPV17 family of proteins and have recently discovered
that one of its members is needed for the normal distribution of
mitochondrial DNA (and mitochondria) in cells (Figure 1).
Gene therapy is still in its infancy, and so the best immediate prospect
for treating mitochondrial dysfunction is to boost mitochondrial biogenesis. Our recent work on mitochondria and amino acid
metabolism suggests that nutrient availability has a major impact on mitochondrial energy production (Figure 2). Therefore, we
have begun to investigate the effects of ‘nutriceutical’ and pharmacological interventions to ameliorate mitochondrial dysfunction.
Figure 2. Amino acid starvation increases mitochondrial respiratory capacity.
Publications
Figure 1. Silencing of MPV17L2 alters mitochondrial DNA
distribution.
Pearce S, Nezich CL and Spinazzola A (2013)
Mitochondrial diseases: translation matters.
Molecular and Cellular Neuroscience 55:1-12
Spinazzola A (2011)
Mitochondrial DNA mutations and depletion in pediatric medicine.
Seminars in Fetal and Neonatal Medicine 16:190-196
Viscomi C, Spinazzola A, Maggioni M, Fernandez-Vizarra E, Massa V, Pagano C, Vettor R, Mora M and Zeviani M (2009)
Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice.
Human Molecular Genetics 18:12-26
73
STRUCTURAL BIOLOGY
Molecular Structure
Ian Taylor
Macromolecular assemblies
Lab members: Laurence Arnold, Neil Ball, Valerie Ennis-Adeniran, Laura Robertson, David Schwefel, Stephanie Cumberworth
Many of the fundamental processes carried out within living cells are
directed by macromolecular assemblies of protein and nucleic acid
molecules, often referred to as “molecular machines”. Malfunction of
a molecular machine resulting in the breakdown of a normal cellular
process is the cause of many human cancers, developmental defects,
neurological disorders and other congenital disease states. In order
to prevent, combat or repair defects that lead to disease it is vital that
we understand how the macromolecular components of molecular
machines assemble, function and cooperate with one another in
order to carry out complex biological processes.
To understand how molecular machines function and perform their
biological task we study molecular assemblies by applying structural,
biophysical and biochemical methodologies. These approaches allow
us to dissect a macromolecular complex, visualise the components
and examine the interactions between the molecules that make
up the complex. Current projects include examining complexes
that mediate transcriptional elongation, 3’-end processing and
polyadenylation, analysis of the interaction of the retroviral Gag
protein with host factors and structural studies of host-cell antiretroviral restriction factors and lentiviral accessory proteins.
Structure of the Human Foamyvirus Gag-Env complex. Monomers
of HFV Gag are shown in green and blue. The helical Env peptides
bound to each Gag are coloured magenta and gold.
Publications
Goldstone DC, Flower TG, Ball NJ, Sanz-Ramos M, Yap MW, Ogrodowicz RW, Stanke N,
Reh J, Lindemann D, Stoye JP and Taylor IA (2013)
A unique spumavirus Gag N-terminal domain with functional properties of
orthoretroviral matrix and capsid.
Goldstone DC, Ennis-Adeniran V, Hedden JJ, Groom HCT, Rice GI, Christodoulou E,
Walker PA, Kelly G, Haire LF, Yap MW, de Carvalho LP, Stoye JP, Crow YJ, Taylor IA and
Webb M (2011)
HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate
triphosphohydrolase.
Nature 480:379-82
Hilditch L, Matadeen R, Goldstone DC, Rosenthal PB, Taylor IA and Stoye JP (2011)
Ordered assembly of murine leukemia virus capsid protein on lipid nanotubes directs
specific binding by the restriction factor, Fv1.
Proceedings of the National Academy of Sciences, USA108:5771–5776
See references 98 in the bibliography at the back for publications from this group in 2013.
74
The SAMHD1 active site. SAMHD1 is shown in grey cartoon. A bound substrate
deoxynucleoside triphosphate is shown as sticks along with residues that
contact the phosphates and bound metal ion.
STRUCTURAL BIOLOGY
Willie Taylor
Protein structure analysis and design
Lab members: Michael Doran, Jens Kleinjung, Jose Saldanha
Proteins are the main essential active agents in biology and
without them almost none of the processes that we associate
with life would take place. Proteins enact their tasks, not as the
linear sequence of amino acids that defies their uniqueness, but
more typically as a compact three dimensional structure. It is the
aim of my group to try to understand the relationship between
the protein sequence and its structure and hence its function.
Recent progress was made on the prediction of protein contacts
from large multiple sequence alignments. Given at least 1000
sequences, our method was able to predict intra-chain contacts
that were sufficient to uniquely specify a three-dimensional
structure for a number of proteins. However, application of the
approach in the determination of structure is currently of limited
use as the proteins that tend to have such large collections of
related sequences are typically bacterial with a good chance that
one of the members of the family already has a known structure that can be used for the much simpler and more reliable approach
of modelling by homology. We have therefore turned our attention to application areas where structural information is sparse but
the sequences remain plentiful. Current applications include the tertiary structure of RNA (in collaboration with Russell Hamilton,
Biochemistry, Oxford and Michael Sadowski ex. Math. Biol., NIMR), with a view to an extension towards protein/RNA interactions.
Another application area is to large molecular systems and here we have begun work on proteins in the bacterial flagellum motor
(in collaboration with Shahid Khan, visiting worker, Physical Biochemistry, NIMR and Morgan Beeby, Imperial College). At NIMR, we
have completed an analysis of the core protein component FliG and are now incorporating other core components. Work with
Imperial will focus more on the ATPase component in combination with cryo-EM studies. Both these applications should provide
data for large-scale coarse-grained molecular modelling (described in last year’s report).
Publications
Sadowski MI and Taylor WR (2013)
Prediction of protein contacts from correlated sequence
substitutions.
Science Progress 96:33-42
Correlated mutation prediction of RNA structure of the SAM Riboswitch. a). A minimum free energy
prediction using RNAfold shows a weak overall similarity to the experimentally determined structure.
b). A stochastic context-free grammar prediction using Infernal is better but lacks base triplets and
pseudoknots. c). The known tertiary structure shows the correlated mutation predicted contacts in
green and red. The blue circles indicate a pseudoknot.
Taylor WR, Hamilton RS and Sadowski MI (2013)
Prediction of contacts from correlated sequence
substitutions.
Current Opinion in Structural Biology 23:473-479
75
STRUCTURAL BIOLOGY
Martin Webb
The molecular mechanisms of motor proteins
Lab members: Claudia Arbore, Colin Davis, Simone Kunzelmann, Daniela Quaglia, Gordon Reid, Lesley Southerden,
Renée Vancraenenbroeck
Movement of proteins along DNA is an essential feature of cells,
for example occurring during DNA replication and repair. Helicases
are enzymes that move along double-stranded DNA, separating the
strands so making them available for further processing. For correct
cell maintenance and division, it is essential that there is tight control
of such processing. We are interested in the mechanism and control
of such processes. We are developing new optical approaches, such as
reagentless biosensors, both to study this movement along DNA, but
also to develop assays for a wide range of enzymatic activities.
Our helicase project aims to understand how these motor proteins
interacts with other proteins as well as move through DNA. Replication
of certain plasmids, which contain antibiotic resistance genes and are
readily transferred between bacteria, exemplifies this. Such replicating
plasmids contain a specific double-stranded origin of replication, and
are bound with a replication initiation factor (RepD), helicase and
polymerase. By constructing this system in vitro, we study the role and
mechanism of each component. The development of biosensors has
included one for ADP or GDP that is suitable for real-time assays and
high-throughput approaches.
Atomic force microscopy (AFM) images of plasmid unwinding by PcrA helicase
RepD initiator and SSB. A. Supercoiled plasmid. B. Plasmid nicked by RepD. C. Partial
unwinding
Publications
Chisty LT, Toseland CP, Fili N, Mashanov GI, Dillingham MS, Molloy JE and Webb MR (2013)
Monomeric PcrA helicase processively unwinds plasmid lengths of DNA in the presence of the initiator protein
RepD.
Toseland CP and Webb MR (2013)
ATPase mechanism of the 5’-3’ DNA helicase, RecD2: evidence for a pre-hydrolysis conformation change.
ATP hydrolysis by RecD2 helicase. A. Hydrolysis of a fluorescent
ATP analogue (mantATP): fluorescence (solid line), mantADP
formation (circles) and phosphate release (dotted line). B.
Model and fit to data
76
Kunzelmann S and Webb MR (2011)
Fluorescent detection of GDP in real time with the reagentless biosensor, rhodamine-ParM.
See references 52, 100, 238, 257 in the bibliography at the back for publications from this group in 2013.
Neurosciences
Developmental Neurobiology
David Wilkinson (Head of Division)
Siew-Lan Ang
Sila Ultanir
Molecular Neurobiology
François Guillemot (Head of Division)
Vassilis Pachnis
Iris Salecker
Neurophysiology
Troy Margrie (Head of Division)
Denis Burdakov
Andreas Schaefer
Physiology and Metabolism
Alex Gould (Head of Division)
Markus Ralser
Mariia Yuneva
77
NEUROSCIENCES
Cancer metabolism
Lab members: Louise Fets, Stefanie Gehrig, Fiona Grimm, Brintha Hayes, Patricia Nunes
Cancer cells utilise nutrients in a distinct manner compared to
most normal cells. This phenomenon reflects, in part, an increased
demand for cellular building blocks to support proliferation, as
well as a need to deal with the unique challenges that cancer cells
face from their environment. Our lab is investigating the molecular
mechanisms that underlie the characteristic metabolism of tumours.
We are further interested in understanding how the metabolic
features of individual cell types within the tumour niche influence
cancer development. These studies are complemented by structurebased design of molecular biosensors to probe metabolism in vivo,
at the single-cell level.
One aspect of our work has focused on the glycolytic enzyme
PKM2. We showed that allosteric regulation of PKM2 alters glucose
metabolism to help cancer cells survive under oxidative stress
elicited by low oxygen concentrations (hypoxia), a condition
often encountered in tumours. We also found that small molecule activators of PKM2 disrupt this process and sensitise cancers
to oxidant-induced death. Our results indicate that expression of enzymes with specific allosteric properties underlies metabolic
re-programming in cancer. In collaboration with Jens Kleinjung (Mathematical Biology), we are currently using computational
approaches to systematically investigate allosteric regulation mechanisms of cancer-specific metabolic enzyme isoforms.
Publications
Fets L and Anastasiou D (2013)
p73 keeps metabolic control in the family.
Nature Cell Biology 15:891-3
Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS,
Tempel W, Dimov S, Shen M, Jha A, Yang H, Mattaini KR, Metallo
CM, Fiske BP, Courtney KD, Malstrom S, Khan TM, Kung C,
Skoumbourdis AP, Veith H, Southall N, Walsh MJ, Brimacombe
KR, Leister W, Lunt SY, Johnson ZR, Yen KE, Kunii K, Davidson
SM, Christofk HR, Austin CP, Inglese J, Harris MH, Asara JM,
Stephanopoulos G, Salituro FG, Jin S, Dang L, Auld DS, Park HW,
Cantley LC, Thomas CJ and Vander Heiden MG (2012)
Pyruvate kinase M2 activators promote tetramer formation
and suppress tumorigenesis.
Nature Chemical Biology 8:839–847
Electrostatic surface representation of PKM2 (left) and docking model of a phosphotyrosine-containing
peptide (sticks) bound to PKM2 (right).
Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang J-K,
Shen M, Bellinger G, Sasaki AT, Locasale JW, Auld DS, Thomas
CJ, Vander Heiden MG and Cantley LC (2011)
Inhibition of pyruvate kinase M2 by reactive oxygen species
contributes to cellular antioxidant responses.
Science 334:1278-1283
78
NEUROSCIENCES
Siew-Lan Ang
Transcriptional control of midbrain dopaminergic neuron development and function
Lab members: Kamal Bouhali, Anita Kociaj, Shabana Khan, Emmanual Metzakopian, Alessandro Pristera
Midbrain dopamine (mDA) neurons are involved in important
brain functions, including motor control and reward-based
behaviours. Disruptions of dopamine signaling underlie a
variety of psychomotor disorders including Parkinson’s disease
and addiction diseases. mDA neurons share the ability to
synthesise, package, release and reuptake the neurotransmitter
dopamine as they express a common set of enzymes, for
example tyrosine hydroxylase and transporters involved in these
processes. However, recent studies demonstrate the presence
of heterogeneous populations of mDA neurons with different
molecular markers and biophysical properties. Our main goals are
to decipher gene regulatory networks regulating common and
distinct properties of mDA neurons.
We currently focus on understanding how the developmental
programmes that specify cell type identity regulate molecular and
cellular traits that underlie normal function and homeostasis of
mDA neurons. We use mouse embryos and in vitro differentiation
of mouse embryonic stem cells to identify genes that regulate
the specification, differentiation, wiring and maintenance of mDA
neurons. Our experimental approaches include a combination
of embryological, genetic, molecular and genomic approaches,
including genetic fate mapping studies, null and conditional
mutant mice, brain slice, biochemical and genome wide analyses.
These studies will provide insights into how embryonic gene
expression leads to mature neuronal phenotypes.
Publications
Stott SRW, Metzakopian E, Lin W, Kaestner KH, Hen R and Ang
S-L (2013)
Foxa1 and Foxa2 are required for the maintenance of
dopaminergic properties in ventral midbrain neurons at late
embryonic stages.
Journal of Neuroscience 33:8022-34
Metzakopian E, Lin W, Salmon-Divon M, Dvinge H, Andersson E,
Ericson J, Perlmann T, Whitsett JA, Bertone P and Ang SL (2012)
Genome-wide characterization of Foxa2 targets reveals
upregulation of floor plate genes and repression of
ventrolateral genes in midbrain dopaminergic progenitors.
Development 139:2625-2634
Yan CH, Levesque M, Claxton S, Johnson RL and Ang S-L (2011)
Lmx1a and Lmx1b function cooperatively to regulate
proliferation, specification, and differentiation of midbrain
dopaminergic progenitors.
Distinct populations of midbrain dopamine
expressing either tyrosine hydroxylase alone
(red) or together with the basic-helix-loop-helix
transcription factor NeuroD6 (yellow cells).
Gene enhancers driving LacZ
expression (blue) specifically in
dopamine progenitors in the ventral
midbrain of chick embryos.
79
NEUROSCIENCES
Neurophysiology
Denis Burdakov
Brain control of sleep and appetite
Lab members: Antonio Gonzalez, Conni Schöne, Sarah Cains, Craig Blomeley, Christin Kosse
How do organisms combine dynamic existence with stable health? What
components are required (sensors, transistors, logic gates, and predictors)? What
are their biological correlates? How is their function orchestrated to achieve unity
of purpose and avoid malfunction? We address these fundamental questions
in two areas: brain state control and metabolic balance in mammals. Not only
are these areas of medical relevance (one in four people suffer from obesity
and/or insomnia), they are also amenable to modern tools for observation and
manipulation.
To probe the functional logic of fast interactions between cells we use optogenetic
tools for millisecond control of signals from specific neuronal types. We work with
transgenic mouse models and sometimes with computer-simulated virtual cells
and cell systems. Ongoing projects also use imaging, electrophysiology, anatomical
tracing, immunolabelling and whole-body physiological assays to explore closely
interrelated themes:
• Cells and mechanisms for internal body-state sensing
• Regulation of firing patterns and transmitter release in brain circuits
• Input / output properties of synapses, cells, and circuits
• Metabolic, chemical, and electrical signalling in the hypothalamus
• Brain and brain↔body orchestration
• Alterations in disorders of brain function and metabolic balance
Genetic targeting of
“light-switches” such
as excitatory ion
channel ChR2 allows
to establish
consequences of
millisecond-scale
changes in
define elements of
vital neurocircuits.
Widely-projecting orx and MCH neurons regulate
sleep and energy balance, and are themselves regulated
by ambient glucose.
Publications
Jego S, Glasgow SD, Herrera CG, Ekstrand M, Reed SJ, Boyce R, Friedman J, Burdakov D and Adamantidis AR (2013)
Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus.
Nature Neuroscience 16: 1637-1643
Karnani MM, Apergis-Schoute J, Adamantidis A, Jensen LT, de Lecea L, Fugger L and Burdakov D (2011)
Activation of central orexin/hypocretin neurons by dietary amino acids.
Neuron 72:616-629
See references 39 in the bibliography at the back for publications
80
Williams RH, Alexopoulos H, Jensen LT, Fugger L and Burdakov D (2008)
Adaptive sugar sensors in hypothalamic feeding circuits.
NEUROSCIENCES
Alex Gould EMBO member, FMedSci
Regulation of growth and metabolism
Lab members: Andrew Bailey, Einat Cinnamon, Clara Fons, Rami Makki, Patricia Serpente, Annick Sawala, Irina Stefana, Vanessa Tixier
All organisms regulate their growth according to internal genetic programmes and
the availability of nutrients from the environment. As human and other animal
embryos develop they increase in size dramatically. We wish to identify the nutritional
factors and genetic networks that promote growth during development and, equally
importantly, those that shut it down in adulthood. This research also aims to shed
light on the complex interactions between nutrition and the genes influencing growth,
metabolism and cancer.
Currently, we are investigating how the growth and metabolism of some, but not
other, body organs is protected against malnutrition. Much of our research uses the
fruit fly Drosophila, a model organism sharing many genes with mammals. We recently
developed a methodology called multi-isotope imaging mass spectrometry (MIMS),
which allows organ metabolism to be quantified with unprecedented spatial resolution.
We have also identified two molecular mechanisms that spare the function of the
developing brain when dietary nutrients are scarce. One of these selectively protects
brain growth while the other ensures that, even if growth is compromised, neuronal
diversity can still be maintained.
Publications
Lanet E, Gould AP and Maurange C (2013)
Protection of neuronal diversity at the expense of neuronal
numbers during nutrient restriction in the Drosophila visual
system.
Cell Reports 3:587–594
Steinhauser ML, Bailey AP, Senyo SE, Guillermier C, Perlstein
TS, Gould AP, Lee RT and Lechene CP (2012)
Multi-isotope imaging mass spectrometry quantifies stem
cell division and metabolism.
Nature 481:516-520
Cheng LY, Bailey AP, Leevers SJ, Ragan TJ, Driscoll PC and
Gould AP (2011)
Anaplastic lymphoma kinase spares organ growth during
nutrient restriction in Drosophila.
Cell 146:435-47
Protection of neuronal diversity at the expense of neuronal numbers during malnutrition in Drosophila.
See references 34, 137, 199 in the bibliography at the back
for publications from this group in 2013.
81
NEUROSCIENCES
François Guillemot EMBO member, FMedSci
Genomic and functional analysis of neurogenesis
Lab members: Angeliki Achimastou, Jimena Andersen, Isabelle Blomfield, Lan Chen, Zachary Gaber, Patricia Garcez,
Sebastien Gillotin, Ayako Ito, Koji Oishi, Noelia Urban, Debbie van den Berg, Benny Yang
Neural stem cells in the developing and adult brain produce a
vast array of neurons that integrate into functional circuits. This
process of neurogenesis involves the division of stem cells and the
production of neuronal precursors that migrate to specific locations
and differentiate. We study the genetic programmes that regulate
and coordinate these different cellular processes. We use genomic
approaches to identify the genes involved in the programme
of neurogenesis and we use functional assays to determine
the contribution of individual genes to the different steps of
neurogenesis.
New neurons are added to the adult hippocampus where they have
important roles in memory formation. The stem cells that generate
these new neurons become quiescent in ageing animals, which
might contribute to loss of memory in old age. We have identified
a transcription factor that promotes the division of stem cells in the adult hippocampus (ASCL1) and another factor that promotes
their quiescence (NFIX). We currently study how these factors control stem cell activity, and how their expression and function is
regulated by extracellular signals provided by the stem cell niche.
Publications
Martynoga B, Mateo JL, Zhou B,
Andersen J, Achimastou A, Urbán N,
van den Berg D, Georgopoulou D,
Hadjur S, Wittbrodt J, Ettwiller L, Piper
M, Gronostajski RM and Guillemot
F (2013)
Epigenomic enhancer annotation
reveals a key role for NFIX in neural
stem cell quiescence.
Genes & Development 27:1769-1786
Castro DS, Martynoga B, Parras C,
Ramesh V, Pacary E, Johnston C,
Drechsel D, Lebel-Potter M, Garcia LG,
Hunt C, Dolle D, Bithell A, Ettwiller L,
Buckley N and Guillemot F (2011)
A novel function of the proneural
factor Ascl1 in progenitor
proliferation identified by genomewide characterization of its targets.
Stem cells in the hippocampus express the stem cell
marker GFAP (red) and a fraction have deleted the
stem cell factor Ascl1 and activated the reporter GFP
(green).
See references 20, 105, 112, 152, 164, 183, 189, 233, 255, 256 in the
82
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Institutefor
forMedical
MedicalResearch
Research
Regulatory regions identified in the genome of neural stem
cells by DHS-Seq were clustered based on the recruitment
of different transcription factors and the presence of
different histone modifications.
Pacary E, Heng J, Azzarelli R, Riou P,
Castro D, Lebel-Potter M, Parras C,
Bell DM, Ridley AJ, Parsons M and
Guillemot F (2011)
Proneural transcription factors
regulate different steps of cortical
neuron migration through Rndmediated inhibition of RhoA
signaling.
Neuron 69:1069-84
NEUROSCIENCES
Neurophysiology
Troy Margrie
The typology of neuronal networks
Lab members: Ed Bracey, Alex Brown, Danielle Carmignac, Christian Niedworok, Ede Rancz, Charly Rousseau, Anja Schmaltz, Molly
Strom, Mateo Velez-Fort
Our goal is to determine how the brain orchestrates the activity
of neurons to encode a sensory stimulus. Understanding how
neural systems achieve this will inform us as to how healthy
and diseased brains develop and maintain normal cognitive
function. We use a top-down, multi-disciplinary approach
that encompasses whole-brain down to the cellular level of
experimental analysis. Specifically, we are investigating several
inter-related aspects:
1. The relationship between biophysical diversity and
neuronal function
2. The relationship between neuronal function and
connectivity
3. The contribution of local and long-range connectivity
to sensory perception
We use the mouse model and focus on two brain regions that offer unique advantages. The olfactory bulb is comparatively simple
and contains anatomically and functionally discrete local networks that may be identified in vivo and directly targeted. This sensory
modality is highly significant to rodents and they are readily trained to perform sensory discrimination based on the activity of the
readily accessible neuronal networks under investigation. The neo-cortex, where functional networks are typically less well defined
and contain a large number of highly diverse cell types, is ideal for investigating the rules of circuit function and connectivity in
complex neuronal pathways.
Publications
Bracey EF, Pichler B, Schaefer AT, Wallace DJ and Margrie
TW (2013)
Perceptual judgements and chronic imaging of altered
odour maps indicate comprehensive stimulus template
matching in olfaction.
Nature Communications 4:2100
Angelo K, Rancz EA, Pimentel D, Hundahl C, Hannibal J,
Fleischmann A, Pichler B and Margrie TW (2012)
A biophysical signature of network affiliation and
sensory processing in mitral cells.
Nature 488:375–378
Analysis of three-dimensional imaging data obtained from serial tomography allows us to chart the
connectivity of neuronal circuits using virus-based tracing methods and a segmented digital atlas (Allen
Brain Institute).
Rancz EA, Franks KM, Schwarz MK, Pichler B, Schaefer AT
and Margrie TW (2011)
Transfection via whole-cell recording in vivo: bridging
single-cell physiology, genetics and connectomics.
Nature Neuroscience 14:527-532
83
NEUROSCIENCES
Vassilis Pachnis EMBO member, FMedSci
Development of the nervous system
Lab members: Werend Boesmans, Myrto Denaxa, Tiffany Heanue, Melanie Kalaitzidou, Panayotis Kabouridis,
Chryssa Konstantinidou, Reena Lasrado, Rita Lopes, Sarah McCallum, Valentina Sasselli
The nervous system mediates the interaction of organisms with
their environment, contributes to the maintenance of internal
homeostasis and is the anatomical substrate of cognitive
activity. Normal function of the nervous system depends
on the generation, at the right time and place, of integrated
cellular networks made up of a large number of diverse neurons.
Understanding the mechanisms that control the generation of
distinct neuronal subtypes and their migration to the appropriate
location is critical for comprehending normal neuronal
development and for treating neuronal deficiencies.
Our studies explore the mechanisms that control the development
of the enteric nervous system in the gut: how enteric neurons and
their progenitors migrate during embryogenesis and how they
differentiate to form complex networks that regulate gut motility
and secretions. We also study the mechanisms that control
neuronal differentiation in the forebrain. We have identified signals
that mediate cellular interactions, molecules that underlie the
functional interconnection of neurons and transcription factors
underlying neuronal cell fate decisions. Our studies provide novel
insight into the development and function of the nervous system
in normal and disease conditions.
Publications
Denaxa M, Kalaitzidou M, Garefalaki A,
Achimastou A, Lasrado R, Maes T and Pachnis
V (2012)
Maturation promoting activity of Satb1 in
MGE-derived cortical interneurons
Cell Reports 2:1351-1362
Laranjeira C, Sandgren K, Kessaris N, Richardson
W, Potocnik A, Vanden Berghe P and Pachnis V
(2011)
Glial cells in the mouse enteric nervous system
can undergo neurogenesis in response to
injury.
Journal of Clinical Investigation 121:3412-3424
Kioussis D and Pachnis V (2009)
Immune and nervous systems: more than just a
superficial similarity?
Immunity 31:705-710
A rich neuronal network within the outer wall
(bottom) and the villi of adult intestine.
84
Maturation of different classes of interneuron precursors
transplanted into the cortex of postnatal mice.
See references 169, 215 in the bibliography at the
NEUROSCIENCES
Markus Ralser
Evolution and structure of metabolic networks
For a long time, cellular metabolism has been viewed as a static
series of biochemical reactions. Recent research however reveals
that the cellular metabolic network is in fact highly dynamic
and flexible. This property is implicated in many biologically
important phenomena, such as ageing, cellular robustness,
and adaptation to ever changing environments. These novel
properties bring metabolism centre-stage both for developing
therapies against cancer and neurodegenerative disorders and
for understanding the ageing process.
We use a combination of mass-spectrometry based
metabolomics and techniques of functional genomics to
characterise cellular metabolism. This research led to the
identification of a dynamic switch in central metabolism, which
prevents cells from oxidative damage, and is an important
mechanism during cancer metabolism. Recently, we found
a second metabolic mechanism that functions as a timer of
the cellular anti-stress reaction: Two metabolites, spermine
and spermidine, are exported when cells encounter oxidising
molecules. This export functions as rheostat regulator of cell
cycle progression and gene expression (Fig 2).
Figure 2. Metabolite export as time-keeper of the cellular stress response.
High concentrations of spermine and spermidine (PA) are exported during
the stress response to coordinate gene expression and cell cycle.
Publications
Mülleder M, Capuano F, Pir P, Christen S, Sauer U, Oliver SG and Ralser M (2012)
A prototrophic deletion mutant collection for yeast metabolomics and systems biology.
Nature Biotechnology 30:1176-8
Figure 1. Structure of the mitochondrial
network during stress conditions illustrates
the dynamics of metabolism. Yeast
expressing mitochondrial GFP was treated
with an oxidant (H2O22O”H2) and analysed
by super resolution microscopy.
Grüning N-M, Rinnerthaler M, Bluemlein K, Mülleder M, Wamelink MMC, Lehrach H, Jakobs C, Breitenbach M and Ralser M (2011)
Pyruvate kinase triggers a metabolic feedback loop that controls redox metabolism in respiring cells.
Cell Metabolism 14:415-27
Ralser M, Wamelink MMC, Latkolik S, Jansen EEW, Lehrach H and Jakobs C (2009)
Metabolic reconfiguration precedes transcriptional regulation in the antioxidant response.
Nature Biotechnology 27:604-5
85
NEUROSCIENCES
Iris Salecker EMBO member
Visual circuit assembly in Drosophila
Lab members: Holger Apitz, Kathleen Dolan, Richard Kaschula, Benjamin Richier, Nana Shimosako
The ability of animals to perceive their environment and to
generate specific behaviours relies on the activity of many
precisely interconnected neuron subtypes in their brains.
Neurons are found in close association with glial cells, and
both cell types show remarkably diverse shapes. How these
cells are generated and assemble into complex neural circuits
in a coordinated manner during development remains poorly
understood. To address this question, our laboratory uses the
visual system of Drosophila as a model, because it enables us to
dissect the stepwise development of a complex neural circuit
with powerful genetic approaches and single cell resolution.
We are particularly interested in elucidating the cellular and
molecular mechanisms that enable photoreceptor axons to
connect with target neurons within highly regular reiterated
columnar and laminated synaptic units. To facilitate the
identification of cell types based on their intricate branching
patterns during development and in adults, we previously have
devised a multicolour cell-labelling approach, called Flybow. This
technique enables us to stochastically label neurons or glia in
different colours in the same sample. In our recent efforts, we
developed this approach further to overcome initial limitations,
adding new sets of Flybow transgenes with brighter fluorescent
proteins to our toolbox.
In the adult Drosophila visual system, photoreceptor axons (red) are
closely associated with the processes of glial cells (green). Glial cell nuclei
are labeled in blue (image from: Benjamin Richier).
Publications
Shimosako N, Hadjieconomou D and Salecker I (2014)
Flybow to dissect circuit assembly in the Drosophila brain.
Methods in Molecular Biology 1082:57-69
Oyallon J, Apitz H, Miguel-Aliaga I, Timofeev K, Ferreira L and Salecker I (2012)
Regulation of locomotion and motoneuron trajectory selection and targeting by the
Drosophila homolog of Olig family transcription factors.
Developmental Biology 369:261–276
Timofeev K, Joly W, Hadjieconomou D and Salecker I (2012)
Localized netrins act as positional cues to control layer-specific targeting of photoreceptor
axons in Drosophila.
Neuron 75:80-93
86
Using a new Flybow 1.1B transgene, single target neurons were visualised by
the expression of membrane-tethered mTurquoise, Green fluorescent protein
(GFP), mCitrine and mCherry. R8/R7 photoreceptors are shown in blue.
See references 133 in the bibliography at the back for publications from this group in 2013.
NEUROSCIENCES
Neurophysiology
Andreas Schaefer
Neurophysiology of behaviour: information processing in the olfactory system
Lab members: Andrew Erskine, Izumi Fukunaga, Jan Herb, Becky Jordan, Nikolai Kiskin, Mihaly Kollo, Romeo Racz, Bill Wray
Understanding how information is processed in the brain is a
key challenge for neuroscience. We aim to tackle one aspect of
this question by using the mouse olfactory system as a model
to understand mechanisms of sensory object representation
and how neural circuits generate these representations. To this
end we employ detailed anatomical analysis, spatiotemporally
controlled molecular perturbations of the local neural circuitry,
and a quantitative analysis of physiological changes associated
with such perturbations in vitro and in vivo, in particular in the
behaving animal.
Using virus-mediated modification of the early olfactory
circuitry we have shown that increased inhibition accelerated
odour discrimination behaviour while reducing inhibition
impaired it. Whole-cell recordings in vivo now allow us to
identify physiological roles of inhibition; notably, inhibition
profoundly impacts the timing of principal neurons. We are
further investigating the distinct functions of the two primary
interneuron circuits. Using a combination of computational
modelling, targeted optogenetic interference of specific circuits
and whole-cell recordings in vivo, we find a double dissociation
between interneuron circuits and timescales. Using large-scale,
automated behavioural approaches and cell-specific optogenetic
manipulations, we now aim to assess the role of these
circuits in governing olfactory object identification and odour
identification.
Tagging individual mice with radio-frequency identification (RFID) chips
allows for group housing with integrated automatic behavioural analysis.
This approach is reproducible and efficient while maximizing animal
welfare by minimizing stress and providing enriched, social environment
(adapted from Claridge-Chang & Schaefer, 2012).
Publications
Angle MR and Schaefer AT (2012)
Neuronal recordings with solid-conductor intracellular nanoelectrodes (SCINEs).
PLOS ONE 7:e43194
Fukunaga I, Berning M, Kollo M, Schmaltz A and Schaefer AT (2012)
Two distinct channels of olfactory bulb output.
Neuron 75:320-329
(right) Organisation of the olfactory bulb, the first processing stage of the
olfactory system. The two interneuron circuits, juxtaglomerular neurons
(JGN) and granule cells (GCs) mediate distinct functions.
Abraham NM, Egger V, Shimshek DR, Renden R, Fukunaga I, Sprengel R, Seeburg PH, Klugmann M,
Margrie TW, Schaefer AT and Kuner T (2010)
Synaptic inhibition in the olfactory bulb accelerates odor discrimination in mice.
Neuron 65:399-411
87
NEUROSCIENCES
Sila Ultanir
Kinase signaling pathways in neuronal development
Lab members: Lucas Baltussen, Suzanne Claxton, Kalbinder Gill, Amy Lin
Neuronal dendrites are input receiving regions and they
contain synaptic specialisations called spines. Development
of dendritic arbors, spines and synapses are critical for
wiring the neural circuitry and its functioning. Although a
wide range of molecular components have been implicated
in dendritic development, we have limited understanding of
the contribution of kinases to this process. Our lab’s goal is
to uncover novel kinase signaling cascades that are critical
in neuronal development and function. Kinases regulate
most cellular processes, however identification of their
downstream targets has been challenging. We use novel
chemical genetic methods to identify kinase substrates.
We study CDKL5, a kinase that when mutated in humans
results in a neurodevelopmental disorder with similarities
to Rett-syndrome. CDKL5 is expressed in the brain and
is thought to regulate synapse development. Molecular
mechanisms of CDKL5 function are unknown. We are
also interested in AAK1 and GAK kinases that are highly
similar in their kinase domains and are both implicated
in Parkinson’s disease. The neuronal functions of AAK1/
GAK and their downstream effectors are largely unknown.
We use a combination of methods including transgenic
mice, neuronal cultures, imaging and electrophysiology to
characterise morphological and physiological properties of
neurons in rodent brain.
Cultured hippocampal neurons expressing GFP to aid visualisation of dendrites and
dendritic spines. A- Dendritic arbor of a hippocampal neurn, B- Dendritic spines,
sites for excitatory synapses.
Publications
Ultanir SK, Hertz NT, Li G, Ge W-P, Burlingame AL, Pleasure SJ, Shokat KM, Jan LY and Jan Y-N (2012)
Chemical genetic identification of NDR1/2 kinase substrates AAK1 and Rabin8 uncovers their roles in
dendrite arborization and spine development.
Neuron 73:1127-1142
88
An analog-sensitive kinase, with a modified ATP binding pocket,
uses bulky ATP analogs to thiophosphorylate its substrates.
Thiophosphorylated peptide purification leads to identification of
substrates and phosphorylation sites by mass spectrometry.
NEUROSCIENCES
David Wilkinson EMBO member, FMedSci
Regulation of boundary formation and neurogenesis
Lab members: Megan Addison, Jordi Cayuso, Angela Cheung, Sean Constable, Mohamed Ismail, Alexei Poliakov, Hannah Somerfield,
Hannah Stanforth, Harriet Taylor, Qiling Xu
The formation of a sharp border and restriction of cell
intermingling between regions that have distinct identity is
important for establishing the correct organisation of tissues, and
when disrupted underlies disease such as the metastatic spreading
of cancer cells. In the vertebrate nervous system, specific borders
have a further crucial role by forming distinct boundary cells
that regulate neuronal differentiation and patterning. We study
the zebrafish hindbrain as an amenable model for uncovering
molecular mechanisms of boundary formation and neurogenesis.
In previous work, we uncovered key roles of Eph receptor and
ephrin signaling in border sharpening and boundary cell formation,
and showed that boundary cells organise neuronal differentiation
within hindbrain segments. Our ongoing studies seek to elucidate
the molecular pathways by which Eph-ephrin signaling acts, and to
identify further regulators of boundary formation and segmental
patterning. In related work, we are dissecting how interactions of a
transcriptional repressor, Plzf, and a ubiquitination adaptor protein,
Btbd6, regulate neural progenitor maintenance and differentiation.
These studies utilise the powerful genetic and transgenic tools
available in zebrafish for imaging and the analysis of gene function,
together with mathematical modelling and in vitro assays of border
formation.
In vitro assay in which EphB2-expressing cells (green) segregate from
ephrinB1-expressing cells (red). This assay enables analysis of cell
behaviour and biochemical mechanisms underlying segregation and
border formation.
Publications
Terriente J, Gerety SS, Watanabe-Asaka T, Gonzalez-Quevedo R and Wilkinson DG (2012)
Signalling from hindbrain boundaries regulates neuronal clustering that patterns
neurogenesis.
Gonzalez-Quevedo R, Lee Y, Poss KD and Wilkinson DG (2010)
Neuronal regulation of the spatial patterning of neurogenesis.
Developmental Cell 18:136-147
Hindbrain segments (two labelled in green), neurons (blue) and fgf20
expression (red) in the zebrafish embryo. Signaling from boundaries positions
fgf20-expressing neurons at segment centres, which locally inhibit neuronal
differentiation.
Sobieszczuk DF, Poliakov A, Xu Q and Wilkinson DG (2010)
A feedback loop mediated by degradation of an inhibitor is required to initiate neuronal
differentiation.
See references 32, 94, 123, 160, 265 in the bibliography at the back for publications from this group in 2013.
89
NEUROSCIENCES
Mariia Yuneva
Oncogenes and tumour metabolism
Lab members: Wei Lin, Andy Lucas Mendez, Emma Still
Altered metabolism is widely accepted as one of the hallmarks of cancer. Metabolic
changes are a part of the cell-transformation programme and are thought to ensure
that transformed cells have an advantage in accessing and metabolising nutrients
required for cellular proliferation. This goal is achieved, however, at the expense of the
normal control of metabolism. As a result, transformed cells become heavily dependent
on certain nutrients and metabolic pathways. Our aim is to understand how various
factors involved in cellular transformation shape the metabolic and nutrient demands
of cancer cells and to exploit this knowledge towards identifying new therapeutic
targets.
Cancer is an extremely heterogeneous disease and creating therapies that would
be most efficient against each tumour is one of the main challenges in the field.
Our research has demonstrated that metabolic changes in cancer depend on both
tumour-initiating genetic lesions and the tissue environment. We are employing genetics and stable isotope-based metabolomic
approaches to further investigate how metabolism is changed in tumours induced by specific pro-tumourigenic events in various
mammalian tissues as well as to evaluate the requirement of metabolic pathways and tumour-specific enzyme isoforms in the
initiation and progression of neoplasia.
NMR profiles of tissue extracts labelled with 13C-glutamine
demonstrate that liver tumours induced by MYC oncogene catabolise
glutamine differently from tumours induced by MET oncogene.
Oncogenes and tumour suppressor genes regulate
major metabolic pathways often by promoting the
expression and activity of enzyme isoforms distinct
from those expressed in a parental normal tissue.
Publications
Timmerman LA, Holton T, Yuneva M, Louie RJ, PadrM, Daemen A, Hu M, Chan DA, Ethier SP, van ‘t Veer LJ, Polyak K, McCormick F and Gray
JW (2013)
Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target.
Cancer Cell 24:450-465
Yuneva MO, Fan TWM, Allen TD, Higashi RM, Ferraris DV, Tsukamoto T, Mates JM, Alonso FJ, Wang C, Seo Y, Chen X and Bishop JM (2012)
The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type.
See references 237 in the bibliography at the back for publications
90
Yuneva M (2008)
Finding an “Achilles’ heel” of cancer: the role of glucose and glutamine metabolism in the survival of transformed cells.
Cell Cycle 7:2083-9
Developmental Biology
James Briscoe (Joint Head of Division)
Jean-Paul Vincent (Joint Head of Division)
Malcolm Logan
Tim Mohun
Andrew Oates
Stem Cell Biology and Developmental Genetics
Robin Lovell-Badge (Head of Division)
Vivian Li
Kathy Niakan
Peter Thorpe
James Turner
Systems Biology
Jim Smith (Head of Division)
Greg Elgar
Mike Gilchrist
91
GENETICS AND DEVELOPMENT
James Briscoe EMBO member
Pattern formation in the vertebrate nervous system
Lab members: Robert Blassberg, Michael Cohen, Sarah French, Mina Gouti, Debora Keller, Anna Kicheva, Eva Kutejova, Neda
Mousavy, Noriaki Sasai, Despina Stamataki
We study how the central nervous system (CNS) is formed in embryos. Despite its
complexity, the CNS is assembled in a remarkably reliable and accurate manner. This
precision is necessary for the wiring of nerves into the functional neural circuits that give
the CNS its function. Our research focuses on the spinal cord, which is the part of the
CNS that contains the nerves that allow us to sense our environment and respond to
it by moving muscles. Our studies contribute to understanding the development of the
spinal cord as well as shed light on diseased and damaged nervous systems. We hope
this will help in the development of therapies for these conditions.
Specifically, we are interested in the cellular and molecular mechanisms responsible
for the growth and pattern of the neural tube. In ventral regions of the caudal neural
tube, this is governed by the secreted molecule Sonic Hedgehog (Shh). We use a
range of molecular, imaging and modelling approaches to identify and reconstruct the
regulatory network that controls the growth and development of the ventral neural
tube. Specifically we are developing and utilising reagents and theoretical approaches that
allow the single cell resolution imaging of neural tube patterning in vitro and in vivo.
Mathematical simulations of a gene regulatory network reveals that it can either
produce a stable spatial pattern of gene expression (top graph) or sustained temporal
oscillations (bottom graph). The choice of behaviour depends on whether the
green repressive link is stronger (stable spatial pattern) than the red repressive links
(oscillations).
Publications
Jacob J, Kong J, Moore S, Milton C, Sasai N, Gonzalez-Quevedo R, Terriente J, Imayoshi I, Kageyama R, Wilkinson David G, Novitch Bennett
G and Briscoe J (2013)
Retinoid acid specifies neuronal identity through graded expression of Ascl1.
Current Biology 23:412-418
Balaskas N, Ribeiro A, Panovska J, Dessaud E, Sasai N, Page Karen M, Briscoe J and Ribes V (2012)
Gene regulatory logic for reading the Sonic Hedgehog signaling gradient in the vertebrate neural tube.
Cell 148:273-284
Kicheva A, Cohen M and Briscoe J (2012)
Developmental pattern formation: insights from physics and biology.
Science 338:210-212
92
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Research
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NationalInstitute
InstituteforforMedical
Medical
Research
A section through a zebrafish early
during neural development. Individual
nuclei (blue) can be distinguished. A
reporter from a genomic region of the
Pax3 gene (green) recapitulates the
activity of the endogenous Pax3 gene
(red) in the zebrafish spinal cord (dotted
outline).
See references 35, 36, 53, 94, 123, 125, 145, 160, 185, 239 in
the bibliography at the back for publications from this group
in 2013.
Systems Biology
i
Greg Elgar
Regulation of early vertebrate development
Lab members: Stefan Pauls, Boris Noyvert, Laura Doglio, Joseph Price, Johanna Fischer, Lillian Hunt
The early development of the human embryo is an extraordinarily
dynamic and exquisitely controlled process. At the molecular level
events are orchestrated by a large repertoire of transcription factors,
proteins that bind to regulatory regions in genomic DNA to control
gene expression. Mutations in these regulatory regions can lead to
developmental anomalies and disease. Many of the patterning events
that occur are common to all vertebrates, as are the transcription factors
and some of the regulatory code embedded in the genome. However,
the protein-DNA interactions are poorly understood, as are the functional
effects they mediate.
We take a systems level approach to decipher the language and grammar
that is encoded in regulatory DNA, particularly that fraction that is
common to all vertebrates and which therefore directs some of the
most fundamental aspects of vertebrate embryogenesis. We do this
by combining computational approaches with functional assays in zebrafish embryos, an important and tractable model for this
sort of work. Once we identify specific regulatory patterns we can search for these throughout the genome, thereby predicting
other regulatory regions. It is important that we know where these regions are in the genome, and what processes they define, as
mutations in them can lead to developmental disorders and genetic disease.
Publications
Two Ciona regulatory
elements drive
very different but
specific patterns of
reporter expression
in zebrafish
embryos despite
an apparent lack of
identity with any
vertebrate genomic
sequences.
Doglio L, Goode DK, Pelleri MC, Pauls S, Frabetti F, Shimeld SM,
Vavouri T and Elgar G (2013)
Parallel evolution of chordate cis-regulatory code for
development.
Parker HJ, Sauka-Spengler T, Bronner M and Elgar G (2014)
A reporter assay in lamprey embryos reveals both functional
conservation and elaboration of vertebrate enhancers.
PLOS ONE 9:e85492
Pauls S, Smith SF and Elgar G (2012)
Lens development depends on a pair of highly conserved
Sox21 regulatory elements.
Developmental Biology 365:310-318
Green and Red Fluorescent Protein expression in the zebrafish embryo eye, driven by
regulatory sequences from (A) pufferfish and (B) zebrafish. (C) Composite image of A and B
showing overlapping expression in the developing lens.
93
Systems Biology
Mike Gilchrist
Gene regulatory networks in early development
Lab members: Brook Cooper, Elena De Domenico, Rosa Faria, Ian Grant, Nick Owens, Ilya Patrushev, Katalin Varga
Embryo development is a complex and tightly controlled process, with a
remarkably precise outcome. Typically, transcription factors regulate the
expression of individual genes through complex gene regulatory networks.
Our aim is to elucidate these networks using molecular and computational
tools that enable a systematic and large scale approach.
From a high-resolution time series of gene expression data we have
developed a clear picture of the temporal landscape of gene activation in the
early Xenopus embryo. We see three waves of activation between fertilisation
and the onset of gastrulation. The first of these is the rapid
(re-)polyadenylation of existing maternal mRNAs, which help sustain the
embryo through the transcriptionally quiet cleavage stages. The second
wave marks the onset of zygotic transcription, and is associated with the
mid-blastula transition (MBT), where control at the molecular level passes from maternal gene products to those derived from the
embryo’s own genes. The third wave we believe to be composed, at least in part, of direct targets of transcription factors activated
in the second wave. Knowing the identity of the genes activated in each wave, we have a structure within which to look for links in
the gene regulatory networks.
Publications
Gentsch GE, Owens NDL, Martin SR, Piccinelli P, Faial T, Trotter MWB, Gilchrist
MJ and Smith JC (2013)
In vivo T-box transcription factor profiling reveals joint regulation of
embryonic neuromesodermal bipotency.
del Viso F, Bhattacharya D, Kong Y, Gilchrist MJ and Khokha MK (2012)
Exon capture and bulk segregant analysis: rapid discovery of causative
mutations using high-throughput sequencing.
BMC Genomics 13:649
Grant J, Mahadevaiah SK, Khil P, Sangrithi MN, Royo H, Duckworth J, McCarrey
JR, VandeBerg JL, Renfree MB, Taylor W, Elgar G, Camerini-Otero RD, Gilchrist
MJ and Turner JM (2012)
Rsx is a metatherian RNA with Xist-like properties in X-chromosome
inactivation.
Nature 487:254-258
See references 21, 93, 221 in the bibliography at the back for publications
94
High resolution gene expression profiles of polyA+ mRNA show successive waves of gene
activation (upper). Interestingly, the first wave, of polyadenylated maternal mRNA, is more
sensitive to activation thresholds used in computational analysis than the following wave of
zygotic transcription (lower).
Vivian Li
Intestinal stem cell and Wnt signalling pathway
Lab members: Pedro Antas, Valentina Foglizzo, Laura Gómez Cuadrado, Ania Kucharska, Laween Meran, Laura Novellasdemunt
The highly conserved Wnt signalling pathway plays critical roles in stem cell
biology and cancer. For both of these, the intestine has emerged as a prime
experimental model. In the adult intestine, it is well established that Wnt
signalling plays complementary roles in physiology and pathology: in normal
physiology it maintains crypt stem cell compartments but when activated by
mutation can lead to colon cancer. We are investigating the regulation of the
Wnt pathway in intestinal stem cells and in cancer development. We aim to
translate basic stem cell research to the clinic to aid cancer treatment and
transplantation.
We have recently redefined the Wnt activating mechanism with a series of
observations that went against the current dogmas. This provides new insights
into the fundamental understanding of Wnt regulation in normal homeostasis
and colorectal cancer (CRC). One of our research focuses is to further characterise how APC mutations in CRC inactivate β-catenin
ubiquitination. These studies may help in the development of therapies for CRC. In an independent research interest, we are
studying intestinal stem cell biology in a spatially restricted manner in order to identify the molecular mechanism that defines stem
cell position. Such a mechanism may represent a key regulatory process in intestinal stem cell homeostasis and tumour initiation/
progression.
(A) Schematic diagram showing our novel Wnt activating mechanism. (B) Failure of
β-catenin ubiquitination in APC truncated-colorectal cancer.
Publications
Li Vivian SW and Clevers H (2013)
Intestinal regeneration: YAP—tumor suppressor and oncoprotein?
Current Biology 23:R110-R112
Li VSW and Clevers H (2012)
In vitro expansion and transplantation of intestinal crypt stem cells.
Gastroenterology 143:30-4
Diagram showing intestinal stem cell differentiation and cell lineage
commitment. Genes in parenthesis are the reported transcription
factors for the indicated cell lineages.
Li VSW, Ng SS, Boersema PJ, Low TY, Karthaus WR, Gerlach JP, Mohammed S,
Heck AJR, Maurice MM, Mahmoudi T and Clevers H (2012)
Wnt signaling through inhibition of β-catenin degradation in an intact Axin1
complex.
Cell 149:1245-56
95
Malcolm Logan
Understanding vertebrate limb development
Lab members: Laurianne Besse, Martin Carkett, Sue Miller, Satoko Nishimoto
Limb defects are a common congenital abnormality present in
human live births and diseases affecting the musculoskeletal
system are a significant clinical problem. The goal of our work is to
understand how the limbs form normally during embryogenesis, the
causes of limb abnormalities and disease in humans and to provide
potential therapeutic approaches to block degeneration or trigger
regeneration of the musculoskeletal system.
At early stages of embryonic development, the forelimb and
hindlimb buds are a similarly shaped mass of cells. During subsequent
steps of development the progenitors are transformed into a
complex of interconnected bones, muscles and tendons. These
limb tissues are exquisitely sculpted to become the correct size and
shape and must also form the appropriate interconnections so that
each muscle group attaches to the skeleton via the correct tendon.
How this network is elaborated is poorly understood. We are using
animal and in vitro models and a combination of genetics, imaging
and bioinformatics approaches to understand the mechanisms that
control limb bud formation and the subsequent construction of the
individual limb elements.
Publications
Minguillon C, Nishimoto S, Wood S, Vendrell E, Gibson-Brown
JJ and Logan MPO (2012)
Hox genes regulate the onset of Tbx5 expression in the
forelimb.
Duboc V and Logan MPO (2011)
Pitx1 is necessary for normal initiation of hindlimb
outgrowth through regulation of Tbx4 expression and shapes
hindlimb morphologies via targeted growth control.
Hasson P, DeLaurier A, Bennett M, Grigorieva E, Naiche LA,
Papaioannou VE, Mohun TJ and Logan MPO (2010)
Tbx4 and Tbx5 acting in connective tissue are required for
limb muscle and tendon patterning.
Embryonic day 10.5 mouse forelimb bud showing
staining of dpERK (green) and cell nuclei with DAPI
(blue).
96
Embryonic day 13.5 forelimb showing developing
digits of the handplate identified with a Coll2-GFP
transgene (green) and cells in G1 of the cell cycle
(red) using the FUCCI transgene.
Robin Lovell-Badge FRS, EMBO member, FMedSci
Sex, stem cells and decisions of cell fate
Lab members: Karine Rizzoti, Silvana Guioli, Nitzan Gonen, Veronica Moncho, Christophe Galichet, Clare Wise, Helen O’Neill, Sam
Goldsmith, Inês Santos, Lisa Henning.
Embryo development relies on cells making choices about which cell type to
become and whether to divide, move or die. During sex determination, cells of the
early gonad have an additional choice to make: to become cells typical of testes
or ovaries. In mammals this usually depends on the presence or absence of the Y
chromosome (males are XY, females XX); more precisely to a single gene on the
Y, termed Sry. This encodes a transcription factor with an HMG box type of DNA
binding domain, also present in proteins encoded by the Sox gene family.
We use many techniques to explore how SRY and other factors act to initiate and
maintain testis or ovary differentiation, with mice as our main experimental model,
Because male birds lack Sry, evolutionary comparisons use chick embryos, and our
work informs the human situation, where disorders affecting sex determination can
have devastating physiological and social consequences. We also study pluripotent stem cells from early embryos (ES cells) or after
reprogramming from adult cells (iPS cells), and multipotent stem cells from the brain and pituitary. Certain Sox genes are critical for
self-renewal and stem cell potential. We therefore explore how these genes impact on cell fate choices, and how stem cells might
be exploited to aid treatments for clinical problems, including stroke, pituitary defects and cancer.
Publications
Rizzoti K, Akiyama H and Lovell-Badge R
(2013)
Mobilized adult pituitary stem cells
contribute to endocrine regeneration in
response to physiological demand.
Cell Stem Cell 13:419-432
Gómez-Gaviro MV, Scott CE, Sesay AK,
Matheu A, Booth S, Galichet C and LovellBadge R (2012)
Betacellulin promotes cell proliferation in
the neural stem cell niche and stimulates
neurogenesis.
Proceedings of the National Academy of
Sciences, USA109:1317-1322
Sekido R and Lovell-Badge R (2008)
Sex determination involves synergistic
action of SRY and SF1 on a specific Sox9
enhancer.
Nature 453:930-4
See references 50, 99, 141, 148, 201, 204,
222, 254 in the bibliography at the back for
SOX9/SOX2 positive stem cells self-renew and give rise to all endocrine cell types in the anterior pituitary. Furthermore,
they can respond to physiological demand, generating the relevant hormone-producing cells.
97
Tim Mohun
Heart development in vertebrates
Lab members: Laurent Dupays, Alexandrine Martineau, Izabella Piotrowska, Stuart Smith, Norma Towers, Robert Wilson
Formation of the heart is a complex process that begins
very early in the vertebrate embryo, remodelling a simple
peristaltic tube into a complex multi-chambered organ capable
of supporting embryo growth. This transformation requires
exquisite coordination of cell differentiation and growth to
produce the dramatic changes in organ shape. Abnormalities
affecting any step will have profound consequences on the
foetal heart and heart defects are the most common birth
defect. By studying the roles of individual genes and cell
populations in normal heart development and integrating that
with an understanding of heart morphogenesis, we aim to gain
a better understanding of heart development and the origins of
cardiac malformations.
Our work combines transgenic techniques and genome-wide
analysis to investigate how cardiac gene expression is regulated
in the developing vertebrate embryo. Novel imaging and
computer modelling procedures that we have developed allow
us to examine the precise three-dimensional structure of the
embryonic heart, map the patterns of gene expression in 3D
and identify changes in morphology resulting from altered
gene expression. This approach not only helps us to understand
normal gene function in the developing heart, but also to
investigate possible causes of congenital heart disease and
genetic conditions (such as Down syndrome) which often result
in heart malformations.
Expression of Adprhl1 transgene in the developing tadpole heart causes
abnormal myofbril branching
Publications
Breckenridge RA, Piotrowska I, Ng K-E, Ragan TJ, West JA, Kotecha S, Towers N, Bennett M,
Kienesberger PC, Smolenski RT, Siddall HK, Offer JL, Mocanu MM, Yelon DM, Dyck JRB, Griffin JL,
Abramov AY, Gould AP and Mohun TJ (2013)
Hypoxic regulation of Hand1 controls the fetal-neonatal switch in cardiac metabolism.
PLOS Biology 11:e1001666
Mohun T, Adams DJ, Baldock R, Bhattacharya S, Copp AJ, Hemberger M, Houart C, Hurles ME,
Robertson E, Smith JC, Weaver T and Weninger W (2013)
Deciphering the Mechanisms of Developmental Disorders (DMDD): a new programme for
phenotyping embryonic lethal mice.
Disease Models & Mechanisms 6:562-566
Dunlevy L, Bennett M, Slender A, Lana-Elola E, Tybulewicz VL, Fisher EMC and Mohun T (2010)
Down’s syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1
mouse.
3D modelling of Islet 1 gene expression in the developing mouse embryo,
highlighting expression in the walls of the heart outflow tract.
98
See references 1, 6, 7, 14, 33, 34, 43, 158, 166, 167, 168, 172, 249 in the bibliography at the
Kathy Niakan
Mechanisms of lineage specification in human embryos and stem cells
Lab members: Sissy Wamaitha, Norah Fogarty, Ignacio del Valle, Paul Blakeley
The allocation of cells to a specific lineage is regulated by the
activities of key signalling pathways and developmentally regulated
transcription factors. The focus of our research is to understand the
influence of signalling and transcription factors on differentiation
during early human development. During preimplantation
development totipotent human zygotes give rise to pluripotent
embryonic cells, which form the fetus, and extra-embryonic cells,
which contribute to the placenta and yolk sac.
We study the molecular mechanisms that regulate pluripotency
and how it is disengaged during cellular differentiation in human
preimplantation embryos and embryonic stem cells. We seek
to define the genetic hierarchy acting during differentiation,
the influence of extracellular signalling and the extent to which
these mechanisms are conserved between humans and mice.
The molecular basis of these early cell lineage decisions are of
fundamental biological importance and have significant clinical
implications for infertility, miscarriages, developmental disorders and
therapeutic applications of stem cells.
Mechanisms underlying human
preimplantation development
are poorly understood.
Immunofluorescence analysis
of human embryos has revealed
differences in the expression of
transcription factors thought to
be required for mouse lineage
specification.
Publications
Niakan KK and Eggan K (2013)
Analysis of human embryos from zygote to blastocyst reveals distinct gene expression patterns relative
to the mouse.
Developmental Biology 375:54–64
Cho LTY, Wamaitha SE, Tsai IJ, Artus J, Sherwood RI, Pedersen RA, Hadjantonakis A-K and Niakan KK (2012)
Conversion from mouse embryonic to extra-embryonic endoderm stem cells reveals distinct
differentiation capacities of pluripotent stem cell states.
While human embryonic stem cells largely express the pluripotencyassociated transcription factor OCT4 (green), they also exhibit
heterogeneous expression of the endoderm transcription factor SOX17
(red).
Niakan KK, Ji H, Maehr R, Vokes SA, Rodolfa KT, Sherwood RI, Yamaki M, Dimos JT, Chen AE, Melton DA,
McMahon AP and Eggan K (2010)
Sox17 promotes differentiation in mouse embryonic stem cells by directly regulating extraembryonic
gene expression and indirectly antagonizing self-renewal.
99
Andrew Oates
Patterning embryos with oscillations
Lab members: Ravi Desai, Christina Eugster, Lisa Holthaus, David Jörg, Victoria King, Bo-Kai Liao, Rachna Naranyan, Annelie Oswald,
David Richmond, Sandra Richter, Laurel Rohde, Ulrike Schülze, Daniele Soroldoni, Guillaume Valentin, Alexis Webb
How do spatio-temporal patterns emerge at the tissue level
from noisy cellular and molecular interactions? What principles
govern transitions from parts to wholes, and determine
precision and robustness? We explore these issues using a
population of genetic oscillators in the vertebrate embryo
termed the segmentation clock. This multi-cellular clock drives
the rhythmic, sequential, and precise formation of embryonic
body segments, exhibiting rich spatial and temporal phenomena
spanning from molecular to tissue scales. Tissue patterning by
cellular oscillations is a recent concept, and the mechanisms
and molecules responsible for this astonishing activity are just
beginning to be understood.
We are biologists, engineers, and physicists using molecular
genetics, quantitative imaging, and theoretical analysis. Because
timing is key to understanding oscillations, we developed
multiple-embryo time-lapse recording methods to enable quantitation and statistical treatment of somitogenesis dynamics.
To understand interactions of noisy cellular oscillators and regulatory networks, we develop theoretical descriptions that are
tested in embryos. We identified the first mutations that change the segmentation clock’s period, opening the door to molecular
understanding of the mechanisms that control the clock’s dynamics. We are exploring new transgenic tools to follow the oscillations
of the segmentation clock in real time.
Publications
Oates AC, Morelli LG and Ares S (2012)
Patterning embryos with oscillations: structure,
function, and dynamics of the vertebrate
segmentation clock.
Schröter C, Ares S, Morelli LG, Isakova A, Hens
K, Soroldoni D, Gajewski M, Julicher F, Maerkl SJ,
Deplancke B and Oates AC (2012)
Topology and dynamics of the zebrafish
segmentation clock core circuit.
Herrgen L, Schröter C, Morreli L, Ares S, Julicher F and
Oates AC (2010)
Intercellular coupling regulates the period of the
segmentation clock.
See references 245 in the bibliography at the back
100
Segmentation of the vertebrate body axis emerges from
a tissue-level oscillatory patterning mechanism termed
the segmentation clock (top), which is converted into
embryonic muscle (middle), and finally adult anatomy
(bottom).
The current model for the segmentation clock’s
core pacemaker circuit in zebrafish involves two
parallel transcription-translation negative feedback
loops, but basic questions about its components,
dynamics and outputs remain open.
Systems Biology
Jim Smith FRS, EMBO member, FMedSci
The molecular basis of mesoderm formation
Lab members: Andreia Bernardo, Camille Bouissou, Clara Collart, Kevin Dingwell, Alex Eve, George Gentsch, Alexander Langley, Rita
Monteiro, Greg Parsonage, Elsie Place, Thom Spruce, Anna Strobl, Alex Watson, Mary Wu
The different cell types of the body are formed in the right
place in response to signals produced by special organiser
regions of the embryo. These ‘morphogens’ act in a
concentration-dependent manner to induce different cell
types at different positions within developing tissues. One of
the earliest interactions of this kind is mesoderm induction,
which causes the formation of cell types such as muscle,
kidney and bone, as well as the heart and vascular system.
We study the events that immediately precede mesoderm
induction as well as the formation of the mesoderm itself and
that of the neural crest.
We use frog, zebrafish and mouse embryos, as well as human
and mouse ES cells, to study mesoderm-inducing factors and
to ask how cells respond to them. In particular we use imaging
approaches to understand how the signals exert long-range
effects, and biochemical and mathematical approaches
to ask how cells distinguish between different morphogen
concentrations. We also use sophisticated molecular
techniques to understand the genetic regulatory networks
that drive the formation of specific cell types in mesoderm
(including vascular cells) and neural crest. As well as helping
understand development, our work will help efforts to direct
stem cells down desired developmental pathways.
T-box proteins Eomes, VegT and Xbra bind neural genes pax3, sox3. Top
right: pax3 expression in control embryo. Bottom right: embryo lacking
T-box proteins, with enlarged neural tube and no mesoderm.
Publications
Collart C, Allen GE, Bradshaw CR, Smith JC and Zegerman P (2013)
Titration of four replication factors is essential for the Xenopus laevis midblastula transition.
Science 341:893-896
Top: Xenopus embryos undergoing cleavage divisions. Cleavage rates
decrease after the midblastula transition (MBT). Bottom: embryos
expressing four replication factors. Smaller cells at 450 minutes
indicate prolongation of rapid divisions.
See references 41, 54, 93, 108, 158 in the bibliography at the back for publications from this
group in 2013.
Gentsch GE, Owens NDL, Martin SR, Piccinelli P, Faial T, Trotter MWB, Gilchrist MJ and Smith JC (2013)
In vivo T-box transcription factor profiling reveals joint regulation of embryonic neuromesodermal
bipotency.
Harvey SA, Sealy I, Kettleborough R, Fenyes F, White R, Stemple D and Smith JC (2013)
Identification of the zebrafish maternal and paternal transcriptomes.
101
Peter Thorpe
Systems microscopy studies of cell fate determination
Lab members: Eleanor Bellows, Lisa Berry, Eva Herrero, Elena Ledesma and Guðjón Ólafsson.
Asymmetric cell division is the process by which one cell
divides to give two cells with different fates. Repeated
asymmetric divisions allow a fertilised egg to generate
diverse cell types during development and in adult
stem cells such divisions maintain the population while
simultaneously generating new, differentiated cells.
The goal of our group is to determine how cellular
asymmetry is established and maintained over multiple
divisions to create cell lineages. Specifically, we focus on
understanding how asymmetry of the mitotic spindle
- the machinery that segregates chromosomes during
division - affects how genetic information is accurately
passed down to daughter cells.
Our model system is the budding yeast, Saccharomyces
cerevisiae, which shows patterns of asymmetric division
like those of more complex organisms. We employ highthroughput fluorescence microscopy techniques that
allow us to rapidly screen the localisation, levels and dynamics of all yeast proteins and integrate them into a visual dataset. We
also use novel high-throughput genomics techniques to redirect proteins to new locations within the cell and assess the effects
upon cell division. Using these tools, we aim to identify the conserved mechanisms controlling asymmetric division, lineage
specification and mitotic spindle function.
Publications
Thorpe PH and Rothstein R (2012)
Visualizing global effects of the DNA damage response.
Thorpe PH, Alvaro D, Lisby M and Rothstein R (2011)
Bringing Rad52 foci into focus.
Journal of Cell Biology 194:665-667
Thorpe PH, Bruno J and Rothstein R (2009)
Kinetochore asymmetry defines a single yeast lineage.
Proceedings of the National Academy of Sciences,
USA106:6673-6678
High-resolution fluorescence imaging of live
cells allows us to track components of the
mitotic spindle (red and yellow) and also the
chromatin/DNA (blue); a dashed line indicates
the cell boundary.
102
We array yeast at high density on agar
plates (top) to determine individual protein
interactions that inhibit growth. Automated
computer analysis of these images (bottom)
allows us to quantify these effects.
James Turner
Sex chromosomes in development and disease
Lab members: Fanny Decarpentrie, Elias Elinati, Takayuki Hirota, Shantha Mahadevaiah, Obah Ojarikre, Greg Polikiewicz, Mahesh
Sangrithi, Daniel Snell, Alex Widger
Males and females differ in their sex chromosome make-up:
females have two X chromosomes (XX), while males have one X
and one Y chromosome (XY). Sex chromosomes control a variety
of developmental processes, and influence male-female differences
in susceptibility to diseases, e.g. cancer. We study many aspects
of sex chromosome biology, focusing recently on the role of the
X chromosome in germ cell development, and on X chromosome
inactivation (XCI), the process that equalises X-gene dosage
between males and females.
We have shown that the DNA damage kinase ATR regulates the
expression of X chromosome genes during spermatogenesis (see
figure), and that the X chromosome is enriched in genes involved
in sperm differentiation, with around 20% of all X-genes expressed
only in male germ cells. These genes are likely to be important
for fertility. In female eutherian mammals, XCI is mediated by the
non-coding RNA Xist, but how XCI is controlled in the second
largest class of mammals, the metatherians, is unknown. We have
discovered a non-coding RNA, called Rsx, which exhibits features
consistent with a role in XCI in these organisms. This work will
allow us to better understand how non-coding RNAs regulate gene
expression.
Publications
Male germ cells
undergoing meiosis.
Chromosomes
are labelled with
the marker SYCP3
(green). The kinase
ATR (red) localises
to and controls gene
expression on the X
chromosome during
this time.
Royo H, Prosser H, Ruzankina Y, Mahadevaiah SK, Cloutier JM,
Baumann M, Fukuda T, Höög C, Tóth A, de Rooij DG, Bradley A,
Brown EJ and Turner JMA (2013)
ATR acts stage specifically to regulate multiple aspects of
mammalian meiotic silencing.
Grant J, Mahadevaiah SK, Khil P, Sangrithi MN, Royo H,
Duckworth J, McCarrey JR, VandeBerg JL, Renfree MB, Taylor
W, Elgar G, Camerini-Otero RD, Gilchrist MJ and Turner JM
(2012)
Rsx is a metatherian RNA with Xist-like properties in
X-chromosome inactivation.
Nature 487:254-258
Mueller JL, Mahadevaiah SK, Park PJ, Warburton PE, Page DC
and Turner JMA (2008)
The mouse X chromosome is enriched for multicopy testis
genes showing postmeiotic expression.
See references 209 in the bibliography at the back for
103
Jean-Paul Vincent FRS, EMBO member, FMedSci
Patterning and homeostasis in developing epithelia
Lab members: Cyrille Alexandre, Luis Alberto Baena-Lopez, Karen Beckett, Sam Crossman, Ben Drury, Satoshi Kakugawa, Joachim Kurt, Paul
Langton, Hisashi Nojima, Lucy Palmer
A small number of signaling molecules orchestrate growth
and cell fate decisions during development. We use
techniques of genome engineering and cell biology to
investigate the mechanisms that control the production,
spread and activity of one signal, Wingless (the main
Drosophila member of the Wnt family). In a separate,
but related strand of research, we aim to understand the
mechanisms that trigger the elimination of cells following
epithelial disruption or cell fate misspecification. These
processes are relevant to tissue homoeostasis since failure
to eliminate defective cells is likely to cause a variety of
diseases, including cancer.
We found that flies develop and grow almost normally
following replacement of the endogenous Wingless
coding region with a cDNA encoding a membranetethered form. This is surprising because Wingless
has been thought of as an archetypical morphogen,
particularly in wing progenitors. Two processes contribute
to obviating the need for Wingless to spread. First,
the target tissue produces its own supply of Wingless
during the early period of growth and patterning. Later,
after local expression terminates, the expression of key
Wingless target genes persists by a mechanism akin
to cellular memory. We are currently determining the
molecular basis of cellular memory.
Extensive apoptosis in the segmentation mutant fushi tarazu. Dying cells are marked
in red with anti-activated caspase.
Publications
Alexandre C, Baena-Lopez A and Vincent J-P (2014)
Patterning and growth control by membrane-tethered Wingless.
Nature 505:180-5
Baena-Lopez LA, Alexandre C, Mitchell A, Pasakarnis L and Vincent J-P (2013)
Accelerated homologous recombination and subsequent genome modification in
Drosophila.
Vincent JP, Kolahgar G, Gagliardi M and Piddini E (2011)
Steep differences in wingless signaling trigger Myc-independent competitive cell
interactions.
APC mutant cells outcompete neighbouring wild type (wt) cells. Right hand panel
shows that the presence of APC mutant cells (not green) leads to the elimination of
wt cells (green).
104
See references 10, 17, 36, 252 in the bibliography at the back for publications from this
group in 2013.
Research facilities
Structural biology facilities
Mass spectrometry
Protein sequence analysis and structure modelling
Imaging
Histology
Electron microscopy
Other scientific facilities
Genomics
High-throughput sequencing
Microarray
Laboratory Infrastructure and Logistics (Bioresources)
Large scale laboratory
Media production
Freezer archive
Human embryo and stem cell unit
Insectary
Flow cytometry
Scientific instrument research and development
Other support services
Estates and engineering
PhotoGraphics
Computing and telecommunications
Library, information and communications
Web Team
Laboratory Infrastructure and Logistics (Central Services)
General Services
Occupational Health
Safety and Security
Human Resources
Finance and Purchasing
105
RESEARCH FACILITIES
Kathleen Mathers
The Division of Biological Services provides a fully integrated laboratory animal and
technical resource to the Institute. The multidisciplinary research of the Institute
requires a range of species and models, and to meet these needs we operate and
manage a number of complex animal facilities. These include an isolation/quarantine
unit, containment facilities at Levels 2, 3 and 4 for animals infected with organisms
potentially harmful to man and/or the environment, specialist procedural, behavioural
and surgical suites, imaging and irradiation facilities, and extensive aquatic facilities. The
vast majority of animals in the facility are rodents, with large numbers of genetically
altered lines of mice and rats. In addition, our facilities house ferrets, rabbits, the
laboratory opossum, zebrafish and Xenopus species. The size, scope and efficiency of
Biological Services provide an extraordinary service to nearly all aspects of the Institute’s
science as well as to many scientists elsewhere.
Xenopus laevis
Routine animal husbandry.
106
The Institute houses over 800 distinct lines of genetically altered mice.
The laboratory opossum: Monodelphis domestica with young.
RESEARCH FACILITIES
We aim to meet all the needs of the scientific Divisions whilst ensuring the highest possible standards of health and welfare for all
species. The Division is active in the field of laboratory animal science, conducting and promoting research and uptake of the 3Rs
(replacement, reduction, refinement) and presents its work at national and international meetings. The animal care and technical
staff are trained in the production, care and use of animals for research purposes to the highest standards of animal husbandry (see
page 26). Additionally they provide a range of centralised procedural support. A full-time veterinary surgeon and microbiologist
offer advice on the health and welfare of our animals. The Division also provides services for the incubation of fertile chicken eggs
and the production of antibodies. In addition, administration and licence control under the Animals (Scientific Procedures) Act
1986, and coordination of the Institute’s Animal Welfare and Ethical Review Body, is managed by Biological Services.
Procedural Service Section
The Procedural Service Section provides a range of services and facilities for the production,
maintenance and preservation of genetically altered rodents. The service produces up to 200 new
genetically altered rodent lines each year by both transgenic and gene-targeted technologies as well
as keeping up with new technologies including CRISPR nucleases and tetraploid injection, and has
started providing an ES cell culture and targeting service. A full range of techniques is employed to
provide a comprehensive service for the cryopreservation of rodent germplasm, and more recently
the service has expanded to include cryopreservation of frog and fish spermatozoa. In addition,
the section is responsible for the rederivation of new lines imported into the Institute. Every year,
together with Biological Services, the Section coordinates over 150 shipments of live animals and
frozen germplasm to collaborators all over the world. The staff are also skilled in a number of assisted
reproductive techniques, including in vitro fertilisation and intracytoplasmic sperm injection, which
are useful for maintenance of lines with poor breeding performance or to provide age-matched
cohorts for experiments. The section is also committed to investigating and implementing the 3Rs by
researching and developing new refinements such as non-surgical methods of embryo transfer.
ES cell microinjection.
Head of Procedural Services
Sarah Johnson.
Analysis of murine sperm motility prior to cryopreservation.
107
RESEARCH FACILITIES
Tom Frenkiel
Co-workers: Geoff Kelly, Alain Oregioni
The MRC Biomedical NMR Centre is a multi-user facility for biomolecular
liquid-state nuclear magnetic resonance (NMR) which was set up by the
MRC in 1979 to provide advanced and well-supported facilities for use
by scientists from NIMR and other academic research establishments.
Currently 19 external groups make use of the Centre’s facilities. NMR
studies of the type carried out at the Centre provide a wide range of
information, ranging from the atomic-level (e.g. determining the pKa of
individual ionisable groups in proteins), through to full determination of
the structure and dynamics of proteins in solution. An important area
of application is the identification of interaction surfaces between the
components of macromolecular complexes.
The Centre’s facilities currently consist of four spectrometers with
1H operating frequencies spanning 600 to 800 MHz, all configured
for studies of biological macromolecules in solution. Three of the
instruments have cryogenically cooled probes and two are equipped with
automatic sample-changers. The Centre has recently received substantial
new investment and a new spectrometer with an operating frequency of
950 MHz is expected to become operational in 2014. This will be only the
second such instrument in the UK.
Study of the ionisation of the N-terminal amino group of ubiquitin (in collaboration with
K. Rittinger and B. Stieglitz, Division of Molecular Structure). The peak position - measured
as a function of pH - can be used to determine the pKa of the group (inset). The resulting
value informs studies on the mechanism of ubiquitin ligation
Magnet of the 800 MHz spectrometer.
108
Representative publications are listed on the Centre’s website, www.nmrcentre.mrc.ac.uk
RESEARCH FACILITIES
Protein X-ray crystallography is a technique that produces a three-dimensional model of the structure of a protein at atomic
resolution. The X-ray crystallography facilities within the Division of Molecular Structure at the Institute are state-of-the art and
include a high intensity X-ray source coupled with an automated robotic sample mounting system that allows the unattended
screening of 80 crystals in a single experiment. Diffracting protein crystals are the culmination of an extensive series of
experimental procedures that include protein purification and protein crystallisation. A range of sophisticated techniques is
employed to help explore the largest number of conditions within each of the projects under investigation. These include those
techniques being developed in the Protein Expression Lab together with a wide range of robotic procedures to set up multi-well
dishes and to automatically screen for protein crystals.
X-ray generator and automated sample mounting robot insert shows the loop
used to hold the protein crystal.
The Protein Expression Lab was established in 2009 to
provide dedicated support to members of the Division of
Molecular Structure. The facility provides a comprehensive
resource for the production of recombinant proteins. Currently
we offer a choice of two expression systems: bacteria and
insect cells. A high-throughput pipeline for cloning DNA
fragments and small-scale expression tests in E. coli has been
established, allowing the generation and screening of 96
expression constructs in a week. In parallel, proteins are also
expressed in insect cells using the baculovirus expression
vector system (BEVS). Services include the generation and
amplification of high-titre baculovirus stocks, analytical scale
productions for optimisation of protein expression, and
preparative scale productions. In addition, the facility maintains
a vector DNA repository, provides in-house vector design,
troubleshooting and training.
A. The structure of the minimal catalytic core of HOIP was solved by X-ray
crystallography. The model of the 214 amino acid polypeptide revealed a novel
superfold. HOIP binds four Zn ions (grey balls) which are coordinated by two Zn
finger domains (cyan and green) and one CBR domain (magenta). The CBR domain
contains the catalytic cysteine 885 (yellow) which is essential for linear ubiquitin
chain synthesis. All three Zn binding elements are tightly interconnected by a
6 helical bundle (blue). B. Electrostatic surface potential HOIP. The molecule is
presented in the same orientation as in A. Cysteine 885 (yellow) forms the centre
of the catalytic side.
Insect cell expression in a Wave Bioreactor™.
109
RESEARCH FACILITIES
Mass spectrometry
Steve Howell
Co-worker: Colin Davis
The facility now operates as one unit together with LRI’s Protein
Analysis and Proteomics facility at Clare Hall. The joint unit
is managed by Dr Bram Snijders, requests for analysis can be
submitted on https://proteomics.london-research-institute.org.uk/
NIMR facility manager: Steve Howell.
The NIMR proteomics and mass spectrometry facility is housed
in a purpose-built suite. It currently houses 3 mass spectrometers
and ancillary equipment, which are used in a range of biochemical
analyses. A state-of-the-art LTQ Velos Orbitrap high resolution
tandem MS coupled to a nano-HPLC is utilised in proteomics
studies and is capable of identifying hundreds of proteins from
a single run. Protein quantification is performed using standard
techniques such as SILAC or iTRAQ labelling. Identification of the
sites of post-translational modifications, such as phosphorylation
and ubiquitination, is also achieved on this instrument.
A quadrupole time-of-flight tandem mass spectrometer, equipped
with an electrospray source, is utilised for protein and peptide
characterisation. A GC-MS is available and is currently used in
metabolomics research, such as the quantification of fatty acids.
Schematic of the Orbitrap analyser.
The nano-electrospray source of the Orbitrap Velos.
Bram Snijders
LRI Core Technology Platform, Protein Analysis and Proteomics.
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RESEARCH FACILITIES
Biocomputing
Protein sequence analysis and structure modelling
José Saldanha
Computational tools for prediction, analysis and visualisation
can provide inspirational new ways to look at data, no matter
which protein family is the main focus of research. Theoretical
methods developed both at NIMR and in the wider academic
community can suggest new hypotheses for experiments or new
explanations of results. Protein sequence analysis and structure
modelling draw on state-of-the-art algorithms being developed
by experts in the Division of Mathematical Biology, as well as
the many computer programs freely available from the scientific
community. There is also an in-house, commercial, computer
graphics package for detailed 3D modelling.
Publications
GTP analogue (centre focus) in a 3D model of human guanylate-binding
protein 3. Hydrogen bonds dotted in azure and water molecules as red spheres
(collaboration with Frickel group).
Léger O and Saldanha JW (2012)
Humanization of antibodies.
In: Antibody drug discovery. Edited by Wood CR.
London, Imperial College Press, 2012. 1-23 (Molecular Medicine and Medicinal Chemistry, 4)
Kaye RG, Saldanha JW, Lu Z-L and Hulme EC (2011)
Helix 8 of the M1 muscarinic acetylcholine receptor: scanning mutagenesis delineates a G protein
recognition site.
Molecular Pharmacology 79:701-709
Grant J, Saldanha JW and Gould AP (2010)
A Drosophila model for primary coenzyme Q deficiency and dietary rescue in the developing nervous
system.
Biological Computing
Nikolay Nikolov
Biological computing is a new addition to NIMR having been
set up in 2013. Our goal during the initial period is to provide
basic bioinformatics analysis and consulting in the area of next
generation sequencing (NGS), more specifically, for RNA-Seq
and Chip-Seq studies. We will be working in collaboration with
the High-throughput sequencing and the IT facilities to provide
infrastructural support for NGS bioinformatics, in particular,
workflow automation and laboratory information management
systems.
NGS is a new technology which offers exciting opportunities in
almost every area of biomedical research. However, it comes
with its own challenges – the ever increasing amount of data
puts under test the existing computational infrastructure and
the relative novelty of the technology means that the methods
are still maturing. We will be working hard to create a world
class facility that is able to address these issues and help NIMR
scientists solve important biomedical research questions.
Statistical analysis of genomic data
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RESEARCH FACILITIES
Yan Gu
Co-workers: Donald Bell, Chen Qian, Kate Sullivan
The Confocal Imaging and Analysis Laboratory (CIAL) provides an imaging
core facility at NIMR. The facility covers six confocal microscopes, three
wide-field fluorescence microscopes, a multiphoton microscope, a slider
reader, a well-plate reader, a spinning disc microscope, a 4-channel TIRF
microscope, two SPIM, two offline workstations, and image processing
software such as Volocity, Imaris, Image J, Metamorph and MatLab.
Currently the facility supports 170 researchers from 16 Divisions. Users
operate the system, but the complexity of imaging makes support an
extremely important aspect of the facility. We routinely provide users
with training, troubleshooting, consultation and microscope maintenance.
We also support special techniques such as thick tissue imaging, live cell
experiments, 2nd harmonic generation imaging, quantitative imaging,
deconvolution imaging, and automatic cell counting.
Research activities in CIAL are focused on techniques of selective plane
illumination microscopy, high-resolution imaging, high-throughput imaging,
automatic cell segmentation and tracking, and others relevant to NIMR
research. The lab has expertise in sample preparation and labelling, live or
fixed sample imaging, and hardware and software development to meet
the needs of NIMR researchers.
Pyramidal neurons in cortex of mouse brain
Publications
Analysis process of cell cycling in fly wing disk. Fluorescent
images are segmented before relative intensities analysed
statistically and plotted (top left to bottom right).
Pacary E, Haas MA, Wildner H, Azzarelli R, Bell DM, Abrous DN and Guillemot F (2012)
Visualization and genetic manipulation of dendrites and spines in the mouse cerebral cortex and hippocampus using in
utero electroporation.
Journal of Visualized Experiments e4163
Sullivan K, Kloess J, Qian C, Bell D, Hay A, Lin YP and Gu Y (2012)
High throughput virus plaque quantitation using a flatbed scanner.
Journal of Virological Methods 179:81-89
Hadjieconomou D, Rotkopf S, Alexandre C, Bell DM, Dickson BJ and Salecker I (2011)
Flybow: genetic multicolor cell labeling for neural circuit analysis in Drosophila melanogaster.
Nature Methods 8:260-268
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RESEARCH FACILITIES
Histology
Radma Mahmood
Co-workers: Radhi Anand
The Histology service provides a range of sectioning techniques for
visualisation of tissue structure and gene expression in animal research
models. By making paraffin blocks of animal tissues, we produce thin
sections that when stained allow for analysis of tissues at a cellular level.
Tissues are automatically processed, embedded into paraffin blocks and
sectioned manually by facility histologists. Slides generated are stained
for cell and nuclear structure or left unstained for the researcher’s own
use. Newly acquired equipment includes the Leica automated tissue
processor (ASP300) and automated slide stainer (Autostainer XL) as well
as two new rotary microtomes and cryostats. The ASP300 processor
utilises ten different processing programs designed to optimally maintain
morphology of all tissues from mouse embryos and neonates, rats, frogs
and fish, as well as human research samples. Paraffin tissue blocks are
sectioned manually and the automated stainer is used for hematoxylin
and eosin (H&E) staining. Special stains, such as Masson’s Trichrome for
collagen, are performed manually.
Shared resources available to researchers include cryostats for frozen
sections and a microtome for paraffin sections. The service also provides
training, protocols, and assistance for investigators on all aspects
of histology, including tissue fixation, tissue processing, vibratome
sectioning, enzyme histo-chemistry and immune-histochemical
techniques.
Human cervix pathology: p16 and MCM are markers of proliferation
and E4 is the HPV protein marker developed in Virology. HSIL is
high-grade squamous intraepithelial lesion and LSIL is low-grade
squamous intraepithelial lesion.
Enzyme histo-chemistry: fresh frozen mouse muscle in cross-section showing cytochrome
c oxidase (COX) staining in mitochondria.
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RESEARCH FACILITIES
Electron microscopy
Liz Hirst
The facility has a Transmission Electron Microscope (TEM: Jeol 1200
EX) and a Scanning Electron Microscope (SEM: Jeol 35CF), both of
which have been upgraded to digital photography (Gatan Orius 1000
and SemAfore respectively contained in a dedicated EM processing
laboratory. Staff from any department at NIMR may request TEM or
SEM investigations in support of their scientific studies. Samples are
provided by the requester and analysed by TEM and/ or SEM with
reference to their specific questions of interest. Results typically consist
of representative micrographs and a written report of the interpretation
of the ultrastructural morphology for discussion and publication.
TEM techniques available include ultra-thin sectioning and ultra-structural
analysis of experimental tissues, cell cultures or sub-cellular pellets.
Immuno-EM techniques provided are post-embedding immuno-gold
labelling of antigens upon ultra-thin sections or pre-embedding by HRP
labelling. SEM techniques available include internal anatomy by dry
fracture or dissection as well as external morphology. Technical advice,
training and support is also provided for staff from any division wishing
to learn EM techniques.
IEM Immuno-gold labelling of Myelin Basic Protein in rat
spinal cord injury
TEM Toxoplasma gondii tachyzoite infected Human Umbilical Vein Endothelial Cell
Publications
Koltowska K, Apitz H, Stamataki D, Hirst EMA, Verkade H, Salecker I and Ober EA (2013)
Ssrp1a controls organogenesis by promoting cell cycle progression and RNA synthesis.
Ruecker A, Shea M, Hackett F, Suarez C, Hirst EMA, Milutinovic K, Withers-Martinez C and Blackman MJ (2012)
Proteolytic activation of the essential parasitophorous vacuole cysteine protease SERA6 accompanies malaria
parasite egress from its host erythrocyte.
SEM Mutant B lymphocyte blood cells (Rac2-deficient) have
abnormal microvilli
114
Cruz C, Ribes V, Kutejova E, Cayuso J, Lawson V, Norris D, Stevens J, Davey M, Blight K, Bangs F, Mynett A, Hirst E,
Chung R, Balaskas N, Brody SL, Marti E and Briscoe J (2010)
Foxj1 regulates floor plate cilia architecture and modifies the response of cells to sonic hedgehog signalling.
RESEARCH FACILITIES
Imaging methods play an increasingly central role in
enabling gene or protein activity to be linked to function
and phenotype, from subcellular to whole organism levels.
Within the Division of Developmental Biology, the Institute
has developed dedicated facilities for imaging complex
morphology and gene expression of embryonic and adult
tissue in 3D using Optical Projection Tomography (OPT)
and High Resolution Episcopic Microscopy (HREM). This
complements existing facilities at NIMR provided by the
Confocal Imaging and Analysis Lab (page 112) and Histology
(page 113). Automated HREM developed at NIMR forms the
basis of an ongoing project funded by the Wellcome Trust
and supported by the Medical Research Council to provide
comprehensive imaging of normal and mutant mouse
embryos at unprecedented resolution. The freely available
data (www.embryoimaging.org) complement standard
anatomical texts and can form the basis for systematic
analysis of mutant morphological phenotypes.
OPT imaging of adult mouse lung. The organ has been stained with
an antibody to reveal smooth muscle tissue and the data used for 3D
modelling.
3D model of a chick embryo heart
revealing the complex internal
architecture of the ventricular
chambers, the developing valves and
the septal walls separating the left and
right chambers.
115
RESEARCH FACILITIES
RESEARCH FACILITIES
Single molecule experiments give insights into how biological molecules work and how they are structured. Several research groups
at NIMR apply and develop methods to study single molecules. Some of these techniques provide high-resolution images of the
molecules, and others give dynamic information about the interactions between proteins, DNA, lipid membranes and small ligand
molecules..
TIRF (right) and Optical Tweezers (left) are powerful tools that assist studies of motor proteins which are the molecular
machines contained in every cell of the body. (Images by Gregory Mashanov and Justin Molloy)
We have developed methods to visualise and manipulate single molecules, with high time resolution, using two laser-based
techniques; Total Internal Reflection Fluorescence (TIRF) microscopy and Optical Tweezers (OT). TIRF microscopy uses the
evanescent field associated with a totally internally reflected laser beam to excite fluorophores at the surface of a microscope
coverslip. Sensitive camera systems are used to detect light emitted by the fluorophores. These measurements have a resolution
of around five nanometres within 50 milliseconds. Optical Tweezers make use of radiation pressure to pick-up and manipulate
individual molecules. Using fast detectors, the position of optically trapped particles are measured with nanometre precision so that
forces and movements produced by single molecules can be measured. The resolution is around one nanometre every millisecond.
Atomic Force Microscopy (AFM) enables us to analyse the
structure of biological molecules by scanning their surface
topology using a microfabricated mechanical probe or “tip”. The
AFM used at NIMR (JPK NanoWizard) is ideally suited to studying
biological materials in aqueous solution at room temperature. As
the AFM tip is scanned over the sample it rides over molecules
fixed to the surface. Deflections of the tip are measured using
a laser-based position sensor producing a three-dimensional
topological map of the surface. The technique is ideally suited to
studies of material for which high-resolution dynamic information
is required. The ultimate resolution depends on the sharpness
and stiffness of the silicon tip, the mechanical properties of the
specimen and also upon the mechanical stability of the laboratory
and microscope system. For soft biological molecules, the
resolution is around five nanometres.
Upper panel shows a single actin filament and a single microtubule (MT) (by
Iwan Schaap); lower panels show different phases of bacterial Plasmid DNA
replication (by Claudia Arbore).
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RESEARCH FACILITIES
High-resolution cryo electron microscopy (cryoEM) enables the
structure of biological molecules and larger materials to be visualised
in a frozen hydrated state without fixation or staining. An aqueous
solution containing the specimen is frozen very rapidly to liquid
nitrogen temperatures. When cooled rapidly, water forms a glass
(rather than forming ice crystals) and the embedded biological
material, locked in this transparent medium, can be viewed by
electron microscopy. Because the electron beam has a much
shorter wavelength than visible light, individual protein molecules
can be visualised. Although the image contrast of each individual
molecule is low, signal averaging can yield very high resolution
pictures. CryoEM is well suited to high-resolution studies of both
the structure and dynamics of large proteins and protein complexes,
such as cytoskeletal proteins or viral capsids. Our latest methods
also enable structures within rapidly frozen mammalian cells to be
visualised. By recording many digital images of a specimen held at
different orientations (tomography), a three-dimensional view of
the molecule or cell is obtained. Individual molecules, whole virus
particles or living mammalian cells embedded in ice can be imaged
in three dimensions.
Slice of a three-dimensional tomogram showing the edge of a frozen hydrated cell
and a computational model for membrane organelles.
Image courtesy of Sebastian Wasilewski
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RESEARCH FACILITIES
Genomics
Abdul Karim Sesay
Co-workers: Leena Bhaw-Rosun, Harsha Jani, Deborah Jackson
The Genomics core facility provides next-generation sequencing
and microarray services to NIMR scientists. Services include sample
preparation, high-throughput sequencing and microarray hybridisation.
Support is also provided for data analysis. The Genomics facility
is equipped with state-of- the-art instrumentation for genomic
sequencing, genotyping and gene expression studies.
High-throughput sequencing technologies are revolutionising molecular
genetics, vastly expanding our ability to study genome structure, gene
regulation and tissue differentiation. Combined with increasingly
sophisticated bioinformatics analysis, these methods of massively
parallel sequencing-by-synthesis are impacting on all areas of basic
biological research, with their ability to generate billions of bases of
high-quality DNA sequence in a matter of days. NIMR’s central nextgeneration sequencing facility supports DNA/RNA sequencing using the Illumina Genome Analyzer IIx for reads up to 150 bases
for both single and paired-end runs and an Illumina HiSeq 2500 sequencer that produces up to 600 Gb in 11 days (2 x 100 bp read
length). The facility has recently added the Illumina MiSeq which can achieve 2 x 300bp reads in 65 hours.
Microarray
Whilst the most common use of Affymetrix Genechip microarrays is to examine the level of expression of many different genes
or mRNA species in a sample simultaneously, there are now chips available for other protocols. Affymetrix arrays are available for
many different organisms such as Mycobacterium tuberculosis,
Drosophila, Xenopus, zebrafish, chicken, dog, mouse, rat and human.
The microarray facility offers full technical support in the preparation
and running of RNA or DNA samples. The facility also includes the
Illumina iScan System with Universal Starter Kit. Based around the
iScan Reader, which incorporates high-performance lasers, optics, and
detection systems, the iScan System offers sub-micron resolution,
higher throughput rates and very economical BeadChips available for
human, rat and mouse.
Combining RNA-Seq and ChIP-Seq in the analysis of Xbra function in the X.
tropicalis Genome during Early Embryogenesis
Data courtesy of George Gentsch in Smith’s Lab, System Biology
118
114
RESEARCH FACILITIES
Laboratory infrastructure and logistics (Bioresources)
Joachim Payne
RESEARCHFACILITIES
FACILITIES
RESEARCH
Large Scale Laboratory
Co-workers: Brian Trinnaman, Jackie
Wilson
Every year the Large Scale Laboratory
team grows thousands of litres of
mammalian, insect, yeast and bacterial
cells for 11 research Divisions at NIMR,
as well as collaborating with other MRC
and academic units. Cells can be supplied
quick-frozen or lysed using a Constant
Systems cell disrupter. For processing
large volumes of supernatants we have a
Sartorius crossflow filtration system and a
Quixstand hollow-fibre unit. The section
also manages NIMR’s culture serum
supply service.
Media Preparation
Co-workers: Charlotte Austin, Laura
Camplese, Ian Oliver, Magdalena Sokalska
Our in-house Media Preparation facility
has formulae for over 2,000 products,
and last year processed 3,600 orders,
totalling over 33,000 litres of research
reagents, including a quarter of a million
tubes of Drosophila food and 45,000
microbiological poured plates. We have
recently invested in automated platepouring technology, allowing us more
time to work with the Drosophila groups
developing their chemically defined diets.
Mellanby Freezer Archive
Inspecting a hybridoma culture.
Brian sets up one of our bioreactors.
The Mellanby Freezer Archive is the
MRC’s central business continuity
cryo-archive. As a purpose-designed
facility for the long-term secure storage
of frozen material, we are responsible
for over half a million samples from
researchers across the MRC.
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RESEARCH FACILITIES
Human embryo and stem cell unit
Clare Wise
Co-worker: Wiola Sheldon
The new Human Embryo and Stem Cell Unit (HESCU) provides
a suite of well-organised rooms, equipment and expertise to
derive and culture human embryonic and induced pluripotent
stem cells. There is space to culture and derive cells in clean,
quarantine and containment level 2 rooms. All of the rooms are
HEPA filtered to maintain high-quality air standards and reduce
the risk of contamination during stem cell culture procedures.
The unit provides facilities, and expertise for the derivation of
human induced pluripotent stem cells. Unit staff can supply
specialised human embryo culture media and derive mouse
embryonic fibroblasts for feeder layers.
The Institute has recently obtained Human Fertilisation and
Embryology Authority (HFEA) approval to store and culture
human embryos and to derive human embryonic stem cells.
Regulatory support including documentation for ethics
approval and HFEA paperwork is provided. The unit has 8
incubators, 7 hoods, a picking hood to sub-clone cells and both bright field and fluorescent microscopes for imaging. There are
also micromanipulators, a laser and microscope to allow manipulation and imaging of human embryos. Storage and cataloguing of
embryos and stem cells is also available.
114
120
RESEARCH FACILITIES
Insectary
Irene Tumwine
The insectary is a designated area for the rearing of insects and initiating malaria infections in mosquitoes. It contains a colony of
Anopheles stephensi mosquitoes, consisting of approximately 20,000 adult mosquitoes. The facility consists of:
• state-of-the-art temperature and humidity controlled breeding cabinets
• incubators for parasite development within the mosquito
• a microscopy area for mosquito dissections and analysis
Anopheles stephensi is an important vector for experimental malaria in both rodents and human. The insectary allows for a high
number of experimental mosquito transmissions, so that laboratory research can more closely mimic conditions in the field.
Replicating the natural route of infection in mouse models makes the models as relevant as possible for mosquito-transmitted
human malaria.
The microscopy area
A view of the insectary interior
The mosquitoes
121
RESEARCH FACILITIES
Flow cytometry
Co-workers: Bhavik Patel, Wayne Turnbull
The flow cytometry facility provides a state-of-the-art, high
speed, sterile cell sorting service. We sort multiple types of cell
populations for both in vitro and in vivo studies, single cell sorting
and cloning. In addition, it offers multi-parameter fluorochrome
analysis of cell markers and measurement of calcium fluxes,
apoptosis, cell cycle and FRET.
The facility serves a large number of NIMR researchers from
the Infections and Immunity, Genetics and Development and
Neurosciences groups. Training is also provided for research staff,
including PhD students and postdoctoral researchers. The facility
is well equipped, with four cell sorters including two 9-colour
Beckman Coulter MoFlo XDP sorters, a 15-colour Becton Dickinson
FACS Aria II and a 10-colour Becton Dickinson Influx. The Influx is
situated inside a containment level 2 (CL2) bio-safety cabinet for
sorting samples classified at CL2. Additionally there are eight flow
cytometric analysers that include a 16-colour Becton Dickinson
Fortessa, a 8-colour Becton Dickinson FACSVerse, an 8-colour
FACSCanto, a 14-colour Becton Dickinson LSRII and a 9-colour
Beckman Coulter Cyan ADP. The facility also houses an Automacs
Cell separator.
Publications
Hirota K, Turner J-E, Villa M, Duarte JH, Demengeot J, Steinmetz OM and Stockinger B (2013)
Plasticity of TH17 cells in Peyer’s patches is responsible for the induction of T cell-dependent
IgA responses.
Schweighoffer E, Vanes L, Nys J, Cantrell D, McCleary S, Smithers N and Tybulewicz VLJ (2013)
The BAFF receptor transduces survival signals by co-opting the B cell receptor signaling pathway.
Immunity 38:475-488
Young GR, Eksmond U, Salcedo R, Alexopoulou L, Stoye JP and Kassiotis G (2012)
Resurrection of endogenous retroviruses in antibody-deficient mice.
Nature 491:774–778
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Graham Preece
RESEARCH FACILITIES
Within the complex of buildings that make up NIMR is a suite of laboratories for handling viruses with high pathogenic potential
for birds, humans or other mammals. Its presence is necessitated by the work of the WHO Influenza Centre (WIC) at NIMR that
involves the handling of influenza viruses from all over the world such as the novel H1N1 virus, prior to its emergence as a full-blown
pandemic virus. In addition, the facility also receives poorly characterised viruses. Some of these, notably viruses from zoonotic
H5N1 infections, have considerable pathogenic potential in both birds and humans. Work with poorly characterised viruses and
viruses that might, or do, have pandemic potential requires a high degree of containment to prevent the spread of influenza viruses
into birds or the environment, as well as operator protection to minimise the risk of handling viruses potentially harmful to man.
The facility is built to Health and Safety Executive requirements and DEFRA regulations under the Specified Animals Pathogen Order.
It was used for the growth and characterisation of samples of the pandemic H1N1 virus, sent from around the world at the early
stages of its global spread, and to generate reference ferret antisera to the emerging pandemic viruses for virus antigenic analyses.
It has also been used for the isolation and characterisation of human isolates of H5N1 avian influenza virus, for example from the
Turkish outbreak in humans in 2006. The laboratory capacity has been extended to have two standard high containment laboratory
areas and two laboratories equipped to handle infected small animals under high level containment. With the enhanced capacity,
in addition to the virus surveillance and characterisation studies of the WIC, simultaneous studies of the mechanisms of disease
causation by avian or other influenza viruses can be carried out.
Features of the laboratory include:
• A negative pressure air regime with HEPA filtered input and double HEPA filtered extract.
• Waste treatment with heating of liquid waste and autoclave sterilisation of solid waste within the body of the laboratory.
• Class III and Class I/III microbiological safety cabinets for handling samples.
• Class III cabinets for handling infected small animals.
• Sealable, so as to permit fumigation.
• Strict codes of practice including the requirement for all workers to undergo a complete change of clothing before entering the
laboratory and to shower when leaving.
In addition to the Level 4 laboratory, there are 11 Level 3 laboratories scattered among the main buildings and biological research
facilities at NIMR. These laboratories allow the safe handling of a number of pathogenic organisms, permitting studies of the
microbiology and immunology of Mycobacterium tuberculosis, the invasion of blood cells by the malaria parasite and the growth of
the retroviruses that cause AIDS.
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RESEARCH FACILITIES
Scientific instrument research and development
Martyn Stopps
Co-worker: Nicholas Burczyk
Scientific research often requires custom instrumentation to
acquire data, control processes & automate tasks. We collaborate
with scientists across the institute to develop new technology
that is not commercially available, providing our researchers with
cutting edge tools.
Custom-built scientific instrumentation integrates software,
electronics, mechanical and fluidic systems. Our research & design
process includes definition of user requirements, risk analysis,
development of proof-of concept devices, functional specification
and prototype development. Our prototypes are evaluated in the
lab and developed to meet the specific scientific requirements.
A critical aspect of the instrument development process is a
continuous dialogue between the research scientist and us at
every stage of the development.
We utilise a range of CAD techniques for schematic and printed circuit board design and 3D CAD for modelling of mechanical
components and fluidic systems. We manufacture our designs within the facility; this includes electronic hardware, software for
a variety of platforms and prototype mechanical components with a precision 3D printer. We also collaborate with the NIMR
Mechanical Engineering team for the manufacture of precision parts.
Our recent completed projects include the development of magnetic tweezers to supercoil DNA (collaboration with Justin
Molloy) and a system for transferring graphene to electron-microscope grids (Peter Rosenthal). Current projects include
development of a robotic high-throughput tissue handling and storage system enabling correlative imaging and histology (Troy
Margrie), a fibre manipulation system for a novel multi-electrode array and olfactory test system (Andreas Schaefer).
The in-house capability to develop innovative scientific instrumentation enables researchers to conduct novel experiments in
emerging areas of science that would otherwise be out of reach.
Research and Development: Schematic Circuit and PCB Design, 3D Printing and
Modelling, Software and Module Development.
124
MRC Centenary Open Day Exhibit. Demonstration of the
prototype robotic high-throughput tissue handling system, magnetic
tweezers for DNA supercoiling, 3D printing and prototype devices.
RESEARCH FACILITIES
Alan Ling
Co-workers: Derek Brewer, Ed Cattle, Steve Clarke, Peter Cookson, Raymond Herriott, Adam Hurst, Richard Jones
Mechanical Engineering provides a design, construction and
commissioning facility for bespoke instruments. This can involve
new developments or modifications to existing equipment.
Facilities include:
• 2D & 3D Design (AutoCAD)
• High precision manufacturing
• Milling (manual and CNC)
• Turning (manual and CNC)
• Sheet metal forming
• Plastic vacuum forming
• Welding
The experienced staff can manufacture quick one-off prototypes,
followed by continued development and modification to produce
the desired item or apparatus. Close liaison is maintained with the
scientific staff during all stages of design and manufacture. On-site
repair and maintenance of laboratory equipment is also carried
out in the workshop.
The varied facilities mean that a diverse range of projects can be
worked on, including:
• Soundproof enclosures
• Temperature controlled chambers
• Microscope stages and inserts
• Specialist adaptors and fittings
• Laser guarding and manipulators
• Prototype mechanical assemblies
125
RESEARCH FACILITIES
Dave Ion
Estates and Engineering is an NIMR administration division of
three departments providing a wide range of support services across
the Institute: Building Services, Mechanical Engineering, and Scientific
Equipment Care. Staff in these departments support NIMR Mon-Fri, and
provide 24/7 duty engineering cover from the resident maintenance
team. Mechanical Engineering is described on page 125 and is a direct
service to end user scientists.
Building Services
Darren Warrington, Ian Tollins, Guy Hallifax, Lynda Gray
Building Services provides a technical base to the Institute
for building projects and lab refurbishments as well as
maintaining the building and its infrastructure. It is the
home of Facility Management with responsibility for
everything supporting the general running of NIMR.
Maintenance and Project Work framework contracts
that are placed with Norland and VINCI Facilities provide
services that are specified and monitored by the Building
Services team.
Scientific Equipment Care
Melvin Ochs, Dennis Oates
Scientific Equipment Care (SEC) provides a triage and repair service to
a comprehensive range of scientific equipment. The current inventory
of equipment in use at NIMR numbers 20,000 items and includes
everything from Gilson Pipettes, benchtop lab kit, incubators through
to ULTRA centrifuges. A typical year will see more than 700 individual
equipment fault resolutions, either repair or equipment replacement,
whichever is most cost effective. Statistically 3.5% of all equipment in
use will receive attention from SEC during the course of a year.
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RESEARCH FACILITIES
PhotoGraphics
Joe Brock
Co-workers: Jamie Brock, Neal Cramphorn, Hayley Wood, Wai Han Yau
The PhotoGraphics service provides a professional design,
illustration and imaging facility to visualise the innovative
research carried out at NIMR. Our fully trained team provides
a wide range of specialist skills using state-of-the-art
equipment, software and techniques. These include digital
manipulation, illustration, Flash™ animation, film making and
editing, 3D modelling, scanning and photography as well as
providing a printing, copying and binding service.
This facility is open to all researchers wishing to relate their
science visually through publication, digital presentation
and posters. Novel methods developed by us for presenting
science using interactive animations provide more dynamic
in-depth explanations and we regularly receive requests for copies by researchers and companies world-wide who recognise this
media as a powerful informative tool.
The PhotoGraphics team design and publish NIMR publications such as this report, the Mill Hill Essays and other in-house
publications. We also present training courses throughout the year for researchers who wish to use applications such as Adobe
Photoshop™ and Microsoft PowerPoint™ to professional level.
As the provider of Audio Visual support to the Institute,
PhotoGraphics maintain the seminar and meeting room
facilities, offering first line support to all staff with regards
to the set–up and running of lectures, seminars and events.
We provide problem solving solutions as well as general
maintenance and repairs, ensuring smooth and effective
running of these resources for both in-house and visiting
speakers. We also develop and effect novel approaches for
disseminating research using visual technologies to keep pace
with current and future trends as visual technologies progress.
Typical illustration produced by PhotoGraphics visualising scientific and
biological processes.
127
RESEARCH FACILITIES
Clive Lunny
Co-workers: Stephen Fearns, Matt Miller, Asif Maqbool, Debbie Harper, Aomar Ayad, Harsha Sheth, Graeme Millar, Chandani Welmillage, Kevin McInerney, Pendar Sillwood and Gareth Burgess
The Computing department is responsible for delivering a broad range of
IT services at NIMR helping staff to achieve their work goals and providing
the support needed to meet NIMR’s evolving scientific requirements.
Services we provide can be broadly categorized as IT support services,
infrastructure facilities, and systems and software services. These include
the management and support of our LAN, wireless network and telephone
systems; communications systems; servers hosting multiple services and a
support section for Windows, Macintosh and Linux desktop and laptop PCs
and other mobile devices.
Services we provide are: a centralised data storage system with a capacity
of 352TB, replicated offsite for disaster recovery and providing automatic
backup for all users and scientific facilities; a Dropbox-like file-sharing system;
VPN for remote access; intranet access available externally; web servers for
intranet and public websites; IT security; collaboration services, including
videoconferencing with remote presentation, POP, IMAP and web-based
email, chat and calendaring; hosting of multiple databases including student
applications and animal records.
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RESEARCH FACILITIES
Library, information and communications
Frank Norman
Co-workers: Patti Biggs, Nicola Weston
The Library serves the information needs of scientific staff
and students at NIMR. It provides online access to over 3000
journals and to literature searching tools like Scopus, PubMed and
Metalib. Online resources are complemented by extensive print
journal backfiles, a printed book collection and easy access to a
document delivery service. Library staff provide individualised
help for scientists in the lab or office. Expert assistance with
information searching is available, including help with systematic
literature reviews, difficult-to-answer questions, and search alerts
for easier literature scanning. We offer assistance with citation
manager software (e.g. Endnote and Mendeley) and extensive
assistance for Open Access compliance. A daily news service
keeps staff informed of current science policy developments.
Casual reading space, dedicated study desks for writing-up and
some desks with computers are provided in the Library. There is a
WiFi network in the Library and iPads are available for borrowing.
The Library Breakout Space, with tables, chairs, whiteboards and
display screens, is used for informal meetings and discussions.
The Library is responsible for managing a number of external
channels of communication about the Institute. News features
about the Institute’s major research outputs and achievements
are published on the Institute website and we manage editorial
production of the Annual Report. It also maintains NIMR’s
historical archives and repository of publications.
The Library and breakout space.
One of the breakout tables.
129
RESEARCH FACILITIES
Web Team
Christina McGuire (up to November 2013)
Co-worker: Oli Chowdhury
The Web Team is responsible for the day-to-day
management of the NIMR website, intranet and online
presence, and longer-term strategic projects such as
the recent redevelopment and implementation of a
content management system on the external website.
Our aims are to ensure that the external website reflects
the excellence of science at NIMR, meets user and
organisational needs, and promotes the research and
outreach work at NIMR. Internally, we aim to provide
easy access to information and resources through online
systems which support effective and efficient working.
We produce microsites for NIMR-sponsored initiatives
such as conference websites; develop innovative
solutions such as our online weekly newsletter for staff;
and are always willing to provide advice and expertise.
The Web Team provides not only technical infrastructure, but also training and support (including tools for easy updating). We
develop cross-platform, user-friendly, visually appealing websites and applications, and ensure compliance with relevant standards
and legislation. We work with staff throughout NIMR, and use one-to-one meetings, focus groups, surveys, feedback forms, instant
polls, and user testing and evaluation to help inform future developments. We also have an open door policy, in common with
others at NIMR.
Online weekly newsletter for staff
130
Customisable intranet homepage
RESEARCH FACILITIES
Laboratory infrastructure and logistics (Central Services)
Joachim Payne
Laboratory Infrastructure and Logistics brings together a number of core support services (including Bioresources) that allow NIMR
scientists to focus on the important task of research. My teams grow your cells, prepare your reagents, archive your samples, wash
your glassware, deliver your consumables and clean your labs, so you don’t have to.
Central and Domestic Services
Julie Davies
The Central and Domestic Services team oversees cleaning,
waste management and recycling services across the site. In
addition, the section is responsible for providing Reception, Post
Room, Glasswash and meeting and hospitality facilities, as well as
managing on-site and off-site accommodation for students and
visiting scientists.
Central Stores
Colin Edwards
Every week, over 2000 items pass through our Central Stores,
destined for research laboratories across the Institute. The team
handle everything from hazardous and temperature sensitive
chemicals to large equipment and have a key role in managing
our vital supply chain and ensuring efficient stock control. The
section also manages the treatment of biological waste and the
delivery of liquid nitrogen and specialist gases.
131
RESEARCH FACILITIES
General services
Safety and Security
The Safety section provides a safe working environment at
the Institute. All staff are provided with general safety training
and advice. Specialist safety and security training and advice
is available from three safety officers, this includes biological,
radiological, chemical and fire safety. There is also specialist
equipment available for use. There is 24 hour security coverage.
The department also responds to all site emergencies.
Occupational Health
Occupational Health (OH) is concerned with the effects of
health on work and of work on health with consideration for
the working environment. Occupational services include health
protection, health promotion and lost time management. Our
professional service observes Health and Safety regulations and
helps to support the overall needs of NIMR. We offer impartial
advice to all employees on health matters related to the
working environment. The OH team also provide specific health
surveillance to staff members exposed to hazards.
Human Resources
The Human Resources section works in partnership across
the Institute to support its objectives and a diverse group of
scientific and support staff. A team of specialists work to embed
shared principles and a culture that support science and provide
expert advice on employment matters such as recruitment,
development, performance, reward and recognition.
Finance and Purchasing
The Finance team provides advice and support to staff in
the costing of grant applications, full economic costing,
expenses and sales invoices. They are also responsible for
the management, reporting and forecasting of the Institute’s
budgets. The Purchasing team assists staff with all aspects of
procurement including tendering for capital equipment, service
contracts, and consumables. They also liaise closely with the
RCUK Shared Service Centre to ensure that we get best value for
money in pricing.
132
Institute management
Executive Group
Jim Smith (Chair), Director
Eileen Clark, Head of Research Governance and Contracts
Steve Gamblin, Director of Research
Michele Marron, Director of Operations
Kathleen Mathers, Director of Biological Services
Nicola McGealey, NIMR Crick Project Director
Heads of Groups Committee
Jim Smith
Victor Tybulewicz
Jonathan Stoye
Vassilis Pachnis
David Wilkinson
Justin Molloy
Heads of Divisions Committee
Jim Smith (Chair)
James Briscoe
Donna Brown
Eileen Clark
Steve Gamblin
Alex Gould Francois Guillemot
Tony Holder Robin Lovell-Badge
Troy Margrie
Michele Marron
Kathleen Mathers
Justin Molloy Anne O’ Garra
Vassilis Pachnis
Steve Smerdon Gitta Stockinger
Jonathan Stoye
Willie Taylor Victor Tybulewicz
Jean-Paul Vincent David Wilkinson Douglas Young
133
Nobel Laureates
Five scientists from NIMR have been awarded Nobel Prizes for their scientific research.
Henry Dale, OM, FRS (1875-1968)
Henry Dale worked at NIMR from its inception in 1914 and was the first Director, serving from 1928-1942.
His research on the functions of nerve cells led to the discovery of acetylcholine as a neurotransmitter and
to the chemical basis of neurotransmission. For this work he received the Nobel Prize for Physiology or
Medicine in 1936.
Henry Dale
Archer Martin, CBE, FRS (1910-2002)
Archer Martin worked at NIMR from 1948-1956. Before arriving at NIMR he worked on amino acid analysis
and the development of partition chromatography for the purification of biological molecules. He received
the Nobel Prize for Chemistry for this work in 1952. At NIMR he developed the method of gas-liquid
chromatography, which has had far-reaching impact on the study of biochemistry.
Archer Martin
Rodney Porter, FRS (1917-1985)
Rodney Porter worked at NIMR from 1949-1960. His research on the many specificities of antibodies led to
the separation of antigen binding (Fab) and crystalline (Fc) proteolytic fragments of antibodies, an essential
step for the determination of their complete sequences of amino acids. For this work he received the 1972
Nobel Prize in Physiology or Medicine.
Rodney Porter
John Cornforth, FRS (1914-2013)
John Cornforth worked at NIMR from 1946-1962. He completed the first total synthesis of the nonaromatic steroids and in collaboration with George Popjak he identified the chemical structure of
cholesterol. He received the Nobel Prize for Chemistry in 1975.
John Cornforth
Peter Medawar, OBE, OM, FRS (1915-1987)
Peter Medawar was Director of NIMR from 1962-1971. He was one of the foremost biologists of his
generation, and also a hugely gifted populariser of science. Earlier in his career he studied how the immune
system rejects foreign tissue grafts and discovered the phenomenon of immune tolerance. For this work he
was awarded the Nobel Prize for Physiology or Medicine in 1960.
Peter Medawar
134
Six famous alumni
Rosa Beddington, FRS (1956-2001)
Rosa Beddington worked at NIMR 1993-2001, as head of the Division of Mammalian Development. Her
research focused on the first few days of mammalian embryo development. Over a period of twenty years
her contributions ranged from incisive analysis using the methods of classical embryology to establishing the
roles of specific genes and molecules in organising the embryonic body plan. Her insights were profoundly
influential in general understanding of how anterior-posterior fates are acquired in mammalian embryos.
Rosa Beddington
Frank Grosveld, FRS (1948- )
Frank Grosveld was head of the Division of Gene Structure and Expression at NIMR from 1981-1993, subsequently
moving to Erasmus University, Rotterdam. He discovered regulatory sequences that govern expression of the
globin gene cluster, and that confer copy number dependence on the expression level of transgenes. He was
awarded the Louis-Jeantet Prize for Medicine in 1991.
Frank Grosveld
Tim Bliss, FRS (1940- )
Tim Bliss worked at NIMR from 1967-2006, and was head of the Division of Neurophysiology from 1988.
Together with Terje Lømo in 1973 he uncovered the phenomenon of synaptic long-term-potentiation (LTP),
one of the major cellular processes underlying learning and memory. Since then he has worked on cellular
mechanisms responsible for the persistent increase in synaptic efficacy that characterizes LTP, and the
relationship between synaptic plasticity and memory. He was the Royal Society’s Croonian Lecturer in 2012.
Tim Bliss
Griffith Pugh, (1909-1994)
Griffith Pugh joined the NIMR Division of Human Physiology in 1950. He became head of the Laboratory for
Field Physiology in 1967 until he retired in 1975. He studied the physiological effects of altitude, temperature
and exertion, combining field and laboratory research. His studies contributed to the success of the 1953
British Himalayan Expedition to Mt. Everest, of which he was a member. He also advised the British Olympic
team on preparations for participation in the 1968 Olympic Games in Mexico City.
Griffith Pugh
Bridget Ogilvie, FRS (1938- )
Bridget Ogilvie worked at NIMR from 1963-1981, in the Division of Parasitology, on the immune response
to parasites, mainly the human parasitic nematodes, hookworm and lymphatic filaria. Studying the
immunogenicity of the secretions and surface coat of the parasites, she demonstrated a remarkable degree
of variation, especially in the latter, as the worms pass through the different stages of their complex life
cycles. After leaving NIMR she joined the Wellcome Trust, and was its Director from 1992-98.
Bridget Ogilvie
Robin Holliday, FRS (1932- )
Robin Holliday worked at NIMR 1965-1988, becoming head of a new Division of Genetics in 1970. He made
discoveries which came to have central importance to the field of epigenetics. In 1975 he suggested that DNA
methylation could be an important mechanism for the control of gene expression in higher organisms, and this
has now become documented as a basic epigenetic mechanism in normal and cancer cells. He was awarded the
Royal Society’s Royal Medal in 2011.
Robin Holliday
135
In memoriam
John Cornforth, (1917-2013)
Sir John ‘Kappa’ Cornforth died on 8 December 2013, aged 96. He worked at NIMR for 16 years
(1946-62) and won the 1975 Nobel Prize for Chemistry for his work on the stereochemistry of
enzyme-catalysed reactions.
John Cornforth was born on 7 September 1917 in Sydney, Australia. He attended Sydney High
School and entered the University of Sydney at the age of 16. He graduated in 1937 with firstclass honours and a University medal. In childhood he showed the first signs of deafness, due to
otosclerosis, and gradually lost his hearing completely. After a year of postgraduate research in
Australia, Cornforth was awarded one of two 1851 Exhibition scholarships in 1939 to study at
Oxford with the renowned chemist Robert Robinson. The other winner of the scholarship that
year was Rita Harradence, also an organic chemist, who Cornforth knew already. They married in
1941 and worked closely together throughout their careers. He said later:
“Throughout my scientific career my wife has been my most constant collaborator. Her
experimental skill made major contributions to the work; she has eased for me beyond
measure the difficulties of communication that accompany deafness; her encouragement
and fortitude have been my strongest supports.”
After completing their PhD work on steroid synthesis the Cornforths worked with Robinson on penicillin, which was the major
chemical project in his laboratory at Oxford during the war. Cornforth had earlier discovered what was to prove a key reaction for
the synthesis of the sterols and after the war he returned to this pursuit. John and Rita Cornforth moved to NIMR in 1946, working
there until 1962. John Cornforth collaborated with George Popjak, in NIMR’s Division of Biochemistry, and they began an extensive
series of studies using radioisotopes to determine how cholesterol is made in the body. They found that the carbon skeleton of
cholesterol is built up in a complex series of enzyme-regulated stages, entirely from two-carbon (acetyl) fragments. The work is
directly relevant to understanding the action of modern cholesterol-reducing statin drugs. Cornforth said:
“At NIMR I came into contact with biological scientists and formed collaborative projects with several of them. In particular
George Popják and I shared an interest in cholesterol. Popják and I began to concert experiments in which the disciplines of
chemistry and biochemistry could be applied to this subject. We were led to devise a complete carbon-by-carbon degradation
of the ring structure of cholesterol and to identify, by means of radioactive tracers, the arrangement of the acetic acid molecules
from which the system is built.”
Amongst his many investigations into natural products and their biosynthesis and possible manufacture was the successful search
to find a natural starting material for the manufacture of cortisone. Later work included new techniques for isotopic labelling and
extensions of the stereochemistry of enzymes. The NIMR Director at the time, Charles Harington, regarded Cornforth as “being
unquestionably in the first rank of organic chemists in this country”. In 1954 Cornforth seriously considered returning to Australia to
work in a proposed new research institute in Melbourne but eventually decided against it, much to Harington’s relief.
In 1962 Cornforth left NIMR to become joint director, with George Popjak, of the Shell Research Milstead Laboratory at
Sittingbourne. This lab was created by Shell at the urging of Robert Robinson, to foster work at the interface of chemistry and
biology. In 1975 Cornforth moved to the University of Sussex as Royal Society Research Professor in the Department of Applied
Science, retiring in 1982.
Cornforth was a modest and unassuming man. While he had hoped that his work would turn out to be important, he refrained from
expecting such a grand Prize as the Nobel. “You could say it was original enough and useful enough to be considered for the Prize.
But my own approach at the time was to put this resolutely out of my mind.”
John Cornforth received many awards throughout his career, becoming FRS in 1953 and receiving the Royal Society’s Royal Medal
(1976) and Copley Medal (1982), as well as the 1975 Nobel Prize for Chemistry, for his work on the stereochemistry of enzymecatalysed reactions, shared with Professor V. Prelog. He was made a Knight Bachelor in 1977.
136
In memoriam
James Lightbown (1918-2013)
James Lightbown died on 11 April 2013, aged 94. He was a member of staff at NIMR, in the
Division of Biological Standards, from 1949 to 1972, when he transferred to the National
Institute for Biological Standards and Control (NIBSC).
James W. Lightbown was born in Blackburn on 2 June 1918. He won a scholarship to
Manchester Grammar School, then studied Pharmacy at Manchester University, 1936-41,
where he was awarded the Wilde Prize in Pharmacology in 1941 for the best MSc thesis of the
year. He stayed in the Department of Pharmacy at Manchester as a Demonstrator and later
Assistant Lecturer, also undertaking some research work. He gained a Diploma in Bacteriology
in 1948 and the following year became a member of the scientific staff in the Division of
Biological Standards at NIMR. He was responsible for the assay of antibiotics and in 1950 he
undertook a study tour of UK pharmaceutical manufacturers to gain experience of chemical
and biological assay of penicillin, and to learn about the manufacturing processes.
In 1952 he was promoted for his “great value in antibiotic assay” work and his substantial
contribution to research. In 1957 he became completely responsible for antibiotic standards
and by 1965 he was effectively deputy to the Head of Division, Derek Bangham, in all matters to do with standards and control. He
was seen as efficient and responsible, and the Director of NIMR, Peter Medawar, had a high opinion of him.
Lightbown was much involved in international standardization work, and a regular visitor to WHO in Geneva. His publications list
is dominated by antibiotic standards. From the 1950s onwards he published reference standards for most of the key antibiotics,
including crucial early work on assaying streptomycin and penicillins.
In 1972 he became Head of the Division of Antibiotics at the newly established National Institute for Biological Standards and
Control (NIBSC), where he remained until his retirement in 1983. He was awarded the OBE for services to science in 1983.
I worked with Jim Lightbown a good deal - he was a great guy to work with. We built the large-scale Countercurrent
Chromatography (CCC) unit and together worked on the international standard for Polyene Macrolide Antibiotics such as Candicidin
and Trichomycin. This research was quite pioneering at the time and not only led to the publication of the WHO international
standard for Candicidin, but also stimulated the growth of counter-current chromatography in China and eventually led to the
successful development, scale-up and commercialization of CCC at Brunel University.
Ian Sutherland, NIMR Engineering 1972-1989
137
In memoriam
Michael Sargent (1943-2013)
Michael Sargent died on 13 March 2013, aged 70. He was a member of scientific staff
at NIMR from 1969 until his retirement in 2007. He pioneered the Institute’s outreach
programme to schools and the U3A.
Michael was born in 1943. He was educated at the Royal Hospital School in Suffolk, then
went to Nottingham University. He chose to study botany because microbial genetics
was taught chiefly in botany departments at that time. He stayed on to complete his
PhD at Nottingham then spent three years as a postdoc with J. Oliver Lampen at Rutgers
University in New Jersey, working on penicillinase secretion in Bacillus sp.
In 1969 he was recruited by Howard Rogers to NIMR’s Division of Microbiology, to study
mechanisms of cell growth and division in Bacillus subtilis. Using synchronous cultures of
B. subtilis, involving the selection of essentially new-born cells by a method he devised,
Michael investigated bulk patterns of synthesis of membrane proteins during the cell
cycle, and the growth kinetics of individual cells by means of thymine starvation or
nutritional shifts to richer media. His results, published in Nature, showed evidence for a
doubling in the number of surface growth zones at nuclear segregation and an absolute
requirement for DNA synthesis.
After Howard Rogers retired in 1984, the Division of Microbiology was closed. Michael moved away from bacteria and joined the
Laboratory of Embryogenesis headed by Jonathan Cooke. Michael’s response to the challenge of switching to a new field midcareer was characteristically strong and positive. He assiduously read the embryology literature and was soon making very valuable
contributions. Indeed his contrasting background knowledge, particularly on the biochemical side, was an asset.
In the early 1990’s Michael transferred to the newly formed Division of Developmental Biology headed by Jim Smith. Working with
Xenopus and chick cDNA libraries, he succeeded in cloning and characterising two vertebrate homologues of the Drosophila gene
Snail - a gene that is required for mesoderm formation. He helped to show that it was possible to interfere functionally with each
gene in turn in chick development, establishing their roles in the origin of the neural crest and of left-right asymmetry. This work
led to Michael’s co-authorship of two highly-cited papers in Science. From 1999 until his retirement in 2007, Michael worked with
Tim Mohun in the Division of Developmental Biology, studying heart development in vertebrate embryos. Michael devised a reliable
protocol for cryopreservation of sperm from both Xenopus laevis and its cousin, Xenopus tropicalis, a method that rapidly gained
widespread use.
Michael was always interested in schools and outreach activities, with expert help from his wife Jean who is a science teacher.
He organised the first Schools Day at NIMR, and ran the Schools Programme at NIMR for many years: Schools Days, the Research
Summer School and the School Essay Competition. For the past ten years he also organised an annual meeting at the Institute for
the University of the Third Age.
Towards the end of his career at NIMR, Michael was awarded a Winston Churchill Travelling Fellowship to visit Ethiopia, India and
Canada in order to study the effect in later life of nutritional and other physiological stress on the developing foetus. Michael’s ideas
about how the prospects for human life might improve, together with an examination of the ethical checkpoints to biomedical
intervention, were discussed in his book Biomedicine and the Human Condition which was published in 2005.
“Michael was the most stimulating of colleagues. He always had some new information to impart and had a fund of stories to tell.
There was never a dull moment when Michael was around and his laugh could often be heard reverberating along the corridor. He
was one of the most fearless of scientists; nothing daunted him, either theoretical or experimental. For example, when restriction
enzymes were first used for molecular cloning they were extremely expensive. Michael set about extracting and purifying his
own and soon had a stock which, characteristically, he shared with others. His advice and opinion on a wide range of ideas and
techniques were valued by many people.”
Roger Buxton
138
Scientific seminars
Nearly 200 seminars and lectures by visiting speakers are given at the Institute each year. Each major area of science has its own
seminar series and the Mill Hill Lecture series is an annual series of about ten lectures given by eminent scientists from around the
world. A selection of highlights from the past year is shown.
Wes Sundquist
Susan Gasser
Edith Heard
Carol Robinson
Hans-Georg Kräusslich
Frank Grosveld
Susan Mango
Mark Krasnow
Chris Schofield
Janet Thornton
Vijay Kuchroo
Gurdyal Besra
Juergen Wienands
Angus Lamond
Peter Parker
Michael Dustin
Robert Sauerwein
Markus Meissner
Robert Ménard
Frank Kirchhoff
Jonathan Weber
Christian Eggeling
Gunter Meister
Kazuhiro Oiwa
Stephen Kent
Roger Goody
Ian Meinertzhagen
Jason Chin
Amanda Fisher
Angela Giangrande
Jorge Ferrer
Erika Bach
Clive Wilson
Susan Ozanne
University of Utah, USA
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
CNRS Institut Curie, Paris
University of Oxford
University of Heidelberg, Germany
Erasmus MC Biomedical Sciences, Netherlands
Harvard University, USA
Stanford University, USA
University of Oxford
European Bioinformatics Institute
Brigham and Women’s Hospital, Harvard Medical School, USA
University of Birmingham
Georg August University Goettingen, Germany
University of Dundee
Cancer Research UK
University of Oxford and Kennedy Institute of Rheumatology
Radboud University Nijmegen Medical Center, Netherlands
University of Glasgow
Institut Pasteur, Paris
Institute of Molecular Virology, University of Ulm, Germany
Faculty of Medicine, Imperial College London
MRC Human Immunology Unit, Weatherall Inst of Molecular Medicine
University of Regensburg, Germany
Advanced ICT Research Institute, NICT, Kobe, Japan
University of Chicago, USA
Max-Planck Institute for Molecular Physiology, Dortmund, Germany
Dalhousie University, Halifax, Canada
MRC Laboratory of Molecular Biology, Cambridge
MRC Clinical Sciences Centre, Hammersmith Hospital
IGBMC, Dept. of Functional Genomics and Cancer, Strasbourg, France
Faculty & Department of Medicine, Imperial College London
New York University School of Medicine, USA
Department of Physiology Anatomy & Genetics, University of Oxford
University of Cambridge
139
Staff honours 2013
Prizes and awards 2013
Alex Gould
Annalisa Pastore
Iris Salecker Jim Smith Gitta Stockinger Pavel Tolar
Jean-Paul Vincent Fellow of the Academy of Medical Sciences
Member of Academia Europaea
Member of EMBO
Waddington Medal, British Society for Developmental Biology
Fellow of the Royal Society
EMBO Young Investigator
Fellow of the Royal Society
Editorial boards
Siew-Lan Ang Mike Blackman James Briscoe Denis Burdakov John Doorbar Paul Driscoll Greg Elgar Alex Gould François Guillemot Maximiliano Gutierrez Tony Holder George Kassiotis Jean Langhorne
Steve Ley Robin Lovell-Badge John McCauley Justin Molloy John Offer Anne O’Garra Markus Ralser Andres Ramos Katrin Rittinger Iris Salecker
Andreas Schaefer Benedict Seddon Steve Smerdon Jim Smith Gitta Stockinger Jonathan Stoye James Turner Victor Tybulewicz Jean-Paul Vincent David Wilkinson Robert Wilkinson 140
International Journal of Developmental Biology
PLoS Pathogens; Eukaryotic Cell
PLoS Biology; Development; Developmental Biology; Neural Development;
Developmental Dynamics
American Journal of Physiology; PlOS ONE; Frontiers in Molecular Neuroscience
Journal or General Virology; Virology
Journal of Structural and Functional Genomics; PLOS ONE
Briefings in Functional Genomics; Genome Biology and Evolution
Development
Development; Developmental Cell; Genes & Development; Neural Development; BMC Developmental
Biology; Neurogenesis
Cellular Microbiology
Eukaryotic Cell; Molecular and Biochemical Parasitology
PLoS ONE
Associate Editor PLoS Pathogens
Biochemical Journal; Cell Research
Organogenesis; Sexual Development; Biology of Sex Differences; PLOS
Virus Research
Journal of Microscopy
Protein and Peptide Letters; Frontiers in Chemical Biology
Journal of Experimental Medicine
BMC Genomics
Open Magnetic Resonance Journal; Springer Encyclopaedia of Biophysics
The Biochemical Journal
Frontiers in Neural Circuits
PLOS ONE
Frontiers in Immunological Memory; Immunology
Science Signaling
Open Biology
Frontiers in Immunology; BMC Biology
Journal of Virology
Biology of Reproduction; Chromosome Research
Frontiers in B cell Biology; Frontiers in T cell Biology; Faculty of 1000
Science Signaling; Developmental Biology; Philosophical Transactions of the Royal Society B
Mechanisms of Development; Gene Expression Patterns; Developmental Biology; BMC
Developmental Biology; Faculty of 1000
International Journal of Tuberculosis and Lung Disease; Tuberculosis; PLOS ONE
Staff honours 2013 (cont.)
Scientific Committees and Scientific Advistory Boards (SAB)
Mike Blackman James Briscoe EU EviMalar Network of Excellence, Executive Committee member
John Doorbar
Paul Driscoll Wellcome Trust Expert Review Group
Company of Biologists, Trustee
Roslin Institute Scientific Advisory Board
International Federation for Cervical Pathology and Colposcopy (IFCPC),
Scientific Advisory Committee.
Chairman, Collaborative Computing Project for NMR
University of Birmingham Henry Wellcome NMR Centre Advisory Board
Alex Gould
Academy of Medical Sciences Sectional Committee 2
François Guillemot Selection Committee, Peter and Patricia Gruber International Research Award in Neuroscience
Tony Holder Wellcome Trust Expert Review Group
Ian Holt EU European Consortium on Freidriech’s Ataxia, Scientific Advisory Committee
Jean Langhorne
Wellcome Trust Expert Review Group
Scientific Advisory Board, Institut für Molekulare Infektionsbiologie der Universität Würzburg,
Germany
Scientific Advisory Board, Hartmut Hoffmann-Berling International Graduate School of Molecular &
Cellular Biology, Heidelberg, Germany.
Robin Lovell-Badge Sense About Science, Advisory Council;
Science Media Centre Advisor Board;
President of the Institute of Animal Technology;
Co-opted member of the Scientific and Clinical Advances Advisory Committee, of the Human
Fertility and Embryo Authority (HFEA);
BBVA Foundation, Frontiers of Knowledge Award, Member and Secretary of the Jury for the
Biomedicine Award;
Member of HFEA working group (and deputy-chair) providing a “Review of scientific methods to
avoid mitochondrial disease”;
UAR, Member of Council;
Royal Society, Member of Council;
Member of Feldberg Foundation Award Committee;
Royal Society, Member of Public Engagement Committee.
Tim Mohun
British Heart Foundation Project Grants Committee
Justin Molloy Wellcome Trust Expert Review Group
BBSRC Tools and Resources Development Fund, Deputy Chair
MRC/BBSRC/EPSRC Next Generation Optical Microscopy Initiative Panel
Dresden CBG MPI, Advisory Review Board
John Offer
Royal Society of Chemistry peptides and protein science group
141
Staff honours 2013 (cont.)
142
Anne O’Garra Scientific Advisory Board, Institute for Biomedical Sciences, Bellinzona, Switzerland.
Scientific Advisory Board, Baylor Institute for Immunology, Dallas, USA.
Scientific Advisory Board, World Premier International Research Center (WPI), Osaka Univ., Japan
Keystone Symposia Scientific Advisory Board
MRC/ABPI, UK Inflammation and Immunology Initiative, Steering Group
Steve Smerdon Diamond Light Source Scientific Advisory Committee
Jim Smith Member, Scientific Advisory Board, TwistDx (ASM Scientific);
Subject Head for Developmental Biology, Biology Image Library,
Member, Scientific Advisory Board, Institute for Toxicology and Genetics, Karlsruhe,
Member, Scientific Advisory Council, Indian Institute of Science Education and Research (IISER),
Member, Scientific Advisory Committee, Biosciences and Bioengineering Group at Indian Institute of
Technology, Indore,
Governor and Chair of Education Committee, Latymer Upper School,
Chair, Royal Society/Wellcome Trust Sir Henry Dale Fellowship Interview Committee,
Director of Research, Francis Crick Institute.
Gitta Stockinger EMBO Fellowship panel
ERC Consolidator panel
Advisory Board Department of Biomedicine, Basel
Advisory Board, DRFZ, Berlin
Jonathan Stoye Member SGM expert panel on Sexually-transmitted infections
James Turner Genetics Society
Society of Reproduction and Fertility
Victor Tybulewicz Academy of Medical Science, Member of Council
Academy of Medical Sciences Sectional Committee 2
Jean-Paul Vincent Chair, Atipe-Avenir career development fellowships of the CNRS and INSERM
Chair, Scientific Advisory Board, Institut de biologie du Developpement de Marseille, France
David Wilkinson Helmholtz Society Biointerfaces Program
Welbio Scientific Council
GXD gene expression database
Robert Wilkinson Scientific Advisory Board, The Africa Centre for Health and Population Studies,
Mtubatuba, Kwa-Zulu-Natal
Trustee and Board Member, South African Centre for Epidemiological analysis and modeling,
Stellenbosch University, Cape Town, South Africa
Douglas Young Wellcome Trust/DBT India Alliance: Intermediate and Senior Fellowship Selection Committee
GSK ORCHID Alliance: Science Advisory Panel
Aeras: Vaccine Advisory Committee
TBVI: Governance Board
CNRS Institute of Pharmacology and Structural Biology: Scientific Advisory Board
IIDMM Cape Town: International Scientific Advisory Committee
PhD theses awarded in 2013
Name
Division
Title of thesis
Suraya Alexandra Das Neves Guevara Diaz
Parasitology
Melania Kalaitzidou
Daniel Marshall
Immune Cell Biology
Cristina Minieri
Panayotis Pachnis
Graham Rose
Ina Corinne Dorothea Schim Van Der Loeff
Maria Irina Stefana
Immune Cell Biology
Christina Untersperger
Virology
Darren Wight
Virology
Claudia Arbore
Roberta Azzarelli
Sorrel Ruth Bryony Bickley
Leonard Cheung
Jennifer Alice Frampton
Ashleigh Frances Howes
Immunoregulation
Reena Lasrado
Dafni Hadjieconomou
Noor Azian Binti Md Yusuf
Parasitology
Jorge Miguel Valente Beira
Elizabeth Natkanski
Immune Cell Biology
Chloe Bloom
Immunoregulation
George Young
Asif Tamuri
Immunoregulation
Elizabeth Underwood
Molecular Structure
Protein interactions in the plasmodium falciparum
merozite motor complex
The role of SATB1 in medial ganglionic eminencederived cortical interneuron differentiation
The role of multiple cell types in the development of
regulatory T-cells
Regulation of neural enhancer activity by Ascl1 and
Sox factors
Growth and metabolism in adult Drosophila
A genomic and transcriptomic study of lineagespecific variation in Mycobacterium tuberculosis
The role of Zap70 in naive T cell homeostasis
Lifelong consequences of protein deficiency during
development in Drosophila
Analysis of pathways affected by the viral oncogenes
in human papillomavirus 16-induced neoplastic
progression
Investigations into the function of the
gammoretroviral protein p12 during the early stages
of infection
Mechanisms and functions of molecular interactions
during plasmid rolling circle replication
Molecular mechanisms mediating Rnd protein promigratory activity in the developing cerebral cortex
The gene Tbx5 links development, evolution and
adaptation of the sternum in terrestrial vertebrates
Genetic manipulation of the Wnt and Notch signalling
pathways in the pituitary gland in vivo
Synaptotagmins and Weibel-Palade body exocytosis
in human endothelial cells
The regulation of interleukin-10 and interleukin-12 in
macrophages: Investigating the differential regulation
of IL-10 and IL-12 in C57BL/6 and BALB/c mice
Characterization of Enteric Nervous System
Progenitors during Embryogenesis
Development of a genetic multicolor cell labeling
approach for neural circuit analysis in Drosophila
Actomyosin motors and malaria parasite invasion of
the host cell
Pathways mediating apoptosis upon developmental
defects
Investigating novel components and mechanisms
involved in B cell receptor-antigen internalisation
The Study of Blood Transcriptional Signatures to
Improve Medical Management and Understanding of
Active Pulmonary Tuberculosis and Similar
Respiratory Diseases Including Sarcoidosis
Endogenous Retroviruses and the Immune System
Using phylogenetic models to characterise natural
selection from molecular data
Nucleotide Regulation of AMP-activated Protein
Kinase
143
Current funding sources
The Medical Research Council (MRC) is the principal source of research funding. The budget - currently £42m p.a.- is set every five
years following an Institute-wide review of resources. This review takes place after the five-yearly peer review (conducted by MRC
Research Boards) of the programmes of the individual Divisions.
The Institute also attracts funding support from a wide range of different agencies, including medical research charities,
international sources, particularly the EU, and from industrial and commercial companies:
A*Star
Academy Medical Sciences
Academy of Science of South Africa
Association for International Cancer Research
Arthritis Research UK
Biotechnology and Biological Sciences Research Council
Boehringer Ingelheim
British Heart Foundation
Carnegie Corporation of New York
Department of Science and Technology of South Africa
European and Developing Countries Clinical Trials Partnership
European Molecular Biology Organization
European Research Council
European Union
Federation of the Societies of Biochemistry and Molecular Biology
Fondation Leduq
German Research Council
GlaxoSmithKline
Human Frontier Science Program
iMOVE
Imperial College
University of Cape Town
International Foundation of CDKL5 Research
Isaac Newton Trust
Kyoto University Fellowship
Lalor Foundation
Leukaemia & Lymphoma Research
March of Dimes Research Foundation Research Grant
Merieux Foundation
Medical Research Council
Medical Research Council Technology
National Institutes of Health
Netherlands Organisation for Scientific Research
Parkinson’s UK
Royal Society
Sanofi Pasteur MSD
Simons Foundation
Swiss National Science Foundation
UCL Biomedical Research Centre
Wellcome Trust
Wellcome-Beit Prize Fellowship
Wellcome Trust African Institutions Initiative
144
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Structural and functional characterization of the recombinant death
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75. Djordjevic S and Driscoll PC (2013)
Targeting VEGF signalling via the neuropilin co-receptor.
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Diagnosis of paediatric tuberculosis: the culture conundrum.
Lancet Infectious Diseases 13:36-42
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Differential influences of the aryl hydrocarbon receptor on Th17 mediated
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PLOS ONE 8:e79819
81. Everitt AR, Clare S, McDonald JU, Kane L, Harcourt K, Ahras M, Lall A, Hale C,
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PLOS ONE 8:e80723
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Infection and Immunity 81:1479-1490
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FEBS Open Bio 3:453-8
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Metabolomics reveal D-Alanine:D-Alanine ligase as the target of
D-Cycloserine in Mycobacterium tuberculosis.
ACS Medicinal Chemistry Letters 4:1233-1237
Reinterpreting the mechanism of inhibition of Mycobacterium
tuberculosis D-alanine:D-alanine ligase by D-cycloserine.
Kinetic mechanism and inhibition of Mycobacterium tuberculosis
D-alanine:D-alanine ligase by the antibiotic D-cycloserine.
FEBS Journal 280:1150-1166
198. Rackham MD, Brannigan JA, Moss DK, Yu Z, Wilkinson AJ, Holder AA, Tate
EW and Leatherbarrow RJ (2013)
Discovery of novel and ligand-efficient inhibitors of Plasmodium
falciparum and Plasmodium vivax N-Myristoyltransferase.
Journal of Medicinal Chemistry 546:371–375
199. Ragan TJ, Bailey AP, Gould AP and Driscoll PC (2013)
Volume determination with two standards allows absolute quantification
and improved chemometric analysis of metabolites by NMR from
submicroliter samples.
Analytical Chemistry 85:12046-12054
200. Rangaka MX and Wilkinson RJ (2013)
Isoniazid prevention of HIV-associated tuberculosis.
Lancet Infectious Diseases 13:825-827
201. Real FM, Sekido R, Lupiáñez DG, Lovell-Badge R, Jiménez R and Burgos M
(2013)
A microRNA (mmu-miR-124) prevents Sox9 expression in developing
mouse ovarian cells.
Biology of Reproduction 89:78
202. Reis AL and McCauley JW (2013)
The influenza virus protein PB1-F2 interacts with IKKβ and modulates
NF-κB signalling.
PLOS ONE 8:e63852
203. Riel JM, Yamauchi Y, Sugawara A, Li HYJ, Ruthig V, Stoytcheva Z, Ellis PJI,
Cocquet J and Ward MA (2013)
Deficiency of the multi-copy mouse Y gene Sly causes sperm DNA
damage and abnormal chromatin packaging.
204. Rizzoti K, Akiyama H and Lovell-Badge R (2013)
Mobilized adult pituitary stem cells contribute to endocrine regeneration
in response to physiological demand.
Cell Stem Cell 13:419-432
153
205. Rock JM, Lim D, Stach L, Ogrodowicz RW, Keck JM, Jones MH, Wong CCL,
Yates JR, Winey M, Smerdon SJ, Yaffe MB and Amon A (2013)
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Phenotypic and functional profiling of CD4 T cell compartment in distinct
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PLOS ONE 8:e55195
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Mapping of genotype-phenotype diversity among clinical isolates of
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208. Rousu J, Agranoff DD, Sodeinde O, Shawe-Taylor J and Fernandez-Reyes D
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209. Royo H, Prosser H, Ruzankina Y, Mahadevaiah SK, Cloutier JM, Baumann M,
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210. Sader K, Stopps M, Calder LJ and Rosenthal PB (2013)
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211. Sadowski MI and Taylor WR (2013)
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Capsid-binding retrovirus restriction factors: discovery, restriction
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The unique structure of the apicoplast genome of the rodent malaria
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154
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RS, Davis EO and Young DB (2013)
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tuberculosis results in growth inhibition, reduced abundance of a subset
of mRNAs and cleavage of tmRNA.
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Efficient high-throughput sequencing of a laser microdissected
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Genetic control of testis development.
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Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the
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An attenuated mutant of the Rv1747 ATP-binding cassette transporter
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Foxa1 and Foxa2 are required for the maintenance of dopaminergic
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Degradation of activated K-Ras orthologue via K-Ras specific lysine
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Journal of Biological Chemistry Epub ahead of print
Sun W, Hu X, Lim MHK, Ng CKL, Choo SH, Castro DS, Drechsel D,
Guillemot F, Kolatkar PR, Jauch R and Prabhakar S (2013)
TherMos: estimating protein–DNA binding energies from in vivo binding
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Tadokera R, Wilkinson KA, Meintjes GA, Skolimowska KH, Matthews K,
Seldon R, Rangaka MX, Maartens G and Wilkinson RJ (2013)
Role of the interleukin 10 family of cytokines in patients with immune
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Tata JR (2013)
The road to nuclear receptors of thyroid hormone.
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236.
Taylor WR, Hamilton RS and Sadowski MI (2013)
Prediction of contacts from correlated sequence substitutions.
Current Opinion in Structural Biology 23:473-479
237.
Timmerman LA, Holton T, Yuneva M, Louie RJ, Padró M, Daemen A, Hu
M, Chan DA, Ethier SP, van ‘t Veer LJ, Polyak K, McCormick F and Gray JW
(2013)
Glutamine sensitivity analysis identifies the xCT antiporter as a
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Cancer Cell 24:450-465
238.
Toseland CP and Webb MR (2013)
ATPase mechanism of the 5’-3’ DNA helicase, RecD2: evidence for a
pre-hydrolysis conformation change.
239.
Tozer S, Le Dréau G, Marti E and Briscoe J (2013)
Temporal control of BMP signalling determines neuronal subtype
identity in the dorsal neural tube.
240.
Trent S, Dean R, Veit B, Cassano T, Bedse G, Ojarikre OA, Humby T and
Davies W (2013)
Biological mechanisms associated with increased perseveration and
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Psychoneuroendocrinology 38:1370-1380
241.
Tschopp R, Abera B, Sourou SY, Guerne-Bleich E, Aseffa A, Wubete A,
Zinsstag J and Young D (2013)
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Turner J-E, Morrison PJ, Wilhelm C, Wilson M, Ahlfors H, Renauld J-C,
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IL-9–mediated survival of type 2 innate lymphoid cells promotes
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Journal of Experimental Medicine 210:2951-2965
243.
Turner J-E, Stockinger B and Helmby H (2013)
IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal
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244.
Uraki R, Kiso M, Shinya K, Goto H, Takano R, Iwatsuki-Horimoto K,
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245.
Valentin G and Oates AC (2013)
Opening a can of centipedes: new insights into mechanisms of body
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Vincent J-P, Fletcher AG and Baena-Lopez LA (2013)
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NIMROD
NIMROD is the NIMR social club. Membership is open to all staff
for a very small annual subscription. A number of functions are
organised throughout the year, including quiz nights, live music,
barbecues, ceilidhs and discos. The NIMROD bar is open Monday
to Friday evenings and provides a relaxed atmosphere in which to
meet colleagues.
The club also organises a wide range of sporting activities and
tournaments. These include football, volleyball, tennis, netball,
running, snooker, pool, table football, table tennis and darts.
In addition, a number of smaller clubs exist within NIMROD,
including:
• Hillwalking - regular excursions in the UK and abroad
• Magazine club - allows sharing of club purchased magazines
• Drama - NIMDram regularly stages performances
• Gardening - exchanging knowledge and hosting an annual
summer sale
• Book club – roughly monthly meetings
The NIMROD Committee
157
Research themes index
Biochemistry
DimitriosAnastasiou
Luiz de Carvalho
Eva Frickel
Ian Holt
Vivian Li
Justin Molloy
John Offer
Martin Webb
Mariia Yuneva
Biophysics
Denis Burdakov
Tom Carter
Justin Molloy
Peter Rosenthal
Andreas Schaefer
Ian Taylor
Martin Webb
158
78
39
41
65
95
66
67
73
76
90
80
61
66
71
87
74
76
Cancer
Steve Gamblin
Vivian Li
Andres Ramos
Steve Smerdon
Jean-Paul Vincent
Martin Webb
Mariia Yuneva
78
63
95
69
72
104
76
90
Cell biology
Kate Bishop
Mike Blackman
Tom Carter
Eva Frickel
37
38
61
41
42
Tony Holder
Ian Holt
Steve Ley
Vivian Li
Tim Mohun
Justin Molloy
Katrin Rittinger
Benedict Seddon
Jim Smith
Jonathan Stoye
Peter Thorpe
Pavel Tolar
Victor Tybulewicz
Jean-Paul Vincent
David Wilkinson
42
43
65
46
95
98
66
70
50
101
73
52
102
53
54
104
56
Chromosome biology
Ian Holt
Peter Thorpe
James Turner
65
102
103
Developmental biology
Siew-LanAng
James Briscoe
Greg Elgar
Mike Gilchrist
Alex Gould
François Guillemot
Malcolm Logan
Robin Lovell-Badge
Tim Mohun
Andrew Oates
Vassilis Pachnis
Andres Ramos
Iris Salecker
Jim Smith
79
92
93
94
81
82
96
97
98
100
84
69
86
101
Sila ULtanir
Jean-Paul Vincent
David Wilkinson
88
104
89
Evolutionary biology
Paul Driscoll
Richard Goldstein
Malcolm Logan
Robin Lovell-Badge
62
64
96
97
Genetics & genomics
Siew-LanAng
Mike Gilchrist
François Guillemot
Malcolm Logan
Robin Lovell-Badge
Tim Mohun
Iris Salecker
Jim Smith
Peter Thorpe
James Turner
Victor Tybulewicz
Jean-Paul Vincent
Robert Wilkinson
Mark Wilson
79
94
82
96
97
98
86
101
102
103
54
104
56
57
Immunity
John Doorbar
Eva Frickel
George Kassiotis
Jean Langhorne
Steve Ley
Anne O’Garra
Andres Ramos
Katrin Rittinger
40
41
42
44
45
46
48
49
69
70
Benedict Seddon
Gitta Stockinger
Pavel Tolar
Victor Tybulewicz
Andreas Wack
Robert Wilkinson
Mark Wilson
Douglas Young
Infectious disease
Kate Bishop
Mike Blackman
Luiz de Carvalho
John Doorbar
Eva Frickel
Steve Gamblin
Richard Goldstein
Tony Holder
George Kassiotis
Jean Langhorne
John McCauley
Anne O’Garra
Peter Rosenthal
Steve Smerdon
Gitta Stockinger
Jonathan Stoye
Ian Taylor
Pavel Tolar
Andreas Wack
Robert Wilkinson
Mark Wilson
Douglas Young
Mathematical biology
Mike Gilchrist
Richard Goldstein
Willie Taylor
50
51
53
54
55
56
57
58
37
38
39
40
41
63
64
42
43
44
45
47
48
71
72
51
52
74
53
55
56
57
58
94
64
75
Neurosciences
Siew-LanAng
James Briscoe
Denis Burdakov
Alex Gould
François Guillemot
Troy Margrie
Vassilis Pachnis
Annalisa Pastore
Iris Salecker
Andreas Schaefer
David Wilkinson
Physiology & metabolism
Siew-LanAng
Denis Burdakov
Tom Carter
Luiz de Carvalho
Paul Driscoll
Steve Gamblin
Alex Gould
Troy Margrie
Andrew Oates
Markus Ralser
Andreas Schaefer
Steve Smerdon
Gitta Stockinger
Mark Wilson
Mariia Yuneva
Stem cell biology
Alex Gould
François Guillemot
Vivian Li
79
92
80
81
82
83
84
68
86
87
73
89
78
79
861
39
62
63
81
83
100
85
87
72
73
51
51
90
Robin Lovell-Badge
Kathy Niakan
Vassilis Pachnis
Peter Thorpe
James Turner
David Wilkinson
97
99
84
102
103
89
Structural biology
Mike Blackman
Paul Driscoll
Steve Gamblin
Annalisa Pastore
Andres Ramos
Katrin Rittinger
Steve Smerdon
Jonathan Stoye
Ian Taylor
Willie Taylor
Martin Webb
38
62
63
68
69
70
72
52
74
75
76
Systems biology
James Briscoe
Denis Burdakov
Luiz de Carvalho
Greg Elgar
Mike Gilchrist
Malcolm Logan
Andrew Oates
Annalisa Pastore
Douglas Young
Mariia Yuneva
78
92
80
39
93
94
96
100
68
58
90
81
82
95
159
Index
Abucewicz, Dorota
Anastasiou, Dimitrios
Ang, Siew-Lan
Ayad, Aomar
Bioresources
Bishop, Kate
Blackman, Mike
Briscoe, James
Brock, Joe
Brown, Donna
Burdakov, Denis
Burke, Melissa
Carter, Tom
Caswell, Sarah
Central Services
Clark, Eileen
de Carvalho, Luiz Pedro
Doorbar, John
Driscoll, Paul
Electron Microscopy
Elgar, Greg
Flow cytometry
Frenkiel, Tom
Frickel, Eva
Gamblin, Steve
General services
Genomics
Gilchrist, Mike
Goldstein, Richard
Gould, Alex
Gu, Yan
Guillemot, Francois
Gutierrez, Max
Hirst, Liz
Histology
Holder, Tony
Holt, Ian
Howell, Steve
Human Embryo and Stem Cell Unit
Insectary
Ion, David
Johnson, Sarah
Johnston, Ashleigh
Kassiotis, George
Langhorne, Jean
Large scale laboratory
Ley, Steve
Li, Vivian
Library, information & communications
Ling, Alan
Logan, Malcolm
Lovell-Badge, Robin
Lunny, Clive
Mahmood, Radma
Management
Margrie, Troy
Marron, Michele
Martino, Luigi
Mass Spectrometry
Mathers, Kathleen
McCauley, John
McGuire, Christina
160
25
78
79
25
106
111
119
11, 37
15, 38
92
127
16
80
21
61
19
131
27
128
112
29, 39
40
62
117
114
93
126
122
108
41
11, 15, 63
132
118
94
64
81
112
82
42
118
114
113
29, 43
65
110
120
121
126
107
18
44
10, 45
119
123
46
4, 28, 95
129
125
96
12, 15, 97
128
113
133
83
133
21
110
106
11, 47, 59
130
Media Preparation
Microarray
Mohun, Tim
Molloy, Justin
Murphy, Jake
Niakan, Kathy
Nikolov, Nikolay
NMR Centre
Norman, Frank
O’Garra, Anne
Oates, Andrew
Occupational Health
Ochs, Melvin
Offer, John
Open Day
Pachnis, Vassilis
Papayannopoulos Venizelos
Pastore, Annalisa
Payne, Joachim
Photographics
Preece, Graham
Procedural Service Section
Protein sequence analysis and structure modeling
Public Outreach
Ralser, Markus
Ramos, Andres
Rana, Neesha
Rittinger, Katrin
Rosenthal, Peter
Safety & Security
Saldanha, José
Salecker, Iris
Schaefer, Andreas
Scientific Equipment Care
Scientific instrument research & development
Seddon, Benedict
Sesay, Abdul
Smerdon, Steve
Smith, Jim
Snell, Daniel
Snijders, Bram
Spinazzola, Antonella
Stockinger, Gitta
Stopps, Martyn
Stoye, Jonathan
Strawbridge, Daniel
Students
Taylor, Ian
Taylor, Willie
Technology Transfer
Thorpe, Peter
Tolar, Pavel
Translation, Clinical
Tumwine, Irene
Turner, James
Tybulewicz, Victor
Ultanir, Sila
Vincent, Jean-Paul
Wack, Andreas
Web Team
Webb, Martin
WHO Collaborating Centre for Reference and
Research on Influenza (WIC)
Wilkinson, David
Wilkinson, Robert
Wilson, Mark
Wise, Clare
Young, Douglas
Yuneva, Mariia
125
119
118
98
10, 66
26
4, 22, 99
24, 111
108
129
15, 23, 30, 48
23, 100
132
126
67
32
115
12, 84
49
68
119, 131
127
20
122
107
111
31
4, 85
69
24
11, 70
71
132
111
86
4, 87
126
124
50
118
116
72
5, 13, 15, 101
18
110
73
10, 15, 28, 51
124
11, 52
26
16
11, 74
75
27
102
10, 22, 53
28
121
103
15, 54
4, 88
13, 104
55
130
76
59
15, 89
30, 56
57
120
109
58
4, 90
The Ridgeway
Mill Hill
London NW7 1AA
Tel +44 (0)20 8959 3666
Fax +44 (0)20 8816 2041
MRC NIMR location map
A1 North
to M25, Heathrow and Stansted Airports
od
Hi
London
La
ay
ew
ers
MRC National
Institute for Medical
Research
dg
Ri
rd
W
ay
The Ri
dgew
La n
e
M25
A1
Bit t a
cy
ll
Hi
Mill Hill East
Dollis R
M1
J2
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H ale
Lan
W
atfo
Hendon
rd W
ay
ll R
oa
e
Daws
ass
B a r ne t B y p
N
Mill Hill
Broadway
ay
A5100
Mill Hill Broadway ThamesLink
to Central London via King’s Cross
M25
NIMR
ll
e
Th
W
at
fo
A41 to
Central London
e
ne
A5109
an
Marsh L
A1
M25
H a mm
B a r n e t Way
Hi
gh
wo
M1
A598
Finchley
Central
A5000 Northern Line
to Central London
e
rs
Hi
A1
oad
H
ol
d
Bus number 240 connects NIMR to both Mill Hill East and Mill Hill Broadway stations. Trains run from Mill Hill East station on the
Northern Line into central London. Main line trains run from Mill Hill Broadway station to Luton Airport, Gatwick Airport and St Pancras
station in central London. The M1, M25 and North Circular Road (A406) are within easy reach of NIMR. Onsite parking is available at
NIMR.

pdfMRC NIMR Annual Report - The Francis Crick Institute

Transcription

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