MRC National Institute for Medical Research

Transcription

MRC National Institute for
Medical Research
2009/2010 Annual Report
and Prospectus
Edited by: David Wilkinson
Designed by: Joe Brock
Photography by: Neal Cramphorn & James Brock
Production: Christina McGuire & Frank Norman
Editorial Assistants: Eileen Clark & Steve Ley
© MRC National Institute for Medical Research
Enquiries about this report should be addressed to:
Assistant Director’s Office
tel +44 (0)20 8816 2281
email: [email protected]
Further information is available on the internet at:
http://www.nimr.mrc.ac.uk
Copies obtainable from the Librarian at NIMR
ISBN-13:
2
978-0-9546302-7-0
Contents
Director’s foreword
NIMR scientific highlights 2009
Science overview
About the MRC National Institute for Medical Research
Recent research highlights
NIMR history and milestones
Special topic review: Protein structure and infectious disease
Student training and development
Training and careers
Public engagement
Research groups :
A to Z list
Infections and Immunity
Structural Biology
Neurosciences
Genetics and Development
Emeritus scientists
Scientific facilities
Technology transfer
In memoriam
Sixty years of Immunology at NIMR
Major funding sources
Scientific seminars
Staff honours
PhD theses awarded 2009
Bibliography
NIMROD social club
Map, location and travel
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Director’s foreword
This 2009/10 Annual Report and Prospectus is published shortly after the end of my first year as Director of the MRC National
Institute for Medical Research. The year has gone well, with some excellent new recruits, honours for our existing Programme
Leaders, new equipment and infrastructure, and some welcome news about the UK Centre for Medical Research and Innovation.
We also say farewell to some of our Programme Leaders and their research teams.
New Programme Leader Track recruits include Pavel Tolar, who comes to us from the National Institute of Allergy and Infectious
Diseases at the NIH and works on the activation of immune receptors; Andreas Wack, who did his PhD at NIMR with Dimitris
Kioussis before going to the Novartis Immunobiological Research Institute in Siena to study influenza infection and vaccination
against it; and John Offer from the Biochemistry Department in Oxford who is developing novel techniques to build biological
macromolecules. More recently, Greg Elgar has joined us from Queen Mary University of London, and Mike Gilchrist has arrived
from the Gurdon Institute in Cambridge. Both bring expertise in bioinformatics and computational biology to the study of early
embryonic development, and their arrival complements our investment in high-throughput sequencing (see below). Finally, we
are delighted that Troy Margrie has joined us as a Programme Leader from the Department of Neuroscience, Physiology and
Pharmacology at University College London. Troy uses a multidisciplinary approach, including two-photon targeted patching, to
ask how the brain integrates neuronal activities to encode a sensory stimulus. We were very pleased that he recently received
the Friedrich Wilhelm Bessel Research Award as well as the Buckston Browne Prize of the Harveian Society. The research
programmes of all these new colleagues are outlined in more detail later in this report.
Troy was not the only Programme Leader to be
recognised during the course of the year. We were all
delighted that Dimitris Kioussis was elected a Fellow of
the Royal Society and everyone enjoyed the party at
which some of his friends and former colleagues sent
videoed messages of congratulation. As well as this
success, François Guillemot was elected a Fellow of the
Academy of Medical Sciences and Anne O’Garra and
Steve Smerdon became members of EMBO. Finally,
Douglas Young was awarded the Gardner Middlebrook
Award for contributions to Mycobacteriology, one of Tim
Mohun’s images received a Wellcome Image Award and
Gitta Stockinger’s paper on Th17 was named a citation
classic in immunology. Congratulations to all.
The year has also seen an expansion in our core facilities,
not least with the purchase of an Illumina GAIIx highLeft to right: Dimitris Kioussis, FRS with Anne O’Garra,FRS and Jim Smith, FRS
throughput sequencing machine, which is soon to be
joined by a HiSeq 2000 sequencing system. The ability to
carry out high-throughput sequencing will allow NIMR scientists to adopt new approaches in coming to understand the regulation
of gene expression and the definition of genetic regulatory networks. Towards the end of 2009 we also took delivery of an
Orbitrap mass spectrometer, and this will revolutionise our analyses of protein structure and function.
This has been a busy year for everyone involved in the UK Centre for Medical Research and Innovation (UKCMRI), and especially
for everyone in the workgroups dedicated to planning the new labs. The building design is taking shape and with some more hard
work we should submit a planning application during the summer. We were encouraged when Prime Minister Gordon Brown,
along with Lord Mandelson (Business and Skills Minister), Andy Burnham (Minister for Health) and Lord Drayson (Minister for
Science) visited the UKCMRI offices to confirm £250m of government funding for the UKCMRI project. This represents a very
important step towards realisation of the project.
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Left to right: Jim Smith, Sir David Cooksey, Sir Paul Nurse, Sir Mark Walport and Gordon Brown
looking at a model of the design for the UKCMRI building
And finally, departures. We were very sad that Iain Robinson took early retirement from NIMR towards the end of 2009. Iain’s
contributions to NIMR have been immense, both scientifically and administratively. He worked tirelessly for the Institute in the
planning of UKCMRI, and served as interim Director before my arrival at the beginning of 2009. An incoming Director could not
have wished for a wiser or more generous advisor and friend, and I am enormously grateful to him. As well as Iain, Nigel Birdsall
and Steve Sedgwick retired last year, Ken Raj left to join the Radiation Effects department at the Health Protection Agency’s
Centre for Radiation, Chemical and Environmental Hazards and Claudia Veigel left to go to the Institute of Physiology at Ludwig
Maximilians University, Munich. We wish them all well.
We also said farewell to Alan Hay, who for many years was Director of the World Influenza Centre, one of the five World Health
Organization (WHO) Collaborating Centres for Reference and Research on Influenza. As I describe in our scientific highlights,
Alan and his team did sterling work during the 2009 swine flu pandemic, and he and new Director John McCauley dealt with the
science and with the media frenzy with equal aplomb.
Saddest of all, I must report the death of John Eccleston, who also retired from NIMR last year. John had worked at NIMR in the
Division of Physical Biochemistry since 1984. His fluorescence stopped-flow work was world-class, and his mastery of physics,
biology and chemistry was a perfect combination for a multidisciplinary institute like NIMR. John met his wife, Sally, while she was
a PhD student at NIMR, and we send her our deepest sympathy. An appreciation of John by his colleagues Justin Molloy, Steve
Martin and David Trentham is on page 123.
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Scientific highlights 2009
As home of the WHO World Influenza Centre, now directed by John McCauley, NIMR was frequently in the news during 2009.
Samples of the swine-like human influenza A H1N1 were received at NIMR from around the world, and were subjected to
detailed nucleic acid sequence analysis, thereby monitoring potential changes in its sensitivity to antiviral agents such as Tamiflu
and Relenza. In particular, we knew from work by Steve Gamblin and colleagues (highlighted in last year’s report) that a particular
mutation in the influenza surface glycoprotein would render the virus resistant to Tamiflu but still sensitive to Relenza. In the event,
only a few Tamiflu-resistant samples were identified, and although the H1N1 virus spread more rapidly than expected, it was less
virulent, and there were fewer deaths than feared. Nevertheless, the events of last year show clearly the importance of the work
of the NIMR World Influenza Centre in monitoring influenza outbreaks and advising the Government on the best way to contain
them.
Of course, there have been many other scientific highlights, and like last year I will mention one or two achievements from each
of the four main scientific areas of NIMR. Thus, to continue the infections theme, George Kassiotis and Dimitris Kioussis have
studied how depletion of activated CD4+T cells, the targets of immunodeficiency virus replication, affects the mouse immune
system. Their work suggests that the generalised immune activation caused by HIV infection may have the same origin as immune
deficiency. By targeting this subset of CD4+ T cells, HIV could achieve both immune deficiency and activation without having to
rely on other microbes to activate the immune response.
The Nbs1 N-terminal regulatory region
Cell periphery with Weibel Palade bodies
Structural biologists at NIMR interact with all areas of the Institute and shed light on many aspects of biology. Using electron
cryomicroscopy, Peter Rosenthal has directly imaged assemblies of the von Willebrand Factor in endothelial cells, working with
Tom Carter and Matthew Hannah, while Steve Smerdon has used X-ray crystallography to reveal the structure of Nbs1, a protein
that plays important roles in the DNA-damage response.
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In the area of developmental biology, several of the groups at NIMR, including those of Smith and Briscoe, are interested in the
way in which morphogen gradients specify cell type within the developing embryo. One of the problems has long been one
of precision: how can a simple gradient specify sharp boundaries between different regions of the embryo? Work in Jean-Paul
Vincent’s group has shown that this occurs when cells produce secondary inhibitory signals that modulate each other’s response
to the morphogen in such a way that interpretation of the gradients becomes more precise.
These results, and many others, are described in more detail in the rest of this report.
The response to Wg signaling is modulated by inhibitory interactions between cells
Marques R, Williams A, Eksmond U, Wullaert A, Killeen N, Pasparakis M, Kioussis D and Kassiotis G (2009)
Generalized immune activation as a direct result of activated CD4+ T cell killing.
Journal of Biology 8:93
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.
Proceedings of the National Academy of Sciences of the United States of America 106:17407-17412
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
Piddini E and Vincent J-P (2009)
Interpretation of the Wingless gradient requires signaling-induced self-inhibition.
Cell 136:296-307
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Science overview
Research programmes at NIMR
Research at NIMR is focused on four scientific areas: Infections and Immunity, Genetics and Development, Neurosciences, and
Structural Biology. There are many cross-disciplinary collaborations that underpin progress in these areas, for example 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
auto-immunity. Auto-immunity 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.
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 how diverse cell types and tissues 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 interactions that control developmental processes. Many of our studies focus on the development of
specific tissues such as the nervous system, heart, liver, gonads and limbs. As many of the genes that control specific processes
are conserved between species, our studies are carried out in a range of model organisms that inform understanding of normal
development and how defects can arise. Since many of the same processes and underlying molecular pathways are also utilised
in the adult, studies of development also uncover 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.
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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 underlies the processing of sensory information and integrates it to achieve appropriate outputs.
We are also analysing how the hypothalamic neuroendocrine system controls the function of the pituitary gland. We use high
resolution methods to visualise the processes controlling secretion from neuroendocrine, endocrine and endothelial cells, leading
to different patterns of protein secretion in the bloodstream. 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.
Structural Biology
Biological systems consist of large molecules such as proteins and DNA, and small molecules that act as substrates and signals
to drive and control cellular processes. Understanding of the molecular basis of biological processes requires analysis at the level
of the structure and interactions of individual molecules. We study the three-dimensional structures and chemical reactions that
underlie the functions of a range of biologically active and medically important molecules. We use theoretical approaches that
enable us to model molecular structures from gene sequences and generate predictive models about the dynamics of molecular
interactions. Structural methods include X-ray crystallography, electron cryo-microscopy and NMR spectroscopy that yield high
resolution information. This is complemented by a diversity of biophysical and biochemical approaches, single molecule methods
and synthetic organic chemistry that enable analysis of molecular interactions both in vitro and within living cells. Our work covers
a diversity of biology systems and is highly collaborative, for example with teams at NIMR who are studying infectious diseases and
fundamental cellular mechanisms.
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About the MRC National Institute for Medical Research
The MRC National Institute for Medical Research (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. It has three main objectives: 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, and 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, which include strong links with University College London.
Scientists at NIMR study normal biological processes and diseases at the molecular, cellular and whole organism level. The specific
research topics include:
How do new influenza epidemics occur?
How does the immune system fight infection?
How can we cure infectious diseases such as influenza,
tuberculosis and malaria?
Sixty years at Mill Hill
How do tissues such as the heart, liver, limbs and
nervous system form?
How are stem cells normally regulated?
How is male-specific development controlled?
How does the nervous system become wired correctly?
How can we diagnose and cure genetic diseases?
How do hormones control body growth?
How is cell division accomplished?
How do muscles generate force?
How do molecules mediate cell signalling?
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In 2010 NIMR is celebrating the 60th anniversary of
opening at its present site at Mill Hill. The building was
officially opened on 5th May 1950 by King George VIth
and Queen Elizabeth. This year’s celebrations will begin
on 5th May 2010, when NIMR hosts a meeting of the
MRC Council. There will be an exhibition of NIMR
science and history.
Recent research highlights
2009
•
•
•
•
•
2008
•
•
•
•
•
Depletion of activated CD4+T cells (George Kassiotis and Dimitris Kioussis)
Structural organisation of Weibel-Palade bodies
(Tom Carter, Matthew Hannah and Peter Rosenthal)
Structure of Nbs1 protein (Steve Smerdon)
Morphogen gradients not needed for proliferation (Jean-Paul Vincent)
Evolution of vertebrate limbs (Malcolm Logan)
Neurogenin2 controls neuronal migration (François Guillemot)
A transcription factor linking environmental toxins to autoimmunity (Gitta Stockinger)
The adult pituitary gland contains stem/progenitor cells
(Iain Robinson and Robin Lovell-Badge)
Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants
(Steve Gamblin, Alan Hay and John Skehel)
Timer genes control brain size (Alex Gould)
2007
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•
•
•
A novel mechanism for reading the concentration of a signal – a clue to embryonic development
(James Briscoe)
Discovery of malaria parasite escape technique leads to new drug target (Mike Blackman)
AAMPK enzyme structure offers hope of effective diabetes treatment (Steve Gamblin)
Fruit fly’s fatty secrets shed light on liver disease (Alex Gould)
2006
•
•
•
Structural changes reveal bird flu pandemic potential (Alan Hay, Steve Gamblin and John Skehel)
The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug
design (Alan Hay, Steve Gamblin and John Skehel)
TGFß supports de novo differentiation of IL-17-producing T cells (Gita Stockinger)
2005
•
Development of mouse model for human Down syndrome (Victor Tybulewicz)
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Determination of the structure and receptor binding properties of the 1918 influenza haemagglutinin (John Skehel and Steve Gamblin)
Role of SOX3 in pituitary development (Iain Robinson and Robin Lovell-Badge)
2003
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Repair of spinal cord injuries by cell transplantation (Geoff Raisman)
2000
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Description of naturally occurring, post-entry, pre-integration restriction factors for retroviruses in human cells (Jonathan Stoye)
2004
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NIMR history and notable milestones
NIMR was the first research institute established by the MRC. Its origins go back to 1914 but it was fully established at Hampstead
in 1920 under the Directorship of Sir Henry Dale. It moved to its present site in Mill Hill in 1950.
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1920-1939
Discovery of the human influenza virus (C. Andrewes, W. Smith and P. Laidlaw)
Discovery of the neuro-transmitter, acetylcholine (H. Dale)
1940-1959
Development of liquid and gas chromatography (A.J.P. Martin)
World Influenza Centre established
Low-temperature preservation of cells (A. Smith, C. Polge and A. Parkes)
Studies of antibody structure (R.R. Porter)
Steroid biosynthesis (J.W. Cornforth)
Human physiology in extreme conditions, including advice to the Everest expedition (L.G.C.E. Pugh)
Discovery of interferon (A. Isaacs)
1960-1979
Lymphocytes of different types co-operate in the immune system (N. Mitchison)
Explanation of long-term potentiation (T. Bliss)
Recombination of avian and human influenza viruses involved in pandemic influenza (H.G. Pereira)
Determination of the structure of adenovirus using electron microscopy (R.C. Valentine)
Discovery of interferon induced nuclease activating oligonucleotide (I. Kerr)
1980-1999
Biomedical NMR Centre established
Structure of influenza haemagglutinin (J.J. Skehel)
Discovery of locus control region of globin gene expression (F. Grosveld)
Definition of protein nuclear location signals (A.E. Smith)
Description of control sequences responsible for co-ordinated expression in yeast cell cycle of enzyme
involved in DNA synthesis (L. Johnston)
Discovery of interleukin 5 (C. Sanderson)
Discovery that cytotoxic lymphocytes recognise antigens which are not normal surface membrane
components (A. Townsend)
Conservation of organisation and expression of mouse and Drosophila homeobox genes (R. Krumlauf)
Discovery of mesoderm inducing factors in Xenopus embryos (J.C. Smith)
Description of a novel mechanism of protein biosynthesis in mycobacteria (J. Colston, E. Davis and S. Sedgwick)
Primary structure of the Herpes saimiri genome (R. Honess)
Discovery of the sex determining gene (R. Lovell-Badge)
Discovery of the first virus ion channel (A.J. Hay)
Discovery that a locus control region is capable of preventing position effect variegation in T-cell development
(R. Festenstein & D. Kioussis)
Discovery of the anterior organising centre in mice (R. Beddington)
Identification and mapping of plastid in apicomplexan parasites (I. Wilson and D. Williamson)
Development of mammalian enteric nervous system (V. Pachnis)
Role of ephrins in cell patterning and positioning in nervous system development (D. Wilkinson)
Developmental diseases of pituitary gland (M. Dattani)
Five members of the Institute have gained Nobel prizes:
 Henry Dale discovered the important neuro-transmitter acetylcholine
 Archer Martin invented paper and gas chromatography
 Rodney Porter was a pioneer in understanding the chemistry of antibodies
 John Cornforth made key discoveries in understanding how steroids are made
 Peter Medawar discovered how transplanted organs are rejected because of attacks by white blood cells that can recognise
foreign cells
Henry Dale
Archer Martin
Rodney Porter
John Cornforth
Peter Medawar
The Jeantet prize has been awarded to three NIMR scientists:
 Robin Lovell-Badge for work on sex determination
 John Skehel for research on influenza
 Frank Grosveld for work on the control of haemoglobin in blood cells
Robin
Lovell-Badge
John Skehel
Frank Grosveld
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Special topic review: Protein structure and infectious disease at NIMR
Each NIMR Report will feature a review of an important area of research at NIMR.This year’s review
focuses on protein structure and infectious disease, written by Ian Taylor and Jonathan Stoye
The study of infectious diseases is fundamental to the MRC mission
and has been at the heart of research carried out at NIMR since
its foundation. The marriage of structural biology with research into
infectious disease has been key to several notable discoveries made
at the Institute. Some examples include: the application of electron
microscopy to the elucidation of the structure of adenovirus;
the use of NMR methods to investigate the binding specificity of
antifolate drugs to bacterial dihydrofolate reductase; structural
analyses of influenza A haemagglutinin proteins; and the use of
analytical ultracentrifugation to analyse the oligomeric state of viral
proteins.
The arrival of high-field NMR and protein X-ray
crystallography at the Institute in the early 1990s,
and cryo-electron microscopy in 2004, have
further cemented this synergy. The three
research Divisions that presently constitute
infectious disease research at NIMR (Virology,
Mycobacterial Research and Parasitology)
each include programmes that incorporate
collaborations with structural biologists, and
significant breakthroughs have been made in
the fields covered by each Division.
There are numerous examples but highlights
include the elucidation of the structures of
Mycobacterium tuberculosis NusB and NusA
proteins, that has advanced the understanding
of how this pathogen regulates rRNA synthesis.
Further work with M. tuberculosis phospho-threonine
binding domains employing both X-ray crystallography and
high-resolution NMR spectroscopy has shed light on phosphodependent metabolic signalling in this pathogen (Fig 1). Both sets of
studies have important implications for the potential design of novel
therapeutic strategies for combating M. tuberculosis.
In the Division of Virology, a wealth of structural data concerning
the influenza virus surface proteins, haemagglutinin and
neuraminidase has contributed to the understanding of influenza
cross-species transmission and drug resistance. This information has
important ramifications for decisions concerning the stockpiling
of anti-influenza drugs. Moreover, the determination of X-ray
structures of retroviral capsid proteins combined with cryo-
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(Fig 1) The phosphorylated FHA domain from Rv1827, the
major downstream target for the M. tb signalling kinase, pknB
electron microscopy (Fig 2) has been crucial to understanding the
process of capsid assembly and disassembly and will be essential to
understanding the interactions of the virus with natural host-cell
anti-viral factors. Similar studies of retroviral structural proteins may
help guide the design of effective vaccines directed against HIV-1.
In the Division of Parasitology, much research is focused on the
merozoite surface protein 1 (MSP1). This protein is the target of
antibodies that prevent red blood cell invasion and is a leading
candidate for use in the development of immunisation strategies
for controlling malaria. The determination of the solution structure
of MSP1 from the two major human malaria parasites, Plasmodium
falciparum and P. vivax (Fig 3) and the subsequent elucidation of
antibody and drug binding sites has been critical for structural
biology work designed to facilitate development of such a malaria
vaccine.
(Fig 3) The merozoite surface protein Msp1 from Plasmodium vivax, a
major target for the development of a malarial vaccine
(Fig 2) Structures of retroviral capsid assemblies. Cryo-electron micrograph of in
vitro assembled capsid, inset capsid monomers (i) pack into hexameric discs (ii)
that associate to generate a capsid assembly (iii)
These recent and current studies in general have
been directed towards molecules in the pathogen
that are likely to make good drug targets. However,
in the near future, as a wealth of genomic, proteomic
and interacteromic information becomes available, the
detailed understanding of many host cell-pathogen
interactions will become paramount in the fight against
existing and emerging diseases. New methods from live
cell imaging through visualisation of cellular ultrastructure
and high-throughput molecular structure determination,
single molecule manipulation and rational drug design
will complement older techniques of epidemiology
and physiology. It is apparent that the integration of
structural biology and infectious disease research is well
placed to form the vanguard of this research and what
used to be proudly heralded as a science that went from
genes to structures in the late eighties can confidently
be rebranded as one that goes from molecules to
medicines in the early 21st century.
15
STUDENT TRAINING AND DEVELOPMENT
PhD studentships
Student training and development
The training and development of future leaders in biomedical
research is one of the Institute’s key goals and we strive to achieve
this by giving school students, undergraduates and graduates the
opportunity to work and study at NIMR.
PhD Studentships
There are over 80 PhD students at NIMR, approximately 80% of
whom are funded through the MRC Doctoral Training Account
and 20% through a variety of other studentships and progammes.
All of our students have access to a wide range of state-of-the-art
facilities and the extensive expertise of institute staff, and combined
with a programme of internal and external workshops, courses and
seminars, our students complete their PhDs with the biomedical
research training and transferable skills necessary for a successful
career.
Donna Brown
Director of Studies
We recognise the importance of student support and in addition to NIMR supervisors, who do not have the teaching
commitments that are often associated with universities, each student has a thesis committee comprising their head of division
and two programme leaders. The purpose of the thesis committee is to ensure the student receives all of the academic support
and guidance needed for the duration of the PhD. Also on hand are the Director of Studies, Student Administrator and the
Student Representatives. The significance of this level of support is reflected in our improving four-year completion rates which
are higher than most universities.
We believe in a good work-life balance and we encourage our students to remember there is a world outside of the lab. Many of
our students take the opportunity to catch up with their colleagues in the onsite licensed bar, restaurant or games room. The TV
room offers a little more solitude and for those with get-up and go there are many social activities and sports teams organised
through the NIMROD social club. Three on-site student cottages make the commute to work virtually non-existent.
During the 2009/10 academic year, by request of the students, we are introducing a careers forum and a tools and techniques
study programme, and later in the year we expect to run new internal courses on statistics, bioinformatics and microscopy.
16
PhD students 2009 in their own words
Chris Toseland
NIMR is a fantastic place to do research, learn and socialise. I was attracted to NIMR
due to its excellent reputation and the diversity of its research, not to mention the
countryside views and London location. My PhD has focused upon the mechanism
by which DNA helicases catalyse DNA unwinding during replication and repair. Since
being here, I have found that whenever I need advice there are always many postdocs
and Group Leaders more than willing to help. This made my PhD more enjoyable and
helped me to advance faster. It is even possible to set up new collaborations and find
a job while playing sports or enjoying a drink. The excellent resources and supportive
environment gives a great start to a research career. No matter where you come
from, or go to, the atmosphere at NIMR will never be forgotten.
Valentina Sasselli
I started at NIMR almost three years ago, when I decided to pursue a PhD in
developmental biology. At the time I knew what I wanted to study, no matter where
and no matter how. It did not take long to realize that NIMR was the perfect place.
At the Institute there is a sincere dedication to science with collaborations between
laboratories and divisions. There are many facilities which make experiments
technically possible and quickly feasible, and, more importantly, there are great people
with great ideas which help to keep motivation high! In such an environment, my PhD
life has been enjoyable and rewarding. Now, in my final year, I am planning to present
my work at international conferences (thanks also to the MRC-NIMR travel prize), to
finalise my thesis and, hopefully, to find my way in science, keeping in mind that, after
all, the where and how do make a difference.
Student Representatives
There is a strong sense of community amongst the students at NIMR and this actively
encourages collaboration between different departments allowing students to take
up multi-disciplinary projects. Regular student seminars allow us to present our work
without the pressure of supervisors or colleagues from our Division being present.
With regular student socials and sporting activities, it’s easy to meet up and make
new friends.
With an intake of around 25 new students per year, the student body are an integral
part of the Institute and as Student Reps we aim to maintain a high standard of
communication between staff and the students. This is achieved by holding regular
meetings with students and representing them on various committees both within
NIMR and at UCL so that their opinions can be voiced.
The 2009 Student Representatives
Andrea Rueker, Claire Hastings and Lasse Stach
17
Sandwich placements and work experience
Sandwich Placements
NIMR sandwich placements provide students an excellent oportunity to apply the lab skills they have learnt during the first
couple of years at university. As you will see from the testimonials, sandwich students come to the Institute because of the
diversity of science and to get a feel of whether research is really for them. A 12 month sandwich placement equips many of the
students with the experience and expertise they need to secure a PhD studentship at NIMR or other leading research institution.
We currently have 15 sandwich students and with over 350 applications received this year it is clear that the popularity of our
sandwich placements is growing.
2009 Sandwich students in their own words
Caroline Morris
I chose to apply for a sandwich placement at NIMR after reading about the variety of projects available to students and the
work conducted at the Institute. My placement was within the Division of Physical Biochemistry, working on the mechanism of
interaction between single-stranded DNA binding protein from E. coli (SSB) with single-stranded DNA. Overall I was very pleased
with my placement year – I thoroughly enjoyed the work I conducted, and all the people I worked with were friendly and helpful.
I learned many new techniques that I have already been able to put into practice during my final year at university, which I feel
demonstrates the value of a sandwich placement. After my degree I hope to study for a PhD, which I was able to decide upon
after the year in the lab. I would highly recommend a sandwich placement at the Institute.
Since returning to university Caroline has successfully interviewed for a PhD studentship at NIMR which will commence September 2010.
Nathan Sweeny
My sandwich placement at NIMR was an excellent experience and helped me to confirm my desire to start a PhD next year. I
applied to NIMR because the Institute is large and well known for its excellence in biomedical research. My project was with Dr
R. Buxton on transcriptional regulation in Mycobacterium tuberculosis. I enjoyed my project and the independence of my lab work.
Most importantly, this year has provided me with excellent experience in molecular biology which will be useful for any research I
undertake in the future. I lived in the student cottages available onsite which are excellent for meeting other students and provide
a sociable atmosphere. I recommend the NIMR sandwich placement scheme to anyone considering a PhD in biological sciences.
Vasja Urbancic
NIMR was a great place to do a placement. Working on my project in zebrafish development, I learned and used a diverse
range of techniques (molecular biology to confocal microscopy, cell culture to biochemistry), many of which I will use again in
my final year or afterwards during a PhD. The multitude of talks and seminars by NIMR scientists and invited speakers provided a
good opportunity to extend my knowledge into diverse areas of biomedical research, and I even got to attend an international
symposium on developmental biology held in London! NIMR is a pleasant place to work: there is a friendly atmosphere, people
from across different Divisions were always happy to help, and its present location is fantastic: a beautiful countryside setting, yet
so close to central London. Living in the onsite cottages with other newcomers made it easy to make friends, and I thoroughly
enjoyed the trips with the hill-walking club, too. If you are considering coming to NIMR, I would warmly recommend it.
18
Work experience for school students
At the Institute we believe in encouraging students from an early age and each year students from local schools work alongside
our researchers for periods of up to four weeks [also see NIMR’s Research Summer School on page 24]. A clear indication of the
success of the research summer school is the number of students who apply to the Institute for one of our sandwich placements
and/or PhD studentships. Over the course of the next year we are looking to revise our work experience programme with the
aim of improving the ‘student experience’ and providing the opportunity for students in the local area to discover what it’s like to
work in science.
The 2009 intake of postgraduate research students
19
TRAINING AND CAREERS
Career development at NIMR
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 steps of their career development benefit from
the very active programme of seminars and internal research meetings, and the availability of courses to learn key scientific and
complementary managerial skills.
NIMR hosts 226 postdoctoral researchers, supported either by MRC core funding or externally-funded fellowships. The MRC
support promotes careers at the postdoctoral level through fixed-term MRC Career Development Fellowships, and for more
experienced researchers by open-ended Investigator Scientist positions.
NIMR also has an important role in providing research training for clinical scientists, and this is an important facilitator of
translational projects and national and international collaborations. M.B. Ph.D. students are hosted at NIMR through the UCL
Programme. In addition, there are many visiting postdoctoral clinical scientists from the UK and abroad carrying out research, for
example on infectious diseases and genetic disorders.
Many group leaders have established their laboratory through being appointed to an MRC Career Track position at NIMR. This
provides core support for a five year period, which following external review can lead to promotion to an open-ended MRC
Career appointment. Career appointments provide 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.
James Briscoe Developmental Neurobiology
The career track system at NIMR was a great way to make the transition from postdoctoral fellow to group leader. I had funding
for two researchers, a technician and my salary, together with consumable expenses and access to all the facilities at the Institute.
I was able to start my research straight away without having to write grants. This, and the low administrative burden, gave me the
maximum amount of time and energy to concentrate on research. The collegiate and collaborative culture of the Institute was
also an enormous benefit. It offered the mentoring and encouragement necessary to launch an independent research programme
and the support to keep it going.
Katrin Rittinger Molecular Structure
I initially came to NIMR as a postdoc and was immediately impressed by the open and highly collaborative atmosphere and the
willingness of everybody to share equipment and knowledge. So when it came to taking the next step in my scientific career, I had
no doubts that NIMR would be an ideal place to start my own group, not only because of this collaborative atmosphere but also
because of the diversity of research carried out and the wide range of expertise available. The combination of these factors creates
an ideal environment to develop an independent research programme that incorporates multiple approaches and techniques that
otherwise may be too difficult to get going at this stage in one’s career. Collaborations across disciplines are actively encouraged, for
example in the form of student or postdoc positions that are held jointly between different Divisions. Coming from a country where
the scientific system has been much more hierarchical, I was also very attracted by the fact that at NIMR, career track positions are
truly independent and that resources are available to everybody on an equal and purely scientific basis.
20
Andreas Wack Immunoregulation
I moved back to NIMR after ten years spent in an industrial research centre in Italy. Prior to that, I had done my PhD with Dimitris
Kioussis here in the Institute. A common theme of NIMR is the spirit of collaboration, the fact that you can go to anyone’s office
or lab (or bar table) and come up with ideas or ask for advice, and this was also for me one of the best features of this place. The
chance to come back to NIMR was therefore a great opportunity. Ten years later, I found that this spirit is still wide awake, carried
on by many of the old familiar faces and many new ones who have joined in.
The differences between industry and academia are less than you might think. In both environments you develop scientific
questions, plan a sequence of experiments and critically appraise results. The range or depth of questions asked and the
hypotheses put forward tend to differ between industry and academia but can also vary a lot within both areas. The two biggest
differences are the speed of change and the group size of researchers working on a specific question. In a company, decisions on
the research direction are often dictated by changes in the market place, which can be fast, and your favourite research subject
may be culled in a board room with little prior notice and little possibility to influence this decision, as it is driven by factors
outside the researcher’s control. This causes pain but happens less often than one might think, as reasonable companies have a
fairly stable long-term strategy and do not follow a research zigzag.
The biggest difference for me was the team size: when companies throw many people at important projects, it can easily happen
that 30 to 50 specialists tackle the same question from different angles. This makes decision-making complex and often slow,
reduces the degree of identification of research staff with their project, and also means that the fun part of putting together all
the pieces is reserved to only a few people. The advantage is that the technical expertise brought to the project is very high.
Getting used to presenting data from colleagues, and handing over your own data to others, is an excellent exercise for big egos
to be reminded of the importance of the team effort.
Academia often presents the extreme opposite. One PhD student or post doc will work on one project with a very high
degree of identification and personal involvement, but there is a tendency for the wheel to be frequently reinvented because
of a constant loss of expertise through student and post-doc turnover. As I am mentally still in the transition phase, I currently
think that doing research most efficiently requires probably a mix between the two approaches, with medium-size groups of
people with different scientific backgrounds sharing in full a project. However, the fact that career and funding depend so much
on authorship questions and senior responsibility certainly does not facilitate such an approach. The way it worked for me to
preserve the possibility of a return to academia was simply to keep publishing and to keep the links to academia. Go to meetings,
invite speakers, collaborate. Depending on the company, publishing is actually not so difficult, as intellectual property issues are less
of a hurdle and cause less delay than commonly assumed. I am very happy to have made the step back from one camp to the
other.
21
Research support careers
Although there is no formal career structure for research support staff, there are regular opportunities for research technicians and
occasional openings for research support managers.
Nick Clark describes his career as Lab Manager
I started at the Institute in 1972 as a Junior Technical Officer in the lab of Dr John Humphrey, Head of the Division of Immunology.
For several years I worked in this and other labs in the Immunology Division, acquiring the necessary skills to provide technical
expertise to the projects in hand. Equipment maintenance and laboratory upkeep were considered an essential part of the role
of technical staff, and I found myself increasingly involved in the technical management of the Division, and deputising for the Head
Technician, so much so that when in 1985 the post became vacant it was offered to me, and I readily accepted it. Since then I have
been the Laboratory Manager for the Immunology Divisions and, for a period, the Division of Virology. The ultimate aim of my
job is to enable the smooth running of the Divisions, ensuring that the work is not hampered by lack of resources. This is achieved
through a good knowledge of the excellent resources and procedures within the Institute, the overseeing of maintenance, budget
monitoring, coordination with service providers, both internal and external, and cooperation with my fellow Laboratory Managers,
working closely as a team. It is a largely reactive role, occasionally stressful and frustrating, but hugely rewarding and enjoyable in its
variety and sense of achievement.
Vicky Millins describes her route to becoming a Lab Manager
Most of my seven-year career at NIMR has been as a Research Technician in Parasitology, where the role morphed from a general
technician to a more specialised one where I managed all the mouse lines for the lab. This gave me a high degree of autonomy,
which I enjoyed. I outgrew the position and sought new challenges, and when I saw a number of Laboratory Manager posts
become available, I applied. I was very happy to be appointed Laboratory Manager for the Divisions of Developmental Biology
and of Molecular Neurobiology, as they are very genetic-based which is where my scientific ‘heart’ is. The job I do now is a varied
one, full of challenge and I recommend it to those who like plenty of variety and a strong amount of interaction day-to-day with
many people.
Yan Gu explains his role as a specialist support manager
Trained as a physicist, I have been involved in the biological imaging field since my first postdoc position. Becoming the manager of
a microscope facility in a biomedical institute was one of the most risky decisions I have ever made. The decision to leave a welldefined physics lab wasn’t meant to be a career change, but rather a research environment change. I still believe that the most
effective way to do the biological imaging is to do it with biologists. For similar reasons I joined NIMR, where the collaborative
atmosphere and positive attitude towards new techniques were very attractive.
Microscopy is a multi-disciplinary technique which requires comprehensive background knowledge. No routine procedures
can be universally applied to all experiments. Imaging design varies with the experiment, the microscope and image processing
requirements. This requires the support staff to have a high level of scientific training and research quality. The rapidly evolving
imaging technology over the last decade has been stimulating the development of biology, which in return demands ever more
technological innovations. Being the introducers of these fast advancing techniques, we need to constantly refresh ourselves with
new knowledge through research. The Confocal Imaging and Analysis Lab will only be able to meet the ever-increasing demands
from cutting edge biology if we can provide quick troubleshooting and effective microscope maintenance. Such pressure means
that we work on two fronts: routine support and technological development. This allows us to provide maximum benefit to NIMR
research.
22
Alan Palmer describes the support for careers in Biological Services
We are 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 various 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 and a
good background in biological sciences. Technicians are also encouraged to spend time in NIMR research labs in order to gain
hands-on experience of experimental procedures, and to attend workshops and seminars held on a regular basis on a variety of
laboratory animal science related subjects. Visits to other scientific establishments, symposiums and international meetings are also
organised which enable technicians to gain experience in more varied aspects of laboratory animal husbandry and science.
23
SCIENCE AND SOCIETY
Public engagement activities
Human Biology Essay Competition 2009
Once again NIMR’s school essay competition, now in its seventh
year, drew a large number of commendable essays. At a time when
science students rarely write an extended essay before they go to
university we provide an opportunity for enthusiasts to develop
their skills. All the entrants receive a prize of the current volume of
Mill Hill Essays, and the winners receive a financial prize and spend
one day at NIMR seeing visually appealing projects. The two best
essays were published in the 2009 Mill Hill Essays.
Research Summer School
In 2009 NIMR was host to 18 students, drawn from 13 local
schools. The scheme is financed by the Nuffield Foundation
who award bursaries to each student. The students undertake
projects devised and supervised by NIMR staff, using the core
techniques of modern molecular biology and biochemistry. The
course starts with a half-day induction in molecular biology,
lab skills, safety and record keeping. Students produce a poster
and report of their work, to be shown at events organised by
the Nuffield Foundation. These reach a very high standard and
this year, as on many previous occasions, some of them were
awarded prizes for their presentations at the Exscitec Science
and Engineering Fair. Teachers report that Nuffield Bursary
Holders are an inspiring example to the next generation at their
schools. Some of our former students are starting careers in
research having emerged from university with First-class degrees.
The University of the Third Age (U3A) at NIMR
In November 2009 NIMR hosted the seventh national meeting
of the science section of the U3A. This is a self-managed
organisation for retired persons with a scholarly bent who are
prepared to travel quite long distances to hear presentations
that interest them. This year the theme was “Making an embryo
from the fertilised egg” at which the Director, Jim Smith, and
David Wilkinson spoke. Once again, we had a capacity crowd of
nearly 150 enthusiasts, keen to understand new approaches to
biomedicine.
24
SCIENCE AND SOCIETY
Annual Schools Days (February 10th and 11th, 2010)
Students in Year 12 are invited to an event designed to enrich their experience of the life sciences. We have a programme of talks
based on an important theme; this year “Modern Cell Biology”. We accommodated a capacity audience of 360 visitors over two
days drawn from 21 local schools. We encourage a lively questioning of the speakers on their subject or about careers and topical
issues. We also present a small demonstration of aspects of developmental biology to provide a glimpse of real experimental
material and a quiz based on posters relating to science in the news.
Researchers in residence and Ambassadors for science
Young scientists from NIMR participate in these two schemes. Workshops at NIMR have been developed by our staff on “DNA
analysis in forensic science”. Others have participated in teaching of the regular curriculum in secondary schools under the
guidance of a teacher on a regular basis over one term.
25
SCIENCE AND SOCIETY
Public engagement activities
NIMRart
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.
Recent loans from the Arts Council Collection include (left) Eduardo Paolozzi, Caprese, bronze 1975, (centre) Victor Newsome, Corner of a bathroom, mixed
media 1975, (right) Liz Pannett, 14.1.79-8.80, mixed media 1980
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/millhillessays/archive/
26
This image was produced by Tim Mohun, working with Mike Bennett, in NIMR’s Division of Developmental Biology. The
animation from which this still was taken received a Special Award in the Wellcome Image Awards 2009. It shows the intricate
structure of a mouse head during development, and was produced using a new imaging technique called high-resolution
episcopic microscopy (HREM), which enables accurate three-dimensional reconstruction at very high levels of detail.
27
A – Z list of NIMR group leaders
Siew-Lan Ang
Kate Bishop
Mike Blackman
James Briscoe
Paul Burgoyne
Tom Carter
Rita Cha
Elaine Davis
John Doorbar
Paul Driscoll
Greg Elgar
Delmiro Fernandez-Reyes
Sebastien Gagneux
Steve Gamblin
Mike Gilchrist
Richard Goldstein
Alex Gould
François Guillemot
Matthew Hannah
Alan Hay
Tony Holder
Ed Hulme
Nobue Itasaki
George Kassiotis
Dimitris Kioussis
Jean Langhorne
Paul Le Tissier
Steve Ley
Malcolm Logan
Robin Lovell-Badge
John McCauley
Troy Margrie
Tim Mohun
Justin Molloy
28
Neuronal subtype specification in the midbrain and hypothalamus
Infection and replication of retroviruses
Proteases in host cell exit and invasion by the malaria parasite
Pattern formation in the vertebrate nervous system
The Y chromosome and infertility
Secretory organelle formation, trafficking and exocytosis
Regulation of eukaryotic chromosome metabolism
Gene regulation and DNA repair in the pathogenesis of Mycobacterium tuberculosis
Human papillomavirus biology and disease
Structural and functional analysis of signalling proteins
Regulation of early vertebrate development
Proteome-wide host-parasite interactions of severe malaria infections
Population genomics and ecology of Mycobacterium tuberculosis
Structural biology of influenza, energy metabolism and cancer
Gene regulatory networks in early development
Modelling of evolution
Regulation of growth and metabolism
Cell fate specification in the mammalian brain
Secretory vesicle formation in human endothelial cells
Influenza virus – vaccines and drugs
Malaria parasites and red blood cells
Structure and function of G protein-coupled receptors
Wnt signalling in vertebrate embryogenesis
Antiviral immunity
Chromatin structure, gene expression and lymphoid development
Immunology and immunopathogenesis of malaria infections
Control of prolactin and growth hormone cell differentiation and function
Regulation of immune responses by NF-k bB and MAP kinases
Understanding vertebrate limb development
Sex, stem cells and decisions of cell fate
Host specificity of influenza viruses
Sensory processing in single cells, circuits and behaviour
Heart development in vertebrates
Single molecule studies of cell motility and cell signalling
Elke Ober
John Offer Anne O’Garra
Vassilis Pachnis
Annalisa Pastore
Alexandre Potocnik
Kenneth Raj
Andres Ramos
Katrin Rittinger
Iain Robinson
Peter Rosenthal
Iris Salecker
Benedict Seddon
Steve Sedgwick
Steve Smerdon
Jim Smith
Gitta Stockinger
Jonathan Stoye
Ian Taylor
Willie Taylor
Pavel Tolar
James Turner
Victor Tybulewicz
Claudia Veigel
Jean-Paul Vincent
Andreas Wack
Martin Webb
David Wilkinson
Robert Wilkinson
Douglas Young
Lyle Zimmerman
Liver development in zebrafish
Acyl transfer for chemical biology and synthesis.
Regulation of the immune response in infectious disease
Development of the nervous system
Understanding the molecular bases of neurodegeneration
Haematopoietic stem cells and lymphocyte development
Life cycle and persistence of human papillomavirus
Molecular recognition in post-transcriptional regulation
Structural biology of signalling networks that regulate innate and adaptive
immunity
The neuroendocrine cascade of growth
Cryomicroscopy of proteins, viruses and cells
Axon guidance in the developing visual system of Drosophila
Regulation of T cell homeostasis by antigen receptor signals and interleukin-7
Regulation of mitosis
Structural biology of phosphorylation-dependent signalling pathways in the cellcycle and the response to DNA damage
The molecular basis of mesoderm formation
Development, maintenance and regulation of peripheral T cell compartments
and immune responses
Retrovirus-host interactions
Macromolecular assemblies
Protein structure analysis and design
Activation of immune receptors
X chromosome inactivation, meiotic silencing and infertility
Signal transduction in B and T cells
Single molecule mechanics of motor proteins
Cell biological basis of patterning and homeostasis in developing epithelia
Immune response to influenza
The molecular mechanisms of motor proteins
Regulation of boundary formation and neurogenesis
Steroid regulated immune responses in tuberculosis
Mycobacterium tuberculosis and the host response
Using frog genetics to understand vertebrate development and disease
29
Immune Cell Biology
Immunoregulation
Molecular Immunology
Mycobacterial Research
Parasitology
Virology
Victor Tybulewicz (Head of Division)
Steve Ley
Benedict Seddon
Pavel Tolar
Anne O’Garra (Head of Division)
George Kassiotis
Andreas Wack
Dimitris Kioussis (Head of Division)
Alexandre Potocnik
Gitta Stockinger
Douglas Young (Head of Division)
Elaine Davis
Sebastien Gagneux
Robert Wilkinson
Tony Holder (Head of Division)
Michael Blackman
Jean Langhorne
Jonathan Stoye (Head of Division)
Kate Bishop
John Doorbar
Alan Hay
John McCauley
Kenneth Raj
WHO Collaborating Centre for Reference and Research on Influenza (WIC)
see also the following groups, all in Structural Biology:
Steve Gamblin
Richard Goldstein
Andres Ramos
Katrin Rittinger
Peter Rosenthal
Steve Smerdon
Ian Taylor
30
INFECTIONS AND IMMUNITY
Virology
Kate Bishop
Infection and replication of retroviruses
Lab members: Virginie Boucherit, Harriet Groom, Mirella Nader, 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. In 2006, a novel retrovirus called
xenotropic murine leukaemia virus-related virus (XMRV) was
isolated from patients with familial prostate cancer. Prostate
cancer is the most prevalent cancer amongst men in the UK,
and hereditary prostate cancer is thought to account for
9-15% of cases. More recently, XMRV has been identified in
patients with chronic fatigue syndrome. At this time, it is not
known whether these diseases are associated with XMRV.
One area of our research is to investigate the link between
XMRV and prostate cancer and chronic fatigue syndrome. We
are also interested in the prevalence of the virus in the general
population and the risk to human health. Our initial focus has
been to set up serological assays for XMRV to test patient sera
for antibodies to the virus. We can also screen for the presence
of viral nucleic acid and proteins. In addition we are interested
in the basic biology of the virus, including its susceptibility to
restriction factors in the host.
Publications
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 of the United States of
America 107:5166-5171
Groom HCT, Boucherit VC, Makinson K, Randal E, Baptista S, Hagan
S, Gow JW, Mattes FM, Breuer J, Kerr JR, Stoye JP and Bishop KN
(2010)
Absence of xenotropic murine leukaemia virus-related virus in UK
patients with chronic fatigue syndrome.
Retrovirology 7:10
An ELISA for viral reverse transcriptase activity shows that XMRV production is reduced in the
presence of mammalian restriction factors. The lighter the colour, the lower the viral titre
Holmes RK, Malim MH and Bishop KN (2007)
APOBEC-mediated viral restriction: not simply editing?
Trends in Biochemical Sciences 32:118-128
31
Parasitology
Michael Blackman
Proteases in host cell exit and invasion by the malaria parasite
Lab members: Marta Campos, Matthew Child, Christine Collins, Fiona Hackett, Natalie Silmon de Monerri, Anna Olivieri,
Andrea Ruecker, Michael Shea, Robert Stallmach, Malcolm Strath, Catherine Suarez, Chrislaine Withers-Martinez, Sharon Yeoh
Malaria is directly responsible for an estimated 2-3 million deaths per annum
worldwide, causing terrible suffering and imposing an immense economic
burden on much of the developing world. There is no malaria vaccine, and
resistance against mainstay antimalarial drugs is widespread. There is a need to
find new ways to treat and control this devastating disease.
The malaria parasite infects and divides within red blood cells. The infected
red cell eventually ruptures, releasing a fresh wave of parasites which rapidly
invade new red cells. Invasion involves the activity of a complex set of proteins
that are released onto the parasite surface to bind to the new red blood cell
and penetrate it. Our work aims to improve our understanding of how these
parasite proteins interact with the host red blood cell to enable invasion, and
how antibodies can interfere with this process. This will help the development
of new drugs and aid vaccine design. In addition, we are studying a family
of parasite-derived proteases that regulate release of the parasite from red
blood cells, and also modify the parasite surface to prime it for invasion. We
are investigating the structure and function of these proteases, and searching
for inhibitory compounds with potential to be developed as antimalarial drugs.
Depiction of the role of a malarial protease called PfSUB1 in surface modification
and release of malarial merozoites from the infected red blood cell
Publications
Collins CR, Withers-Martinez C, Hackett F and Blackman MJ (2009)
An inhibitory antibody blocks interactions between components of the malarial invasion machinery.
PLoS Pathogens 5:e1000273
Koussis K, Withers-Martinez C, Yeoh S, Child M, Hackett F, Knuepfer E, Juliano L, Woehlbier U, Bujard H and
Blackman MJ (2009)
A multifunctional serine protease primes the malaria parasite for red blood cell invasion.
EMBO Journal 28:725-735
Atomic structure of a conserved domain from a malarial red blood
cell-binding protein called EBA-175
Yeoh S, O’Donnell RA, Koussis K, Dluzewski AR, Ansell KH, Osborne SA, Hackett F, Withers-Martinez C,
Mitchell GH, Bannister LH, Bryans JS, Kettleborough CA and Blackman MJ (2007)
Subcellular discharge of a serine protease mediates release of invasive malaria parasites from host
erythrocytes.
Cell 131:1072-83
See references 39, 60, 116, 120, 122 in the bibliography at the back for publications from this group in 2009.
32
Elaine Davis
Gene regulation and DNA repair in the pathogenesis of Mycobacterium tuberculosis
Lab members: Nicola Beresford, Laura Brady, Joanna Dillury, Amanda Fivian-Hughes, Alison Gaudion, Katherine Smollett,
Alan Williams
Tuberculosis (TB) remains a major worldwide
cause of death due to infectious disease and drug
resistance is becoming an increasing problem.
Furthermore, it has been estimated that one-third
of the world’s population is infected with the
causative agent, Mycobacterium tuberculosis, in a state
termed latent infection, in which the immune system
holds the bacterium in check but is unable to
eliminate it. Our research is aimed at understanding
how M. tuberculosis is able to adapt to and survive
under the various conditions it encounters following
infection. We anticipate that a clearer understanding
of these processes will facilitate the development of
new drugs to treat TB.
During infection, M. tuberculosis becomes exposed
to various stresses including conditions that damage
DNA. As the repair of damaged DNA is crucial to
survival, we are focusing on the bacterial response
to DNA damage and the roles of particular DNA
repair processes in M. tuberculosis, particularly with
respect to pathogenesis. Where appropriate, we
are seeking to identify inhibitors that may provide a
starting point for drug development.
Publications
Dawson LF, Dillury J and Davis EO (2009)
RecA-independent DNA damage induction of Mycobacterium
tuberculosis ruvC despite an appropriately located SOS box.
Journal of Bacteriology 192:599-603
Güthlein C, Wanner RM, Sander P, Davis EO, Bosshard M, Jiricny J,
Böttger EC and Springer B (2009)
Characterisation of the mycobacterial NER system reveals novel
functions of uvrD1 helicase.
Curti E, Smerdon SJ and Davis EO (2007)
Characterization of the helicase activity and substrate specificity of
Mycobacterium tuberculosis UvrD.
During the course of infection and transmission, M. tuberculosis is
exposed to a range of conditions to which it must adapt, ultimately
resulting in persistence or replication
See references 51, 53, 95, 198 in the bibliography at the back for publications from this group in 2009.
33
Virology
John Doorbar
Human papillomavirus biology and disease
Lab members: Clare Davy, Pauline McIntosh, Qian Wang, Heather Griffin. Deborah Jackson, Zhonglin Wu, Gareth Maglennon,
Christina Untersperger, Emilio Pagliarulo, Rebecca Marnane
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 accounts for around 12% of all female cancers
worldwide and is almost always caused by high-risk HPV.
Central to understanding papillomavirus-associated disease are
model systems, which allow us to examine in the laboratory
how the virus disrupts the normal growth and differentiation
of the epithelial cells that it infects. Using such approaches,
we can study the initial events during lesion formation, the
mechanism of disease resolution and viral persistence, and
how viral latency and re-activation might be mediated. In our
group, such studies are supported by strong links with clinical
laboratories, and by appropriate molecular studies which look
at viral protein function and the cellular pathways that they
disrupt in order to support the normal or de-regulated virus
life cycle. Our work is ultimately driven by the need to better
understand HPV disease and how to limit its impact.
The E4 protein is cleaved by the protease calpain, which removes
sequences from the N-terminus (red) and exposes the C-terminal amyloid
fold (purple arrows) to allow E4 multimerisation
Publications
Davy C, McIntosh P, Jackson DJ, Sorathia R, Miell M, Wang Q, Khan J, Soneji Y and Doorbar J (2009)
A novel interaction between the human papillomavirus type 16 E2 and E1Ê4 proteins leads to
stabilization of E2.
Virology 394:266-275
Wang Q, Kennedy A, Das P, McIntosh PB, Howell SA, Isaacson ER, Hinz SA, Davy C and Doorbar J
(2009)
Phosphorylation of the human papillomavirus type 16 E1Ê4 protein at T57 by ERK triggers a
structural change that enhances keratin binding and protein stability.
Journal of Virology 83:3668-3683
McIntosh PB, Martin SR, Jackson DJ, Khan J, Isaacson ER, Calder L, Raj K, Griffin HM, Wang Q, Laskey P,
Eccleston JF and Doorbar J (2008)
Structural analysis reveals an amyloid form of the HPV 16 E1Ê4 protein and provides a molecular
basis for its accumulation.
See references 52, 79, 221 in the bibliography at the back for publications from this group in 2009.
34
B. E4 multimers exist as amyloid fibrils, which can be seen under the
electron microscope
C. HPV infection of the cervix leads to cervical neoplasia of different grades.
The E4 protein (which is stained in green) assembles into amyloid structures
in the upper epithelial layers. The red staining marks cells that are
progressing through the cell cycle, while cell nuclei are counter stained blue
Parasitology
Proteome-wide host-parasite interactions of severe malaria infections
Lab members: Dimitrios Athanasakis, Francesca Battaglia, Barry Ely, Juho Rousu, Gurjinder Sandhu, Olugbemiro Sodeinde
Human malaria caused by Plasmodium falciparum represents a global disease burden
with an estimated 500 million clinical episodes per year. Cerebral malaria and severe
malarial anaemia are major complications with significant mortality and morbidity. Our
research focuses on understanding how the proteomes of host and parasite interact
to establish severe disease states. Proteome-wide profiling of the infectious process
provides us with disease-specific molecular fingerprints reflecting host-pathogen
interactions.
We study the parasite–host interactions using high-throughput proteome-wide
mass spectrometry that reveals a snapshot of the state of the host during infection.
We develop computational statistics and systems biology algorithms to discover
complex patterns of interactions. Subsequent study of the patterns is essential for
understanding the pathogenesis of different severe malaria clinical presentations
and provides information for development of new diagnostic tests and therapeutic
strategies. The establishment of the Childhood Malaria Research Unit with our
collaborators at the Department of Paediatrics of the University College Hospital
Ibadan, Nigeria allows us to sample the malaria disease process. This involves
recruiting severe and non-severe malaria cases, as well as associated clinical,
epidemiological, demographical and geographical information.
Publications
Rojas-Galeano S, Hsieh E, Agranoff D, Krishna S and FernandezReyes D (2008)
Estimation of relevant variables on high-dimensional biological
patterns using iterated weighted kernel functions.
PLoS ONE 3:e1806
The Childhood Malaria Research Group
(CMRG) based at University College Hospital
(UCH Ibadan-Nigeria) has been established as a
partnership between NIMR and the Department
of Paediatrics of the College of Medicine
University of Ibadan
(a) Plasma proteome-wide profiles of hostparasite interactions in patients with Severe
Malaria Anaemia (Red), Cerebral Malaria (Purple),
Uncomplicated Malaria (Orange).
(b) Principal components analysis of complex
patterns within plasma proteome profiles shows
discrimination between clinical classes
Agranoff D, Fernandez-Reyes D, Papadopoulos MC, Rojas SA,
Herbster M, Loosemore A, Tarelli E, Sheldon J, Schwenk A, Pollak R,
Rayner CFJ and Krishna S (2006)
Identification of diagnostic markers for tuberculosis by proteomic
fingerprinting of serum.
Lancet 368:1012-1021
Rojas SA and Fernandez-Reyes D (2005)
Adapting multiple kernel parameters for support vector machines
using genetic algorithms.
2005 IEEE Congress on Evolutionary Computation, Proceedings:
Edinburgh.
IEEE, 2005. 1:626-631
35
Sebastien Gagneux
Population genomics and ecology of Mycobacterium tuberculosis
Lab members: Sonia Borrell, Inaki Comas, Thembela Huna, Graham Rose
We have previously shown that Mycobacterium tuberculosis, the
causative agent of human tuberculosis (TB) consists of genetically
distinct strain lineages that are associated with different regions of the
world. Understanding the forces that shape this variation is crucial for
the development of improved diagnostics, drugs, and vaccines against
TB. We are using large-scale DNA sequencing of M. tuberculosis clinical
strains to address this question.
Recent data from 89 genes in 108 strains has shown that the genetic
distance between two human strains of M. tuberculosis can be as
pronounced as the distance between a human strain and M. bovis,
which is a classical animal pathogen. These data also support an
‘out-of-and-back-to-Africa’ scenario for the evolutionary history of
human TB. According to this scenario, M. tuberculosis originated in
Africa and spread out of Africa together with ancient migrations of
modern humans. More recently, the evolutionary ‘modern’ lineages of
M. tuberculosis expanded as a result of the strong human population
increases in Europe, India, and China, and spread globally following
waves of colonization, trade, and conquest.
Global phylogeny of M. tuberculosis based on 89 gene
sequences in 108 strains
Publications
Borrell S and Gagneux S (2009)
Infectiousness, reproductive fitness and evolution of drug-resistant
Mycobacterium tuberculosis.
International Journal of Tuberculosis and Lung Disease 13:1456-1466
Comas I and Gagneux S (2009)
The past and future of tuberculosis research.
(A) Different M. tuberculosis lineages accompanied
the ‘Out-of-Africa’ migrations of modern humans
~50,000 years ago. (B) Recent gobal spread of the
‘modern’ M. tuberculosis lineages as a consequence
of colonization, trade, and conquest
Hershberg R, Lipatov M, Small PM, Sheffer H, Niemann S, Homolka
S, Roach JC, Kremer K, Petrov DA, Feldman MW and Gagneux S
(2008)
High functional diversity in Mycobacterium tuberculosis driven by
genetic drift and human demography.
PLoS Biology 6:2658-2671 e311
See references 23, 41, 42, 55, 70, 76, 77, 145, 230 in the bibliography
at the back for publications from this group in 2009.
36
Virology
Alan Hay
Influenza virus – vaccines and drugs
Lab members: Patrick Collins, Sergiy Tokar, Steve Wharton, Yi Pu Lin, Rod Daniels, Victoria Gregory, Xiang Zheng,
Lynne Whittaker,Ting Hou, Joannes Kloess, Nicholas Cattle, Takashi Yamanaka
Viruses causing influenza change in two ways: gradual small changes which
reduce immunity to re-infection, and infrequent major changes which result
in the emergence of novel viruses, such as the “swine-origin” H1N1 virus
responsible for the 2009 influenza pandemic. Worldwide surveillance by the
WHO Global Influenza Network, including the World Influenza Centre at
NIMR, is therefore essential to detect and monitor such changes. This allows
assessment of the pandemic risk of e.g. H5N1 Bird Flu, as well as of changes that
reduce the effectiveness of vaccines and drugs.
My group also researches the two target proteins of anti-influenza drugs, the
virus neuraminidase (NA) and M2 proton channel. We aim to gain a better
understanding of the molecular mechanisms of drug action and acquisition of
resistance. Our recent X-ray crystallographic analyses of NA-drug complexes
have provided a structural explanation for specific resistance to oseltamivir
(Tamiflu). Such information is important in understanding the recent spread
of oseltamivir resistance among seasonal A H1N1 viruses and its potential
emergence among the novel pandemic H1N1 viruses.
Publications
Childs RA, Palma AS, Wharton S, Matrosovich T, Liu Y, Chai W,
Campanero-Rhodes MA, Zhang Y, Eickmann M, Kiso M, Hay A,
Matrosovich M and Feizi T (2009)
Receptor-binding specificity of pandemic influenza A (H1N1) 2009
virus determined by carbohydrate microarray.
Nature Biotechnology 27:797-9
dos Reis M, Hay AJ and Goldstein RA (2009)
Using non-homogeneous models of nucleotide substitution to
identify host shift events: application to the origin of the 1918
‘Spanish’ influenza pandemic virus.
Journal of Molecular Evolution 69:333-345
X-ray crystallographic structures of NA-drug complexes, showing the effects of the His274 Tyr
oseltamivir resistance mutation on the interactions of oseltamivir (A) and zanamivir (B) with the active
sites of wild-type (green) and mutant (yellow) NAs of A H5N1 virus
Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Skehel JJ, Martin
SR, Hay AJ and Gamblin SJ (2008)
Crystal structures of oseltamivir-resistant influenza virus
neuraminidase mutants.
Nature 453:1258-61
See references 18, 19, 31, 36, 40, 61, 122, 141, 207 in the bibliography
37
Parasitology
Tony Holder
Malaria parasites and red blood cells
Lab members: Barbara Clough, Suraya Diaz, Muni Grainger, Judith Green, Claire Hastings, Madhu Kadekoppala, Ellen Knuepfer,
Robert Moon, David Moss, Sola Ogun, Kaveri Rangachari, Ridzuan Razak, Shigeharu Sato, Oniz Suleyman, Noor Azian Yusuf
Malaria is caused by a parasitic protozoan that invades red blood cells, where
it develops and multiplies before bursting out and invading new red cells. This
cycle is responsible for the disease. There is much interest in understanding the
interaction between the parasite and the host immune system, to contribute 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
much needed new therapeutic interventions.
In one project, focused on how the parasite invades host cells, we study the
actomyosin-based motor that drives invasion. We have shown that an unusual
calcium-dependent protein kinase phosphorylates two of the proteins in the
motor complex, a process that may be important in its assembly. Together
with colleagues at MRC Technology we have identified chemical compounds
that inhibit this kinase and kill the parasite at very low concentrations. These
compounds have the potential to be developed into drugs against malaria and are
powerful reagents to dissect the exact role of this kinase in the parasite’s biology.
Location of an apical rhoptry protein (RhopH2), an
invasion motor protein (GAP45) and a surface protein
(MSP1) in merozoites within a schizont
Publications
Holder AA (2009)
The carboxy-terminus of merozoite surface protein 1: structure, specific antibodies and immunity to malaria.
Parasitology 136:1445-1456
Within the parasite’s cycle of invasion and development
we study several aspects of its cell biology and
biochemistry to understand the complex interaction
between parasite and host
Green JL, Rees-Channer RR, Howell SA, Martin SR, Knuepfer E, Taylor HM, Grainger M and Holder AA (2008)
The motor complex of Plasmodium falciparum: phosphorylation by a calcium-dependent protein kinase.
Journal of Biological Chemistry 283:30980-30989
Kadekoppala M, O’Donnell RA, Grainger M, Crabb BS and Holder AA (2008)
Deletion of the Plasmodium falciparum Merozoite Surface Protein 7 gene impairs parasite invasion of erythrocytes.
Eukaryotic Cell 7:2123-2132
See references 20, 22, 45, 60, 98, 100, 101, 102, 120, 151, 152 in the bibliography at the back for publications from this
group in 2009.
38
Immunoregulation
George Kassiotis
Antiviral immunity
Lab members: Urszula Eksmond, Dorothy Ng, Rebecca Pike, Mickaël Ploquin, George Young
Viral infections represent a major challenge to the immune
system. Certain viruses cause acute infections in humans, which
can be rapidly fatal within days (e.g. 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) and 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 progressive immune deficiency, HIV infection
is characterised by generalized immune activation, with
lymphadenopathy and accelerated turnover of lymphocytes, both
infected and uninfected. The origin of immune activation in HIV
infection is unknown, but it is thought to arise from increased
microbial exposure due to diminishing immunity. Instead, we
showed in a virus-free mouse model that conditional ablation
of activated CD4+ T cells, the targets of immunodeficiency
viruses, reproduces both HIV-associated immune deficiency and
activation, attributable to insufficiency in memory and regulatory
CD4+ T cells, respectively. This suggests activated CD4+ T cell
killing as a common aetiology for both immune deficiency and
activation in HIV infection.
Publications
Marques R, Williams A, Eksmond U, Wullaert A, Killeen N, Pasparakis
M, Kioussis D and Kassiotis G (2009)
Generalized immune activation as a direct result of activated
CD4+ T cell killing.
Pike R, Filby A, Ploquin MJ-Y, Eksmond U, Marques R, Antunes I,
Hasenkrug K and Kassiotis G (2009)
Race between retroviral spread and CD4+ T cell response
determines the outcome of acute Friend virus infection.
Journal of Virology 83 11211-11222
Lymphadenopathy (lymph node enlargement) in
mice with conditional ablation of activated CD4+
T cells (DTA) in comparison with control wildtype (WT) mice
Lymphocyte activation (expression of CD44) in
non-targeted CD8+ T cells isolated from mice
with ablation of activated CD4+ T cells (DTA) or
control wild-type (WT) mice
Antunes I, Tolaini M, Kissenpfennig A, Iwashiro M, Kuribayashi K,
Malissen B, Hasenkrug K and Kassiotis G (2008)
Retrovirus-specificity of regulatory T cells is neither present nor
required in preventing retrovirus-induced bone marrow immune
pathology.
Immunity 29:782-794
See references 112, 132, 157 in the bibliography at the back for
publications from this group in 2009.
39
Dimitris Kioussis FRS, EMBO member, FMedSci
Chromatin structure, gene expression and lymphoid development
Lab members: Mauro Tolaini, Eleni Ktistaki, Nicky Harker, Ursula Menzel, Kathleen Roderick, Amisha Patel, Anna Garefalaki,
Dimitris Karamitros, Trisha Norton, Keith Williams
Image of mouse chromosome 6. Multi colour chromosome banding
(MCB) with CD8a and CD4 gene probes
Immune cells comprise a major component of our arsenal
to fight disease. In order for the B and T lymphocytes of the
immune system to function appropriately and protect the body
from pathogens (viruses, bacteria) and aberrant cells (cancer)
they must express specific sets of genes. This specific pattern
of gene expression constitutes the signature of the cell and
defines its identity and function. It is therefore important to
understand what controls the decisions to establish a specific
gene expression programme.
We are studying how sequential gene expression patterns are
controlled during the development of thymocytes to generate
mature T cells. Our studies focus on two genes, CD2 and CD8,
that are expressed during thymocyte differentiation. We are
interested in identifying the chromatin structures established
in open (expressing) or closed (non-expressing) states of
these genes. In other studies, we are investigating the cellular
and molecular requirements for lymphoid organ formation
by in vivo and in vitro imaging of specific lymphoid cell types
expressing fluorescent proteins.
Imaging of the lymphoid system and associated organs. B Cell follicles:
EYFP. T Cell zone: DsRed
Publications
Kioussis D and Pachnis V (2009)
Immune and nervous systems: more than just a superficial similarity?
Immunity 31:705-710
Kioussis D and Georgopoulos K (2007)
Epigenetic flexibility underlying lineage choices in the adaptive immune system.
Science 317:620-622
Veiga-Fernandes H, Coles MC, Foster KE, Patel A, Williams A, Natarajan D, Barlow A, Pachnis V and
Kioussis D (2007)
Tyrosine kinase receptor RET is a key regulator of Peyer’s Patch organogenesis.
Nature 446:547-551
See references 64, 83, 115, 132, 162, 229 in the bibliography at the back for publications from this
group in 2009.
40
Parasitology
Jean Langhorne
Immunology and immunopathogenesis of malaria infections
Lab members: Deirdre Cunningham, Peter Gardner, Ana Paula Freitas do Rosario, William Jarra, Gertrude Kiwanuka, Agathe Lang,
Jennifer Lawton, Beatris Mastelic, Philip Spence, Anne-Marit Sponaas, Robin Stephens, Sophie Roetynck, Christine Tshitenge,
Bettina Wagner
We study the immune response to the malaria parasite,
components of this response involved in protection against
infection and in pathology, and parasite antigens that may
stimulate these responses. For most of our work we study
mouse models, but where possible also human immune
reponses to Plasmodium falciparum and P. vivax.
The innate immune system is an important component of the
early host response to the blood stages of the malaria parasite.
We have shown that a population of inflammatory monocytes
is produced in the bone marrow in response to infection, and
contributes to killing and removal of parasites. However, the
innate response is not sufficient to eliminate an infection, and
long-term protective immunity to re-infection depends on B
cells and antibodies. Long-lived responses do develop after a
single malaria infection to some antigens, but it is thought that
protective immunity is directed towards variant antigens on
the infected red blood cells, which may induce only short-lived
or ineffective antibody responses. There is a large multigene
family in rodent and human malaria parasites that codes for a
set of variant proteins. We are investigating whether these are
expressed on the surface of infected red blood cells and are the
targets of a protective immune response.
Publications
Cunningham D, Fonager J, Jarra W, Carret C, Preiser P and
Langhorne J (2009)
Rapid changes in transcription profiles of the Plasmodium yoelii yir
multigene family in clonal populations: lack of epigenetic memory?
PLoS ONE 4:e4285
Ndungu FM, Cadman ET, Coulcher J, Nduati E, Couper E, Macdonald
DW, Ng D and Langhorne J (2009)
Functional memory B cells and long-lived plasma cells are
generated after a single Plasmodium chabaudi infection in mice.
Sponaas A-M, Freitas do Rosario AP, Voisine C, Mastelic B, Thompson
J, Koernig S, Jarra W, Renia L, Mauduit M, Potocnik AJ and Langhorne
J (2009)
Migrating monocytes recruited to the spleen play an important
role in control of blood stage malaria.
Blood 114:5522-5531
See references 22, 47, 142, 151, 183, 199, 201, 219 in the
bibliography at the back for publications from this group in 2009.
Immune responses to Plasmodium chabaudi malaria in mice
41
Immune Cell Biology
Steve Ley
Regulation of immune responses by NF-κB and MAP kinases
Lab members: Hakem Ben-Addi, Thorsten Gantke, Emilie Jacque, Julia Janzen, Agnes Mambole, Matoula Papoutsopoulou,
Srividya Sriskantharajah, Karine Roget, Huei-Ting Yang, Rachel Zillwood
Following infection, pathogenic microorganisms such as viruses
and bacteria are initially recognised by specific receptors on
the surface of neutrophils and macrophages. This triggers an
immediate ‘innate’ immune response involving the production of
proteins called chemokines and cytokines. These attract other
immune cells to the sites of infection and also initiate the adaptive
immune response that culminates in the production of protective
antibodies and killing of infected cells.
Coordinating the expression of genes that control innate and
adaptive immune responses involves activation of the NF-κB
family of transcription factors and the ERK MAP kinase signalling
enzyme. We study a signalling pathway that regulates both NF-κB
and ERK MAP kinase activation by inducing proteolysis of the
inhibitory protein NF-κB1 p105. We have recently found that
p105 regulation of NF-κB is critical for the function of CD4
T cells during an immune response. Our current studies aim
to determine whether blockade of p105 proteolysis might be
useful for the treatment of specific autoimmune diseases, such as
rheumatoid arthritis and multiple sclerosis.
TPL-2 regulates ERK MAP kinase activation in inflammatory responses
Publications
Kaiser F, Cook D, Papoutsopoulou S, Rajsbaum R, Wu X, Yang HT, Grant S, Ricciardi-Castagnoli P, Tsichlis PN,
Ley SC and O’Garra A (2009)
TPL-2 negatively regulates interferon-β production in macrophages and myeloid dendritic cells.
Journal of Experimental Medicine 206:1863-1871
Sriskantharajah S, Belich MP, Papoutsopoulou S, Janzen J, Tybulewicz V, Seddon B and Ley SC (2009)
Proteolysis of NF-κB1 p105 is essential for T cell antigen receptor-induced proliferation.
Nature Immunology 10:38-47
Regulation of NF-κB and ERK activation in innate immune responses
Papoutsopoulou S, Symons A, Tharmalingham T, Belich MP, Kaiser F, Kioussis D, O’Garra A, Tybulewicz V and Ley
SC (2006)
ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses.
42
Virology
John McCauley
Host specificity of influenza viruses
Lab members: Haixia Xiao, Nicole Runkler, Ana Luisa Reis, Michael Bennett, Steve Wharton, Saira Hussain
Influenza viruses infect a variety of species. Humans, horses
and pigs are the main mammalian hosts of the virus in which
infection is sustained. Avian species, particularly water fowl
and gulls, harbour a very wide variety of influenza viruses.
New pandemic strains of human influenza viruses arise from
an animal reservoir either directly, as in the 2009 pandemic
virus, or as a result of gene reassortment, as occurred in the
1957 and 1968 pandemics. The interaction between a virus
particle and its receptor on a host cell is a vital feature that
limits the host range of influenza viruses, but additional factors
following entry of virus into the cell also control the outcome
of infection.
In our laboratory, 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. We are also characterising the factors that influence
the replication of avian influenza viruses in avian species.
In collaboration with colleagues at The Institute for Animal
Health, the Veterinary Laboratories Agency and the Wellcome
Trust Sanger Institute we have been examining how the virus
varies within the infected avian host. The techniques used have
allowed us to analyse polymorphisms within the virus and the
background genetic variation seen within samples amplified
directly from experimentally infected birds.
Publications
Iqbal M, Xiao H, Baillie G, Warry A, Essen SC, Londt B, Brookes SM, Brown IH and McCauley JW
(2009)
Within-host variation of avian influenza viruses.
Philosophical Transactions of the Royal Society B-Biological Sciences 364:2739-2747
Iqbal M, Yaqub T, Reddy K and McCauley JW (2009)
Novel genotypes of H9N2 influenza A viruses isolated from poultry in Pakistan containing NS
genes similar to highly pathogenic H7N3 and H5N1 viruses.
PLoS ONE 4:e5788
Kuiken T, Holmes EC, McCauley J, Rimmelzwaan GF, Williams CS and Grenfell BT (2006)
Host species barriers to influenza virus infections.
Science 312:394-397
cDNA clones were prepared directly from samples taken from an
experimentally infected chickens. The numbers of nucleotide changes (black
bars) and amino acid changes (grey bars) in individual clones differing from
the consensus sequence clone are indicated
43
Immunoregulation
Anne O’Garra FRS, AAAS Fellow, EMBO member, FMedSci
Regulation of the immune response in infectious disease
Lab members: Chloe Bloom, Jillian Christensen, John Ewbank, Leona Gabrysova, Christine Graham, Ashleigh Howes, Finlay McNab,
Jonathan Pitt, Paul Redford, Vangelis Stavropoulos, Xuemei Wu, Matthew Berry
The immune system is effective in eradicating pathogens via many mechanisms,
including soluble mediators called cytokines. Immune cells can produce different
cytokines to control infection, but can cause host damage if uncontrolled. We are
researching the molecular mechanisms underlying the development and function of
discrete subsets of immune cells that produce different cytokines protective against
pathogens, and the induction and function of a regulatory cytokine, IL-10. We use
diverse tools to study the mechanisms of IL-10 gene regulation in macrophages,
dendritic cells and T cells, and the consequences of IL-10 action in mouse models
of infectious diseases, with strong emphasis on tuberculosis (TB) caused by
TB is a major global cause of morbidity and mortality. Using a systems biology
approach we identified a robust blood transcriptional signature for active TB,
and longitudinal analysis revealed that this signature disappears during successful
treatment. We are combining immunological research with interrogation of gene
expression data to identify the immune factors involved in protection or pathogenesis
important for disease control.
Regulation of IL-10 production in immune cells
Publications
Transcriptional signatures for rapid diagnosis, disease monitoring and identification of
factors involved in protection/immunopathogenesis in disease
Saraiva M and O’Garra A (2010)
The regulation of IL-10 production by immune cells.
Nature Reviews Immunology 10:170-81
Kaiser F, Cook D, Papoutsopoulou S, Rajsbaum R, Wu X, Yang HT, Grant S, Ricciardi-Castagnoli P, Tsichlis PN, Ley SC and O’Garra A (2009)
TPL-2 negatively regulates interferon-β production in macrophages and myeloid dendritic cells.
Saraiva M, Christensen JR, Veldhoen M, Murphy TL, Murphy KM and O’Garra A (2009)
Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose.
Immunity 31:209-219
See references 17, 110, 112, 149, 180, 216 in the bibliography at the back for publications from this group in 2009.
44
Alexandre Potocnik
Haematopoietic stem cells and lymphocyte development
Lab members: Nikolai Belyaev, Judit Biro, Douglas Brown, Rebecca Leyland, Demetrios Vassilakos, Ana Isabel, Garcia Diaz
All lymphocytes derive from
haematopoietic stem cells, which are
located in specialised niches within the
bone marrow. In the adult, these stem cells
are relatively immobile. However, in the
foetus, or in response to some infections
in the adult, these stem cells leave the
bone marrow and appear in the blood.
Our main focus is on understanding the
processes that govern retention of stem
cells in the bone marrow or their release
into the blood and migration to other
organs, and their subsequent development
into lymphocytes.
We have shown that in the absence of
β1 integrin, haematopoietic progenitors
are generated normally during ontogeny
in the embryo and are released into the
circulation, but fail to colonise foetal liver,
thymus or bone marrow. Extending this
study we comprehensively analysed T cell
development using a genetic approach
based on the lineage restricted expression
of a fluorescent reporter. Ongoing work is
concentrating on the dynamic regulation
of lymphoid differentiation and the role
of adhesion molecules for the proper
compartmentalisation in health and
disease.
Publications
Lamikanra AA, Brown D, Potocnik A, Casals-Pascual C, Langhorne J and
Roberts DJ (2007)
Malarial anemia: of mice and men.
Blood 110:18-28
Early lymphocyte development
See references 199 in the bibliography at the back for publications
from this group in 2009.
45
Virology
Kenneth Raj
Lifecycle and persistence of human papillomavirus
Lab members: Joanna Laurson, Lietta Nicolaides, Yeong-Lih Hiew, Jason Piper, Rachel Chung, Karen Cross
The association between human papillomavirus (HPV) infection
and cervical cancer is one of the clearest examples of how viral
infection can lead to cancer. Although a single HPV infection
by itself is unlikely to result in malignant transformation, the
maintenance and persistence of the viral DNA in the cervical
tissue considerably raises the risk of cancer development at a
later stage.
The main thrust of our work is to understand how HPVs infect
cells, what happens to the viral DNA after infection, and how the
viral DNA is replicated and maintained in the cells for prolonged
periods. We are also investigating the consequences of HPVinduced inactivation of host tumour suppressor proteins and
how this might be manipulated to kill cells harbouring the viral
DNA. By characterising the differences between infected and
non-infected cells, we hope to identify more points in the viral
life cycle that might be suitable for therapeutic drug targetting.
Publications
Garner E and Raj K (2008)
Protective mechanisms of p53-p21-pRb proteins against DNA damage-induced cell death.
Cell Cycle 7:277-282
Human epithelium generated in the laboratory from cultured cells: (a)
Cells harbouring HPV DNA that cannot express the viral E7 oncoprotein
allow gradual differentiation of the stratified cells (diamond-shaped,
granular cells), in the upper layers as is present in normal epithelia. (b)
Cells harbouring wild-type HPV16 DNA form a disorganised epithelium
largely consisting of proliferating cells
46
Garner E, Martinon F, Tschopp J, Beard P and Raj K (2007)
Cells with defective p53-p21-pRb pathway are susceptible to apoptosis induced by p84N5 via caspase-6.
Cancer Research 67:7631-7637
Hoffmann R, Hirt B, Bechtold V, Beard P and Raj K (2006)
Different modes of human papillomavirus DNA replication during maintenance.
Immune Cell Biology
Benedict Seddon
Regulation of T cell homeostasis by antigen receptor signals and interleukin-7
Lab members: Thea Hogan, Daniel Marshall, Ina Schim van der Loeff, Ana Silva, Charles Sinclair, Sim Tung
Thymus derived T cells play a central role in regulating
immune responses. The number and type of T cells found in
the immune system is carefully regulated by processes that
control their production, survival and replication. Defects in
any of these processes can upset the fine balance that exists
between the different T cell types within the immune system,
causing them to malfunction. Abnormal responses by T cells
can result in autoimmune diseases, such as diabetes, or the
development of leukaemia. Furthermore, the effectiveness
of vaccines can depend on the successful generation and
survival of appropriate T cell types.
We have developed an in vivo model in which we can
specifically control expression of Zap70, a key kinase involved
in transmitting T cell antigen receptor signals. Using this
model, we have discovered a role for Zap70 in helping
developing thymocytes make the decision to become either
helper CD4 T cells or cytotoxic CD8 T cells.
Publications
Saini M, Pearson C and Seddon B (2009)
Regulation of T cell-dendritic cell interactions by IL7 governs T cell
activation and homeostasis.
Blood 113:5793-5800
Yates A, Saini M, Mathiot A and Seddon B (2008)
Mathematical modeling reveals the biological program regulating
lymphopenia-induced proliferation.
Journal of Immunology 180:1414-22
Saini M, Sinclair C, Marshall D, Tolaini M, Sakaguchi S and Seddon B
(2010)
Regulation of Zap70 expression during thymocyte development
enables temporal separation of CD4 and CD8 repertoire
selection at different signaling thresholds.
Science Signaling 3:ra23
Dynamic regulation of Zap70 levels controls CD4+CD8+ thymocyte sensitivity to selection signals at
different stages of T cell development
See references 83, 97, 176, 200 in the bibliography at the back for
47
Gitta Stockinger EMBO member, FMedSci
Development, maintenance and regulation of peripheral T cell compartments and
immune responses
Lab members: Marc Veldhoen, Keiji Hirota, Joao Duarte, Ceri Wiggins, Christoph Wilhelm, Eve Hornsby, Nachima Khattoun, Ying Li
Our main interest is the functional analysis of peripheral T cell responses, aiming to
understand complex interactions in vivo that lead to antigen presentation, tolerance
induction, activation, autoimmunity and memory formation. Our current focus is
on the development and function of new CD4 effector T cells, such as Th17 cells,
and modulation of effector functions by exogenous and endogenous environmental
factors.
Th17 cells are important for defence against fungal pathogens and many extracellular
bacteria, and are causally involved in autoimmune diseases such as rheumatoid
arthritis, myocarditis, multiple sclerosis and psoriasis. Understanding their mode of
action and regulation may ultimately lead to improved therapies for such diseases.
We are currently focusing on the role of the aryl hydrocarbon receptor in Th17 cell
biology, trying to unravel its impact on their physiological function in the defense
against pathogens as well as their role in autoimmune diseases.
Publications
Martin B, Hirota K, Cua DJ, Stockinger B and Veldhoen M (2009)
Interleukin-17-producing γδ T cells selectively expand in response
to pathogen products and environmental signals.
Immunity 31:321-330
Veldhoen M, Hirota K, Christensen J, O’Garra A and Stockinger B
(2009)
Natural agonists for aryl hydrocarbon receptor in culture medium
are essential for optimal differentiation of Th17 T cells.
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 14, 21, 67, 133, 203, 204, 205, 216 in the bibliography
48
Immune regulation by AhR ligand or inhibitor
Virology
Jonathan Stoye
Retrovirus-host interactions
Lab members: Emily Colbeck, Vicky Felton, Seti Grambas, Kate Holden-Dye, Laura Hilditch, Sadayuki Okura, Melvyn Yap
Comparative genome analysis suggests that vertebrates
and retroviruses have co-existed 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 means
to overcome such defences by the virus. Understanding
such natural anti-viral genes might suggest novel means of
combating retroviral infection.
The primate TRIM5α genes provide an example of
such a host defence gene. They can interact with the
polymerised viral capsid proteins present on infecting
retroviruses. One key question in their study concerns
the specificity of target recognition. On the one hand,
they are capable of recognising and restricting a wide
range of viruses. However, each TRIM5α restricts a
different panel of viruses. We are attempting to define the
sequences responsible for recognition of different viruses
and to describe the structures with which they interact.
We anticipate that these studies will shed new light on
the early stages of retrovirus replication and the control
of cross-species infection.
Publications
Yap MW, Lindemann D, Stanke N, Reh J, Westphal D, Hanenberg H, Ohkura S and Stoye JP (2008)
Restriction of foamy viruses by primate Trim5α.
Yap MW, Mortuza GB, Taylor IA and Stoye JP (2007)
The design of artificial retroviral restriction factors.
Ohkura S, Yap MW, Sheldon T and Stoye JP (2006)
All three variable regions of the TRIM5α B30.2 domain can contribute to the specificity of retrovirus
restriction.
Potential restriction factor binding pocket in the N-terminal
domain of the MLV CA protein. Amino acids that can affect
viral tropism are highlighted
49
Immune Cell Biology
Pavel Tolar
Activation of immune receptors
Lab members: Jason Lee, Antonio Casal
Antibodies are an integral part of human immunity to
infections and their induction has proven successful in many
vaccines. However, some of the most dangerous pathogens
of today’s world, such as HIV, influenza and 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 focus on the B-cell antigen receptor, the primary receptor
that controls the activation of B lymphocytes and the specificity
of the antibody response. Our initial studies are investigating the
role of membrane-proximal domains of the B-cell receptor in
the mechanism of signal transduction from the pathogen binding
sites to the intracellular signalling units. We combine structural
techniques with molecular imaging of the B-cell receptor in living
B cells that recognise a range of viral epitopes.
Imaging of an individual B-cell receptor on B lymphocytes shows
activation of the receptor in antigen-induced clusters
Publications
Tolar P, Hanna J, Krueger PD and Pierce SK (2009)
The constant region of the membrane immunoglobulin mediates B cell-receptor clustering and signaling in response to
membrane antigens.
Immunity 30:44-55
Tolar P, Sohn HW and Pierce SK (2008)
Viewing the antigen-induced initiation of B-cell activation in living cells.
Immunological Reviews 221:64-76
Schematic structure of the B-cell receptor
50
Tolar P, Sohn HW and Pierce SK (2005)
The initiation of antigen-induced B cell antigen receptor signaling viewed in living cells by fluorescence resonance
energy transfer.
Immune Cell Biology
Immune Cell Biology
Victor Tybulewicz EMBO member, FMedSci
Victor Tybulewicz
Signal transduction in B and T cells
Lab members: Alexander Saveliev, Olga Ksionda, Agnieszka Zachacz, Amy Slender, Lesley Vanes, Robert Köchl, Sheona Watson,
Eva Lana Elola, Jonathan Rapley, Edina Schweighoffer, Josquin Nys, Pete Gardner
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 auto-immune 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. In a recent study
we have shown that proteins called Rac GTPases are critical for
controlling the migration of both B and T cells into, through and out of
lymph nodes.
Mouse models of Down syndrome
Trisomy of human chromosome 21 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. To do this,
we created a novel mouse strain carrying a freely segregating copy of
human chromosome 21, which displays many of the features of Down
Syndrome, including learning difficulties and cardiac abnormalities.
Publications
Dumont C, Corsoni-Tadrzak A, Ruf S, de Boer J, Williams A, Turner M,
Kioussis D and Tybulewicz VL (2009)
Rac GTPases play critical roles in early T cell development.
Blood 113:3990-3998
Saveliev A, Vanes L, Ksionda O, Rapley J, Smerdon SJ, Rittinger K and
Tybulewicz VLJ (2009)
Function of the nucleotide exchange activity of Vav1 in T cell
development and activation.
Rapley J, Tybulewicz VLJ and Rittinger K (2008)
Crucial structural role for the PH and C1 domains of the Vav1
exchange factor.
EMBO Reports 9:655-661
The Vav1 signalling protein (green) accumulates
in a T cell at the interface with an antigen
presenting cell (red). Nuclei are stained in blue
T cells missing Rac GTPases (green) are stuck
on the endothelium (purple), unable to enter
the cortex of the lymph node (blue), unlike wildtype T cells (red)
See references 43, 48, 64, 72, 78, 94, 170, 184, 185, 200, 212, 227 in
the bibliography at the back for publications from this group in 2009.
51
Immunoregulation
Andreas Wack
Immune response to influenza
Lab members: Stefania Crotta, Sophia Davidson
Seasonal influenza represents a constant burden to public health,
and influenza pandemics caused by new virus strains pose a
serious global threat. The influenza virus causes damage to the
infected lung tissue and induces an immune response which is
necessary to eliminate the virus but contributes to lung pathology.
It is not completely known which factors tip the balance between
damage or death versus successful clearance of the virus with no
long term damage.
Our work aims to identify which features of the virus and host
determine the outcome of disease. We focus on early events after
infection, and in particular on the interface between the infected
epithelium and the immune system. We have established a culture
system of mouse airway epithelium and use this in co-culture with
innate immune cells to dissect cellular cross-talk after infection
with a variety of influenza virus strains. Complemented by in vivo
studies, this approach will allow us to identify early events that
pave the way for immune-mediated pathology or protection.
Publications
Crotta S, Brazzoli M, Piccioli D, Valiante NM and Wack A (2010)
Hepatitis C virions subvert natural killer cell activation to generate a
cytokine environment permissive for infection.
Journal of Hepatology 52:183-90
Pesce I, Monaci E, Muzzi A, Tritto E, Tavarini S, Nuti S, De Gregorio E and
Wack A (2009)
Intranasal administration of CpG induces a rapid and transient cytokine
response followed by dendritic and natural killer cell activation and
recruitment in the mouse lung.
Journal of Innate Immunity Epub ahead of print
Gallorini S, Berti F, Mancuso G, Cozzi R, Tortoli M, Volpini G, Telford JL,
Beninati C, Maione D and Wack A (2009)
Toll-like receptor 2 dependent immunogenicity of glycoconjugate
vaccines containing chemically derived zwitterionic polysaccharides.
America 106:17481-17486
52
Mouse airway epithelial cultures stained with the tight junction protein ZO-1
(green) and the cilia constituent beta tubulin IV (magenta)
Robert Wilkinson FRCP
Steroid regulated immune responses in tuberculosis
Lab members: Katalin Wilkinson, Anna Coussens, Adrian Martineau
Our studies are based at NIMR and at the University of
Cape Town, South Africa. Our interest is the modulation of
the immune response in human tuberculosis by vitamin D
and corticosteroids. Both studies rely on recently completed
clinical trials: first, of the efficacy of vitamin D as an adjunct to
the treatment of active tuberculosis; and second of prednisone
versus placebo for treatment of the HIV-TB associated
immune reconstitution inflammatory syndrome (TB-IRIS).
Immunopathology is a hallmark of tuberculosis, which is
necessary for transmission of the disease and responsible for
its sequelae, including death. TB-IRIS arises as a consequence
of restoration of pathological immunity in HIV-infected
persons with tuberculosis who receive antiretroviral therapy,
and is an opportunity to better understand this phenomenon.
It was unknown until our trial whether corticosteroids would
be beneficial in reducing symptoms. Our demonstration that
they are effective now focuses attention on a rich specimen
bank to determine the mode of action so that more specific
immune modulators of immunopathology in tuberculosis can
potentially be discovered.
Publications
Wilkinson KA, Seldon R, Meintjes G, Rangaka MX, Hanekom WA, Maartens G and Wilkinson RJ (2009)
Dissection of regenerating T cell responses against tuberculosis in HIV infected adults sensitized by
American Journal of Respiratory and Critical Care Medicine 180:674-683
Maartens G and Wilkinson RJ (2007)
Tuberculosis.
Lancet 370:2030-2043
Martineau AR, Newton SM, Wilkinson KA, Kampmann B, Hall BM, Nawroly N, Packe GE, Davidson RN,
Griffiths CJ and Wilkinson RJ (2007)
Neutrophil-mediated innate immune resistance to mycobacteria.
Journal of Clinical Investigation 117:1988-94
See references 11, 17, 49, 62, 111, 130, 134, 135, 144, 154, 155, 181, 186, 224, 225, 226, 235 in the
Symptom score at week 2 and 4
The distribution of symptom scores in percentage at week 2 and 4 in
3 categories (deteriorated, no change, improved/resolved) is shown.
There were significant differences between the 2 arms at week 2
(p=0.001) and week 4 (p=0.03)
53
Douglas Young FMedSci
Mycobacterium tuberculosis and the host response
Lab members: Kristine Arnvig, John Brennan, Stephen Coade, Damien Portevin, Vivek Rao, Min Yang
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
persistence of the pathogen in an asymptomatic, latent
infection. We are testing the hypothesis that the pathogen
misleads the host into mounting a suboptimal response.
Ultimately, we aim to develop drugs that rapidly eliminate
persisting bacteria and vaccines that elicit more effective
immunity.
Innate immune responses to M. tuberculosis involve
recognition of molecules on the surface of the bacteria
by receptors expressed on phagocytic cells. Variation in
surface ligands expressed by M. tuberculosis strains from
different phylogenetic lineages may cause differences in
immune recognition and disease. By labelling with different
fluorescent colours, we can follow multiple strains in mixed
infection experiments. Strains also differ in the way they
respond to the host. Using next-generation sequencing to
screen the entire transcriptome of M. tuberculosis, we have
identified a previously unknown repertoire of regulatory
RNA molecules that vary between strains.
Publications
Arnvig KB and Young DB (2009)
Identification of small RNAs in Mycobacterium tuberculosis.
Molecular Microbiology 73:397-408
Young DB, Gideon HP and Wilkinson RJ (2009)
Eliminating latent tuberculosis.
Trends in Microbiology 17:183-188
Labelling with red and green probes allows us
to compare the behaviour of different strains
of M. tuberculosis during infection of host
macrophages
54
Northern blot analysis shows differences in the
expression of a small regulatory RNA molecule
between different strains of M. tuberculosis
Young D, Stark J and Kirschner D (2008)
Systems biology of persistent infection: tuberculosis as a case
study.
Nature Reviews Microbiology 6:520-528
See references 7, 11, 224, 232, 234, 235 in the bibliography at the
back for publications from this group in 2009.
Microarray Laboratory
Molecular pathogenicity of mycobacteria
Lab members: Roger Buxton, Yvonne Braun, Debbie Hunt, Kathryn Lougheed, Luisa Mori, Nathan Sweeney, Vicky Spivey
Mycobacterium tuberculosis infects macrophage cells in
the lungs, the very cells that have evolved to destroy
most infecting pathogens. We are investigating the gene
regulatory systems M. tuberculosis uses to allow it to grow
in this hostile environment, particularly those controlled
by cyclic AMP and protein phosphorylation. This may give
clues to potential new drug targets.
Reversible protein phosphorylation is a major regulatory
mechanism, and in mycobacteria there is a large number of
serine-threonine protein kinases (STPKs). These enzymes
are attractive drug targets, as some have an essential role
in virulence, they have a low sequence identity with human
STPKs, and there is expertise available for the design of
specific inhibitors. In collaboration with Steve Smerdon
(Molecular Structure), we are investigating the mode of
action of one STPK, PknF, which has an ABC transporter
as a target that is essential for growth of M. tuberculosis in
mice. We are also carrying out drug screening for inhibitors
of another essential STPK, PknB, in collaboration with MRC
Technology. High throughput screening has also been used
to find anti-TB agents amongst known drugs.
Mycobacterium tuberculosis is a rod-shaped bacterium with a
complex cell wall containing very long and unique lipids. In this
transmission electron micrograph, most bacteria have been
sectioned transversely and so appear round
Publications
Stapleton M, Haq I, Hunt DM, Arnvig KB, Artymiuk PJ, Buxton RS and Green J (2010)
Mycobacterium tuberculosis cAMP receptor protein (Rv3676) differs from the Escherichia
coli paradigm in its cAMP binding and DNA binding properties and transcription
activation properties.
Journal of Biological Chemistry 285, 7016-7027
Lougheed KE, Taylor DL, Osborne SA, Bryans JS and Buxton RS (2009)
New anti-tuberculosis agents amongst known drugs.
Tuberculosis 89:364-370
Curry JM, Whalan R, Hunt DM, Gohil K, Strom M, Rickman L, Colston MJ, Smerdon SJ and
Buxton RS (2005)
An ABC transporter containing a forkhead-associated domain interacts with a serinethreonine protein kinase and is required for growth of Mycobacterium tuberculosis in mice.
Infection and Immunity 73:4471-7
Biolog Phenotype MicroarraysTM allow the simultaneous testing of nearly 2000
phenotypes. A redox dye is used to measure growth of bacteria in 96-well plates
containing a range of sole nutrient sources and stress agents
See references 127, 148, 232 in the bibliography at the back for publications from this group
in 2009.
55
Virology
WHO Collaborating Centre for
Reference and Research on Influenza
Director: John McCauley
Lab members: Rod Daniels, Yi Pu Lin, Vicky Gregory, John Xiang, Ting Hou, Lynn Whittaker, Nick Cattle, Johannes Kloess,
Chandrika Halai
The World Health Organisation (WHO) Influenza Centre
(WIC) at NIMR has been part of the WHO Global Influenza
Surveillance Network since it was established over 50 years
ago. The laboratory is now one of four Collaborating Centres
(the others are in Atlanta, Melbourne and Tokyo) that integrate
the surveillance of influenza around the world by some 120
National Influenza Centres (NICs).
With the emergence of the A/H1N1 2009 pandemic of
influenza, the role of the laboratory was to assist NICs in
countries around the world in their assessment of the local
situation. The WIC at NIMR has collaborated with the NICs
from over 60 countries in Europe, Africa, the Middle East and
Asia since the onset of the spread of the new virus. We were
able to confirm the first cases in many countries. Viruses have
been examined for antigenic, genetic and drug resistance
characteristics. In many cases, full genome sequences have
been determined. To date there has been little change in the
A/H1N1 2009 virus in terms of emergence of distinct genetic
and antigenic groups, and only sporadic instances of resistance
to anti-neuraminidase drugs have been detected as the virus
continues to evolve.
In addition to assessing the most appropriate virus for use as a
Pandemic Vaccine, the Collaborating Centres are responsible for
making twice yearly recommendations for the composition of
seasonal influenza vaccines. The recommendation for the vaccine
for the 2010 influenza season in the Southern Hemisphere and
for the Northern Hemisphere 2010-2011 was to include the
pandemic vaccine strain and change the H3N2 component to a
variant that was first detected at the beginning of 2009.
All the studies are carried out with the various NICs, the other
WHO Collaborating Centres, the UK Health Protection Agency
Centre for Infection (Colindale), members of the European
Community Network of Reference Laboratories for human
influenza and the Wellcome Trust Sanger Institute.
See references 27, 90 in the bibliography at the back for publications from this group in 2009.
56
The haemagglutinin based phylogenetic dendogram illustrates the relatively
low divergence of the A/H1N1 2009 pandemic virus since its emergence
Publications
Barr IG, McCauley J, Cox N, Daniels R, Engelhardt OG, Fukuda K, Grohmann G, Hay A, Kelso A, Klimov A,
Odagiri T, Smith D, Russell C, Tashiro M, Webby R, Wood J, Ye Z and Zhang W (2009)
Epidemiological, antigenic and genetic characteristics of seasonal influenza A(H1N1), A(H3N2) and B
influenza viruses: basis for the WHO recommendation on the composition of influenza vaccines for
use in the 2009-2010 Northern Hemisphere season.
Vaccine Epub ahead of print
Recommended composition of influenza virus vaccines for use in the 2010 southern hemisphere
influenza season.
http://www.who.int/csr/disease/influenza/recommendations2010south/en/index.html
Recommended composition of influenza virus vaccines for use in the 2010-2011 northern
hemisphere influenza season
http://www.who.int/csr/disease/influenza/recommendations2010_11north/en/index.html
Structural Biology
Mathematical Biology
Molecular Structure
Physical Biochemistry
Willie Taylor (Head of Division)
Richard Goldstein
Steve Gamblin (Joint Head of Division)
Steve Smerdon (Joint Head of Division)
Paul Driscoll
Annalisa Pastore
Andres Ramos
Katrin Rittinger
Ian Taylor
Justin Molloy (Head of Division)
Ed Hulme
John Offer
Peter Rosenthal
Claudia Veigel
Martin Webb
see also the following groups:
Mike Blackman (Infections and Immunity)
Tom Carter (Neurosciences)
Matthew Hannah (Neurosciences)
Jonathan Stoye (Infections and Immunity)
57
STRUCTURAL BIOLOGY
Molecular Structure
Paul Driscoll
Structural and functional analysis of signalling proteins
Lab members: Diego Esposito, Acely Garza-Garcia, Timothy Ragan, Andrew Sankar, Lily Nematollahi, Masooma Rasheed,
Simon Greenwood
Nuclear magnetic resonance (NMR) spectroscopy provides
a valuable means to probe the three dimensional structure,
dynamic characteristics and binding properties of biological
macromolecules. Our group employs state-of-the-art methods
in NMR to probe the nature of interactions between proteins
implicated in fundamental cellular and organismal processes.
These processes include the activation of death receptor
signalling cascades in apoptosis, limb regeneration in the adult
newt, the regulation of phospholipases by small G proteins, and
the underlying basis of antigen recognition in Hughes Syndrome.
We have recently investigated the 3D solution structure and
phylogeny of the protein Prod-1 which has been recognised as
an important marker of the positional identity of the blastema
that forms at an amputation site in the adult newt, a structure
that when transplanted gives rise to regeneration of the missing
limb parts. Our analysis indicates that, whilst this three-finger
superfamily member is superficially similar to well known
mammalian proteins, it is nevertheless restricted to salamanders.
This result may have important implications for realisation of the
promise of this classic example of regeneration for development
of medical applications in humans.
Ribbon and bundle representations of the 3D solution structure of Prod-1
Publications
Garza-Garcia A, Harris R, Esposito D, Gates PB and Driscoll PC (2009)
Solution structure and phylogenetics of Prod1, a member of the three-finger protein superfamily
implicated in salamander limb regeneration.
PLoS ONE 4:e7123
Garza-Garcia A, Esposito D, Rieping W, Harris R, Briggs C, Brown MH and Driscoll PC (2008)
Three-dimensional solution structure and conformational plasticity of the N-terminal scavenger
receptor cysteine-rich domain of human CD5.
Journal of Molecular Biology 378:129-144
Ferguson BJ, Esposito D, Jovanovic J, Sankar A, Driscoll PC and Mehmet H (2007)
Biophysical and cell-based evidence for differential interactions between the death domains of
CD95/Fas and FADD.
58
Phylogenetic tree analysis of three-finger protein sequence: Prod-1 homologues
cluster separately from the CD59 subgroup with which it had previously been
associated
STRUCTURAL BIOLOGY
Molecular Structure
Steve Gamblin EMBO member, FMedSci
Structural biology of influenza, energy metabolism and cancer
Lab members: Neil Justin,Valeria De Marco, Bing Xiao, Chun Jing, Richard Heath, Peter Saiu, Junfeng Liu, Peter Coombs, Sebastien Vachieri,
Elizabeth Underwood
We study the structure and function of molecules involved in
diseases 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 techniques, the data help us elucidate
the function of relevant proteins and provide information for
development of therapeutic approaches.
We have a long-term interest in how covalent modifications
of histones, that package DNA into chromatin, regulate
gene expression through epigenetic mechanisms. Polycomb
Repressive Complex 2 (PRC2) is essential for the maintenance
of repressive chromatin domains in early development, and its
overexpression is linked with a number of different cancers.
We have uncovered how the PRC2 complex is able to trimethylate K27 on H3 in the context of existing repressive methyl
marks on neighbouring chromatin, but not in the absence of
these marks. We have shown that the EED subunit of PRC2
specifically recognises H3K27Me3 and that this leads to activation
of the methyltransferase activity of the PRC2 complex. These
collaborative studies provide the first mechanistic insight into
the propagation of repressive chromatin domains, and may lead
to the identification of small molecule inhibitors that could be
tested for activity against certain cancers.
Schematic model of the propagation of repressive chromatin domains. PRC2
(shown as its component subunits EED, Ezh2, Suz12 and RbAp48) binds to
H3K27Me3 marks on pre-existing histones.
Publications
Margueron R, Justin N, Ohno K, Sharpe ML, Son J, Drury III WJ, Voigt P, Martin SR, Taylor WR, De Marco V,
Pirrotta V, Reinberg D and Gamblin SJ (2009)
Role of the polycomb protein EED in the propagation of repressive histone marks.
Nature 461:762-7
Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Skehel JJ, Martin SR, Hay AJ and Gamblin SJ (2008)
Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants.
Nature 453:1258-61
Structure of EED bound to a trimethylated H3K27Me3 peptide
(shown in stick representation)
Xiao B, Heath R, Saiu P, Leiper FC, Leone P, Jing C, Walker PA, Haire L, Eccleston JF, Davis CT, Martin SR,
Carling D and Gamblin SJ (2007)
Structural basis for AMP binding to mammalian AMP-activated protein kinase.
Nature 449:496-500
59
STRUCTURAL BIOLOGY
Richard Goldstein
Modelling of evolution
Lab members: Mario dos Reis Barros, Chrisantha Fernando, Kyriakos Kentzoglanakis, Seena Shah, Asif Tamuri
All life 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 the evolution of viruses such as influenza
in order to better understand the way they act now and how
they might change in the future. In particular, we have been
investigating how influenza is able to shift from one host to
another, as it did with such deadly consequences in 1918 and as
it is doing now. We are modelling the evolution of chemotaxis,
the process that allows bacteria to find nutrients. Insights into
the evolutionary history of the chemotaxis control network
can give us insight into how its form reflects the constraints of
their environment. We also are modelling the evolution of our
ability to understand language, to put constraints on the way in
which the brain is able to perform this task.
Phylogenetic tree of influenza, showing the division into the human, ‘classical’
swine, and bird lineages. Hosts are colour-coded, red for human, blue for
swine, black for avian. Notice the few cases of human influenza in the middle
of the bird lineage, representing H5N1 ‘Bird-flu’.
Publications
dos Reis M, Hay AJ and Goldstein RA (2009)
Using non-homogeneous models of nucleotide substitution to identify host shift events: application to the
origin of the 1918 ‘Spanish’ influenza pandemic virus.
Tamuri AU, dos Reis M, Hay AJ and Goldstein RA (2009)
Identifying changes in selective constraints: host shifts in influenza.
PLoS Computational Biology 5:e1000564
Goldstein RA and Soyer OS (2008)
Evolution of taxis responses in virtual bacteria: non-adaptive dynamics.
60
Evolution of chemotaxis in virtual bacteria inhabiting a virtual world.
Bacteria quickly develop a biochemical network allowing them to explore
the space and exploit the found food. Inserts show the time-averaged
distribution of the bacteria. At each generation, the bacteria start at a
location towards the bottom-left of the space. The food is in a Gaussian
distribution at the centre of the space.
STRUCTURAL BIOLOGY
Ed Hulme
Structure and function of G protein-coupled receptors
Lab members: Carol Curtis, Robert Kaye
Living cells are delimited by a membrane which isolates their
internal machinery from the external world. However, cells
such as the neurons which form the information-transduction
networks of the brain must still be able to respond to
incoming chemical signals. The 7-transmembrane helix G
protein-coupled receptors (GPCRs) are a superfamily of
genetically-encoded nanomachines that have evolved to
enable this. Since GPCRs are the targets of about 40% of
clinically prescribed drugs, a detailed understanding of their
structures and molecular mechanisms of action is essential for
the modern program of rational drug development.
Muscarinic acetylcholine receptors (mAChRs) regulate the
activity of over 50% of the nerve cells in the brain. Recently,
we have used targeted mutations of the M1 mAChR, a
major mediator of cortical attention mechanisms, to show
how a binding site for highly-selective activating agents may
be created by a novel conformational isomerisation of a
tryptophan side-chain. Such agonist ligands are targeted at
the cognitive defects in Alzheimer’s and schizophrenia. We are
making stable ligand complexes of M1 mAChRs, using both
pharmacological and mutational methods, working towards an
atomic resolution structure by X-ray crystallography. This will
provide a starting point for quantitative molecular dynamics
calculations of drug-receptor interactions.
Conformational isomerisation of the side-chain of tryptophan 101 (purple)
creates abinding pocket for 77-LH-28-1: (a) trans (b) gauche
Publications
Lebon G, Langmead CJ, Tehan BG and Hulme EC (2009)
Mutagenic mapping suggests a novel binding mode for selective agonists of M1 muscarinic acetylcholine
receptors.
Molecular Pharmacology 75:331-341
(a) Chemical structure of the selective M1 agonist 77-LH-28-1
(b) Interacting amino acids studied by mutation of the M1 mAChR
Goodwin JA, Hulme EC, Langmead CJ and Tehan BG (2007)
Roof and floor of the muscarinic binding pocket:Variations in the binding modes of orthosteric ligands.
61
STRUCTURAL BIOLOGY
Justin Molloy
Single molecule studies of cell motility and cell signalling
Lab members : Suleman Bawumia, Rachel Farrow, Stephen Martin, Gregory Mashanov, Martyn Stopps
The principal goal of the lab is to understand the molecular
mechanism of force production by acto-myosin and how
proteins and organelles move around within living cells. Laserbased optical methods like optical tweezers and total internal
reflection fluorescence microscopy allow us to observe,
track and manipulate individual molecules either in isolated
preparations or within living cells.
Molecular motors convert chemical energy into mechanical
work and power processes like muscle contraction, cell
migration and DNA processing; they are critical to the healthy
function of our cells. We are interested in diverse aspects of
human health, including how the malarial parasite gains entry
into human blood cells, the mechanism of human hearing,
and how the two strands of DNA are separated and copied.
Our laser-based tools enable us to visualise and manipulate
individual molecules so that we can understand molecular
mechanisms with unprecedented precision. Recent work has
shown how actin filaments become aligned by myosin motors
in migrating cells, and dual-colour fluorescence imaging has
allowed us to image individual G-protein coupled receptors at
the cell membrane.
Optical tweezers (left) and Total Internal Reflection Fluorescence Microscopy
(right) enable individual molecules to be manipulated and imaged.
Publications
Butt T, Mufti T, Humayun A, Rosenthal PB, Khan S, Khan S and Molloy JE (2010)
Myosin motors drive long-range alignment of actin filaments.
Hern JA, Baig AH, Mashanov GI, Birdsall B, Corrie JET, Lazareno S, Molloy JE and Birdsall NJM (2010)
Formation and dissociation of M1 muscarinic receptor dimers seen by total internal reflection
fluorescence imaging of single molecules.
Proceedings of the National Academy of Sciences of the United States of America Epub ahead of print
Actin filaments become aligned by myosin motors due to lateral mechanical
interactions between neighbouring filaments. These weak mechanical forces
might be responsible for the coordinated response of a cell as it migrates
through tissue.
62
Baboolal TG, Sakamoto T, Forgacs E, White HD, Jackson SM, Takagi Y, Farrow RE, Molloy JE, Knight PJ, Sellers
JR and Peckham M (2009)
The SAH domain extends the functional length of the myosin lever.
STRUCTURAL BIOLOGY
Synthetic Protein Laboratory
John Offer
Acyl transfer for chemical biology and synthesis.
Lab members: Lotta Holm, George Papageorgiou
Post translationally-modified proteins can now be synthesised with a combination
of ligation and optimised peptide synthesis, giving atom by atom control over the
product. Chemical ligation can be combined with biological expression systems,
enabling the semi-synthesis of proteins containing non-natural amino acids with a
broad range of applications. The focus of this laboratory is to use emerging ligation
techniques to build biological macromolecules. However, the generality of chemical
ligation is limited to a handful of favorable ligation sites, and so in our lab novel
auxiliary approaches have been developed to universalise it. We are aso applying
chemical ligation to the synthesis of chemically defined peptide-oligosaccharide
glycoconjugates as HIV vaccines.
Auxiliary–assisted ligation chemistry can chemoselectively join a wide range of
peptides together without needing elaborate protecting group strategies. We are
applying it to the synthesis of small cyclic peptides, attractive lead compounds for
screening and the development of orally available therapeutics.
Chemical ligation methods for the synthesis of proteins
and post-translationally modified proteins
Publications
Burlina F, Dixson DD, Doyle RP, Chassaing G, Boddy CN, Dawson P
and Offer J (2008)
Orthogonal ligation: a three piece assembly of a PNA-peptidePNA conjugate.
Chemical Communications 2785-2787
Single amino acid incorporation using orthogonal ligation
Scanlan CN, Offer J, Zitzmann N and Dwek RA (2007)
Exploiting the defensive sugars of HIV-1 for drug and vaccine
design.
Nature 446:1038-1045
63
STRUCTURAL BIOLOGY
STRUCTURAL BIOLOGY
Molecular
Structure
Synthetic Protein
Laboratory
Annalisa Pastore EMBO member
Understanding the molecular bases of neurodegeneration
Lab members: Laura Masino, Cesira de Chiara, Salvatore Adinolfi, John McCormick, Filippo Prischi, Miquel Adrover, Kris Pauwels,
Raj Menon , Veronica Esposito, Ljiljana Sjekloca
Our main line of research concerns the study of proteins involved in
neurodegenerative processes of the central nervous system, with the ultimate aim of
understanding the causes of pathology and developing new theurapeutic strategies.
We are addressing the problem by studying the function/structure relationship of the
non-pathologic forms of the proteins involved, and by investigating the mechanisms
which lead to neurodegeneration, such as protein misfolding, aggregation, and
misfunctioning. The families of diseases we focus on involve dominant and recessive
ataxias, such as Joseph-Machado disease and Friedreich’s ataxia. We are also
investigating the bases of intelligence through studying what leads to Fragile X mental
retardation syndrome. To carry out our studies, we use biophysical, biochemical, and
bioinformatics techniques, which range from different spectroscopies, calorimetry,
molecular dymamics and comparative modelling. We use advanced Nuclear Magnetic
Resonance techniques to determine the structure and dynamics of the protein we
are interested in.
Publications
Díaz-Moreno I, Hollingworth D, Frenkiel TA, Kelly G, Martin S, Howell
S, García-Mayoral M, Gherzi R, Briata P and Ramos A (2009)
Phosphorylation-mediated unfolding of a KH domain regulates
KSRP localization via 14-3-3 binding.
Nature Structural & Molecular Biology 16:238-246
de Chiara, C., Menon, R. P., Strom, M., Gibson, T. J. & Pastore, A.
Phosphorylation of s776 and 14-3-3 binding modulate ataxin-1
interaction with splicing factors.
PLoS ONE, 2009, 4(12): e8372.
See references 2, 54, 56, 143, 153, 160, 179, 192, 237 in the
64
The structure of frataxin and a model of its cellular role. Frataxin is an iron dependent inhibitor of
the enzymatic activity of the desulphurase IscS, the protein responsible for formation of iron sulfur
cluster formation on the transient acceptor IscU.
STRUCTURAL BIOLOGY
Molecular Structure
Andres Ramos
Molecular recognition in post-transcriptional regulation
Lab members: Adela Candel, Cyprian Cukier, David Hollingworth, Silvia Kralovicova, Giuseppe Nicastro, Sunil Prasannan
Post-transcriptional regulation plays a central role in cell fate and
is based on the synergy existing between the different steps of
mRNA metabolism (capping, polyadenylation, splicing, nuclear
export, degradation and localisation) and of translation. This synergy
is maintained by a network of reversible protein-protein and
protein-RNA interactions. Malfunction of the post-transcriptional
regulatory network is responsible for pathologies ranging from
cancer to auto-immune and neurodegenerative diseases.
The rules of RNA recognition by multi-domain RNA binding
proteins that function at the core of post-transcriptional regulation
are still largely unexplained. We use a range of techniques that
enable us to relate functional and structural information in premiRNA processing, pre-mRNA processing, mRNA degradation
and mRNA localisation. In this way, we are constructing a general
biophysical framework for the study of inter-molecular recognition
in protein-RNA regulatory complexes.
15N-1H correlation NMR spectra of KSRP KH3, KH23 and KH34 when bound to
Let-7a miRNA TL.
Publications
Díaz-Moreno I, Hollingworth D, Frenkiel TA, Kelly G, Martin S, Howell S, García-Mayoral M, Gherzi R, Briata P and
Ramos A (2009)
Phosphorylation-mediated unfolding of a KH domain regulates KSRP localization via 14-3-3 binding.
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
3D representation of a HNCACB NMR spectrum, and
structure of KSRP KH2-KH3 construct.
65
STRUCTURAL BIOLOGY
Molecular Structure
Katrin Rittinger
Structural biology of signalling networks that regulate innate and adaptive immunity
Lab memebers: Veronica Fridh, Frank Ivins, Aylin Morris-Davies, Jonathan Rapley, Kovilen Sawmynaden, Ben Stieglitz, Edmond Wong
The innate immune response constitutes the first line
of defence against invading micro-organisms. Pathogen
recognition is mediated by specific pattern recognition
receptors (PRRs) that activate diverse signalling pathways
and initiate a pro-inflammatory response. These signalling
events need to be tightly controlled as misregulation can lead
to chronic inflammation and auto-immune disease. Innate
immune responses can also trigger adaptive immunity and the
two systems are linked through complex signalling networks.
Our research is focused on characterisation of the structural
and mechanistic properties of protein complexes that regulate
signalling in innate and adaptive immunity. We are currently
studying members of the NLR (NOD-like receptor) family
of intracellular pattern recognition receptors. NLRs respond
to the presence of bacteria and danger signals by triggering
cytokine production and the activation of MAP kinases and
the transcription factor NF-kB. In addition, we are examining
the mechanism of activation of the IKK complex, a key
regulator of NF-kB. Furthermore, we are investigating the
role and regulation of Vav1, an activator of small Rho-family
GTPases, in T cell development and signalling.
Binding of di-ubiquitin to NEMO monitored by ITC and AUC
Publications
Saveliev A, Vanes L, Ksionda O, Rapley J, Smerdon SJ, Rittinger K, Tybulewicz VL
Function of the nucleotide exchange activity of vav1 in T cell development and activation.
Ivins FJ, Montgomery MG, Smith SJ, Morris-Davies AC, Taylor IA and Rittinger K (2009)
NEMO oligomerisation and its ubiquitin-binding properties.
Biochemical Journal 421:243-251
Rapley J, Tybulewicz VLJ and Rittinger K (2008)
Crucial structural role for the PH and C1 domains of the Vav1 exchange factor.
EMBO Reports 9:655-661
See references 106, 169, 173, 185, 188 in the bibliography at the back for publications from this group in
66
Signalling through NLRs
STRUCTURAL BIOLOGY
Peter Rosenthal
Cryomicroscopy of proteins, viruses, and cells
Lab members: Lesley Calder, Saira Hussain, Rishi Matadeen, Kasim Sader, David Wright, 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 virus infection.
We apply electron cryomicroscopy
and image analysis to study the
structure of purified protein complexes
in frozen solution. We use 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.
A major focus of the lab is the
ultrastructure of viruses. We are
interested in understanding how
lipid-enveloped viruses such as
influenza and retroviruses enter cells
by membrane fusion and how new
particles are assembled and released
by budding through host membranes.
As part of our studies of organelle
formation and transformation, we build
structural models for Weibel-Palade
bodies, which are storage granules for
the adhesive blood glycoprotein von
Willebrand factor. We are working to
improve experimental methods for high
resolution imaging of proteins and to
develop new computational procedures
for image analysis. We are also interested
in designing and imaging nanoscale
assemblies with novel functions.
Structural model for a Weibel-Palade
body containing von Willebrand factor
tubules.
Publications
Butt T, Mufti T, Humayun A, Rosenthal PB, Khan S, Khan S and Molloy
JE (2010)
Myosin motors drive long-range alignment of actin filaments.
Map of the pyruvate dehydrogenase E2
complex by cryomicroscopy and image
analysis.
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 cryoEM of vitrified endothelial cells.
America 106:17407-17412
67
STRUCTURAL BIOLOGY
Molecular Structure
Steve Smerdon EMBO member
Structural biology of phosphorylation-dependent signalling in the cell-cycle and the
response to DNA damage
Lab members: Julie Clapperton, Richard Li, Simon Pennell, Amy Cherry, Otto Kyrieleis, Lasse Stach, Mohamed Ismail, Jan Lloyd, Oliver De peyer
The dynamic nature of signalling processes in cells requires
them to be rapidly reversible, and this is generally achieved
through protein phosphorylation by kinases. There are more
than 500 distinct kinases encoded in the human genome and
misregulation of phosphorylation is a primary cause of many
cancers and other diseases. The response to DNA damage
is mediated by a phosphorylation cascade that originates
at the site of the lesion and is transduced to a variety of
effector molecules and complexes. We are studying a group
of proteins that may function as phosphorylation-dependent
adaptors or scaffolding molecules in pathways that regulate
the response to DNA damage.
Our studies have revealed the structures of 14-3-3,
Forkhead-associated, Brca1-C-terminus and Polo-box domain
complexes and have found a remarkable diversity in binding
modes. These observations have led to an additional interest
in the regulation of several kinases that play crucial roles in
the DNA damage response and its integration into the cell
cycle. By understanding the molecular basis of specificity
within such an extensive web of regulatory interactions, we
aim to determine why these processes run amok, and how
drugs might be designed to combat the devastating effects
associated with cancer and other diseases.
The FHA-domain protein Rv1827 regulates three enzymes of the TCA
cycle in Mycobacterium tuberculosis to control glutamate flux and nitrogen
assimilation.
Publications
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
Nott TJ, Kelly G, Stach L, Li J, Westcott S, Patel D, Hunt DM, Howell S, Buxton RS, O’Hare HM and Smerdon
SJ (2009)
An intramolecular switch regulates phosphoindependent FHA domain interactions in Mycobacterium
tuberculosis.
Stucki M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ and Jackson SP (2005)
MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA doublestrand breaks. (See also erratum:Vol 124, pg 1299, 2006).
Cell 123:1213-26
68
The structure of Nijmegen-breakage syndrome protein 1 (Nbs1) shows
how an unusual molecular architecture underpins its function through
phosphorylation-dependent interactions.The green nuclear speckles show the
locations of individual double-stranded DNA breaks that are under repair.
STRUCTURAL BIOLOGY
Molecular Structure
Ian Taylor
Macromolecular assemblies
Lab members: Christina Pancevac, David Goldstone, Joe Hedden, Laurence Arnold, Valerie Ennis-Adeniran
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 and the investigation
of the retroviral capsid together with assemblies that mediate the retroviral
restriction in host cells.
Structures of the transcriptional 3’-end processing factor, Rna15, bound to different ribonucleotides; Left,
guanosine nucleotide located in binding site. Right, uracil bound in binding site.
Publications
Pancevac C, Goldstone DC, Ramos A and Taylor IA (2010)
Structure of the Rna15 RRM-RNA complex reveals the molecular basis of GU specificity in transcriptional 3’-end processing factors.
Nucleic Acids Research Epub ahead of print
Mortuza GB, Goldstone DC, Pashley C, Haire LF, Palmarini M, Taylor WR, Stoye JP and Taylor IA (2009)
Structure of the capsid amino terminal domain from the Betaretrovirus, Jaagsiekte sheep retrovirus.
Mapping the residues that determine MLV
tropism and restriction factor susceptibility
onto the viral capsid. Residues that are the
major determinants of N- and B-tropism are
highlighted in blue. Other residues that result in
NB and other minor tropisms are highlighted
in red.
Mortuza GB, Dodding MP, Goldstone DC, Haire LF, Stoye JP and Taylor IA (2008)
Structure of B-MLV capsid amino-terminal domain reveals key features of viral tropism, gag assembly and core formation.
69
STRUCTURAL BIOLOGY
Willie Taylor
Protein structure analysis and design
Lab members: Viji Chelliah, James MacDonald, Katarzyna Maksimiak, Michael Sadowski, Zoe Katsimitsoulia
A view of protein fold space showing the location of “dark” folds (white) between known fold
families (red, green) with example structures marked by stars.
Publications
Sadowski MI and Taylor WR (2010)
Protein structures, folds and fold spaces.
Journal of Physics-Condensed Matter 22:033103
Macdonald JT, Maksimiak K, Sadowski MI and Taylor WR (2009)
De novo backbone scaffolds for protein design.
Proteins 78:1311-25
Taylor WR, Chelliah V, Hollup SM, MacDonald JT and Jonassen I
(2009)
Probing the “dark matter” of protein fold space.
Structure 17:1244-52
See references 131, 139, 208 in the bibliography at the back for
70
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 to function.
Such studies can help us to understand the workings of normal proteins and also
how abnormal states, such as mutant proteins, can lead to disease. Computer
methods that we have developed have been used to construct models for all possible
protein folds and we find that only 10% of these model structures correspond to
known folds. The remainder, which we call ‘dark’ folds, appear quite normal under all
the computer tests we have applied. We are currently using some of these folds as
frameworks for design and synthesis.
STRUCTURAL BIOLOGY
Claudia Veigel
Single molecule mechanics of motor proteins
Lab members: Sarah Adio, Frederic Eghiaian, Iwan Schaap, Stephan Schmitz
We are using single molecule techniques to study molecular
mechanisms underlying cellular motility. We focus on the basic
mechanisms of chemo-mechanical energy transduction and
regulation of myosin motors, using mechanical and imaging
techniques including optical tweezers, fluorescence and atomic
force microscopy. We are also applying these techniques to
study membrane fusion.
Our principal aim is to study mechanisms of force generation
and motility from the molecular to the cellular level. At
the molecular level we aim to understand the details of
conformational changes, timing and energetics of the forceproducing process. To achieve this we need to precisely identify
and correlate structural, biochemical and mechanical states
of these nanomachines. The mechanical interaction between
motors, interactions with regulatory agents in local complexes,
or in more extended networks, introduces complexity that
needs to be investigated and modelled.
We also study the invasion of red blood cells by malaria
parasites. This process is driven by myosin class 14 molecules,
interacting with a network of actin filaments and other
structural and regulatory components inside the parasite. We
are investigating the structural and dynamic characteristics of
malarial actin and its interactions with myosin in vitro.
Mechanics of cellular motors are characterised
using optical tweezers.
Publications
Veigel C and Schmidt CF (2009)
Friction in motor proteins.
Science 325:826-7
Albet-Torres N, Bloemink MJ, Barman T, Candau R, Frolander K, Geeves
MA, Golker K, Herrmann C, Lionne C, Piperio C, Schmitz S, Veigel C and
Månsson A (2009)
Drug effect unveils inter-head cooperativity and strain-dependent ADP
release in fast skeletal actomyosin.
Journal of Biological Chemistry 284 22926-22937
Sellers JR and Veigel C (2006)
Walking with myosin V.
Current Opinion in Cell Biology 18:68-73
Parasites and viruses are studied by
atomic force microscopy (AFM).
Single molecules can be localised in vitro and
in vivo using fluorescence microscopy.
71
STRUCTURAL BIOLOGY
Martin Webb
The molecular mechanisms of motor proteins
Lab members: Claudia Arbore, Lori Callum, Liisa Chisty, Colin Davis, Simone Kunzelmann, Gordon Reid, Lesley Southerden, Chris Toseland
ParM scaffold for the ADP biosensor:
structure showing position of mutations
introduced and conformation change on ADP
binding
A major way of achieving movement within the cell is by motor proteins that move
along tracks that could be filaments of proteins or nucleic acid. In particular, we are
interested in the way that helicases move along double-stranded DNA, separating
the two strands, which is essential for DNA replication and repair. We are developing
new optical approaches to study this process. Some of our methods, such as to
detect inorganic phosphate, are being used widely in research laboratories and in
development of drug screening assays.
In order to further understand how helicases work as part of a system, we are
investigating the replication of certain plasmids that contain antibiotic resistance
and are readily transferred between bacteria. The essential parts of this system are
plasmids containing a specific double-stranded origin of replication, a replication
initiation factor, a helicase and polymerase. We are currently building up this system in
vitro to study the role and mechanism of each component.
We have recently developed a novel biosensor for ADP, based on a protein, ParM,
that binds ADP specifically and has been labeled with either rhodamine or coumarin
fluorophore. This can measure micromolar concentrations of ADP in real time, in the
presence of high concentrations of ATP, so is suitable for real-time assays of kinases
and ATPases.
Fluorescence increase on ADP binding to the
biosensor, ParM labeled with a coumarin
Publications
Kunzelmann S and Webb MR (2009)
A biosensor for fluorescent determination of ADP with high time
resolution.
Slatter AF, Thomas CD and Webb MR (2009)
PcrA helicase tightly couples ATP hydrolysis to unwinding doublestranded DNA, modulated by the initiator protein for plasmid
replication, RepD.
Biochemistry 48:6326-6334
Sakamoto T, Webb MR, Forgacs E, White HD and Sellers JR (2008)
Direct observation of the mechanochemical coupling in myosin Va
during processive movement.
Nature 455:128-32
72
Neurosciences
Developmental Neurobiology
David Wilkinson (Head of Division)
Siew-Lan Ang
James Briscoe
Alex Gould
Nobue Itasaki
Jean-Paul Vincent
Molecular Neurobiology
Vassilis Pachnis (Head of Division up to Nov 2009)
François Guillemot (Head of Division from Dec 2009)
Iris Salecker
Molecular Neuroendocrinology
Iain Robinson (Head of Division up to Sept 2009)
Tom Carter (Acting Head of Division from Oct 2009)
Matthew Hannah
Paul Le Tissier
Neurophysiology
Troy Margrie (Acting Head of Division)
see also the following groups::
Ed Hulme (Structural Biology)
Robin Lovell-Badge (Genetics and Development)
Annalisa Pastore (Structural Biology)
73
NEUROSCIENCES
Siew-Lan Ang
Neuronal subtype specification in the midbrain and hypothalamus
Lab members: Neal Anthwal, Suzanne Claxton, Maria Flavia Guinazu, Melanie Kalaitzidou, Nicolaos Mathioudakis,
Emmanouil Metzakopian, Wei Lin, Martin Levesque, Gautam Rishi and Simon Stott
The mammalian midbrain and hypothalamus contain many types of
neurons that regulate voluntary movement and energy homeostasis,
respectively. How the multitude of cell types in these brain regions
is generated and their identity specified remains a central question
in developmental neurobiology. We study how neural progenitors
in the brain give rise to midbrain dopaminergic (mDA) neurons and
hypothalamic neurons that regulate food intake. Our findings have
direct medical relevance, since loss of mDA neurons is correlated with
Parkinson’s Disease, and dysfunction of feeding circuits in the brain can
lead to obesity in humans.
We use mouse embryos and in vitro differentiation of mouse embryonic
stem cells to identify genes that regulate the specification, differentiation,
and migration of mDA neurons and of hypothalamic arcuate proopiomelanocortin and neuropeptide Y neurons. A combination
of embryological, genetic, molecular and genomic approaches are
employed, including genetic fate mapping studies, null and conditional
mutant mice, brain slice culture, time lapse imaging, biochemical and
transcriptome analyses. These studies will provide insights into how
embryonic gene expression leads to mature neuronal phenotypes.
Midbrain dopaminergic neurons generated by differentiation of mouse embryo
stem cells
Publications
Lin W, Metzakopian E, Mavromatakis YE, Gao N, Balaskas N, Sasaki H, Briscoe J, Whitsett JA, Goulding M, Kaestner KH
and Ang SL (2009)
Foxa1 and Foxa2 function both upstream of and cooperatively with Lmx1a and Lmx1b in a feedforward loop
promoting mesodiencephalic dopaminergic neuron development.
Developmental Biology 333:386-396
Ferri ALM, Lin W, Mavromatakis YE, Wang JC, Sasaki H, Whitsett JA and Ang S-L (2007)
Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent
manner.
Development 134:2761-2769
Optical projection tomography of a E175 Pitx3tauLacZ/+
mouse brain
74
Ang SL (2006)
Transcriptional control of midbrain dopaminergic neuron development.
NEUROSCIENCES
James Briscoe EMBO member
Pattern formation in the vertebrate nervous system
Lab members: Nikos Balaskas, Natascha Bushati, Rachel Chung, John Jacob, Anna Kicheva, Eva Kutejova, Victoria Lawson,
Steven Moore, Ana Ribeiro, Vanessa Ribes, Noriaki Sasai, Samuel Tozer
A remarkable feature of embryo development is the reliable and
accurate pattern in which cell types arise. This is particularly true in
the nervous system where the generation of many different types
of neurons in a precise organisation is the first step in the assembly
of neuronal circuits. Our studies focus on the molecular and cellular
mechanisms that produce and organise neuronal cell types in the
spinal cord.
A central interest of the lab is the secreted molecule Sonic
Hedgehog (Shh), which forms a gradient that controls the pattern
of cellular differentiation in the ventral neural tube. Using a range
of molecular, imaging and modelling approaches in mouse, chick
and zebrafish embryos we are examining how graded Shh signalling
is perceived and interpreted by cells to regulate transcriptional
responses and cell behaviour. This system provides insight into the
mechanisms and strategies of pattern formation that are relevant to
many developing tissues. In addition, understanding the process of
normal neural development will shed light on conditions in which the
nervous system is diseased or damaged.
Publications
Jacob J, Storm R, Castro DS, Milton C, Pla P,
Guillemot F, Birchmeier C and Briscoe J (2009)
Insm1 (IA-1) is an essential component
of the regulatory network that specifies
monoaminergic neuronal phenotypes in the
vertebrate hindbrain.
Kutejova E, Briscoe J and Kicheva A (2009)
Temporal dynamics of patterning by morphogen
gradients.
Current Opinion in Genetics & Development
19:315-322
Dessaud E, Yang LL, Hill K, Cox B, Ulloa F, Ribeiro
A, Mynett A, Novitch BG and Briscoe J (2007)
Interpretation of the sonic hedgehog
morphogen gradient by a temporal adaptation
mechanism.
Nature 450:717-20
A gradient of Shh (green; inset graph) controls the expression of
transcription factors (red, orange, blue) in neural progenitors
Serotonergic neurons
in the hindbrain of an
embryonic mouse
See references 26, 35, 66, 80, 107, 118, 123, 166 in
the bibliography at the back for publications from
this group in 2009.
75
NEUROSCIENCES
Tom Carter
Secretory organelle formation, trafficking and exocytosis
Lab members: Nikolai Kiskin, Nicola Hellen, Laura Knipe, Emma Cookson, Jennifer Frampton
To survive and function correctly, cells must sense and respond to
their environment. This is largely achieved through the cell surface
expression of integral membrane proteins (e.g. hormone receptors)
and the secretion of soluble proteins to the external environment
(e.g. hormones, transmitters, morphogens). The correct delivery of
virtually all such proteins to the cell surface or extracellular space
involves a complex intracellular machine collectively called the
secretory pathway. We study the secretory pathway using molecular,
biochemical and live cell optical imaging techniques to analyse the
formation, trafficking and exocytosis of secretory organelles, which
are the containers that store and ultimately deliver proteins to the
cell surface and extracellular milieu. We use endothelial cells (ECs)
and the Weibel-Palade body (WPB), as our model system.
In collaborative studies, high resolution cryo-EM tomographic images
of individual WPBs in intact vitrified ECs have led to the elucidation
of the three dimensional structure and packaging of the coagulation
factor VWF, and have begun to reveal structural transformations in
VWF tubules during WPB exocytosis.
Human endothelial cell stained for the coagulation factor Von Willebrand factor (VWF).The rod shaped structures are Weibel Palade bodies, the storage
organelle for VWF. Images courtesy of Lindsay Hewlett and Matthew Hannah
Publications
Babich V, Knipe L, Hewlett L, Meli A, Dempster J, Hannah MJ and Carter T (2009)
Differential effect of extracellular acidosis on the release and dispersal of soluble and membrane
proteins secreted from the Weibel-Palade body.
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
76
Upper panel: images from time lapse movie of a fluorescently labeled WPB during
hormone stimulated exocytosis. Lower panel: one section from tomogram of a
marrow shaped WPB showing a thin tube like extension at one end projecting to
the plasma membrane (arrow).
NEUROSCIENCES
Alex Gould EMBO member
Regulation of growth and metabolism
Lab members: Andrew Bailey, Einat Cinnamon, Louise Cheng, Rami Makki, Panayotis Pachnis, Fabrice Prin, Patricia Serpente,
Rita Sousa-Nunes, Irina Stefana, Linda Yee
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,
obesity and diabetes.
Our current work aims to understand how sub-optimal
nutrition during embryonic and foetal growth can lead to
aberrant metabolism and insulin-resistance later on in adult life.
Much of our research in this area uses the fruit fly Drosophila,
a model organism that shares many genes with mammals. We
recently found that restricting nutrient intake during Drosophila
development reduces growth and insulin signalling in certain
organs, such as the brain, to a much lesser extent than in others.
We have now identified several conserved genes regulating this
selective sparing process and are currently examining whether
they play a similar role in mammals.
A Drosophila neural stem cell (NB) divides to generate multiple neurons/glia
(progeny) during development. Some of the genes expressed during this process
are indicated. Data from C. Maurange et al., 2008.
Publications
Maurange C, Cheng L and Gould AP (2008)
Temporal transcription factors and their targets schedule the end
of neural proliferation in Drosophila.
Cell 133:891-902
Miguel-Aliaga I, Thor S and Gould AP (2008)
Postmitotic specification of Drosophila insulinergic neurons from
pioneer neurons.
PLoS Biology 6:e58
The head of a fruit fly in cross section, showing the brain (blue), compound eyes (red) and adipose
tissue (green). Image by A. Bailey
Gutierrez E, Wiggins D, Fielding B and Gould AP (2007)
Specialized hepatocyte-like cells regulate Drosophila
metabolism.
Nature 445:275-280
lipid
77
NEUROSCIENCES
François Guillemot EMBO member, FMedSci
Cell fate specification in the mammalian brain
Lab members: Roberta Azzarelli, Diogo Castro, Daniela Drechsel, Laura Galinanes-Garcia, Matilda Haas, Barbara Hammerle, Julian
Heng, Christopher Hindley, Charles Hunt
Stem cells in the brain generate an amazingly diverse array of
neurons and glial cells during embryonic development, and they
continue to produce neurons in a few discrete brain locations
during adulthood. We study the genetic programmes that
control the differentiation of these neural stem cells into diverse
types of neurons, focusing on the generation of neurons of the
telencephalon, which are lost in neurodegenerative diseases such
as Alzheimer’s disease and Huntington’s disease.
We use a combination of genomic techniques, such as transcript
profiling, chromatin immunoprecipitation coupled to high
throughput sequencing and bioinformatics, to decipher the gene
regulatory networks that control the differentiation of neural
stem cells into neurons and glia. We then use functional assays
and imaging techniques to identify the genetic pathways that
control defined steps in neurogenesis, including the proliferation
of progenitor cells and the migration of new neurons, and to
determine how these pathways differ for the generation of
different types of neurons. By gaining insight into mechanisms
driving the differentiation of stem cells into specific types of
neurons, we hope to help devise strategies to replace lost cells in
diseased brains.
Migrating neurons in the cerebral cortex of a mouse embryo, labelled
by in utero electroporation of Green Fluorescent Protein
Publications
Gohlke JM, Armant O, Parham FM, Smith MV, Zimmer C, Castro DS, Nguyen L, Parker JS, Gradwohl G,
Portier CJ and Guillemot F (2008)
Characterization of the proneural gene regulatory network during mouse telencephalon
development.
BMC Biology 6:15
Heng JI-T, Nguyen L, Castro DS, Zimmer C, Wildner H, Armant O, Skowronska-Krawczyk D, Bedogni F,
Matter J-M, Hevner R and Guillemot F (2008)
Neurogenin 2 controls cortical neuron migration through regulation of Rnd2.
Nature 455:114-8
Guillemot F (2007)
Spatial and temporal specification of neural fates by transcription factor codes.
See references 25, 85, 93, 107, 147, 150, 158, 172, 194, 220, 228, 238 in the bibliography at the back
for publications from this group in 2009.
78
Gene regulatory network for dorsal and ventral telencephalon
development, based on transcript profiling datasets, evolutionary conserved
transcription factor binding sites data and prior literature- based knowledge
NEUROSCIENCES
Matthew Hannah
Secretory vesicle formation in human endothelial cells
Lab members: Lindsay Hewlett, Ruben Bierings, Robert Rowlands, Melanie Scarisbrick,
Secretory vesicles are microscopic, membrane-bound
compartments found inside cells that are essential for
communication between cells and their environment. They are
used to transport soluble biological signalling molecules such as
enzymes, hormones or neurotransmitters out of the cell and they
also deliver membrane proteins such as receptors or transporters
to the cell surface. We study the formation of secretory vesicles in
human endothelial cells grown in culture, focusing mostly on the
Weibel-Palade body (WPB) a distinctive endothelial-cell specific
secretory vesicle, responsible for the storage and stimulationdependent release of von Willebrand factor (VWF) a protein
involved in blood clotting. Analysis of this process will increase
our understanding of cardiovascular biology and cellular secretory
processes in general.
We have recently carried out a kinetic analysis of the biosynthesis,
storage and secretion of VWF in our cells using a metabolic
labelling approach. Contrary to previously published work,
we found that VWF was very efficiently sorted into regulated
secretory vesicles, but these were not efficiently stored due to
spontaneous, non-stimulated secretion.
Publications
Giblin JP, Hewlett LJ and Hannah MJ (2008)
Basal secretion of von Willebrand factor from human endothelial cells.
Blood 112:957-964
Hannah MJ, Skehel P, Erent M, Knipe L, Ogden D and Carter T (2005)
Differential kinetics of cell surface loss of von Willebrand factor and its propolypeptide after
secretion from Weibel-Palade bodies in living human endothelial cells.
Weibel-Palade bodies and Golgi apparatus visualised in a cultured human
endothelial cell
79
NEUROSCIENCES
Nobue Itasaki
Wnt signalling in vertebrate embryogenesis
Lab members: Katherine Lintern, Sara Howard, Sonia Guidato, Tom Deroo
During embryogenesis and in adulthood, cells undergo dynamic
tissue reorganisation processes. One example is the epithelial
to mesenchymal transition that occurs in gastrulation during
embryogenesis and in cancer metastasis in adulthood, where
cells in the epithelial layer delaminate and become migratory.
While these processes are regulated by activation of specific
pathways and gene expression, the cell shape changes in turn
affect activities of some signal transduction pathways. Our
interest is in the interplay between these.
The Wnt/b-catenin pathway is involved in many aspects of
biological events such as cell proliferation, differentiation,
stem cell maintenance and carcinogenesis. In addition to this
functional diversity, the pathway is unique in that the key
regulator, b-catenin, possesses dual functions: one as a part
of adherens junctions, and the other as a transcriptional coactivator of Wnt signal target genes. We currently investigate
the role of b-catenin in the interplay between morphogenetic
changes and pathway activation. We also study the mechanism
whereby Wnt signals result in a different outcome depending
on the context, and focus on extracellular factors that affect
Wnt signaling.
Publications
Kajita M, Hogan C, Harris AR, Dupre-Crochet S, Itasaki N, Kawakami
K, Charras G, Tada M and Fujita Y (2010)
Interaction with surrounding normal epithelial cells influences
signalling pathways and behaviour of Src-transformed cells.
Journal of Cell Science 153:171-80
Itasaki N and Hoppler S (2010)
Crosstalk between Wnt and bone morphogenic protein signaling:
A turbulent relationship.
Developmental Dynamics 239:16-33
Lintern KB, Guidato S, Rowe A, Saldanha JW and Itasaki N (2009)
Characterization of Wise protein and its molecular mechanism to
interact with both Wnt and BMP signals.
Journal of Biological Chemistry 284: 23159-23168
See references 4, 124 in the bibliography at the back for publications
80
MDCK cells undergoing epithelial-to-mesenchymal transition (left to right panels), a process seen
during normal embryogenesis as well as in cancer metastasis. Changes in subcellular localisation of
ß-catenin (red) and E-cadherin (green), from cell borders to intracellular, are shown.
NEUROSCIENCES
Paul Le Tissier
Control of prolactin and growth hormone cell differentiation and function
Lab members: Leonard Cheung, Arnaud Jaubert, Molly Strom, James Turton
The hormones prolactin (principally involved in pregnancy and
production of milk) and growth hormone (required for normal
growth and metabolism) are secreted from specialised cells of
the anterior pituitary gland, located just under the brain. The
function, development and regulation of prolactin and growth
hormone cells are closely related and we are studying the
control of their function and interrelationship using transgenic
mice. These studies also reveal the effects of alterations of
prolactin and growth hormone cells on other pituitary hormones
regulating stress, reproduction and metabolism. Knowing how
these cell populations are controlled normally is important for
understanding how hormone deficiencies or pituitary tumours
occur when this regulation fails.
We have generated transgenic mice with different proportions of
growth hormone cell ablation. The degree of ablation correlates
with effects on the other pituitary hormones, with prolactin
the most affected. Loss of growth hormone cells also leads to a
disruption of the normal organisation of cells within the pituitary,
which may have consequences for the secretory response to
releasing factors.
Publications
Lafont C, Desarménien MG, Cassou M, Molino F, Lecoq J, Hodson D,
Lacampagne A, Mennessier G, El Yandouzi T, Carmignac D, Fontanaud
P, Christian H, Coutry N, Fernandez-Fuente M, Charpak S, Le Tissier P,
Robinson ICAF and Mollard P (2010)
Cellular in vivo imaging reveals coordinated regulation of pituitary
microcirculation and GH cell network function.
America 107:4465-4470
Real-time monitoring of inhibition of prolactin secretion from a pituitary
slice in response to different concentrations of dopamine
Waite E, Lafont C, Carmignac D, Chauvet N, Coutry N, Christian H,
Robinson I, Mollard P and Le Tissier P (2010)
Different degrees of somatotroph ablation compromise pituitary
growth hormone cell network structure and other pituitary
endocrine cell types.
Endocrinology 151:234-243
Le Tissier PR, Carmignac DF, Lilley S, Sesay AK, Phelps CJ, Houston P,
Mathers K, Magoulas C, Ogden D and Robinson ICAF (2005)
Hypothalamic growth-hormone-releasing-hormone (GHRH)
deficiency: targeted ablation of GHRH neurons in mice using a
viral ion channel transgene.
Molecular Endocrinology 19:1251-1262
See references 33 in the bibliography at the back for publications
Growth hormone cells are normally organised in a network in the pituitary gland, shown by expression
of green fluorescent protein (left panel). Ablation of growth hormone cells disrupts this organisation
but cells still form clusters (middle panel), whereas transgenic mice with a loss of growth hormone cell
proliferation fail to form clusters, despite a similar cell density (right panel).
81
NEUROSCIENCES
Neurophysiology
Troy Margrie
Sensory processing in single cells, circuits and behaviour
Lab members: Alexander Arenz, Agota Biro, Ed Bracey, Ede Rancz, Bruno Pichler
Our goal is to understand how the brain uses the activity of
individual and collections of neurons to encode a sensory
stimulus. We use a top-down, multi-disciplinary approach
towards understanding sensory representation that allows
us to explore this fundamental issue from the systems to
the cellular level. Specifically, we are investigating several key
aspects: (1) The relationship between neuronal connectivity
and function, (2) How sensory information is encoded and
integrated by individual synapses and cells, (3) How sensory
representation is distributed across populations of cells, and
(4) The significance of distributed neuronal activity to sensory
perception.
One particularly useful technique, referred to as two-photon
targeted patching, allows us to optically record activity over
large populations of cells while simultaneously examining
synaptic integration using intracellular whole-cell recordings.
This technique can also be used in combination with genetic
indicators that permit imaging and electrophysiological
characterisation of specific populations of cells. Wherever
possible we apply both optical and electrophysiological
techniques in behaving animals that allow us to quantify
sensory signaling through neuronal circuits.
In vivo optical imaging of structure and function of the mammalian olfactory
bulb. An anatomical reconstruction of the olfactory bulb (drawn by the
Nobel Laureate Ramon y Cajal) highlighting the glomerular organization
(red circle) of this brain structure (left). Odour-evoked patterns of
glomerular activity resulting from presentation of pineapple and banana
Publications
Chadderton P, Agapiou JP, McAlpine D and Margrie TW (2009)
The synaptic representation of sound source location in auditory cortex.
Journal of Neuroscience 29:14127-35
Arenz A, Silver RA, Schaefer AT and Margrie TW (2008)
The contribution of single synapses to sensory representation in vivo.
Science 321:977-980
Pimentel DO and Margrie TW (2008)
Glutamatergic transmission and plasticity between olfactory bulb mitral cells.
Journal of Physiology 586:2107-2119
82
MRC National
National Institute
Institute for
for Medical
Medical Research
Research
MRC
In vivo whole-cell recordings and two-photon imaging. Intracellular
recordings carried out in anesthetized and awake mice (above). 2
photon image of calcium dye- loaded cells in the cortex of an
anaesthetized mouse (below).
NEUROSCIENCES
Vassilis Pachnis EMBO member, FMedSci
Development of the nervous system
Lab members: Angelliki Achimastou, Myrto Denaxa, Tiffany Heanue, Chryssa Konstantinidou, Catia Laranjeira, Reena Lasrado,
Rita Lopes, Ulrika Marklund, Valentina Sasseli, Nicole Verhey van Wijk.
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 of 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:
Laranjeira C and Pachnis V (2009)
Enteric nervous system development: recent progress and future challenges.
Autonomic Neuroscience: Basic and Clinical 151:61-69
Fragkouli A, van Wijk NV, Lopes R, Kessaris N and Pachnis V (2009)
LIM homeodomain transcription factor-dependent specification of bipotential MGE progenitors into
cholinergic and GABAergic striatal interneurons.
Kioussis D and Pachnis V (2009)
Immunity 31:705-710
See references 12, 30, 57, 74, 75, 115, 119, 195 in the bibliography at the back for publications from
this group in 2009.
The enteric nervous system of adult mice is made up of thousands of
interconnected ganglia similar to the one shown here. Each ganglion
contains many different types of neurons (red nuclei) and glial cells (blue
cytoplasm.
83
NEUROSCIENCES
Iain Robinson FMedSci
The neuroendocrine cascade of growth
Lab members: Randip Bains, Danielle Carmignac, Keith Fairhall, Evelien Gevers, Zhenhe He, Catherine Peters, Molly Strom, Izbel Yusuf
The brain regulates many vital functions - including growth,
reproduction, metabolism and stress - by controlling the
production and secretion of different hormones from the
pituitary gland. Specialised neuroendocrine neurons in the
hypothalamus release their products into a blood supply that
carries them to the pituitary gland, containing endocrine cells
that each express specific receptors for the hypothalamic
neuronal products.
We are particularly interested in the neuroendocrine control
of growth hormone (GH), which is essential for normal
growth in children and regulates metabolism in adults. We
have developed transgenic approaches to identify, image, study
and manipulate the activity of individual GH cells and whole
populations of cells in normal and dwarf animal models. The
pituitary and hypothalamus show remarkable changes in cell
number and/or activity in response to changing physiological
demands, pointing to the likely presence of stem cells present
in the adult pituitary gland, which we have recently identified.
We have identified other key genes that are important for
pituitary development and normal GH secretion, shedding new
light on developmental and post-natal growth and pituitary
deficits in children.
Fauquier T, Rizzoti K, Dattani M, Lovell-Badge R and Robinson ICAF (2008)
SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary
gland.
McGuinness L, Magoulas C, Sesay AK, Mathers K, Carmignac D, Manneville JB, Christian H, Phillips JA
and Robinson ICAF (2003)
Autosomal dominant growth hormone deficiency disrupts secretory vesicles in vitro and in vivo in
transgenic mice.
Endocrinology 144:720-731
Bains RK, Wells SE, Flavell DM, Fairhall KM, Strom M, Le Tissier P, Robinson IC. (2004)
Visceral obesity without insulin resistance in late-onset obesity rats.
Endocrinology. 145:2666-79
See references 28, 33, 86, 96, 113, 191 in the bibliography at the back for publications from this
group in 2009.
84
Stem cells in the pituitary gland
NEUROSCIENCES
Iris Salecker
Axon guidance in the developing visual system of Drosophila
Lab members: Holger Apitz, Dafni Hadjieconomou, Emily Richardson, Benjamin Richier, Nana Shimosako, Katarina Timofeev
A defining feature of many brain areas in vertebrates and invertebrates is the
organisation of neuronal networks into columns and layers. In each of these units,
afferent axons establish synaptic contacts with distinct sets of target neurons to
ensure correct information processing in the mature brain. Our understanding of
how such specific connections are formed during development is still limited.
We use genetic and imaging approaches to study neural circuit assembly in the
Drosophila visual system. Photoreceptor neurons extend axons from the retina into
two areas of the optic lobe, the lamina and medulla, where they connect with target
neurons in highly regular patterns. Visual circuit formation depends on intricate
bidirectional interactions between photoreceptor axons, glia and target neurons. Our
ongoing studies aim at identifying the molecular determinants that control the initial
development of neurons and glia in the optic lobe. Furthermore, we investigate the
mechanisms that mediate layer-specific targeting of photoreceptor axons and their
postsynaptic partners. As the molecular mechanisms are highly conserved, our studies
will provide insights into the principles underlying normal brain development and, in
the long term, associated neurological dysfunctions.
In the adult visual system of Drosophila, R1-R6 photoreceptor axons
terminate in the lamina, connecting with sets of lamina neurons within
columns, while R7 and R8 axons establish connections with target
neurons in two specific layers in the medulla
Publications
Photoreceptor axons (red) are in close
contact with glial cells and their extensive
processes (green) in the late pupal visual
system
Bazigou E, Apitz H, Johansson J, Lorén CE, Hirst EMA, Chen P-L, Palmer RH and Salecker I (2007)
Anterograde Jelly belly and Alk receptor tyrosine kinase signaling mediates retinal axon targeting in Drosophila.
Cell 128:961-75
Chotard C and Salecker I (2007)
Glial cell development and function in the Drosophila visual system.
Neuron Glia Biology 3:17-25
Chotard C, Leung W and Salecker I (2005)
glial cells missing and gcm2 cell autonomously regulate both glial and neuronal development in the visual system of Drosophila.
Neuron 48:237-51
85
NEUROSCIENCES
Jean-Paul Vincent EMBO member
Cell biological basis of patterning and homeostasis in developing epithelia
Lab members: Cyrille Alexandre, Eugenia Piddini, Maria Gagliardi, Golnar Kolahgar, Luis Alberto Baena Lopez, Karen Beckett, Paul
Langton, Satoshi Kakugawa, Hisashi Nojima, Laurynas Pashakarnis
A relatively small number of signaling molecules orchestrate
growth and cell fate decisions during development. We are
particularly interested in studying these processes in epithelia,
sheets of cells that make up most tissues. We investigate the
mechanisms that control the production and activity of one
such signal, the secreted lipoglycoprotein encoded by wingless.
This is relevant to human disease because Wingless is the fly
equivalent of Wnt1, a molecule implicated in many cancers.
We also investigate how this signal controls patterning, growth
and cell death within developing appendages of the fly. In
a distinct but related strand of work, we are exploring the
homeostatic mechanisms ensuring that weak or mis-specified
cells are eliminated from epithelia. How tissues recognise
rogue cells and how this information is transduced to the
cell death machinery remain outstanding questions in cell
and developmental biology. Again, this is relevant to cancer
as damaged cells that fail to be eliminated can contribute to
tumours.
Impaired Wingless secretion on VPS35 mutants. The Wingless gradient fails
to form and Wingless accumulates in producing cells.
Publications
Baena-Lopez LA, Franch-Marro X and Vincent J-P (2009)
Wingless promotes proliferative growth in a gradient-independent manner.
Piddini E and Vincent J-P (2009)
Interpretation of the Wingless gradient requires signaling-induced self-inhibition.
Cell 136:296-307
Bardet P-L, Kolahgar G, Mynett A, Miguel-Aliaga I, Briscoe J, Meier P and Vincent J-P (2008)
A fluorescent reporter of caspase activity for live imaging.
See references 10, 99, 156, 217, 218 in the bibliography at the back for publications from
this group in 2009.
86
An apoptosis sensor. The top panel shows the design of the sensor,
which is tethered to membranes in live healthy cells. Upon caspase
activation, the green moiety is released and targeted to the nucleus.
The bottom panel shows cultured cells either exposed to UV irradiation to trigger apoptosis (right) or mock treated (left)Note the
accumulation of GFP in the nucleus of dying cells.
NEUROSCIENCES
David Wilkinson EMBO member, FMedSci
Regulation of boundary formation and neurogenesis
Lab members: Marie Breau, Sebastian Gerety, Rosa Gonzalez-Quevedo, Lauren Gregory, Mohamed Ismail, Rosie Morley,
Alexei Poliakov, Dorothy Sobieszczuk, Javier Terriente, Hannah Williams, Qiling Xu
During early stages of nervous system development in
vertebrates, neural tissue is subdivided into building blocks, each
with a distinct regional identity. Within these subdivisions, the
proliferation and differentiation of progenitor cells is regulated
in time and space to form the correct number and organisation
of neuronal and glial cells. In order for these precise patterns to
form and be maintained, it is essential that cells do not migrate
into inappropriate locations. Disruption of the mechanisms that
regulate cell proliferation, differentiation or migration can lead to
diseases such as cancer.
Our studies aim to elucidate molecular and cellular mechanisms
that regulate formation of precise tissue subdivisions and patterns
of differentiating cells in the vertebrate nervous system. We
are analysing how signaling through Eph receptors and ephrins
inhibits intermingling and establishes sharp boundaries between
distinct cell populations. In other studies, we have identified a
pathway mediated by targeted protein degradation required
for the onset of neuronal differentiation, and uncovered a novel
mechanism underlying spatial patterning of neurogenesis involving
FGF signaling from neurons
Detection of neurons (green), cell proliferation (red) and cell nuclei
(blue) in the developing hindbrain
Publications
Gonzalez-Quevedo R, Lee Y, Poss KD and Wilkinson DG (2010)
Neuronal regulation of the spatial patterning of neurogenesis.
Developmental Cell 18:136-147
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.
Genes & Development 24:206-218
Jørgensen C, Sherman A, Chen GI, Pasculescu A, Poliakov A, Hsiung M, Larsen B, Wilkinson DG, Linding R
and Pawson T (2009)
Cell-specific information processing in segregating populations of Eph receptor ephrin-expressing cells.
Science 326:1502-9
Expression of specific genes that mark segment boundary cells (green) and
alternating segments (red) in the hindbrain
87
Systems Biology
Jim Smith (Head of Division)
Greg Elgar
Mike Gilchrist
Developmental Biology
Tim Mohun (Head of Division)
Malcolm Logan
Elke Ober
Lyle Zimmerman
Stem Cell Biology and Developmental Genetics
Robin Lovell-Badge (Head of Division)
Paul Burgoyne
Rita Cha
Steve Sedgwick
James Turner
see also the following groups, all in Neurosciences:
Siew-Lan Ang
James Briscoe
Alex Gould
Nobue Itasaki
Vassilis Pachnis
Iris Salecker
Jean-Paul Vincent
David Wilkinson
88
GENETICS AND DEVELOPMENT
Paul Burgoyne FMedSci
The Y chromosome and infertility
Lab members: Áine Rattigan, Obah Ojarikre, Shantha Mahadevaiah, Julie Cocquet, Nadege Vernet, Louise Reynard
The first evidence that the mammalian Y chromosome carried genetic information
essential for male fertility was obtained in 1976 for man, and 1986 for mouse, from
the study of individuals with partially deleted Y chromosomes. Evidence that the
Y chromosome is incompatible with female fertility comes from studies of XY
individuals that have a deletion removing the male determinant SRY.
Conventional gene targeting has so far proved unsuccessful in disrupting Y
gene functions, so we have been using mouse models harbouring Y deletions in
combination with the selective addition of Y genes by transgenesis to elucidate the
role of specific Y genes in male and female fertility. However, very recently we have
been successful in disrupting the function of a Y gene, Sly, that is present in >70
copies; this was achieved by targeting the transcripts with a transgenically delivered
small interfering RNA. This gene proved to repress X and Y gene expression in
developing sperm; the up-regulation of these X and Y genes in Sly-deficient mice is
associated with sperm head abnormalities and severely impaired sperm function.
Publications
Burgoyne PS, Mahadevaiah SK and Turner JMA (2009)
The consequences of asynapsis for mammalian meiosis.
Nature Reviews Genetics 10:207-16
Cocquet J, Ellis PJ, Yamauchi Y, Mahadevaiah SK, Affara NA, Ward MA
and Burgoyne PS (2009)
The multicopy gene Sly represses the sex chromosomes in the
male mouse germline after meiosis.
PLoS Biology 7:e1000244
In males, SLY protein co-localises with the X or the Y chromosome and represses sex chromosome
genes in haploid post-meiotic germ cells (i.e. spermatids).
Upper panel: Co-localisation of SLY protein (in green) with the X or the Y chromosome (in red) in
spermatids.
Bottom panel: Micro-array experiments were carried out to compare gene expression in testes from
Sly-deficient mice and WT mice
Reynard LN, Cocquet J and Burgoyne PS (2009)
The multi-copy mouse gene Sycp3-like Y-linked (Sly) encodes
an abundant spermatid protein that interacts with a histone
acetyltransferase and an acrosomal protein.
Biology of Reproduction 81:250-257
See references 29, 37, 50, 163, 231 in the bibliography at the back
for publications from this group in 2009.
89
Rita Cha
Regulation of eukaryotic chromosome metabolism
Lab members: Jesus Carballo, James Cauwood, Tony Johnston, Ana Penedos, and Chaim Sagal
Genome duplication and segregation are two fundamental
processes in biology. We study the ways in which signal
transduction regulates these events. A key component in
eukaryotic chromosome metabolism is the ATR/ATM family
of proteins. These evolutionarily conserved signal transduction
proteins are involved in a number of chromosomal processes
including DNA replication, recombination, and checkpoint
regulation. Inactivation of these genes leads to cell death, genome
instability, and meiotic dysfunction as well as the genetic disorders,
Ataxia Telengiectasia (AT) and Seckle syndrome.
We use genetically tractable S. cerevisiae to study the molecular
basis for the ATR/ATM functions. We found that inactivation of
Mec1/Tel1, the budding yeast homologues of ATR/ATM, leads
to chromosome breakage during proliferation and disruption of
essential meiotic chromosomal processes. Currently, our research
focuses on the roles of Mec1/Tel1 in meiotic recombination and
fragile site stability. The results of our studies will provide insights
into how disruption of these genes leads to failure of fundamental
chromosomal processes.
Structure of human Chromosome I during mitotic or meiotic divisions.
The intimate interaction between maternal (m) and paternal (p)
chromosomes is observed only during meiosis
Targets of ATR/ATR proteins during yeast meiosis. The targets (red circles)
are activated during pairing of maternal and paternal chromosomes (red
and blue lines). Targets disappear once the pairing is complete (green lines)
Publications
Carballo JA, Johnson AL, Sedgwick SG and Cha RS (2008)
Phosphorylation of the axial element protein Hop1 by Mec1/Tel1 ensures meiotic interhomolog
recombination.
Cell 132:758-70
Carballo JA and Cha RS (2007)
Meiotic roles of Mec1, a budding yeast homolog of mammalian ATR/ATM.
Chromosome Research 15:539-50
Machin F, Torres-Rosell J, De Piccoli G, Carballo JA, Cha RS, Jarmuz A and Aragon L (2006)
Transcription of ribosomal genes can cause nondisjunction.
Journal of Cell Biology 173:893-903
90
Systems Biology
Greg Elgar
Regulation of early vertebrate development
Lab members: Stefan Pauls, Paul Piccinelli, Hugo Parker, Dilrini DeSilva
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 interestingly, 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
Goode DK and Elgar G (2009)
The PAX258 gene subfamily: A comparative perspective.
McEwen GK, Goode DK, Parker HJ, Woolfe A, Callaway H
and Elgar G (2009)
Early evolution of conserved regulatory sequences
associated with development in vertebrates.
PLoS Genetics 5:e1000762
Elgar G and Vavouri T (2008)
Tuning in to the signals: noncoding sequence conservation
in vertebrate genomes.
Trends in Genetics 24:344-352
Conservation of non-coding sequences across the
Meis2/c15orf41 locus in vertebrates
Transient GFP expression after the injection of a
Fugu Sox21:GFP BAC into zebrafish
91
Systems Biology
Mike Gilchrist
Gene regulatory networks in early development
Embryo development is a complex and tightly controlled process, with a
remarkably precise outcome. The underlying control system is only partly
understood. Typically, transcription factors regulate the expression of
individual genes, and the many relationships between transcription factors
and their target genes combine to make gene regulatory networks. Our
aim is to elucidate these networks using molecular and computational tools
developed in the last few years that enable a systematic and large-scale
approach.
We plan to use these methods to study the timing and localisation of gene
expression in developmental model systems such as Xenopus. In particular
we will be analysing time based profiles of gene expression generated by
massively parallel, deep-sequencing technology, and combining this with
expression co-localisation data derived from the computational comparison
of in situ expression images, in order to generate large numbers of candidate
relationships between genes. These relationships will then be validated and
characterised, using both bioinformatic and experimental methods, and from
these we can build more extensive and informative models of the gene
regulatory networks controlling early development.
Publications
Embryonic gene expression profiles
for Xenopus tropicalis derived from
existing EST data. Using cDNA library data
and gene-clustered ESTs, we can reconstruct the
time-based behaviour of gene expression in frog
embryos from the fertilised egg (stage 1) through
to late metamorphosis. Here we see a clear
distinction between maternal (upper profiles)
and early zygotic (lower profiles) mRNAs, with
shorter and longer persistence times. Highthroughput sequencing technology will yield
a hundred times better resolution and should
enable clear inferences to be drawn about the
progression of the embryonic transcriptional
program
92
Armisen J, Gilchrist MJ, Wilczynska A, Standart N and Miska EA
(2009)
Abundant and dynamically expressed miRNAs, piRNAs, and other
small RNAs in the vertebrate Xenopus tropicalis.
Genome Research 19:1766-1775
Clustering in situ image data to extract
candidate gene relationships. Using
computerised representation of embryonic
gene expression patterns, we can cluster the
images using a similarity metric, looking for
pairs of genes with highly congruent expression
patterns at the same stage of development.
These co-localised genes are likely to have some
direct or indirect functional relationship, and this
can be further dissected using a combination of
bioinformatic and experimental techniques
Gilchrist MJ, Christensen MB, Bronchain O, Brunet F, Chesneau A,
Fenger U, Geach TJ, Ironfield HV, Kaya F, Kricha S, Lea R, Massé K,
Néant I, Paillard E, Parain K, Perron M, Sinzelle L, Souopgui J, Thuret R,
Ymlahi-Ouazzani Q and Pollet N (2009)
Database of queryable gene expression patterns for Xenopus.
Gilchrist MJ, Christensen MB, Harland R, Pollet N, Smith JC, Ueno N
and Papalopulu N (2008)
Evading the annotation bottleneck: using sequence similarity to
search non-sequence gene data.
BMC Bioinformatics 9:442
Malcolm Logan
Understanding vertebrate limb development
Lab members: Anna Kucharska, Sue Miller, Natalie Butterfield, Veronique Duboc, Peleg Hasson, Satoko Nishimoto, Jutta Roth,
Sorrel Bickley, Fatima Sulaiman
Limb defects are the second most common congenital
abnormality in human live births, and diseases affecting the
musculoskeletal system are a significant clinical problem in
older people. The goal of our work is to understand how
limbs normally form during embryogenesis, the genesis of limb
abnormalities and disease in humans, and to provide potential
therapeutic approaches to block degeneration or trigger
regeneration of the musculoskeletal system.
The forelimb and hindlimb buds are morphologically uniform
and indistinguishable from one another at early stages of
development. They are then transformed into a complex of
interconnected limb elements comprised of different tissues,
for example bones, muscles and tendons, that are exquisitely
sculpted to the correct size and shape. Each of these individual
tissue elements must form the appropriate connections so that
each muscle group connects to the skeletal scaffold via the
correct tendon. For each muscle to function it must connect
to the central nervous system via an axon that originates from
a nerve cell within the spinal cord. How this complex array
of interconnected tissues is elaborated is poorly understood.
We are using vertebrate animal models to understand the
mechanisms that control the initiation of limb bud formation,
the subsequent construction of the individual limb elements
during development and the maintenance of these structures
in later life.
Publications
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.
Minguillon C, Gibson-Brown JJ and Logan MP (2009)
Tbx4/5 gene duplication and the origin of vertebrate paired
appendages.
America 106:21726-21730
DeLaurier A, Burton N, Bennett M, Baldock R, Davidson D, Mohun TJ
and Logan MPO (2008)
The Mouse Limb Anatomy Atlas: An interactive 3D tool for
studying embryonic limb patterning.
BMC Developmental Biology 8:83
See references 63, 138 in the bibliography at the back for publications
Confocal microscope image of the embryonic mouse forepaw, illustrating
the interconnected network of muscle (red) and tendon (green) fibres. A
dorsal view of the back of the hand and forearm is shown
93
Robin Lovell-Badge FRS, EMBO member, FMedSci
Sex, stem cells and decisions of cell fate
Lab members: Sarah Booth, Christophe Galichet, Maria-Victoria Gomez-Gaviro, Silvana Guioli, Susanne Jakob, Ander Matheu,
Adam Nunn, Karine Rizzoti, Charlotte Scott, Ryohei Sekido, Clare Wise
Embryo development relies on cells making choices about which cell type to become
and whether to divide, move or die. During the process of 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). This is due to just one gene on the Y,
termed Sry, which encodes a transcription factor. SRY contains an HMG box type of
DNA binding domain, also present in proteins encoded by the Sox gene family.
We use a wide range of techniques to explore how SRY and other factors act
to initiate and then maintain testis and ovary differentiation. Mice are our main
experimental model, and we study the chick for evolutionary comparisons since
the initial trigger is different, but downstream effectors are probably the same. Our
work informs the human situation, which when it goes wrong leads to devastating
physiological and social consequences for affected individuals.
We also study stem cell types, including pluripotent stem cells from very early
embryos (ES cells) or after reprogramming from adult cells (iPS cells), and
multipotent stem cells from the developing and adult central nervous system and
pituitary. Certain Sox genes are critical for self-renewal and to confer potential to
stem cells. We therefore explore how these genes impact on cell fate choices, and
how they might be exploited to aid the treatment of a range of clinical problems,
such as stroke and cancer.
Publications
Uhlenhaut NH, Jakob S, Anlag K, Eisenberger T, Sekido R, Kress J,
Treier A-C, Klugmann C, Klasen C, Holter NI, Riethmacher D, SchG,
Cooney AJ, Lovell-Badge R and Treier M (2009)
Somatic sex reprogramming of adult ovaries to testes by FOXL2
ablation.
Cell 139:1130-4
Fauquier, T., Rizzoti, K., Dattani, M., Lovell-Badge, R., Robinson, ICAF.
(2008).
SOX2-expressing progenitor cells generate all of the major cell
types in the adult mouse pituitary gland.
Proc. Natl. Acad. Sci. USA. 105, 2907-12.
Sekido, R. and Lovell-Badge, R (2008).
SRY and SF1 act on a specific enhancer of SRY in sex
determination.
Nature 453, 930-4.
GFP expression driven by a testis-specific
enhancer of Sox9 in transgenic mice
94
Pituispheres contain progenitors expressing
SOX2 (green) and S100 protein (blue), able to
differentiate into hormone-producing cells (green)
Tim Mohun
Heart development in vertebrates
Lab members: Mike Bennett, Yuval Cinnamon, Laurent Dupays, Surendra Kotecha, Catherine Shang, Stuart Smith, Norma Towers
Formation of the heart is a complex process that begins
very early in the vertebrate embryo. A simple pulsatile
tube is progressively remodelled into a complex multichambered organ capable of supporting embryo growth.
This transformation requires exquisite coordination of cell
differentiation and growth, and dramatic changes in organ
shape. Abnormalities affecting any step will have profound
consequences on the foetal heart. Consequently, heart defects
are the most common birth defect. Genetic and environmental
factors are both implicated as causes, but their identities and
the reasons for their effect are poorly understood. By studying
the roles of individual genes and cell populations in normal
heart development, we will gain a better understanding of the
origins of cardiac malformations and a model of how complex
organs are formed in the developing embryo.
Since many of the basic steps in heart formation are similar
in all vertebrates, valuable information can be obtained from
studying a variety of different species. We are using transgenic
and genomic methods to examine how gene expression is
regulated in the developing heart of frog and mouse embryos
and their contribution to adult heart disease. 3D imaging
and computer modelling procedures are used in parallel to
monitor effects of normal and altered gene expression on
heart morphology.
The developing heart of a frog tadpole can be visualised by it expression of
the heart muscle gene XMLC2 (A: blue staining). At high magnification, the
different portions of the tadpole heart can be distinguished (B)
Publications
Breckenridge RA, Zuberi Z, Gomes J, Orford R, Dupays L, Felkin LE, Clark JE, Magee AI, Ehler E, Birks EJ,
Barton PJ, Tinker A and Mohun TJ (2009)
Overexpression of the transcription factor Hand1 causes predisposition towards arrhythmia in mice.
Journal of Molecular and Cellular Cardiology 47:133-141
3D reconstruction of a chick embryo heart reveals the complexity
of its internal structure. At this stage of development, distinct heart
chambers can be recognised and the inside surface of the heart wall
is a complex mesh of muscle tissue
Dupays L, Kotecha S and Mohun TJ (2009)
Tbx2 misexpression impairs deployment of second heart field derived progenitor cells to the arterial
pole of the embryonic heart.
95
Elke Ober
Liver development in zebrafish
Lab members: Jordi Cayuso Mas, Johanna Fischer, Katarzyna Koltowska, Despina Stamataki, Morgane Poulain
During development, the liver, gall bladder and pancreas arise from neighbouring
domains within the foregut, and a highly regulated network of signals is required
to specify each organ. Our research aims to elucidate the molecular network and
cellular mechanisms underlying liver formation in vertebrates using zebrafish as a
model. Understanding the genetic programme of liver formation provides insights
into embryonic development, tissue homeostasis in adults, regeneration following
tissue damage and more recently, the development of novel therapies, such as
hepatic stem cells.
Hepatic precursors form in the ventral foregut endoderm of the embryo in
response to signals from the adjacent mesoderm, ultimately differentiating into a
functional liver. Previous work has uncovered that prometheus mutants, encoding
the signalling factor wnt2bb, exhibit a profound but transient defect in the
specification of liver fate from multipotential progenitors. Ongoing studies employ
genetic approaches to uncover factors that (i) compensate for loss of wnt2bb
in prometheus mutants, (ii) modulate or interact with components of the Wnt
signalling pathway during liver specification, and (iii) direct the morphogenesis of
the organ bud in newly specified hepatic precursor cells.
Publications
Noël ES, Casal-Sueiro A, Busch-Nentwich E, Verkade H, Dong PDS,
Stemple DL and Ober EA (2008)
Organ-specific requirements for Hdac1 in liver and pancreas
formation.
Ober EA, Verkade H, Field HA and Stainier DY (2006)
Mesodermal Wnt2b signalling positively regulates liver
specification.
Nature 442:688-691
96
Newly specified liver cells (red) in
the zebrafish digestive tract (green)
Digestive organs at 3 days of development: liver
(red), pancreas (green) and gall bladder (blue)
Steve Sedgwick
Regulation of mitosis
Lab members: Marco Geymonat, Adonis Spanos
Equal segregation of the newly replicated chromosomes during
mitosis is one of the fundamental requirements for a successful cell
cycle. For this to occur correctly, the mitotic spindle must be aligned
at right angles to the plane of cell division. Complex spatial sensing
systems called checkpoints exist that prevent unequal chromosome
partitioning. Such mechanisms reduce the chances of progeny cells
receiving no chromosomes. They also protect against cells receiving
multiple complements of chromosomes, a contributory factor to
malignant transformation in higher eukaryotic cells.
We currently study the mechanism that coordinates the
morphological development of a cell with the segregation of its
replicated chromosomes in budding yeast. We have characterised
how a protein called Lte1 plays a central role in both these
processes. On one hand Lte1 limits the growth of the cell to a
particular moment of the cell cycle while at the same time it ensures
that the cell cycle is completed only when the chromosomes are
correctly segregated.
Publications
Geymonat M, Spanos A, de Bettignies G and Sedgwick SG (2009)
Lte1 contributes to Bfa1 localization rather than stimulating
nucleotide exchange by Tem1.
Geymonat M, Spanos A and Sedgwick S (2009)
Production of mitotic regulators using an autoselection system for
protein expression in budding yeast.
Methods in Molecular Biology 545:63-80
Altered budding pattern in yeast expressing a
mutant Lte1 protein
Colocalization of a mitotic regulator (red) with an
effector of polarized growth (yellow).
DNA is in blue
Darieva Z, Bulmer R, Pic-Taylor A, Doris KS, Geymonat M, Sedgwick
SG, Morgan BA and Sharrocks AD (2006)
Polo kinase controls cell-cycle dependent transcription by
targeting a coactivator protein.
Nature 444:494-498
97
Systems Biology
Jim Smith FRS, EMBO member, FMedSci
The molecular basis of mesoderm formation
Lab members: Liz Callery, John Cannon, Nicolette Chan, Clara Collart, Kevin Dingwell, Amand Evans, Tiago Faial, George Gentsch,
Steve Harvey, Helle Jorgensen, Mary Wu
The different cell types of the body are formed in the right
place and at the right time in response to signals that are
produced by special organiser regions of the embryo. These
so-called morphogens act in a concentration-dependent
manner to induce the formation of different cell types at
different positions within developing tissues. One of the
earliest interactions of this kind is mesoderm induction,
which results in the formation of organs and cell types such
as heart, muscle, kidney and bone.
We use frog, zebrafish and mouse embryos 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 in
the embryo, as well as biochemical and mathematical
approaches to ask how cells distinguish between
different morphogen concentrations to activate different
developmental pathways. We also use a range of molecular
techniques to identify the genes that are activated by these
signalling pathways and which go on to activate the genetic
regulatory networks that result in the formation of specific
cell types. We hope that our work will help in efforts to
direct stem cells down the desired developmental pathways.
Spread of labelled activin (green) through a responding tissue. The source of
activin is to the left. At 2 hours (top) activin is predominantly extracellular; at
3.5 hours (bottom) much has become internalised
Publications
Collart C, Ramis JM, Down TA and Smith JC (2009)
Smicl is required for phosphorylation of RNA polymerase II and affects 3'-end processing of RNA at the
midblastula transition in Xenopus.
Hagemann AI, Xu X, Nentwich O, Hyvonen M and Smith JC (2009)
Rab5-mediated endocytosis of activin is not required for gene activation or long-range signalling in
Xenopus.
Harvey SA and Smith JC (2009)
Visualisation and quantification of morphogen gradient formation in the zebrafish.
98
Use of bimolecular fluorescence complementation reveals that signalling
by nodal family members is strong near the margin of the zebrafish
embryo (bottom of image) and weak near the animal pole (top)
James Turner
X chromosome inactivation, meiotic silencing and infertility
Lab members: Jeff Cloutier, Jennifer Grant, Helene Royo, Mahesh Sangrithi, Grzegorz Polikiewicz
In mammals, X chromosome inactivation (XCI) occurs in all
cells in the female and in developing germ cells in the male.
In females, XCI serves to equalise X-dosage with males and
abnormalities in this process cause various diseases, including
mental retardation. The precise role of XCI in male germ cells is
unclear, but defects lead to infertility. We study the mechanisms
underlying both forms of XCI and the influence of XCI on the
gene content of the X chromosome.
We have shown that XCI in the male occurs because the
X chromosome has no pairing partner during meiosis.
Furthermore this form of X-silencing requires the tumour
suppressor BRCA1. We have found that male XCI drives
amplification of genes involved in late spermatogenesis on the
X chromosome, with 18% of X-linked genes being expressed
exclusively in developing sperm. Recently, we have used a new
model organism, the marsupial Monodelphis domestica, to
trace the evolution of XCI in mammals. These studies showed
that most of the molecular features of XCI arose very early in
mammalian evolution.
Publications
Mahadevaiah SK, Royo H, Vandeberg JL, McCarrey JR, Mackay S and
Turner JMA (2009)
Key features of the X inactivation process are conserved between
marsupials and eutherians.
Current Biology 19:1478-1484
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.
Nature Genetics 40:794-9
Turner JMA, Mahadevaiah SK, Fernandez-Capetillo O, Nussenzweig
A, Xu X, Deng CX and Burgoyne PS (2005)
Silencing of unsynapsed meiotic chromosomes in the mouse.
Nature Genetics 37:41-47
Localisation of BRCA1 to the X and Y
chromosomes during male meiosis
The inactive X chromosome, labeled with H3K27methylation, in female marsupial brain cells
99
Lyle Zimmerman
Using frog genetics to understand vertebrate development and disease
Lab members: Anita Abu-Daya, Tim Geach, Holly Ironfield, Tosikazu Amano, Elisenda Vendrell
Harvesting medical benefits from the human genome depends on understanding
the tasks specific genes perform in living organisms. Our group uses genetics
to describe gene roles important for initial formation and function of tissues
and organs, by comparing normal embryogenesis to mutations with disruptions
in individual genes. Since all vertebrates (including humans) share most gene
functions, we use a frog, Xenopus tropicalis, as a genetic model because of its
simple chromosomal structure and easily-studied eggs.
We are developing procedures for rapidly cloning X. tropicalis mutations,
taking advantage of the abundant meioses (up to 10,000) provided by a single
mating and the ease of gynogenesis and haploid genetics. In the first cloning
of an X. tropicalis mutation, we showed that a defect in the myh6 gene (which
can lead to atrial-septal defects in human) causes the non-contractile hearts
in the frog muzak phenotype. This mutation ablates both myh6 protein and
heartbeat, so the roles played by myosin thick filaments and contractile activity in
myofibrillogenesis and cardiogenesis can be studied, helping model human disease
states in both heart and skeletal muscle.
Myofibril mutation dicky ticker. Top panel, sarcomere structure in wild type skeletal muscle shown by
z-discs (green, α-actinin) and actin filaments (red, phalloidin); bottom panel, disorganized sarcomeres
in the dicky ticker mutation deficient in a myosin chaperone protein
Cardiac development in the absence of heartbeat.
3-D models of wild type (top) and muzak mutant
(bottom) X. tropicalis tadpole hearts. Endocardium is
on the right; myocardium is on the left
Publications
Abu-Daya A, Sater AK, Wells DE, Mohun TJ and Zimmerman LB (2009)
Absence of heartbeat in the Xenopus tropicalis mutation muzak is caused by a nonsense mutation in cardiac myosin myh6.
Khokha MK, Krylov V, Reilly MJ, Gall JG, Bhattacharya D, Cheung CYJ, Kaufman S, Lam DK, Macha J, Ngo C, Prakash N, Schmidt P, Tlapakova T,
Trivedi T, Tumova L, Abu-Daya A, Geach T, Vendrell E, Ironfield H, Sinzelle L, Sater AK, Wells DE, Harland RM and Zimmerman LB (2009)
Rapid gynogenetic mapping of Xenopus tropicalis mutations to chromosomes.
Goda T, Abu-Daya A, Carruthers S, Clark MD, Stemple DL and Zimmerman LB (2006)
Genetic screens for mutations affecting development of Xenopus tropicalis.
PLoS Genetics 2:e91.
100
Emeritus scientists
Distinguished retired scientists who keep alive the connections with the place where their careers began provide a salutary link with
former times and remarkable historical milestones.
Tim Bliss, FRS
Tim Bliss has been a key figure in neuroscience research at NIMR,
leading a productive and internationally renowned research program at
Mill Hill spanning four decades. Though born in England, Tim gained his
early scientific training in Canada, taking a PhD at McGill in Montreal.
He was attracted back to London in 1967, to join the Division of
Neurophysiology and Pharmacology at NIMR. This was the time of
the ‘flower power’ generation, and whilst Tim’s experiments at the
time may have concentrated on the electrophysiology of the rodent
nervous system, it is clear that his own nervous system absorbed
something of the zeitgeist of pyschedelia, as the colours of his socks,
shirts and ties continue to remind us. Tim was keenly interested
in the processes underlying learning and memory, following the
conceptual and experimental studies of Hebb and Penfold, suggesting there were synaptic mechanisms of plasticity that would
somehow enable neural structures to learn and encode engrams of previously experienced events. Tim’s initial hunt for this in the
neocortex was fruitless, but he recognised that there were many reasons to focus on the hippocampus, not least the compelling
observations from a remarkable patient (H.M.) with hippocampal damage who exhibited specific and profound deficits in new
memory formation. It was Tim’s seminal studies with Terje Lømo in Per Andersen’s lab in Oslo in the late 1960’s that uncovered
the phenomenon of synaptic long-term-potentiation (LTP). In LTP, certain repeated stimulus patterns are able to ‘strengthen’
hippocampal synapses, which then maintain a sustained increase in response to the same stimulus, once LTP has been induced.
LTP rapidly became the dominant synaptic model of how the mammalian brain learns, and remains the benchmark paradigm for
studies of neural mechanisms of memory formation.
Tim’s work generated many important further questions such as: how long could LTP last; what were the molecular mechanisms
of LTP; was the origin pre-synaptic (an increase in transmitter release) or post-synaptic (an increase in response to transmitter)
or both; could LTP be evoked and detected at a single synapse. Over his productive career Tim and his many colleagues
and collaborators have provided answers to many of these questions. Tim’s contributions to neuroscience have been widely
recognised. He was elected FRS in 1994 and he has become one of the most prominent and highly cited neuroscientists in the
world, with numerous prizes, honours and awards.
Tim was, and is, a tireless champion of the importance of Neurosciences at NIMR and of the Institute’s great value. He became
Head of the Division of Neurophysiology in 1988, and head of the Neurosciences Group in 1996 and he has nurtured a
generation of neuroscientists now flourishing in labs all over the world. Although Tim formally retired in 2006 he continues as a
visiting worker and, when not at home in Norwich, is to be encountered travelling to speak in response to numerous invitations
from all over the world. Those that have heard Tim speak after a good dinner (or on any occasion, actually) appreciate a born
raconteur and bon vivant (where did he find the time?) regaling his listeners with stories of food, wine and crewing sailing ships
(perhaps not the wisest maritime combination), art and architecture. We wish him well.
101
Emeritus scientists
Guy Dodson, FRS
Guy Dodson established protein crystallography at NIMR and
played a leading role in integrating structural biology into the
scientific life of the Institute. He came as an internationally
recognised structural biologist, and quickly became intoxicated
with the Institute’s biology and collegiality.
Guy was educated in New Zealand, and as a PhD student solved
the crystal structure of a plant alkaloid – the biggest crystal
structure in the Southern hemisphere at the time! Dorothy
Hodgkin’s papers had a strong influence on him and he joined
her group at Oxford in 1962 to work on insulin. The symmetry
of the crystals made this very technically challenging but thanks
to greatly improved methods, the problem was solved in 1969
using the physics of anomalous scattering. He found Hodgkin’s
laboratory a paradise: like J.D. Bernal’s laboratory, it knew no
boundaries. He gained a thorough grounding in biological perspectives from Bernal and Don Steiner, and in chemical structure and
mechanism from Jack Dunitz and Bob Williams. In 1971 Dorothy Hodgkin mused that perhaps Guy should move to NIMR but the
idea took another twenty years to flower! After leaving Oxford in 1976, Guy established a group in the Chemistry Department at
the University of York. The Professor of Chemistry, Dick Norman, was very supportive, tolerating Guy’s exclusive commitment to
proteins, their crystallography, structure and mechanism. Guy focused on proteins of medical and industrial importance, especially
insulin, collaborating with Eleanor Dodson. Thus the proposal by John Skehel to establish a crystallography division at NIMR fitted
naturally with his interests. For Guy there were two major attractants: the Institute was screaming out for crystal structures, and
the magnificent library, which was only deficient with respect to one journal – Acta Crystallographica! There was a third reason,
not adequately appreciated before joining – the smooth and wholly intelligent and effective administration.
Guy decided to leave his York research there and to start new interests at the Institute. The first white powder quickly appeared,
thanks to Alistair Aitken, a protein egregiously called 14-3-3. At the time it was evident that the protein was important but not
what it did! The division was quickly up and running, with key appointments like Kim Hendrick and Bing Xiao. Bing soon obtained
good crystals of 14-3-3, and the structure was solved; it had a remarkable and lovely structure and organisation. The shape
and nature of its surface suggested the molecule performed an adaptor function, and so it proved. From here on, the division
developed very happily with programmes in signal transduction and cell-cycle regulation. Guy collaborated with Tony Holder on
malaria, the late Jo Colston on mycobacteria and Iain Robinson on molecular endocrinology. One effect of these tough projects
was that awareness grew across the Institute of the potential for crystallographic projects to inform biological interests. The
division was an immediate success. Some projects were particularly close to Guy’s heart. One favourite, with Peter Bayley in
Physical Biochemistry, was on the prion protein. It was ferociously difficult and had safety issues, but the combination of superb
molecular biology, biochemistry, biophysics and crystallisation by Lesley Haire led to a surprising and revealing dimeric structure.
Another interest was the catalytic reaction associated with particular thrombin inhibitors. This research explained the unusual
binding properties of these ligands as well as revealing unexpected plasticity in the enzyme’s catalytic chemistry.
Guy was a member of NIMR staff from 1993 to 2004. He appreciated particularly the Institute’s multidisciplinary approach to
science.He retired, reluctantly, from research and involvement in shaping the future of NIMR.
102
Scientific facilities
Biological and Procedural Services
MRC Biomedical NMR Centre
Other structural biology facilities
X-ray crystallography
Analytical ultracentrifugation
Mass spectrometry
Protein sequence analysis and structure modelling
Confocal imaging and analysis laboratory
Histology
Electron microscopy
Single molecule techniques
Total internal reflection fluorescence microscopy
Optical tweezers
Atomic force microscopy
Cryo electron microscopy
Bioresources
Large scale laboratory
Media production
Freezer archive
Flow cytometry facility
High-throughput sequencing
Affymetrix microarray facility
Level 4 high-containment virus laboratory
Engineering and Electronics
Technology transfer
Other support services
Library
Computing and telecommunications
Web team
PhotoGraphics
Engineering services
Safety and security
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SCIENTIFIC FACILITIES
Biological and Procedural Services
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.
We aim to meet all the needs of the scientific Divisions whilst ensuring the
highest possible standards of health and welfare for all species. It 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. Additionally they provide a range of centralised procedural
support. A full time veterinary surgeon and microbiologist are available
for advice on the health and welfare of our animals. The Division
provides services for the production of antibodies and the incubation of
fertile chicken eggs. Moreover, administration and licence control under
the Animals (Scientific Procedures) Act 1986 and coordination of the
Institute’s local Ethical Review Process is managed by Biological Services.
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Procedural Service Section
The Procedural Service Section provides a range of services and facilities for
the production and archiving of genetically altered rodents. More than 200 new
genetically altered lines are produced each year by pronuclear and embryonic
stem cell microinjection. The Section offers a comprehensive service for the
cryopreservation of rodent germplasm and has extended this service to include frog
and fish spermatozoa. Currently in excess of 2100 mouse strains are cryopreserved.
The section also coordinates the rederivation of imported rodent lines and is
skilled in a number of assisted reproduction techniques. A small DNA isolation and
genotyping service is available. Every year Biological Services and Procedural Services
together coordinate over 150 shipments of live animals or frozen germplasm to
collaborators all over the world.
Procedural Services Manager:
Sarah Johnson
NC3Rs/LASA Small Awards awarded to Biological and Procedural Services (2005-2008)
Y. Saavedra-Torres: Ultrasound imaging of murine in utero development
S. Johnson: A non-surgical method of embryo transfer.
A. Palmer: CPD for Animal Technicians.
M. Franchi: An assay to quantify stress in Xenopus.
C. Langhorne: A reliable method for the cryopreservation of zebrafish spermatozoa.
J.M. Sanchez-Morgado: Training in amphibian & zebrafish medicine.
S. Wood: Training in a laser assisted method of ICSI.
K. Mathers: Animal technician exchange visits and training.
J M Sanchez-Morgado: Replacement of the Mouse Antibody Production test with PCR - evaluation of the
quality of DNA extracted from biological samples
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MRC Biomedical NMR Centre
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 1980 to provide advanced and well-supported
facilities for use by scientists from NIMR and other academic research
establishments. 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 histidine 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 consist of four spectrometers, including one
operating at 800 MHz, a recently-funded 700 MHz instrument, and two
600 MHz instruments. Centre staff have a high level of expertise in
designing, implementing, and analysing macromolecular NMR studies. The
spectrometers are suitable for investigating a wide range of biological
systems in solution. Three of the four are equipped with the latest
cryogenically-cooled probes for enhanced sensitivity. The facilities are
currently used by 19 research groups from 16 different universities and
institutes from around the UK. Within NIMR our closest links are with the
Division of Structural Biology.
1
NMR study of the interaction between a signalling protein and a phosphopeptide.
Left: Overlay plot of successive spectra obtained after stepwise additions of
the peptide to the protein solution. The peaks that change position identify the
residues involved in the binding interaction. Right: Mapping the affected residues
onto the structure of the protein reveals the interaction surface.
Publications
Nott TJ, Kelly G, Stach L, Li J, Westcott S, Patel D, Hunt DM, Howell S, Buxton RS, O’Hare HM and Smerdon SJ (2009)
An intramolecular switch regulates phosphoindependent FHA domain interactions in Mycobacterium tuberculosis.
Díaz-Moreno I, Hollingworth D, Frenkiel TA, Kelly G, Martin S, Howell S, García-Mayoral M, Gherzi R, Briata P and Ramos A
(2009)
Phosphorylation-mediated unfolding of a KH domain regulates KSRP localization via 14-3-3 binding.
Martino L, He Y, Hands-Taylor KLD, Valentine ER, Kelly G, Giancola C and Conte MR (2009)
The interaction of the Escherichia coli protein SlyD with nickel ions illuminates the mechanism of regulation of its peptidylprolyl isomerase activity.
FEBS Journal 276:4529-4544
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Magnet of the Centre’s 800 MHz spectrometer
X-ray crystallography
X-ray crystallography enables atomic resolution structures of biological molecules to be determined from protein crystals. At
NIMR we have an in-house X-ray source and an automated (robotic) crystal mounting machine. We use robotic systems for
protein expression and crystallisation trials and for high-throughput screening of protein expression constructs.
Protein crystal
X-ray diffraction
atomic structure
Analytical ultracentrifugation
The Institute has two analytical ultracentrifuges located in
the Division of Physical Biochemistry. These instruments
provide first-principle hydrodynamic and thermodynamic
information concerning the size, shape and association state of
macromolecules. For basic applications, the two instruments
(XL-A and XL-I) are equipped with UV/Vis optics that record
radial absorbance measurements and monitor evolving
(sedimentation velocity) or static (sedimentation equilibrium)
concentration gradients. The XL-I is additionally equipped
with Rayleigh interference optics that measure concentration
profiles directly from solute refractive index gradients. The
interference and absorbance data are recorded simultaneously
in the XL-I and are used in combination for the analysis of
complex associating systems.
The optical detection system of the XL-I analytical ultracentrifuge
consisting of a combined UV/Vis spectrophotometer and laser
interferometer is shown in the bottom image. A fringe displacement
pattern produced by a moving concentration boundary measured by
the Rayleigh interference optics of the XL-I is shown above
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Mass spectrometry
The Institute has two mass spectrometers which are used in
a range of biochemical applications. A research grade MALDITOF is primarily employed in proteomics studies, coupled
with SDS-PAGE, to identify proteins from their peptide
mass fingerprints by database searching. This instrument
is also used to analyse peptide structure by post source
decay fragmentation. A quadrupole time-of-flight (Q-TOF)
tandem mass spectrometer, equipped with electrospray and
nanospray sources, is utilised for protein characterisation,
peptide sequence confirmation and de novo sequencing. This
instrument is also used in the investigation of post-translational
modifications such as phosphorylation.
Protein sequence analysis and structure modelling
The Division of Mathematical Biology contains a support service
for protein sequence analysis and structure modelling. It draws on
the state-of-the-art algorithms being developed by the experts
in Mathematical Biology as well as the many computer programs
freely available from the scientific community. There is also an inhouse, commercial computer graphics package for detailed threedimensional modelling. The service is available to all NIMR scientists
and external collaborators.
Structural model of an immunoglobulin binding site showing amino
acid residues in gold, important for the shape of the binding loops
(CDRs) shown in yellow.
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Confocal Imaging and Analysis Laboratory
Yan Gu
Co-workers: Kate Sullivan, Donald Bell, Chen Qian
The Confocal Imaging and Analysis Laboratory (CIAL) provides a
core imaging and support facility for NIMR scientists. The facility has
six confocal microscopes, three wide-field fluorescence microscopes,
four offline workstations, a data storage system, and image processing
software such as Volocity, Imaris, Image J, Metamorph and MatLab.
Currently the facility is used by more than 160 scientists from 15
Divisions. Users operate the equipment by themselves, but the
complexity of imaging makes support an extremely important part of
the facility. We routinely provide users with training, troubleshooting,
consultation and microscope maintenance. In 2009, we also provided
special techniques such as thick tissue imaging, 2nd harmonic generation
imaging, spectral unmixing of multiple labelling, quantitative imaging,
deconvolution imaging, and automatic cell counting.
Research in CIAL focuses on the technological development of
biological microscopy and image processing methodologies that bring
benefits to NIMR scientists. These include techniques of intravital imaging,
super resolution imaging, correlative microscopy, high throughput
imaging, automatic cell segmentation and tracking. The lab has expertise
in sample preparation and labelling, live and fixed sample imaging, and in
hardware and software development. In 2009, we have carried on nine
projects and research collaborations, covering new imaging techniques,
microscope improvements, and image enhancement and quantification.
2nd harmonic generation image (red) of the non-labelled
muscle, and GFP-labelled neural network (green) in an
adult mouse gut. Courtesy of Reena Lasrado.
. Green, red, purple, and grey-level in the image
correspond to positive labeling of transcription
factors including Nkx2.2, Olig2, and Pax6, and DNA
in nuclear respectively. Courtesy of Ana Ribeiro
Publications
D. Zhu, S. Jarmin, A. Ribeiro, F. Prin, S.Q. Xie, K. Sullivan, J. Briscoe, A.P. Gould,
F.M. Marelli-Berg & Y. Gu. (2010)
Applying an adaptive watershed to the tissue cell quantification during
T-cell migration and embryonic development
Methods in Molecular Biology 616 (in press)
109
Histology
Radma Mahmood
Co-worker: Elena Grigorieva
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 10 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 used for hematoxylin and eosin 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 facility also provides training,
protocols, and assistance for investigators on all aspects of histology, including
tissue fixation, tissue processing, and immunohistochemical techniques.
Kidney stained with Periodic acid Schiff stain (E. Grigorieva)
Bone stained with Mallory’s Trichrome (E. Grigorieva)
Colon stained with Hematoxylin and Eosin (E. Grigorieva)
110
Electron microscopy
Liz Hirst
The Institute has both Transmission (Jeol 1200 EX
conventional scattering optics) and Scanning Electron
Microscope (Jeol 35CF) facilities which are currently being
upgraded to CCD photography. There is also a dedicated
EM processing laboratory.
Staff from any department at NIMR may request TEM or
SEM investigations for the purpose of providing supporting
data for scientific studies ongoing within their own
laboratory.
TEM techniques available include ultrathin sectioning and
ultrastructural analysis of experimental tissues, cell cultures
or pellets. Immuno-EM techniques can be post-embedding
immuno-gold labelling of antigens upon ultrathin sections
or pre-embedding HRP labelling. SEM techniques available
include internal anatomy by dry fracture or dissection as
well as external topology. Elsewhere within the Institute, a
second Jeol 1200EX is set up for low dose high resolution of single molecules and viruses
Generally samples are provided by the requester and analysed by TEM and/or SEM with reference to the questions of specific
interest for their project. Results normally consist of representative micrographs and a written report of the interpretation
of the ultrastructural morphology for discussion and publication. No previous experience of electron microscopy is required
as expertise and advice is provided by the EM Unit. Alternatively, should staff/students wish to learn any EM techniques for
themselves, technical advice, training and support can be provided.
TEM M. tuberculosis infected macrophage
SEM Drosophila eye mutation
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Single molecule techniques
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 biomolecules. Some of these techniques provide high resolution
images of the moelcules 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
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 optical 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 per 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.
The AFM tip is scanned over the sample and deflections of the
tip, as it rides over molecules fixed to the surface, are measured
using a laser-based position sensor. 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.
Atomic Force Microscopy (AFM) works by scanning an ultra sharp, silicon probe over a surface that
has been sparsely coated with biological molecules or biological cells. The JPK nano-wizard used at
NIMR enables simultaneous imaging by optical microscopy and AFM
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Cryo electron microscopy
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 turns to 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 reveal near-atomic resolution structural information. CryoEM is well-suited to highresolution studies of both the structure and dynamics of large proteins and protein complexes (e.g. 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).
113
Bioresources
Joachim Payne
Co-workers: Brian Trinnaman, Jackie Wilson, Ian Oliver, Charlotte Austin, Wioletta Berg, Viktoria Janusova
The Large Scale Laboratory team has
over 40 years of combined cell culture
experience, and offers a full consultation
service for all requests. Today we grow
a wide range of animal, insect, yeast and
bacterial cells for eight research divisions
at NIMR, as well as collaborating with
other MRC units, the Marie Curie
Research Institute, NIBSC and the
Wellcome Trust Sanger Institute.
Last year we grew 1200 litres of
hybridoma cells and 2400 litres of
yeast and bacterial cultures. Cells can
be supplied quick frozen or lysed using
a Constant Systems cell disrupter. For
concentrating supernatants we have a
Sartorius crossflow filtration system and
a Quixstand hollow fibre unit.
Our in-house Media Production facility
has formulae for over 1200 types of
product, and last year processed 2800
orders, totalling around 36000 litres of
media and associated solutions including
quarter of a million tubes of Drosophila
food and a variety of microbiological
poured plates.
The Mellanby Freezer Archive is a
purpose-designed facility for the longterm, secure storage of frozen material.
At the moment we are responsible for
over half a million samples belonging to
the MRC’s Prion and Clinical Trials Units
and researchers as far away as the MRC
Social and Public Health Sciences Unit in
Glasgow.
Jackie inspects a hybridoma culture
114
Brian sets up one of our bioreactors
Flow cytometry facility
Aaron Rae
Co-workers: Graham Preece, Nadine Biboum
The Flow Cytometry Facility provides state-of-the-art technology
for high speed, sterile sorting of multiple types of cell populations
for cellular, molecular, signalling and in vivo studies. The facility
also provides single cell sorting and cloning. In addition, it
offers multiparameter fluorochrome analysis of cell markers,
and measurement of calcium fluxes, apoptosis and cell cycle
parameters. The facility serves a large number of NIMR researchers
from the Infections and Immunity, Genetics and Development and
Neurosciences Groups. In addition to providing NIMR scientists
with an essential cell sorting service and FACS analyser facility,
the Facility trains research staff, including PhD students and
postdoctoral researchers. The facility is well equipped, with four
Cell Sorters that range from 4-colour to 13-colour machines
(Beckman Coulter MoFlo; Becton Dickinson FACS Aria II) and
eight FACS Analysers that include 4-colour and 9-colour machines
(Becton Dickinson FACS Calibur, Canto and LSRII; Beckman
Coulter Cyan ADP).
FACS profile of T-cells dividing in different host environments. (Image courtesy of
Benedict Seddon).
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High-throughput sequencing
Abdul Karim Sesay
High-throughput sequencing technologies are revolutionising
molecular genetics, vastly expanding our ability to study genome
structure, how genes are regulated and how cell and tissue
differentiation occurs. Combined with increasingly sophisticated
bioinformatic analysis, these methods of massively parallel
sequencing-by-synthesis are likely to impact 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. In order to
maintain its position at the forefront of basic research, NIMR has
established a central next-generation sequencing facility.
This facility provides a cost-efficient service, producing rapid and
highly accurate DNA and RNA sequence data for researchers
at NIMR. By assisting at all stages from experimental design to
data assembly and analysis, the service dramatically extends
the ability of our scientists to make discoveries in genomics,
epigenomics, gene expression analysis and protein-nucleic acid
interactions. Establishment of the sequencing service coincides
with the formation of the Division of Systems Biology and the
appointment of two new research Programme Leaders.
High throughput sequencing data from a ChIP experiment in mouse. Major peaks show likely binding sites of the transcription factor
under investigation, at different positions within a 144kb region around a known gene. Traces are derived from density of mapped sequence
reads at 100 base intervals. Upper chart shows ChIP read density in blue and ‘input’ (control) read density in red; lower chart shows the
difference between the ChIP and input read densities in green.
Courtesy of Eva Kutejova
116
Affymetrix microarray facility
Roger Buxton
Co-worker: Bob Butler
This facility enables a wide range of highly parallel genomic
analyses, making use of the sequence data from a diverse
range of organisms. A major use is for the generation of gene
expression profiles, enabling the understanding of complex
biological processes and disease through approaches such
as Systems Biology analysis; other applications include ChIPon-chip experiments to analyse the global interactions
between DNA and regulatory proteins and single nucleotide
polymorphism (SNP) analysis for use in genome wide
association studies.
The Institute has an Affymetrix GeneChip® system for which
microarrays are available for a number of species; we have
used those for Mycobacterium tuberculosis, Drosophila, Xenopus,
zebrafish, chicken, dog, mouse and human. It is equipped with
an Affymetrix 7G scanner and GeneChip 450 fluidics station.
We have the necessary equipment for RNA and DNA QC
analysis using the Nanodrop spectrophotometer and Agilent
2100 Bioanalyzer. Scientists prepare RNA or DNA which
is then used to perform the necessary fluorescent labelling,
hybridisation, washing and scanning. The data is then available
for individuals to analyse with their preferred software; we have
two licences for GeneSpring which can be used. The facility is
available to NIMR scientists as well as external collaborators.
Agilent Bioanalyzer trace showing minimal degradation of RNA
Image of hybridised probe array
117
Level 4 high containment virus laboratory
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 World Influenza Centre (WIC) 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 poorly characterised viruses are also received. Some of these viruses, notably viruses
from zoonotic H5N1 infections, will 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 Animal Pathogens
Order. It was used for the growth and characterisation of samples of the pandemic H1N1 sent from around the world, and to
generate under high containment reference post-infection ferret antisera to the emerging pandemic viruses for virus antigenic
analyses. It has also been used for the isolation and characterisation of multiple human isolates of H5N1 avian influenza virus,
for example from the Turkish outbreak in humans in 2006. The laboratory capacity has been extended (to 160 m2) 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 facility 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 facility
• 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 facility, there are 11 level 3
laboratories scattered among the main buildings and
biological research facilities of 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.
118
Engineering and Electronics
Engineering workshop: Alan Ling
The workshop 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)
• Milling (CNC)
• Turning
• High precision (watch making)
• Sheet metal forming
• Welding
• Plastic vacuum forming
• Injection moulding (plastic components)
The experienced staff can manufacture quick one-off prototypes,
followed by continued development and modification to produce
the desired item or apparatus.
On site repair and maintenance of laboratory equipment is also
carried out in the workshop. The varied facilities means that a
very diverse range of projects have been worked on, including:
• micromanipulators
• microscope set-ups
• custom made parts
• temperature controlled chambers
• drug infusers and nebulisers
• blood flow measurement devices
Alternating two colour fluorescence imaging
A custom-built control unit synchronises an EMCCD digital
camera and two lasers together with a computer data
acquisition program.
Electronics: John Sawkins and Martyn Stopps
An Electronics & Programming Workshop
A two day practical workshop providing basic electronics and
programming techniques enabling exploration of novel research
beyond what commercial apparatus may provide.
Electronics facilities support scientific groups requiring
bespoke electronic and software-based instrumentation.
Utilising up-to date technologies, employing microcontrollers
and mixed signal devices we provide a complete product
development lifecycle from initial specification and proof of
concept to the final solution.
119
Technology transfer
Eileen Clark
Scientists are skilled in conducting research but are not expected to be
experts in research protection and commercial development. NIMR’s
dedicated Technology Transfer Liaison officer supports staff by providing
mechanisms and structures and encouraging scientists to be alert to
potential exploitation opportunities. Basic technology transfer activities
such as material transfer agreements, collaboration agreements and
confidentiality agreements can be dealt with locally and speedily.
Research at NIMR supports the primary mission of the MRC, to
encourage and support research to improve human health. Research
findings can influence healthcare in many ways including bringing new
drugs to the market, improving diagnostics, and assisting industry research.
Scientists at NIMR actively engage in this translational process in a variety
of ways. MRC Technology (MRCT), the exclusive commercialisation catalyst
for the MRC, works to translate cutting edge scientific discoveries into
commercial products and it offers support to NIMR translational activities.
Some NIMR research findings are patented and some patents are licensed
for further development. One recent patent, that is now available for
industrial exploitation, concerns the crystal structure of the influenza virus
neuraminidase protein. This may help in the development of new drugs
against the influenza virus.
NIMR have been involved in the production of
diagnostic equipment for field use in malaria and
regularly supply reagents such as flu serum/viruses,
hybridomas and transgenic mice for use in diagnostic
and pharmaceutical research laboratories as well
as other academic laboratories. Scientists are also
involved in collaborations with industry or hosting/
supervising PhD students funded by industry.
Many have consultancies with biotechnology and
pharmaceutical companies. One major current area
of collaboration is influenza research.
Structure of N1 neuraminidase complexes
120
Development of drugs against malaria
Collaboration between NIMR’s Division of Parasitology and the MRC Technology Centre for Therapeutics Discovery has made substantial
progress in identifying highly effective inhibitors of a malaria parasite kinase that has been implicated in parasite development and invasion
of red blood cells. The kinase phosphorylates two components of an acto-myosin motor that drives the invasion process. Such inhibitors
will prevent the multiplication of the parasite in the blood stream, which is the stage of the life cycle responsible for the disease. There is an
urgent need for new drugs to help control and potentially eliminate malaria and the hope is that the inhibitors identified in this collaboration
will be developed into such therapies.
Parasites developing in a red blood cell. Each blue spot is an individual nucleus detected with a DNA-binding stain. The periphery of each parasite
is marked by the red stain which identifies one of the phosphorylated proteins of the motor complex and the green stain identifies a protein
essential for invasion of fresh red cells. The parasites will burst out of this red blood cell and each will bind to and invade a new cell where the
cycle of development and multiplication will be repeated.
Cervical cancer
Studies in the Division of Virology on the life cycle of Human Papillomaviruses have provided key information as to how these viruses cause
neoplasia and cancer. A spin-off from this work is the rational selection of biomarkers which can be used to identify disease and to predict
the risk of progression. We have been developing one of these markers (E4) with a commercial partner, as a disease severity marker and
as an end-point marker for the current HPV vaccine trials. This approach is now attracting the attention of clinical scientists who are familiar
with the problems of cytology screening for cervical cancer.
E4 staining (green) identifies HPV infection in a cervical biopsy. The protein is abundant in the cells that are taken
during the cervical smear test. Cell nuclei are stained in blue.
Red shows cells that are driven through the cell cycle by the virus
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Other support services
The NIMR library is dedicated to serving the information
needs of the scientific staff and students of NIMR and MRCT.
It provides access to a broad range of electronic journals and
other printed and electronic information resources, harnessing
the best available tools and technologies. Assistance with
information searching and handling is also available.
Computing and telecommunications provides a
helpdesk, central computing services, network infrastructure,
email, desktop computer support, wireless networks, archiving
and the internal phone system. The Institute is connected to
the internet via a 100Mb JANET connection.
The NIMR web team is responsible for maintenance,
support and development of the external website and intranet.
They provide standards-compliant, cross-platform and userfriendly websites and applications and work with a range
of staff throughout NIMR, collaborating in particular with
Computing, the Library and PhotoGraphics.
Engineering services supply internal emergency and
repair services for laboratory equipment breakdown, in
particular for centrifuges and incubators. Rotor inspections
and pipette service/repair can also be dealt with. These services
minimize downtime and costs.
Safety and security provide a safe working environment
at the Institute. All staff are offered safety training and advice.
Radiation monitoring and dosimetry is undertaken as well
as chemical and biological waste disposal. There are also
specialised laboratories available e.g. for radioactive work, plus a
cell irradiator.
The Photographics section provides a professional
graphic, design and imaging service offering a wide range of
skills and facilities for the presentation of science through
publication, digital presentation and posters. Services include
illustration, graphics, audio-visual production and presentation,
interactive animation, photography, publishing, binding and high
quality copying. The section also provides in-house training for
NIMR staff on graphic applications such as Adobe Photoshop
and Microsoft Powerpoint.
122
In memoriam
John Eccleston (1943 -2009)
John Eccleston was an international leader in research on small G proteins, and the
mechanisms of their interactions with effector proteins. He gained a high reputation
for his development and application of fluorescent probes, especially guanine
nucleotide analogues. John spent 25 years as a group leader at NIMR in the Division
of Physical Biochemistry and formally retired just 6 months ago, though he remained
a very active scientist until he became seriously ill very recently. He died aged 66 on
30th September 2009.
John began his academic career the hard way, earning his first degree over four years
through the Graduate Membership education programme of the Royal Society of
Chemistry at Warley Technical College and Liverpool Polytechnic. He joined David
Trentham’s small research group at Bristol University in a technical post and shortly
afterwards registered for a PhD. During this time he made seminal contributions
towards understanding the ATPase mechanism of myosin. In 1977 John launched
his independent scientific career at the University of Pennsylvania, studying the
enzyme mechanisms of the GTPases EF-Tu and EF-G that were involved in protein
biosynthesis. This was a very percipient choice of research topic given all that we
now know about the role of small G proteins in cellular regulation.
In 1984 he joined the staff of NIMR as a group leader and authored nearly
100 papers during his career at Mill Hill. He pioneered fluorescence anisotropy
measurements to analyse protein association and dissociation in regulatory pathways
- key events that are otherwise difficult to monitor in real time. The introduction of
X-ray crystallography facilities to the Institute gave great impetus to John’s science
and led to very fruitful collaborations with the new crystallographers’ research
group, including three Nature papers in 1997. In the last five years he produced
several papers in which seemingly intractable problems at the molecular level have
been addressed, collaborating with research groups in the Virology and Parasitology
Divisions.
No appreciation of John would be complete without a memory of the
warmth, dry humour and friendship that John extended to all around him, and
his careful and committed instruction and guidance to students at all levels.
123
Sixty years of Immunology at NIMR
A history of immunology research at Mill Hill, written by Anne O’Garra and Dimitris Kioussis.
Immunology at NIMR, Mill Hill, evolved from scientists in different Divisions being drawn together to address convergent questions
related to how whole bodies, mouse and man, responded to threats from parasites, bacteria and viruses, and how this response
impinged on the newly emerging clinical disciplines of transplantation, allergy and autoimmune disease. The Institute has served
as a training ground for young fellows as well as a hub for exchange of ideas in immunology research internationally. Through the
years wide collaborations and interactions between Divisions and with colleagues throughout the world have continued and
remain the philosophy of NIMR research. The use of immunological techniques and/or immunological approaches has been an
important driver of this process, influencing many researchers during their time at the Institute and in their later careers. We will
attempt to unfold the salient points in this brief history.
John Humphrey was invited in 1949 to join the Division of Biological Standards at
NIMR, when it was located in Hampstead, by Sir Charles Harington, the then Director
of the Institute. Humphrey’s mandate was to focus 50% of his time on Standards
and for the remainder of his time to pursue his own research interests. In addition
to contributing greatly to the development of Standards, Humphrey made the most
of the interdisciplinary nature of the Institute. In 1950 when NIMR moved to Mill
Hill, Humphrey was put in charge of development of standards for antibiotics and
enzymes in clinical use and, most importantly, developed quantitative assays for
biological activities and had long-lasting involvement with the WHO. His interest
in immune reactivities was broad and his work on the fate of radiolabelled antigen
in vivo attracted many researchers to the NIMR. In addition, in collaboration with
colleagues in various Divisions at the Institute, he helped to develop immunological
techniques and their application to the study of immunological problems. Projects
included the application of newly available isotopes of iodine and carbon to studies
of immunoglobulin metabolism, pharmacological studies of anaphylaxis and of platelet
involvement in allergic reactions, and demonstration of the role of granulocytes in
John Humphrey
Arthus reactions. By 1957, immunology had developed so far at NIMR that Humphrey
was relieved of duties in the Biological Standards Division to set up the first Immunology
Division composed of researchers working on immunological problems. These included Brigitte Askonas, Walter Brocklehurst
and Brigid Balfour. Askonas had been recruited earlier to the Division of Biochemistry by Tommy Work, whose Division had a
strong influence on the development of immunology at NIMR. In 1958 Rodney Porter, working in the Biochemistry Division at
NIMR, showed that immunoglobulin molecules could be split by enzymes into two parts; one was heterogeneous but had antigen
specificity, the other was more homogeneous and could be crystallised. He later received the Nobel Prize in 1972 for his work
on the structure of immunoglobulins. Among young recruits and fellows that Humphrey attracted, to name but a few, were Frank
Austen, Hugh McDevitt, Gordon Ada, Charles Janeway, Abul Abbas and Gerry Klaus, the latter working on B cell responses and
later demonstrating with Humphrey the role of follicular dendritic cells in B memory cell generation. Brigid Balfour was one of the
first generation to appreciate the value of studying cellular morphology and ultrastructure in relation to immune function and in
understanding the importance of the architecture of lymphoid tissues. She pioneered contributions to the study of dendritic cells,
describing these as “veiled cells”, and realised they were derived from Langerhans cells and played an important role in promoting
immune reactions.
Sir Peter Medawar became director of NIMR in 1962, having been the Jodrell Professor of Zoology at University College
London for the previous eleven years. His ground-breaking studies, in collaboration with Leslie Brent and Rupert Billingham, on
124
the immunology of tissue graft rejection and the establishment of the phenomenon
of acquired immunological tolerance had led to his being awarded the Nobel Prize
in Medicine in 1960, together with the Australian virologist/immunologist, Frank
Macfarlane Burnet. Peter Medawar’s appointment as Director in 1962 and the
appointment of N.A. (Avrion) Mitchison, one of Medawar’s early PhD students in
Oxford, to succeed A.S. Parkes as Head of the Division of Experimental Biology,
substantially increased the overall strength in immunology at NIMR. Medawar and
Brent, who accompanied him to NIMR, joined the Division of Experimental Biology. As
Director, an important innovation of Medawar’s was the restructuring and modernising
of the animal house, recognising the indispensable role of animals in the research of
many Divisions. Medawar set up the Animal Division to provide these services, but
continued to play an important role in strategic matters, arguing the case with the
MRC for funding to construct the first Specific Pathogen Free (SPF) building and
appointing the first veterinary pathologist. The Animal Division evolved and grew and
today, under the name of Biological Services, represents one of the strongest in Europe.
Another highly effective introduction by Medawar was extension of the building to
Sir Peter Medawar
allow the creation of a common recreational area with a bar adjacent to the cafeteria,
to provide a place for scientists to exchange ideas in relaxed surroundings, an arrangement that continues to this day.
Medawar loved conducting his own laboratory research, and designated two and a half days a week for working at the bench,
including skin grafting mice. In addition, he set an example at the Institute by interacting with scientists in every Division, as well as
bringing about infrastructural changes following negotiation of adequate funds from the Medical Research Council to support the
cutting-edge research at the institute. In addition to his administrative load and his research, Medawar gave public lectures, including
philosophical discourses on the scientific method, on radio and elsewhere. He became famous for these and published a number
of books in this area. He represented science and the Institute widely, to lay and
scientific audiences. In his area of scientific work, transplantation biology, Medawar’s
research attracted surgeons, such as Gene Lance, to the Institute from the US and
other countries and they contributed to the immunological work, including the use
of anti-lymphocyte serum (ALS) as an immunosuppressive agent in blocking allograft
rejection. Elizabeth Simpson, trained as a veterinary pathologist, joined Medawar
at NIMR due to her interest in lymphocytes and used ALS in the study of tumour
rejection and tolerance.
Avrion Mitchison
The Division of Experimental Biology, led by Avrion Mitchison, concentrated mainly on
mechanisms of induced antigen-specific immunological unresponsiveness (tolerance).
Interests ranged from a theoretical angle to experimental research, exploring the role
of the “carrier” components of antigen in studies of anti-hapten antibody responses
elicited by haptens conjugated to such “carrier” proteins. At that time an iodinecontaining synthetic immunological determinant, 4-hydroxy-3-iodo-5-nitrophenylacetic
acid, NIP, was developed by Alan Brownstone, Mitchison and Rosalind Pitt-Rivers
(Division of Biochemistry) and this was fundamental to the hapten-carrier work. Klaus
Rajewsky joined Mitchison’s laboratory at NIMR in 1969 as an EMBO fellow with a
125
Sixty years of Immunology at NIMR contd.
desire to learn to handle experimental mice, but also intrigued by experiments in which both he and Mitchison had been involved
previously which suggested a mechanism of T-B interaction. Their seminal findings demonstrated the hapten-carrier effect in T-B
collaboration, describing the role of T-cells responding to the “carrier” moiety as helpers of B cells, which are responsible for
hapten-specific antibody secretion. On another topic, in collaboration with David Dresser who had accompanied Mitchison from
Edinburgh, they researched the mechanisms of immunological paralysis and showed that it could be achieved in adult hosts by
injection of high or low doses of antigen. Thence the concept of low zone and high zone tolerance was developed by Mitchison.
Mitchison not only hosted a breadth of immunological thinking and ideas, but was also broadly interested in other disciplines, and
accepted to his laboratory Martin Raff, who in his own words had “been in clinical medicine and neurology and knew nothing
about science”. On his arrival at Mill Hill in 1968 Mitchison suggested that Raff follow up the work of Reif and Allen and test
whether the Thy-1 alloantigen, to which Mitchison had already begun to raise an antiserum, was expressed on mouse T cells
but not B cells, in which case it could be used as a T-cell marker. Raff ’s subsequent work demonstrating Thy-1 as a T-cell specific
marker was an important contribution to immunology. Raff collaborated with Stefanello de Petris from the Division of Biophysics,
making the discovery that cross linking of surface immunoglobulin molecules, normally distributed over the entire B cell surface,
leads to capped distribution at room temperature, followed by endocytosis of the surface Ig. These findings had major implications
for much of cell biology and ligand receptor interactions. Through the years the Division of Biochemistry continued to contribute
immensely to the development of molecular immunology and included scientists such as Alan Williamson and Michael Crumpton.
Crumpton defined molecules on the surface of lymphocytes at an early stage, making
reagents to study them, and leading to the isolation of major histocompatibility type
(MHC) molecules.
Brigitte Askonas initially focused on antibody synthesis, showing that antibody
secreting cells did not just reside in lymphoid tissue, but also in bone marrow and
lung. This work, in collaboration with Alan Williamson (Division of Biochemistry),
enabled the characterisation of antibody forming cells, assembly of heavy and light
chains and the establishment of the clonal dominance of B cells forming high affinity
antibodies, studies which Andrew McMichael continued. Her second interest was
macrophages and antigen processing studies, to which Emil Unanue contributed
greatly. Following uptake of radio-labelled protein antigens they showed that, although
most of the antigen was degraded, a small amount remained that could stimulate
antibody responses in vivo. This finding set the stage for the discovery of antigen
processing and peptide-MHC antigen presentation to T cells.
From 1963 to 1972 the Immunology Division had remained relatively small, headed
by John Humphrey and with a few staff scientists, but it was augmented by a large
number of visiting scientists, so that there were often more visitors than there were
NIMR scientific staff members. Collaboration was the norm and Immunology at Mill Hill grew famous internationally, becoming
a hub for innovative discovery with contributions from numerous scientists, including Roger Taylor, Mel Greaves, Harvey Cantor
and Henry Wortis, Stuart Schlossman, William Paul, to name but a few. When Medawar and Mitchison left the NIMR in the
early 1970’s, the Divisions of Experimental Biology and Immunology were combined into one single Immunology Division and
immunology continued as a strong discipline in the institute. Following work from immunologists in the USA describing IgD in
humans, Abney and Parkhouse were the first to demonstrate IgD on mouse lymphocytes and went on to describe IgD in the
context of the ontogeny of Ig isotype diversification. During these years Alick Isaacs, the co-discoverer of interferons and one of
Britain’s leading virologists, was the Head of the Division of Bacteriology and Virus Research and then the Laboratory for Research
Brigitte Askonas
126
on Interferon at NIMR, before the strong link between innate and adaptive immunity was established.
By the time Askonas took on the leadership of the Division of Immunology in 1976 it consisted of group leaders, Parkhouse,
Thomas, Dresser, Klaus and herself. She had by then started her work on the immune response to infectious agents. David Sacks
and Murray Selkirk worked with Askonas and Bridget Ogilvie, then in the Parasitology Division, to study immunosuppression
during trypanosomiasis. Askonas also worked on the cell-mediated immune response to influenza and demonstrated that
influenza virus specific cytotoxic T lymphocytes (CTL) were MHC restricted and, unexpectedly, did not distinguish influenza
virus variants within a serotype. Michael Crumpton (Division of Biochemistry) and John Skehel (Division of Virology), with a
joint PhD student, Sara Courtneidge, were also working on influenza/MHC interactions. Askonas and collaborators isolated and
grew the first virus specific T cell clones, leading the way to understanding the nature of viral antigen presentation to T cells.
Alain Townsend, a PhD student with Askonas, distinguished influenza virus subtypes; he identified its target as nucleoprotein and
went on to show how viral proteins were degraded to peptides, which were presented bound to MHC proteins, a fundamental
discovery in immunology. Many past PhD students and Fellows, who are now established and successful researchers in their own
right, worked with Askonas through the years including Mike Bevan, Greg Bancroft, Peter Openshaw, Charles Bangham and David
Wraith. A key area of research was to define the function of CTL in vitro and in vivo, where Askonas and colleagues described
their role in viral clearance, and also their ability to cause lung immunopathology.
Richard Flavell founded the Division of Gene Structure and Expression at NIMR in
1979. During his time at NIMR Flavell initiated his research in immunology, until then
having focused his research on elucidation of molecular events in the regulation of
eukaryotic genes in general and in particular the haemoglobin genes. With his highly
talented Postdoctoral Fellows, Frank Grosveld and Henrik Dahl, Flavell developed
the first cosmid libraries facilitating the recovery of large pieces of DNA encoding
multiple genes and gene transfer experiments. He then used these technologies to
isolate essentially all of the mouse MHC genes and to analyze their function and
structure, and with his Postdoctoral Fellows, Andrew Mellor and Elizabeth Weiss,
elucidated the molecular basis of polymorphism in MHC genes in general. This work
at NIMR led to the broadening of Flavell’s interest in functional immunology, a career
path that he continued to follow. Dimitris Kioussis, as a Postdoctoral Fellow with
Flavell, worked with George Kollias and Frank Grosveld who introduced transgenesis
to the NIMR, bearing a strong influence on Kioussis’s future work on thymic
development.
Richard Flavell
Ita Askonas, who retired as Head of Immunology at NIMR, in 1989, has had
a profound and sustained influence in the field, and in the development and
advancement of major internationally acclaimed investigators in immunology (see photo below of her 80th Birthday meeting),
and continues actively to advise scientists at all levels, taking a particular interest in training young researchers.
Immunology continues at NIMR
Kioussis, along with Rose Zamoyska, Brigitta (Gitta) Stockinger and Andrew Mellor, established a new Division of Molecular
Immunology at NIMR in 1991. Kioussis has made discoveries on how chromatin regulates gene expression and therefore fate
decisions during thymocyte development, including functional commitment within the T cell lineage. His work has not only had
127
Sixty years of Immunology at NIMR contd.
Ita Askonas Group Photo 80th Birthday meeting: Celebratory Immunology Meeting for Ita Askonas’s 80th Birthday, Trinity College, Oxford, 2003.
From Left Standing: Alain Townsend FRCP, FRS (Prof. Molecular Immunology, Univ of Oxford), Charles Bangham (Chair of Immunology, Imperial College),
Greg Bancroft (London School of Hygiene and Tropical Medicine), Peter Openshaw (Prof. Experimental Medicine, Imperial College), David Wraith (Prof.
Experimental Pathology, Univ of Bristol), Alan Williamson, Helen Bodmer, (Head, MRC and Health Research Team), Tracy Hussell (Prof. Inflammatory
Diseases, Imperial College), Bridget Ogilvie DBE, FRS, FAA, Emil Unanue (Prof. Pathology, Washington University Unversity School of Medicine, St. Louis),
Colin Gelder, David Sacks (NIAID, NIH), Leszek Borysiewicz KBE, FRCP, FRS (Chief Executive of the MRC).
From Left Sitting: Michael Parkhouse (Head of Infection and Immunity Group, Gulbenkian Institute), Andrew McMichael KBE FRS (Director Weatherall
Institute of Molecular Medicine & MRC Human Immunology Unit, Oxford), Ita Askonas FRS, Hugh McDevitt (Prof. Microbiology and Immunology, Stanford
University).
impact on our knowledge of lymphocyte development and commitment but also on the strategies employed in transgenesis and
gene therapies. Stockinger has made crucial contributions on the development, maintenance and regulation of peripheral T cell
compartments and immune responses since her arrival at the NIMR in 1991. More recently she has described the mechanisms
for the differentiation of a new subpopulation of CD4+ T cells, the Th17 subset, critical for eradication of fungal pathogens and
yet also causal of dysregulated autoimmune processes. Gerry Klaus became Head of the Division of Cellular Immunology in 1991
after Askonas had left NIMR. He recruited Victor Tybulewicz and Steven Ley to the Division, influenced by Klaus’s original findings
of signalling through the B cell receptor leading to polyphosphoinositide degradation. Tybulewicz has since taken over the Division,
now renamed Immune Cell Biology, and made important contributions to two distinct areas; firstly, the field of signal transduction
in the immune system, around which he has built the Division, and secondly, generation of a trans-chromosomic mouse strain to
create a model of human Down Syndrome, leading to broad interactions throughout the Institute. Study of the immune response
to infection has also continued at NIMR. Jean Langhorne, who joined the Division of Parasitology in 1998, has made fundamental
128
contributions to defining the mechanisms of protection and pathogenesis in malaria. Finally, O’Garra, who completed a PhD in
bacterial adhesion, followed by a Postdoctoral Fellowship on cytokines and B lymphocytes with Gerry Klaus at the NIMR. During
her 15 years at the DNAX Research Institute in the USA, O’Garra collaborated with Kenneth Murphy at Washington University,
St. Louis, to show how pathogens and their products induce the production of cytokines such as IL-12 in macrophages and
dendritic cells and in this way induce the differentiation of TH1 T cells producing IFN-g, critical for pathogen eradication. O’Garra
then demonstrated that IL-10 inhibits macrophages and dendritic cells including their production of IL-12, thus regulating TH1
responses, and demonstrating IL-10’s broad anti-inflammatory role. O’Garra returned to the UK in 2001 and set up the new
Division of Immunoregulation at NIMR, whose groups focus on the immune response in tuberculosis and viral infections, bringing
together the divisions of immunology and infections at the institute.
Immunology at NIMR is still exciting and strong internationally and the philosophy of interaction, free exchange and collaboration
still prevails.
Present Immunology at NIMR
Many contributed greatly to immunology at NIMR through the years. Not all of them have been acknowledged in this piece due to restrictions in space.
Our apologies to all you who have not been mentioned – rest assured you have not been forgotten.
We thank Brigitte Askonas, Avrion Mitchison, Elizabeth Simpson, Michael Crumpton, Richard Flavell and Martin Raff for their helpful input.
129
Major funding sources
Biotechnology and Biological Sciences Research Council (BBSRC)
British Council
British Heart Foundation
Dana Foundation
European Commission
FARA
Genentech
GlaxoSmithKline
Great Ormond Street Hospital Charity
Jeantet
Lady Tata Memorial Trust
Leukaemia Research Fund
Medical Research Council
Medical Research Council Technology
Novartis
NC3Rs
Oxford University
Parkinsons Disease Society
Prix Scientifique
Roche
Royal Society
Wellcome Trust
Yamanouchi
130
Scientific seminars
Selected major seminar speakers: 2009
C C Hui
Chaya Kalcheim
Cliff Tabin
Naama Barkai
Ryoichiro Kageyama
Carole Goble
Anne Cooke
Antonio Lanzavecchia
Doreen Cantrell
Hergen Spits
Tasuku Honjo
Steve Smale
Adolfo Garcia-Sastre
Debbie Smith
Jonathan Leis
Christian Doerig
Brian Kobilka
Eric Rubin
Jacques Banchereau
John Coffin
Joshua Sanes
Jules Hoffmann
Lew Cantley
Matthew Freeman
Olivier Pourquie
Ottoline Leyser
Peter Rigby - Harington Lecture
Richard Treisman
Uri AlonWeizmann
Alan Jasanoff
Craig M Crews
Angela Gronenborn
Marek Cieplak
Marc Fontecave
Dr Emmanuel Skordalakes
Gerhard Schratt
Prof Dominic M Walsh
Steve Pollard
Hospital for Sick Children, Toronto
Hebrew University of Jerusalem, Hadassah Medical School
Dept of Genetics, Harvard Medical School
Weizmann Institute of Science, Israel
Institute for Virus Research, Kyoto University, Japan
University of Manchester
Dept of Pathology, University of Cambridge
IRB Institute for Research in Biomedicine, Bellinzona, Switzerland
University of Dundee
Genentech
Kyoto University
UCLA, Jonsson Comprehensive Cancer Center
Mount Sinai School of Medicine
Centre for Immunology and Infection, Hull, York Medical School
Northwestern University, Feinberg School of Medicine, Chicago
Wellcome Centre for Molecular Parasitology, Glasgow
Stanford School of Medicine, California
Harvard School of Public Health
Director, Baylor Institute, Dallas
Sackler School of Biomedical Science
University of Havard, USA
University of Strasbourg, France
Harvard Medical School
MRC Laboratory of Molecular Biology
Stowers Institute for Medical Research, Kansas City
University of York
The Institute of Cancer Research
CRUK, London Research Institute
Institute of Science
Department of Biological Engineering, MIT
Yale University
Dept of Structural Biology, University of Pittsburgh
Institute of Physics, Polish Academy of Science, Warsaw, Poland
Institute of Metals in Biology (CEA-UJF-CNRS), Grenoble, France
The Wistar Institute, Philadelphia, USA
University of Heidelberg, Interdisciplinary Center for Neurosciences (IZN)
UCD School of Biomolecular and Biomedical Science, University College, Dublin
Wellcome Trust Center for Stem Cell Research, Cambridge
131
Staff honours
Prizes and awards
Margrie
Young
Alexander von Humboldt Research Award; Buckston Browne Prize (Harveian Society)
Gardner Middlebrook Award (for Contributions in Mycobacteriology), May 2009
Editorial boards
Ang
Blackman
Briscoe
Buxton
Doorbar
Driscoll
Elgar
Guillemot
Holder
Langhorne
Logan
Lovell-Badge
McCauley
Margrie
Ober
O’Garra
Pastore
Ramos
Rittinger
Smith
Stoye
Turner
Tybulewicz
Wilkinson D
Wilkinson R
Young
Zimmerman
International Journal of Developmental Biology
Associate Editor: PLoS Pathogens
Development, Developmental Biology, Developmental Dynamics, Neural Development, Faculty of 1000
FEMS Microbiology Letters
Journal of Clinical Dermatology, Journal of General Virology.
Journal of Functional and Structural Genomics
Genome Biology and Evolution, Managing Editor, Briefings in Functional Genomics and Proteomics
BMC Developmental Biology, Neural Development.
Molecular and Biochemical Parasitology, Eukaryotic Cell.
Associate Editor: PLoS Pathogens, Malaria Journal, Specialist Editor: International Journal of Parasitology,
Development, Developmental Biology, Developmental Dynamics
Organogenesis, Sexual Development
Journal of General Virology, Virus Research
Frontiers in Neural Circuits
Journal of Experimental Medicine, Immunology
Prion; The Open Biochemistry Journal; The Open Spectroscopy Journal.
Open Magnetic Resonance Journal
Biochemical Journal
Trends in Genetics, Development (editor in chief), Biology Image Library (subject head for developmental
biology)
Journal of Virology
Biology of Reproduction, Chromosome Research
Immunology
Mechanisms of Development (editor in chief ), Gene Expression Patterns (editor in chief), Developmental
Biology, Biochemical Journal, Faculty of 1000, BMC Developmental Biology
Tuberculosis, PLoS One, International Journal of Tuberculosis and Lung Disease.
Co-Editor in Chief, Tuberculosis
Genesis
Scientific committees
Blackman
Burgoyne
Briscoe
Doorbar
Driscoll
Elgar
Gould
132
Wellcome Trust Immunity and Infectious Diseases Funding Committee
MRC College of Experts
British Society for Developmental Biology, Company of Biologists
Society for General Microbiology Translational Virology Group.
Member of the External Advisory Board of the Henry Wellcome Biomolecular NMR Facility at Birmingham
University
BBSRC Bioinformatics and Biological Resources Panel
Wellcome Trust Molecules, Genes and Cells Funding Committee.
Guillemot
Hulme
Kioussis
Langhorne
Ley
Lovell-Badge
McCauley
Margrie
Mohun
Molloy
O’Garra
Pastore
Smerdon
Smith
Stockinger
Turner
Vincent
Wilkinson D
Young
European Research Council Advanced Investigator Grants, Neurosciences and Neural Disorders panel;
Wellcome Trust Neuroscience and Mental Health Funding Committee.
Scientific Advisory Board of Heptares Therapeutics
Member of the Lady Tata Memorial Trust Scientific Advisory Committee, Member of the Scientific
Advisory Board of Basel University Biomedicine, Member of the Sectional Committee of the Academy of
Medical Sciences, Member of EMBO long term fellowships committee ERC Advanced Investigator grant
committee
Scientific Advisory Board of the Research Centre for Infectious Diseases, University of Wuerzburg,
MRC Infection and Immunity Board
MRC Infection and Immunity Board
UK Stem Cell Bank joint Clinical and User Liaison Committee, Sense about Science Advisory Council,
Hinxton Group Organizing Committee, Science Media Centre Advisory Board, Scientific and Clinical
Advances Advisory Committee of the Human Fertilization and Embryology Authority (co-opted member),
President of the Institute of Animal Technology, Royal Society Animals in Research Committee, Academy
of Medical Sciences Council, Academy of Medical Sciences Communications Group, Royal Society
Sectional Committee 7, Royal Society GSK Prize Committee, Member of the jury for the BBVA
Foundation Frontiers of Knowledge Biomedicine Award, Member of Academy of Medical Sciences
Working Group on “Animals containing human material”,Distinguished Visiting Professor, University of
Hong Kong
BBSRC Animal Sciences Committee, Society for General Microbiology Virus Division Committee
Human Frontier Science Programme, European Union
MRC Molecular and Cellular Medicine Board;
Chair LM-Section, RMS, Chair of Tools and Resources Development Fund (TDRF) Panel,
BBRSC Tools and Resources Strategy Panel, Strategic Advisory Board, Dresden CBG MPI
Strategic Review Panel, Dept. of Physics and LCN, UCL;
Scientific Advisory Board, Baylor Institute for Immunology, Dallas, USA., Scientific Advisory Board, Institute
for Biomedical Sciences, Bellinzona, Switzerland.
National Grants in Italy (MURST, MIUR, PRIN), Belgium, France (Pasteur Institute, BLANC), UK (MRC,
Welcolme BBSRC), Swiss National Science Foundation, Spain and Portugal, Sub-chairman for the 2009
Grant Call of the Portuguese Ministry.
Advisory Boards of Structural Genomics Consortium, MRC-Technology Governing Board, ASM Scientific/
TwistDX Inc., MRC Molecular & Cellular Medicine Board, NIH Structural Genomics Study Group (PSI-1 &
SGCID), BBSRC IGF & Genomics Evaluation Panel, Diamond Peer Review Panel.
Member of the Scientific Advisory Board of TwistDX, Member of the Board of Directors of the Babraham
Institute, Chair of the Scientific Advisory Board of the Institute for Toxicology and Genetics, Karlsruhe,
Chair of the Royal Society Research Appointment Panel (Bi), Chair of the Wellcome Trust Sir Henry
Wellcome Postdoctoral Fellowship Committee, Member of the Scientific Advisory Board of the Indian
Institute of Science Education and Research
ERC Young investigator Panel Multiple Sclerosis Society panel
Hinxton GroupScientific Advisory Board; Institut de Génétique et Développement de Rennes. Interview panel: Wellcome
Trust-NIH four year PhD Programme.
Advisory committees: GXD Advisory Board, EMAGE Advisory Board, Grant committees: EMBO Long
Term Fellowships, Academy of Finland
Chair, DEFRA Vaccine Programme Advisory Group for Bovine TB, Chair, International Scientific Advisory
Board, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Board of Directors, Aeras Global
TB Vaccine Foundation, Steering Committee, European Tuberculosis Vaccine Initiative (TBVI)
133
PhD theses awarded: 2009
134
Name
Division
Title of thesis
James Cauwood
Stem Cell Biology and
Developmental Genetics
Identification of CIS and transfactors that regulate genetic
stability in Saccharomyces Cerevisiae
Timothy Nott Molecular Structure
Structural and functional analysis of a Phospho Dependent
Molecular Switch Rv1827 from Mycobacterium tuberculosis
Ricardo Rajsbaum Immunoregulation
Expression of TRIM genes in different immune cells and
mechanism of regulation of their expression: implications for
the immune response to pathogens
Karen Houston Molecular Neuroendocrinology
The role of membrane lipids in Weibel Palade Body formation
Gian Felice De Nicola Molecular Structure
Ines Antunes Immunoregulation
Stretch Activation in Muscle: A CA 2+ Independent
Mechanism 9
Role and specificity of regulatory T cells during retroviral
infection
Anna Garner Developmental Biology
Interactions Between the Developing Limb Bud and Spinal
Motor Neurons
Nadia Hashash Stem Cell Biology and
Developmental Genetics
The molecular bases underlying chromosome fragility at
Replication Slow Zones in Saccharomyces cerevisiae
Alan Kennedy Virology
Functional regulation of the human papillomavirus type 16
E1Ê4 protein by phosphorylation
Rute Marques Immunoregulation
A mouse model for the pathogenesis of immunodeficiency
virus infection
Emily Noel Developmental Biology
Early liver formation in zebrafish: a molecular and
morphological approach
Claire Pearson Immune Cell Biology
Genetic and functional analysis of IL7 signalling in control of T
cell homeostasis
Andrew Slatter
Kinetic mechanism of the interaction of RepD and PcrA
helicase during plasmid replication
Srividya Sriskantharajah
Immune Cell Biology
The Role of IKK Induced NF-kB1p105 Proteolysis in T
Lymphocytes
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145
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
146
147
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
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MRC National
Institute for Medical
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Mill Hill East
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Mill Hill Broadway ThamesLink
to Central London via King’s Cross
Daws
e
Mill Hill
Broadway
ay
A5100
e
M25
NIMR
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e
Th
W
at
fo
A41 to
Central London
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ne
A5109
an
Marsh L
A1
M25
H a mm
B a r n e t Way
Hi
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M1
A598
Finchley
Central
A5000 Northern Line
to Central London
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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 are within easy reach of NIMR. On-site parking is available
at NIMR.
148
2009/20010 Annual Report and Prospectus
2009/2010 Annual Report and Prospectus
MRC National Institute
for Medical Research
Science for health

MRC National Institute for Medical Research

Transcription

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