pdfMRC NIMR Annual Report - The Francis Crick Institute

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2010/2011 Annual Report and Prospectus
MRC National Institute
for Medical Research
Science for health
MRC National Institute for
Medical Research
2010/2011 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 our website at:
http://www.nimr.mrc.ac.uk
Copies obtainable from the Librarian at NIMR
ISBN-13:
2
MRC National Institute for Medical Research
978-0-9546302-9-4
Contents
Director’s foreword
Scientific highlights
Science overview
About the MRC National Institute for Medical Research
Recent research highlights
NIMR history and milestones
Student training and development
Careers
Technology transfer
Public engagement
Research groups :
A to Z list
Infections and Immunity
Structural Biology
Neurosciences
Genetics and Development
Emeritus scientists
Research facilities
A history of chemistry research at NIMR
In memoriam
Scientific seminars
Staff honours
Scientific committees
PhD theses awarded
Current funding sources
Bibliography
NIMROD social club
Map, location and travel
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Director’s foreword
This has been another eventful year for NIMR, with more excellent science (see Scientific Highlights, page 8), honours for current
and former members of staff, a new arrival, some farewells, and the usual rounds of meetings and new initiatives.
Institutions often lay tenuous claim to Nobel Prize winners, but NIMR took justified and particular pleasure in the award to Bob
Edwards of the 2010 Nobel Prize in Physiology or Medicine. Bob Edwards worked at NIMR from 1958 to 1962, during which
time his interests moved from pure science to biomedicine, and a desire to do something about human infertility. His studies on
induced ovulation and superovulation in mice presaged his work with Patrick Steptoe in which they applied such approaches to
humans, thus bringing about the revolution in in vitro fertilisation. Four million people have been born through IVF, including my
eight-year-old twins. I and many others have great cause to be thankful to him.
Bob Edwards
Iain Robinson
Some of our present and recently retired scientists have also received recognition. In particular, we were delighted that former
interim Director Iain Robinson was made an MBE and that Jean-Paul Vincent was elected to the Fellowship of the Academy of
Medical Sciences. In addition, Robin Lovell-Badge was awarded the Waddington Medal of the British Society for Developmental
Biology and Alex Gould the Hooke Medal of the British Society for Cell Biology. It is very gratifying that NIMR scientists received
this recognition from two of our national societies.
And of course, NIMR joined other MRC scientists in welcoming Sir John Savill as our new Chief Executive Officer. Sir John took
up his post in October, 2010.
Arrivals and Departures
We were joined this year by Mark Wilson, a new Programme Leader Track. Mark
comes from Thomas Wynn’s lab at the National Institute of Allergy and Infectious
Diseases, Bethesda, Maryland. His work, in the Division of Molecular Immunology,
investigates the mechanisms by which the immune system responds to parasitic
helminth infections and allergens. As we welcomed Mark, we said farewell to Dimitris
Kioussis, former Head of the Division of Molecular Immunology, and to other
Programme Leaders including Sebastien Gagneux (who retains close contact with
the Division of Mycobacterial Research as a visiting worker), Elaine Davis, Matthew
Hannah and Nobue Itasaki.
Former NIMR scientists Milan Nermut, James Porterfield, Henry Rogers, Bob
Rosenberger and Don Williamson all died last year or at the end of 2009, as did Jashu
Mistry, Janey Antoniou, Herbert Rose and Les Rowell. We send our condolences to
their families.
Mark Wilson
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Facilities
Last year I reported that we had taken order of an Illumina GAIIx sequencing machine, and this now forms the core of our new
high-throughput sequencing facility. Abdul Sesay and his colleagues are already producing large amounts of valuable data, and our
capacity will soon increase further, with the impending receipt of a HiSeq 2000 sequencing system. In addition, our new Orbitrap
mass spectrometer has been installed and we anticipate that this will make a huge difference to our analyses of protein structure
and function.
Finally, a real landmark in the life of our Bioflo 5000 fermentor: its 500th run. Since its installation 13 years ago it has cultured over
30,000 litres of cells for the Institute’s scientists. Thanks to Brian Trinnaman and everyone in his team.
Meetings and events
May 5 2010 marked the sixtieth anniversary of the official opening of the new site at Mill Hill by King George VI and Queen
Elizabeth, and the Institute celebrated by hosting an MRC Council meeting and by organising talks and a reception. Members of
Council recreated a group photograph of their predecessors taken almost exactly 60 years previously.
MRC Council visit 16 June 1950
MRC Council visit 5 May 2010
The same month saw the inaugural Medawar Lecture, where the PhD students chose and hosted the speaker. This first lecture
was by Tom Jessell from Columbia University, who gave a beautiful talk on ‘Measured Motion: The Neurons and Networks of
Spinal Motor Control’. We thank Fatima Sulaiman and all the NIMR students for organising the seminar and hosting Tom so well.
The lecture was, of course, named after one of NIMR’s most distinguished Directors, Nobel Laureate Sir Peter Medawar, OM,
CBE, FRS. We were delighted that Sir Peter’s daughter, Dr Caroline Garland, came to the lecture.
The Institute organises many symposia and meetings, but noteworthy amongst these last year was one that celebrated the life and
work of John Eccleston. Several members of the Institute spoke at the meeting, as did John’s friend and colleague Dave Jameson,
from the University of Hawaii at Manoa.
UKCMRI
Plans for our new home at the UK Centre for Medical Research and Innovation are proceeding well at every level: 2010 has been
a wonderful year for the project. I reported last year that the then Prime Minister, Gordon Brown, had visited the UKCMRI offices
at the Wellcome Trust to announce his Government’s support for the project. Since then, and as part of the Spending Review,
David Cameron, the Prime Minister and George Osborne, the Chancellor, have also pledged support for the project, and we
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are gaining in confidence that the money really will be there to fund the Institute. Certainly, the founding partners - the Medical
Research Council, Cancer Research UK, the Wellcome Trust and University College London - are keen to press ahead, and a real
achievement was the signing of the Joint Venture Agreement that allows the four parties (subject to agreement of the Charity
Commission) to set up UKCMRI as a charitable foundation. Signing took place in the presence of David Willetts MP, Minister for
Universities and Science, and Lord Howe, Health Minister.
The signing of the joint venture agreement
The year has seen great advances in the design of the UKCMRI building. Externally, architects PLP and HOK have produced
significant changes that have responded to comments from the scientific community, from local people, from Camden Council
and from bodies such as the Commission for Architecture and the Built Environment. As a result, the height of the building has
been reduced, with about one-third now below ground, the roof has been changed to a curved form to reduce the effect on
local views, and a north-south atrium has been introduced to give the building a more open feel. Inside the building there is an
elegant state-of-the art lecture theatre, and all aspects of the design are intended to encourage interactions between UKCMRI
scientists.
Computer generated images of the proposed building for UKCMRI
In addition to these structural changes, we have now included a community facility in the building, the public entrance has been
lowered to improve access, and a new east-west route passes between UKCMRI and the British Library.
These changes have resulted in a superb building that complements Sir Colin Wilson’s British Library building to the south and
whose roof echoes the famous Barlow Shed of St Pancras, to the east. It was this design that was submitted to Camden Council
for planning permission in September, and we were very pleased that the Camden Development Control Committee gave their
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consent at its meeting on 16th December. Final approval is subject to completion of a ‘Section 106’ agreement, which amongst
other things provides support for local services and infrastructure, and to the agreement of the Mayor of London.
While this work was under way, members of the UKCMRI team have been examining tenders for the first stage of the two-stage
construction process. A decision should be made early in 2011, and construction should begin in the spring.
As for the science to be carried out at UKCMRI, the fruits of the deliberations of the Scientific Planning Committee were
published in abridged form in a UKCMRI Scientific Vision document that is available from the UKCMRI web site (www.ukcmri.
ac.uk)
Sir Paul Nurse
Director and Chief Executive of UKCMRI
UKCMRI Scientific Vision document
And as many will know, the science will be carried out under the direction of Sir Paul Nurse, who was appointed Director and
Chief Executive of UKCMRI in July 2010. Everyone knows Paul: Nobel Laureate; until recently President of Rockefeller University;
President of the Royal Society; and named recently by the Times Eureka supplement as the most influential scientist in the UK. We
are delighted that Paul has accepted the position of UKCMRI Director, and we look forward to working with him in the future.
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Scientific highlights
It is always hard to select individual research highlights for a particular year, and for 2010 it was particularly difficult. One or two
achievements from each of the four main scientific areas of NIMR are highlighted here.
NIMR has always had great strengths in infectious disease, and one of the most important results of the year came from Anne
O’Garra’s group, which has used microarray analysis to identify a unique pattern of gene activity in the blood of patients with
active tuberculosis (TB). This ‘immune signature’ is not seen in the blood of people with other infections and it disappears when
people are successfully treated with drugs. Intriguingly, the signature is also observed in some 10–20% of patients with latent
TB, who are infected with Mycobacterium tuberculosis but are asymptomatic. This raises the exciting possibility that the immune
signature will predict which patients will go on to develop the active disease.
The Plasmodium species that cause malaria, and Toxoplasma gondii, the causative agent of toxoplasmosis, both replicate within
the safe environment of host cells. Mike Blackman has been studying how these parasites invade the host cells, and he and his
colleagues have found that the process that drives invasion simultaneously induces replication. Thus, cleavage of a protein called
AMA1 by the membrane protease Rhomboid 4 releases both an extracellular domain that is required for invasion and an
intracellular domain that provides a signal for the invading parasite to begin replication inside the host cell. The work provides new
routes to combat this group of parasites.
Expression of a dominant negative ROM4 results in arrest of parasites late in the cell cycle.
Montage showing the transient formation of a
muscarinic receptor dimer.
In immunology it is known that CD4 helper and CD8 killer T cells both derive from common precursor cells, and that the
decision to become one or the other depends on signalling through the T cell receptor (TCR). Ben Seddon has shown that
Zap70, a protein essential for TCR signalling, is up-regulated during development so as to create a temporal gradient of TCR
signalling activity. This, together with use of an inducible Zap70 transgenic model, has allowed him to deduce that the two lineages
develop at different times and at different thresholds of TCR signalling. A similar phenomenon occurs in the development of the
neural tube, where James Briscoe has shown that the duration of Sonic Hedgehog signalling specifies different cell types in the
neural tube.
And Sonic Hedgehog does not only specifiy different differentiated cell types. With Robin Lovell-Badge, James Briscoe has shown
that it also helps induce and maintain neural stem cells. It does this by activating the expression of Sox9, which can convert
early neuroepithelial cells into neural stem cells. Manipulation of the stem cell state may assist efforts to relieve degenerative
diseases such as Alzheimer’s, or to treat brain tumours derived from the unregulated growth of neural stem cells. The treatment
of neurodegenerative disorders will require an understanding of how to drive neural differentiation along the appropriate
pathways, and work in David Wilkinson’s group has shown how the inhibitory mechanisms that maintain the progenitor cell state
are relieved to allow differentiation to proceed. The process involves a positive feedback loop between several genes. Genetic
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regulatory networks of this sort are key to many developmental processes, and indeed these observations may also shed light on
processes such as spermatogenesis.
NIMR has a long history of work on sex determination and differentiation. Groups led by James Turner and Paul Burgoyne have
investigated the phenomenon of meiotic sex chromosome inactivation (MSCI), in which the X and Y-chromosomes, because
they do not pair during meiosis, fail to be transcribed. The two teams made use of the XYY mouse, which has two copies of
the Y chromosome, rather than one, and the two copies do pair during meiosis. This pairing prevented the Y-chromosomes
from undergoing MSCI. Interestingly, the resulting continual expression of Y chromosomal genes triggered a complete arrest in
spermatogenesis, specifically during meiosis. The group went on to demonstrate that the cause of this germ cell arrest could be
narrowed down to the expression of a specific gene on the Y chromosome called Zfy1/2.
Studies of development require sophisticated imaging technologies to allow one to follow cell behaviour in the embryo in
real time. Different sorts of imaging underlie work by Nigel Birdsall and Justin Molloy, who have used total internal reflection
fluorescence microscopy to visualise individual molecules of the M1 muscarinic acetylcholine receptor, a G-protein-coupled
receptor (GPCR). By tracking the positions of individual receptors on the membrane surface in real time, their work resolved the
question of whether this GPCR exists as a monomer or a constitutive dimer. The experiments show that there is rapid conversion
between monomers and dimers, such that at any given time about 20-30% of the receptors are present as dimers. And at
even higher magnification, Peter Rosenthal’s group has used electron cryotomography to determine the structural organisation
of filamentous influenza A virus. The remarkable new images provide an understanding of how the virus assembles itself, and
may suggest new targets for drugs, and the technique offers the opportunity for new ways of looking at cells important to
understanding a variety of diseases.
Berry MPR, Graham CM, McNab FW, Xu Z, Bloch SAA, Oni T, Wilkinson KA, Banchereau R, Skinner J,
Wilkinson RJ, Quinn C, Blankenship D, Dhawan R, Cush JJ, Mejias A, Ramilo O, Kon OM, Pascual V, Banchereau
J, Chaussabel D and O’Garra A (2010)
An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis.
Nature 466:973-977
Santos JM, Ferguson DJP, Blackman MJ and Soldati-Favre D (2011)
Intramembrane cleavage of AMA1 triggers Toxoplasma to switch from an invasive to a replicative mode.
Science 331:473-477
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
Scott CE, Wynn SL, Sesay A, Cruz C, Cheung M, Gaviro M-VG, Booth S, Gao B, Cheah KSE, Lovell-Badge R
and Briscoe J (2010)
SOX9 induces and maintains neural stem cells.
Nature Neuroscience 13:1181–1189
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
Royo H, Polikiewicz G, Mahadevaiah SK, Prosser H, Mitchell M, Bradley A, de Rooij DG, Burgoyne PS and
Turner JMA (2010)
Evidence that meiotic sex chromosome inactivation is essential for male fertility.
Current Biology 20:2117-23
Cells expressing the adaptor protein Btbd6a.
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 107:2693-2698
Calder LJ, Wasilewski S, Berriman JA and Rosenthal PB (2010)
Structural organization of a filamentous influenza A virus.
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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
autoimmunity. Autoimmunity is the cause of allergies such as hay fever and more serious conditions such as asthma, rheumatoid
arthritis, and multiple sclerosis. We are analysing how the cells of the immune system are triggered to mount an immune response
when faced with an infectious agent, how the process can go awry in autoimmunity, and how complex checks and balances in the
system ensure activation of the immune system only when needed.
Infectious diseases result from the transmission of pathogenic micro-organisms. Examples studied at NIMR include malaria,
tuberculosis, AIDS and influenza which are responsible for the deaths of millions of people every year. This death toll is exerted
mainly in the poorer countries of the world, and is also a significant and increasing burden for the National Health Service. Our
research seeks to understand the fundamental biology of the causative micro-organisms and their interaction with hosts. We use
this understanding to promote the development of new drugs, vaccines and diagnostic reagents. The study of pathogenic agents is
also a rich source of important information on basic mechanisms of cell and molecular biology.
Understanding how a fertilised egg generates a functional organism is an important area of biology that has many implications
for medicine. We are studying the fundamental mechanisms that underlie embryo development, including how cells proliferate,
migrate and communicate, how stem cells form and are maintained, and how diverse cell types are generated, each at the correct
location in the forming organism. A major focus is on identifying the underlying genes, how they function and are regulated, and
their role in networks of molecular and cellular interactions that control developmental processes. These studies include the use
of powerful genome-wide techniques and systems biology approaches in order to uncover gene regulatory networks. Much
of our work focuses 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 have distinct strengths for uncovering mechanisms of normal development and how defects can arise. Since many
of the same processes and underlying molecular pathways are utilised in the adult, studies of development also reveal the basis
of disorders such as cancer in which the proliferation and migration of cells is abnormal. In addition, elucidation of the normal
mechanisms that maintain stem cells and that direct them to form specific cell types is essential for potential therapeutic use of
these cells.
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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. NIMR’s mission is:
• to carry out innovative, high-quality, biomedical research
• to be a major contributor to the MRC’s commitments in the training of scientists
• technology transfer
• the presentation of its science to the public
Research at NIMR covers a broad spectrum of basic biomedical science, including infectious diseases, immunology, cell and
developmental biology, neuroscience and structural biology. The world-class facilities for research include biological imaging
resources, the MRC Biomedical NMR Centre and the UK’s largest academic facility for small animal research. There is a major
emphasis on cross-disciplinary interactions, stemming from the pervasive culture of collaboration and strategic recruitment to
complement and bridge scientific areas. There are research collaborations with many other academic and clinical centres in the
UK and internationally, including strong links with University College London.
Scientists at NIMR study normal biological processes and diseases at the molecular, cellular and whole organism level. 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?
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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Winners of the 2010 Travel Prize - John Ewbank, Immunoregulation (left) and
Steven Moore, Developmental Neurobiology (right), pictured with with the
Director, Jim Smith.
Recent research highlights
2010
•
•
•
•
•
•
•
•
Immune signature for tuberculosis (Anne O´Garra and Robert Wilkinson)
Parasite invasion and replication (Mike Blackman)
Zap70 creates a temporal gradient in T-cell lineage development (Ben Seddon)
Role of Sox9 in neural stem cell induction and maintenance (Robin Lovell-Badge and James Briscoe)
Initiation of neuronal differentiation (David Wilkinson)
Meiotic sex chromosome inactivation is essential for male fertility (Paul Burgoyne and James Turner)
Formation and dissociation of muscarinic receptor dimers (Nigel Birdsall and Justin Molloy)
Electron cryomicroscopy of influenza virus (Peter Rosenthal)
2009
•
•
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)
•
•
•
2008
•
•
•
•
•
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
•
•
•
•
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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NIMR history and milestones
1933 Discovery of flu virus
Christopher Andrewes, Patrick
Laidlaw and Wilson Smith first
isolated the human influenza
virus.
1957 Interferon
1951 Steroid
biosynthesis
John Cornforth
1940
1950
1952 Gas chromatography
After receiving the Nobel Prize
in 1950 for his earlier
discovery of partition
chromatography, Archer Martin
joined NIMR and with A.T
James he developed gas
chromatography, a technique
now widely used in
laboratories and the chemical
industry.
1936 The role of acetylcholine as
a neurotransmitter
Henry Dale established the chemical
basis of neurotransmission and the
role of acetylcholine as a
neurotransmitter, receiving the Nobel
prize for this work in 1936.
14
John Skehel revealed the structure of
influenza virus proteins involved in
the infection of cells, for which he
was awarded the Louis-Jeantet Prize
for Medicine in 1988. This work
opened new perspectives for the
design of antiviral drugs.
1960s Cryobiology
Audrey Smith discovered how
to store biological material at
low temperature, pioneering
techniques for the freezing of
sperm, blood, bone marrow,
corneas and many other
tissues.
completed the first total
synthesis of the
non-aromatic steroids
and identified the
chemical structure of
cholesterol. He received
the Nobel prize in 1975.
1930
1981 Structure of influenza
haemagglutinin
Alick Isaacs discovered
interferon, a factor that can
transfer a virus-resistant state
to cells that had not been
infected, and is now used to
treat many infections and
cancers.
1960
1970
1986 Globin locus control
region
Frank Grosveld discovered
regulatory sequences that
govern expression of the
globin gene cluster, and that
confer a copy number
dependent level of transgenic
gene expression. He was
awarded the Louis-Jeantet
Prize for Medicine in 1991.
1980
1973 Long-term
potentiation
Tim Bliss and Terje Lømo
discovered the phenomenon of
synaptic long-term potentiation,
one of the main mechanisms
by which the brain learns and
remembers.
1958 Immunoglobulin
structure
Rodney Porter was given the
Nobel Prize in 1972 for the
discovery of the structure of
immunoglobulins. The work
increased understanding of the
immune system and led to novel
approaches to diagnosis and
therapy.
1989 Hox gene
colinearity
Robb Krumlauf showed that
the linear relationship
between the organisation of
Hox genes along the
chromosome and their
expression along the
head-to-tail axis is conserved
in vertebrates.
1993 Mesoderm-inducing
factor
2005 Mouse model of
Down syndrome
Jim Smith discovered that activin
is a mesoderm-inducing factor,
opening up understanding of
how signalling factors control
the formation of tissues during
embryo development.
Victor Tybulewicz created a
genetically manipulated mouse
that carries almost all of
human chromosome 21. The
resulting strain of mice has
become a valuable tool in
research on Down syndrome.
2010 Transcriptome
signature in human
tuberculosis
Anne O’Garra discovered a
novel transcriptomic signature
that provides insights into
fundamental pathogenesis of
tuberculosis and has
application to the
development of improved
diagnostic tools.
1996 Discovery of the
anterior organising
centre
2007 AMP-activated
protein kinase (AMPK)
structure
Rosa Beddington discovered
a novel signalling centre in the
mouse embryo required for
correct formation of the
head-to-tail axis during
embryonic development.
Steve Gamblin determined
the structure of the
enzyme that regulates
cellular energy levels, AMPK.
The discovery paves the
way for better treatments
of type II diabetes.
1990
2000
2010
1999 Eph receptors mediate cell
segregation
2007 Malaria release
mechanism
David Wilkinson uncovered a new
mechanism that maintains the correct
organisation of tissues, mediated by
signalling through Eph receptors and
ephrins.
Mike Blackman identified an
enzyme that triggers release of the
malaria parasite from infected red
blood cells thereby enabling it to
invade new cells. The enzyme is a
new target for improved
anti-malarial drug design.
1991 The sex determining gene
Robin Lovell-Badge showed that the
presence of the Sry gene on the Y
chromosome is sufficient to cause the
embryonic gonad to develop as testis
rather than ovary. He received the
Louis-Jeantet Prize for Medicine in 1995.
2006 Discovery of Th17 subset
Gitta Stockinger defined the developmental
steps that lead to the Th17 immune
response. Th17 cells are important in the
pathogenesis of many autoimmune diseases.
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 Programme
Our PhD students have the opportunity to conduct their research
projects in an environment where state-of-the-art facilities and
an extensive range of expertise are available to all. One of the
Institute’s major strengths is the interaction between scientists in
all four main areas of research. Many of these interactions lead to
new and exciting collaborations which our students are often a part
of, thereby broadening their general understanding of science and
practical expertise. There are 80 PhD students at NIMR at any one
Donna Brown
time, representing 14% of researchers and contributing significantly
Director of Studies
towards the Institute’s research output as indicated by their publication
rate - 62% of students who have completed three years of research have published at least once.
In addition to their supervisor, each student is allocated a thesis committee to ensure they receive all of the support and guidance
they need for the duration of their PhD. Supervisors are not distracted by heavy teaching loads, as there is no undergraduate
teaching at the Institute. Also on hand are the Director of Studies, Student Administrator and the Student Representatives. The
significance of this level of support is reflected in the four-year submission rates which are higher than many universities, this year
standing at 86%. We believe in a good work-life balance and we want our students to remember there is a world outside of the
lab, so onsite you can find a licensed bar, restaurant, games room and television room. In addition there are many social activities
and sports teams organised through the NIMR social club. The Institute also has three onsite student cottages which can house up
to 12 students, making the commute to work virtually non-existent.
One of our aims over the last academic year was to improve our training programme which we achieved through delivery of
career development sessions, a methods and techniques study programme and microscopy and bioinformatics courses. Over the
next year we plan to develop our training programme further still and run a four-year PhD programme which will help increase
students’ skills sets, independence, publication rates and ultimately employability.
The 2010 travel prize
Each year NIMR awards a £1000 travel prize for the best upgrade report. This year judges split the prize between two students
who wrote equally excellent upgrade reports:
• Steven Moore (Developmental Neurobiology) for ‘Comparative Genomic Analysis of Pax3 and Pax7 Regulation’
• John Ewbank (Immunoregulation) for ‘An analysis of the effect of strain variation on the interactions of Mycobacteria with the
immune system, and the role of type I interferon in the outcome of infection’.
The prizes were awarded by Jim Smith at the student barbecue in August (see photo page 12).
16
Student representatives
There is a strong sense of community amongst the students at NIMR. This
actively encourages collaboration between different Divisions allowing
students to take up multi-disciplinary projects. Regular student seminars
allow them to present work without the pressure of supervisors or
colleagues from their Division being present. With regular student socials
and sporting activities, it is easy to meet and make new friends.
With an intake of around 25 new students each year, the student body
is an integral part of NIMR and student representatives aim to maintain
the high standard of communication between staff and 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 2010 student representatives
Christina Untersperger, Sorrel Bickley and Lizzi Underwood
The 2010 intake of PhD students
17
PhD students 2010 - in their own words
John Ewbank
“I started my PhD at NIMR almost three years ago, studying the innate immune response to
Mycobacterium tuberculosis. NIMR is a great place to do a PhD. A key reason is the social and
collaborative atmosphere of the Institute - everyone is very friendly and it is easy to wander into
any lab and ask for help and advice. My own project is a collaboration between two Divisions;
Immunoregulation and Mycobacterial Research. Collaborations are helped by the onsite bar, as well
as sporting activities, such as a football league. I’ve also found the student study programme very
enjoyable - there are various lecture series given by senior academics, as well as student seminars,
where students present their work. This has enabled me to hear talks on subjects totally different to
my own project - from protein structure to neurobiology. As students we are also encouraged (and
funded) to attend conferences; I will be presenting my results in a Keystone meeting in Vancouver
next year. It’s been a great experience and I’ll be sorry to leave NIMR.”
Andrea Ruecker
“I am a second year PhD student at NIMR. I was always fascinated with biology, nature and
how to preserve the environment. I decided to study biology focusing on general biology but quite
quickly became interested in malaria. After a three-month job in Tanzania, and suffering from
malaria myself, I wanted to know more about the disease and why it is so difficult to develop
drugs and vaccines against it. I completed my BSc at the University of Marburg, with a nine month
undergraduate project in malaria research. I then went to the Liverpool School of Tropical Medicine
to complete a Masters in Molecular Biology of Parasites and Disease Vectors where I learned about
other parasitic diseases. I continued to work on malaria during my Masters project and decided to
stay in malaria research. I had heard about NIMR - the Division of Parasitology is highly regarded in
the field of malaria research - and I was very excited to apply for a PhD project at NIMR.
Visiting the Institute for my interview I found the people that work here appeared very friendly
and I was very happy when I got my PhD offer. My project in Mike Blackman’s laboratory is based
around a putative malarial protease which is essential for the survival of the malarial parasite,
Plasmodium falciparum. One year into my PhD I can say that NIMR is an outstanding research
environment and I love to come into work in the morning. I couldn’t have had a better start in our
lab and I am really looking forward to the next two years and what they will bring. It is always scary
to start work at a new place but the people in the Institute and our lab make it very easy to feel
comfortable to work and enjoy my time as a PhD student.”
18
Sandwich placements and work experience
Sandwich placements
There is no better way to put the lab skills learned in the first
few years of your university degree into practice than to spend
up to 12 months working in one of the NIMR labs. As you will
see from the testimonials below, Sandwich students come to the
Institute because of the diversity of science and to get a better
feel of whether research is really for them. Many of our Sandwich
students go on to do a PhD at NIMR and other leading research
institutes.
Sandwich students-in their own words
The 2010 intake of sandwich students
Leslie Southerden
“While studying for my undergraduate degree at the University of Surrey, I applied to NIMR for my Sandwich year because of its
excellent reputation for world-class research. I spent a year in the Division of Physical Biochemistry and found the collaboration between
research groups particularly useful. In the Webb Lab I had my own research project for the year, investigating the interactions of
fluorescently labeled single-stranded DNA binding proteins with single-stranded DNA. During the year I gained practical experience in
a wide range of research techniques and also gained an insight into the demands of a research career. I found the learning experience
of overcoming challenges very rewarding. Following my year at NIMR I am now keen to pursue a career as a research scientist, the next
stage being a PhD. Having enjoyed my year so much, it is my hope to return to the Institute for a PhD studentship within Structural
Biology.”
Lih Ling Yee
“At the point of applying for a Sandwich placement I was determined to look for an opportunity to work in an academic environment
which would be creative and dynamic. This was indeed what I saw at NIMR. I joined Dr Alex Gould’s research team, under the
supervision of Dr Rita Sousa-Nunes, on the regulation of Drosophila neural stem cells quiescence. From the start to the end, it was an
amazing experience. I learnt different experimental techniques as well as scientific writing skills. It was hard work, but it definitely paid
off. And the good thing is, it didn’t put me off science. I would like to keep my mind open in terms of future plans. At the moment, I am
looking for a PhD position in clinical neuroscience and am also considering a job as a research assistant.”
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 Research Summer School p28). Many of these students come back in
subsequent years and apply to our Sandwich placements and 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 is like to work in science.
19
CAREERS
Career development
In addition to its role in the training of PhD students, NIMR is a major centre for further research training and career
development. It attracts researchers from the UK and across the world due to the breadth and quality of the research, and the
emphasis on interactions and cross-disciplinary collaborations. Researchers at all stages of their career 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.
Postdoctoral careers
NIMR hosts approximately 220 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.
Martin Levesque Division of Developmental Neurobiology
“For my second postdoc, I chose to come here from Canada because of NIMR’s
excellent international reputation in developmental biology. Over the past two
years I have enjoyed fruitful collaborations and exchange of ideas with colleagues
across the Institute, and exposure to a rich and frequent programme of high
calibre external and internal speakers. I also have benefited from access to
extensive animal facilities and world-class scientific tools, including OPT, multiphoton
microscopy, ChIP-Seq, RNA-Seq to name just a few. Furthermore the MRC offers
a wide variety of useful courses, encompassing both scientific and personal
development, as such I would highly recommend NIMR as a fantastic and
stimulating choice for postdoctoral training.”
20
CAREERS
Harriet Groom Division of Virology
“If I am honest, like most postdocs I chose to apply for a position at NIMR
not because of the Institute itself but because of the group leader I would
be working for, the project I would be working on and the city in which it was
located. I intended to move to London after doing my PhD at Cambridge and
met my current boss at a conference. When she later advertised a position at
NIMR during a seminar I was very interested. Initially I had reservations about
working at an Institute (my previous experiences being entirely universitybased), however when I came up for interview, the advantages of working at
this particular institute became clear and I decided to accept the position when
it was later offered. Since working here all of these advantages have manifest
themselves along with some unforeseen ones. The high standard and availability
of equipment is especially attractive, allowing you to carry out pretty much any
experiment you desire. Most importantly I have found that being surrounded
by enthusiastic, helpful scientists makes working here very enjoyable and the
opportunity to foster collaborations is always there. It is great to always have an
expert down the corridor
and sometimes to be that expert!”
Mohamed Ismail (Soly)
Division of Molecular Structure and Division of Developmental Neurobiology
“It is a privilege for any researcher at any stage of their career to
experience working at NIMR. The scientific atmosphere is amazing
and everyone who works here is more than willing to help. I started
working at NIMR almost two years ago and I am still enjoying
every moment of it. My project is a collaboration between the
Divisions of Developmental Neurobiology and Molecular Structure,
studying the function and structure of a ubiquitin ligase complex
in the early stages of neurogenesis. NIMR strongly supports
multidisciplinary projects that increase the scientific interaction
between scientists from different Divisions, provides excellent
training for postdocs and enhances the possibility of big discoveries.
The Institute is equipped with state-of-the-art facilities that make
any experiment possible. You learn something new every day at
NIMR, through scientific conversations with colleagues, meetings
or through the Mill Hill Lectures where world-class scientists are
invited to present their work. There are plenty of opportunities
to socialise through sport, social gatherings and theatre. It is not
surprising that NIMR has an excellent worldwide reputation and is
a place where many researchers would love to be.”
21
CAREERS
Career development
Career Track appointments
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. The following staff were appointed to Career Track positions.
Greg Elgar, Systems Biology - joined NIMR in 2009
“My motivation for coming to NIMR was simple; I wanted to carry out the highest quality interdisciplinary research. This kind of research,
often involving longer term projects and more than one researcher, is difficult to sustain purely through grant funding, especially in the
current economic climate. It also demands more time and resources than more focused projects and is therefore well suited to a large
institute. My particular area of research requires widespread collaboration and regular contact with developmental biologists. The breadth
of expertise in this area at NIMR is exceptional and there is almost always someone here who is happy to discuss things over a coffee.
There is great support too, which means I can spend all my time doing what I have been recruited to do. I have been here less than a
year but I have already learned so much new stuff. It is what makes research so exciting.”
Mark Wilson, Molecular Immunology - joined NIMR in 2010
“As with many senior postdoctoral researchers, the looming and often intimidating prospect of establishing an independent research
group had to be faced. I was four years into my visiting fellowship at the National Institutes of Health (NIH) in Bethesda, USA when I was
informed of the opening at NIMR, better known as Mill Hill. Although having never visited the Institute, it carried with it an immediately
recognisable name and reputation for many things, including great research. This was probably influenced by the fact that my PhD
supervisor and, at the time head of my division at the NIH, had both trained for several years at Mill Hill. After soliciting their, and other
peoples advice I arrived for ‘the interview’.
“Is that it! A fenced-in, but rather grand looking building with a strange, and frequently referenced, sea green-ish roof out on the periphery
of London”, were some of my earliest thoughts. However, beyond the exterior, as I have now learned, is ‘Mill Hill’. I was welcomed with
open arms and within a few weeks felt like I had been here for years. A true triumph for generosity, support and inter-dependence had
me up and running within a few months of my arrival back in the UK. I, as anyone would, have benefitted immensely from the close
working relationships, certainly within the immunology-related groups, and the open-door policy throughout the Institute.
This, I think, is built upon the relative freedom from grant-dependent research and undergraduate teaching; in-depth financial
management; extensive human resource skills; common buffer preparation and glass cleaning (all of which are expertly taken care of and
for which we are extremely grateful). This is coupled with competent and supportive ‘core facilities’ which has allowed me to establish our
research group and start addressing the specific aims of our projects within months of starting. NIMR, so far, has given me a fantastic
start. I hope in the future I can give an equal amount back to NIMR and the NIMR community. It isn’t hard to find, but I think I can see
and feel some of the ‘Mill Hill’ that I was once told about.”
22
CAREERS
Kate Bishop, Virology - returned to NIMR in 2008
“I had a fantastic time at NIMR as a PhD student. Everyone was very friendly and helpful and it was a great start to my scientific career.
I particularly enjoyed the collaborative culture within the Institute and I missed the critical mass when I left to commence postdoctoral
work at Kings College London. When I was offered the chance to come back and start my own group six years later, I jumped at the
chance. I am enjoying catching up with old acquaintances and working with new friends.”
Andreas Wack, Immunoregulation - returned to NIMR in 2008
“I moved back to NIMR after ten years spent in industrial research in Italy. Prior to that, I had done my PhD with Dimitris Kioussis here in
the Institute and was glad to come back again. The spirit of collaboration, the fact that you could go to anyone’s office or lab and come
up with ideas or ask for advice, was for me one of the best features of NIMR. Ten years later I find this spirit wide awake, carried on by
many of the old familiar faces and many new ones. There are fewer differences between industry and academia than most people (in
particular in academia) think. You develop scientific questions, plan a sequence of experiments, critically appraise results. The range or
depth of questions asked and hypotheses put forward may differ between industry and academia but vary within both areas. The biggest
differences are the speed of change and the research group size.
In a company, decisions on research direction are often driven by factors outside your control, dictated by changes in the market place,
which can be fast. Your favourite research subject may be culled in a board room with little prior notice and no chance to influence the
decision. 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. When companies throw many people at important projects, there may be up to 50 specialists
tackling the same question from different angles. Decision-making becomes complex and often slow, and the degree of identification
of research staff with their project is relatively low. The advantage is that the technical expertise brought to the project is very high. Also
getting used to presenting data from colleagues and vice versa, handing over your data to others, is an excellent exercise for big egos to
be reminded of the team effort.
Academia often presents the extreme opposite: one PhD student or postdoc, one project, a very high degree of identification and
personal involvement, but a danger that the wheel is frequently reinvented because of a constant loss of expertise through student and
postdoc turnover. I think that doing research most efficiently requires a mix between the two approaches: medium size groups of people
with different scientific backgrounds sharing in full a project. However, because career and funding depend so much on authorship
questions and senior responsibility such an approach can be hard to achieve. The way it worked for me to preserve the possibility of a
return to academia was: keep publishing and 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 for sure am happy to have made the step back from one camp to the other.”
23
CAREERS
Research support careers
There are regular opportunities for research technicians and occasional openings for research support managers.
Matt Williams - Laboratory Manager, Developmental Neurobiology / Stem Cell Biology and
Developmental Genetics / Systems Biology
“After some years working as a Postdoctoral Research Associate at Imperial College London I
wanted a change in direction, and so I moved into research support working as a Postdoctoral
Research Assistant in the Division of Developmental Biology at NIMR. This change allowed me to
continue to do exciting research, but also enabled me to provide support to the other researchers
in the group by maintaining the lab, keeping it up and running, and ensuring a clean, tidy and safe
working environment. Then, back in spring 2008, I became a Laboratory Manager, working with
the Divisions of Developmental Neurobiology, Stem Cell Biology and Developmental Genetics, and,
latterly, Systems Biology. I was keen to develop my research support role, to assume a position with
more responsibility, and to get involved in the organising and management of many aspects of the
Institute. My experience has really helped with this position, with the significant level of knowledge
and competence I have gained in the lab over the years. Being able to help a large number of
researchers with their work is very satisfying, and seeing the benefits of ideas I have implemented
has been extremely rewarding.”
Rose Gonsalves - Laboratory Manager, Division of Virology
“I joined NIMR many years ago as a technician in the WHO Influenza Centre. Ten
years later I transferred to a research group, also working on influenza. Although
my background was in bacteriology I gradually acquired a great deal of knowledge
of virology, particularly practical issues. Then 16 years ago I became the Head
Technician for the Division of Virology. I kept strong links to the lab work and even
now I carry out some lab duties for one or two scientists, though this has reduced
over time. My role, now called Laboratory Manager, is to ensure that the Division
runs smoothly, pre-empting problems when possible and “firefighting” when
necessary. I also manage the Divisional budgets. I am a problem solver, diagnosing
what has gone wrong (e.g. faulty equipment) and fixing it. I enjoy talking to staff in
the Division about their research and their plans, and have good interactions with
those in other Divisions and with representatives from companies we deal with”.
24
CAREERS
Radma Mahmood - Specialist support manager in Histology
“I never imagined myself running a research group after completing my
PhD and postdoctoral training, even though I enjoyed research and was
well supported and published. But then I never imagined running a core
service in histology, which I have now done for ten years in New York
and London. During my postdoctoral training, I decided that my future in
science should not only use the knowledge I had gained and techniques I
had learned, but should also use my personal strengths: my affability, my
need for order (standard operating procedures) and my desire to ensure
that the people who I work with are continuously learning (if they choose
to be) and are thriving happily in a scientific environment. I found that
both my skills and my personal strengths have been put to good use at
NIMR and previously at the histology service at Albert Einstein College of
Medicine in New York.
NIMR has given me the freedom to develop the service through
refurbishment and the introduction of new technology. The researchers
and numerous support staff have been particularly welcoming and willing to give me their time and assistance with all aspects of the
service’s expansion which makes the ongoing endeavor both straightforward and enjoyable.”
Alan Palmer - Training and Technical Manager, 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
attend workshops and seminars held on a regular basis on subjects related
to laboratory animal science. Visits to other scientific establishments, symposia
and international meetings are also organised which enable technicians to gain
experience in more varied aspects of laboratory animal husbandry and science.”
25
SCIENTIFIC FACILITIES
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
26
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 (HPV) 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
27
SCIENCE AND SOCIETY
Public engagement activities
Human Biology Essay Competition 2010
NIMR’s essay competition is now in its eighth year. At a time
when school 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 a day at NIMR seeing visually appealing
projects. The best essay by Thomas Elliott of Queen Elizabeth’s
Boys School on “What makes bone marrow such a versatile
resource for curing human diseases” was published in Mill Hill
Essays 2010.
Research Summer School
In 2010 NIMR was host to 14 students over the summer,
drawn from nine 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 excellent posters and reports of their work, to be
shown at events organised by the Nuffield Foundation. Teachers
tell us that bursary holders are a vivid advertisement for the
Summer School and they inspire the next generation of science
students to follow the same route. Some of our earlier cohorts
of students are now researchers having emerged from university
with first-class degrees.
The University of the Third Age (U3A) at NIMR
In December 2010 NIMR hosted the eighth national meeting
of the science section of the U3A, a self-managed organisation
for retired people who enjoy learning about science. Many
travel quite long distances to attend. This year the theme was
“Understanding the heart in health and disease” at which Tim
Mohun and Ross Breckenridge spoke. Once again, we had a
capacity crowd of nearly 150 enthusiasts.
28
SCIENCE AND SOCIETY
Annual Schools Days
Students in Year 12 are invited to an event designed to enrich their experience of the life sciences. The theme for this years event
was “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.
Professional development for teachers
In June 2010 we held a meeting for local teachers focused on recent developments in biomedical science. We had 75 participants
from 32 schools. Talks included “New approaches to cell biology”; “Recent progress in molecular biology”; “The potential of stem
cells for refurbishing the human body” and “How the brain stores memories”. The speakers found exactly the right level with
sufficient novel material to interest teachers but not too far removed from the curriculum to make it irrelevant. Judging by the
lively discussion the event was clearly a great success, and we look forward to welcoming teachers again to NIMR.
Direct involvement in schools
NIMR staff participate directly in science education in the “Science Ambassadors” scheme providing a distinctive enrichment to
complement the normal school curriculum. NIMR staff are asked to give talks about their research or other topics to Year 12
classes from time to time. A growing development is the involvement of NIMR staff in “extended projects” required for some A
level courses at two excellent local schools. We have set up programmes with appropriate staff members answering questions
and putting students on the right track.
29
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) Dick Gilbert, Approaching Wave, 1965, (right)
Stassinos Paraskos, Bathing, 1968
Mill Hill Essays
Since 1995, NIMR has produced an annual booklet of essays to increase public awareness of topical scientific issues. Written by
members of staff, each booklet includes a range of topics, ranging from emerging infections, to stem cells and cloning. They are
given to visitors and distributed to local schools and other organisations.
PDF versions of all the published Mill Hill Essays can be accessed at: http://www.nimr.mrc.ac.uk/mill-hill-essays
30
a
b
Using Flybow as genetic multicolor labelling tool to examine the arborization patterns of wild type (a) and N-Cadherin deficient (b) higher order neurons
(green, red and yellow) in the adult visual system of Drosophila. Photoreceptor axons are labelled in blue.
31
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
Sebastian Gagneux
Steve Gamblin
Mike Gilchrist
Richard Goldstein
Alex Gould
Francois Guillemot
Matthew Hannah
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
Elke Ober
32
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 discovery of biomarkers of childhood severe malaria
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
Genomic and functional analysis of neurogenesis
Secretory vesicle formation in human endothelial cells
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
Immunity and immunopathogenesis in malaria infections
Control of prolactin and growth hormone cell differentiation and function
Regulation of immune responses by NF-kB 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 behavior
Heart development in vertebrates
Single molecule studies of cell motility and cell signalling
Liver development in zebrafish
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John Offer
Anne O’Garra
Vassilis Pachnis
Annalisa Pastore
Alexandre Potocnik
Andres Ramos
Katrin Rittinger
Peter Rosenthal
Iris Salecker
Benedict Seddon
Steve Smerdon
Jim Smith
Gitta Stockinger
Jonathan Stoye
Ian Taylor
Willie Taylor
Peter Thorpe
Pavel Tolar
James Turner
Victor Tybulewicz
Jean-Paul Vincent Andreas Wack
Martin Webb
David Wilkinson
Robert Wilkinson
Mark Wilson
Douglas Young
Lyle Zimmerman
Synthetic protein laboratory: 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
Molecular recognition in post-transcriptional regulation
Structural biology of signalling networks that regulate innate and adaptive immunity
Cryomicroscopy of proteins, viruses and cells
Visual circuit assembly in Drosophila
Regulation of T cell homeostasis by antigen receptor signals and interleukin-7
Structural biology of phosphorylation-dependent signalling in the cell cycle and DNA
damage response
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
Systems microscopy studies of cell fate determination
Activation of immune receptors
X chromosome inactivation, meiotic silencing and infertility
Signal transduction in B and T cells
Patterning and homeostasis in developing epithelia
Immune response to influenza
The molecular mechanisms of motor proteins
Regulation of boundary formation and neurogenesis
Understanding and intervening in HIV-associated tuberculosis
Regulation of Th2 cells during allergic inflammation and anti-helminth immunity
Mycobacterial pathogenesis: gene expression and innate immune response
Using frog genetics to understand vertebrate development and disease
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Immune Cell Biology
Immunoregulation
Molecular Immunology
Mycobacterial Research
Victor Tybulewicz (Head of Division)
Steve Ley
Benedict Seddon
Pavel Tolar
Anne O’Garra (Head of Division)
George Kassiotis
Andreas Wack
Gitta Stockinger (Head of Division)
Dimitris Kioussis
Alexandre Potocnik
Mark Wilson
Douglas Young (Head of Division)
Elaine Davis
Sebastien Gagneux
Robert Wilkinson
Microarray Laboroatory
Parasitology
Virology
34
Tony Holder (Head of Division)
Michael Blackman
Jean Langhorne
Childhood Malaria Research Group
Jonathan Stoye (Head of Division)
Kate Bishop
John Doorbar
John McCauley
WHO Collaborating Centre for Reference and Research on Influenza (WIC)
INFECTIONS AND IMMUNITY
Virology
Kate Bishop
Infection and replication of retroviruses
Lab members: Virginie Boucherit, 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. In 2006, a novel retrovirus called xenotropic murine
leukaemia virus-related virus (XMRV) was isolated from
patients with familial prostate cancer. More recently, XMRV
has been identified in chronic fatigue syndrome patients. It is
not known whether the virus causes either disease. Innovative
therapeutics for retroviral infections will hopefully arise from a
better understanding of how retroviruses reproduce in the cell,
how they interact with host cell factors, and how they subvert
the host innate and adaptive immune systems.
We are interested in the early post-entry stages of the
retroviral life cycle, as these are potential therapeutic targets
but are currently poorly defined. We are studying the p12
protein of murine leukaemia virus that is essential during
these stages. By combining virological assays with biochemical/
biophysical techniques and microscopy, we hope to build up
a picture of how p12 interacts with both viral and cellular
factors, where p12 localises in the cell and why p12 function is
important.
Publications
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
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
Holmes RK, Malim MH and Bishop KN (2007)
APOBEC-mediated viral restriction: not simply editing?
Trends in Biochemical Sciences 32:118-128
Co-localisation of the viral p12 and nucleocapsid (NC) proteins from Moloney murine leukaemia virus
in a D17 cell, six hours post-infection. The cell nucleus is shown in blue.
See reference 107 in the bibliography at the back for publications
from this group in 2010.
35
Parasitology
Mike Blackman
Proteases in host cell exit and invasion by the malaria parasite
Lab members: Christine Collins, Sujaan Das, Fiona Hackett, Natalie Silmon de Monerri, Maria Penzo, Andrea Ruecker,
Michael Shea, Robert Stallmach, Malcolm Strath, Catherine Suarez, Chrislaine Withers-Martinez, Sharon Yeoh
Malaria causes immense suffering, killing at least one million people each year,
and is a major contributor to poverty. The disease is caused by a single-celled
parasite and spread by mosquitoes. 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. These eventually
rupture, releasing a fresh wave of parasites to invade new red cells. Our work
focuses on how the parasite invades and escapes from its host red cell, in
anticipation that a better understanding of this will aid the development of
much-needed new antimalarial drugs and a vaccine. We have a particular
interest in a family of parasite enzymes called proteases that regulate release
of the parasite from the red blood cell, and also modify the parasite surface
to ‘prime’ the parasite for invasion. We are investigating the structure, function
and regulation of these proteases, and searching for inhibitory compounds
with potential to be developed as antimalarial drugs.
Release of PfSUB1 from exonemes leads to parasite surface ‘priming’ and host cell rupture.
Publications
Child MA, Epp C, Bujard H and Blackman MJ (2010)
Regulated maturation of malaria merozoite surface protein-1 is
essential for parasite growth.
Molecular Microbiology 78:187–202
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
Molecular structure of SERA5, a putative parasite protease involved in rupture of the
parasite-infected red blood cell.
See references 33, 64, 86, 272 in the bibliography at the back for publications from this group in 2010.
36
Elaine Davis
Gene regulation and DNA repair in the pathogenesis of Mycobacterium tuberculosis
Lab members: Nicola Beresford, Joanna Dillury, Amanda Fivian-Hughes, Alison Gaudion, Joe James, Dorothée Schuessler,
Katherine Smollett, Alan Williams
Despite the most frequent outcome of infection with Mycobacterium
tuberculosis being asymptomatic latent infection, tuberculosis is a leading
infectious cause of death globally, with devastating consequences in parts of the
world such as South-East Asia and sub-Saharan Africa. Although a treatment
regimen is available, this is a lengthy process and the development of drug
resistance threatens its efficacy. Therefore, there is an urgent need for new
drugs to treat TB.
During infection, M. tuberculosis is exposed to adverse conditions as the host
tries to defend itself. The bacteria need to adapt to and withstand these
conditions in order to survive and establish an infection. One way the bacteria
respond is by altering the expression of certain genes. We are investigating
aspects of how M. tuberculosis does this. A key target of the host defence
mechanisms is the bacterial DNA. It is vital to the bacteria that damage to its
DNA is repaired. Therefore, we are also studying the processes M. tuberculosis
uses for this with a view to identifying novel targets for the development of
new drugs to combat TB.
Publications
Detection of promoter activity using a reporter construct in
mycobacteria. Colonies in which the promoter is active express
β-galactosidase and are identified by the blue colour.
Dawson LF, Dillury J and Davis EO (2010)
RecA-independent DNA damage induction of Mycobacterium tuberculosis ruvC despite an appropriately located SOS box.
Journal of Bacteriology 192:599-603
Fivian-Hughes AS and Davis EO (2010)
Analysing the regulatory role of the HigA antitoxin within Mycobacterium tuberculosis.
Assessment of the sensitivity of different strains of
M. tuberculosis to a DNA damaging agent. The blue dye
is reduced to produce a pink colour only by viable
bacteria. Using a serial dilution of the compound across
the plate, it can be seen that the strains in the middle
rows are more susceptible than those in the upper and
lower rows. This assay can also be used to compare the
ability of potential new drugs to act on M. tuberculosis.
Singh P, Patil KN, Khanduja JS, Kumar PS, Williams A, Rossi F, Rizzi M, Davis EO and Muniyappa K (2010)
Mycobacterium tuberculosis UvrD1 and UvrA proteins suppress DNA strand exchange promoted by cognate and non-cognate
RecA proteins.
Biochemistry 49:4872-83
See references 53, 81, 230 in the bibliography at the back for publications from this group in 2010.
37
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.
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.
See references 60, 146, 147, 165, 228 in the bibliography at the back for publications from this group in 2010.
38
Parasitology
Proteome-wide discovery of pathogenesis biomarkers of childhood severe malaria
Lab members: Ianina Conte, Dimitrios Athanasakis, Barry Ely, Juho Rousu, Olugbemiro Sodeinde
Half of the world population is at risk of malaria. Human
malaria caused by Plasmodium falciparum represents a
global disease burden with an estimated 300 million clinical
episodes per year leading to an estimated one million deaths.
Cerebral malaria and severe malarial anaemia are both major
complications with significant global childhood mortality and
morbidity in Sub-Saharan Africa. Biomarkers that predict
the commitment of the infection to a severe presentation,
its specific severity factors and progression will not only be
important for understanding of the pathogenesis, but could
also provide clinical tools for patient care. We focus on
understanding how the proteomes of host and parasite interact
to establish the pathological changes observed during severe
malaria in children.
We use high-throughput mass spectrometry methods that
enable unbiased discovery of host-parasite plasma proteomepatterns during the establishment and progression of childhood
severe malarial disease. The approach employed is based on
the idea that distinctive complex combinations of circulating
proteins define different pathological states, reflecting hostpathogen interactions of the infectious process. We develop
computational algorithms to discover disease-specific patterns
of the proteome response to the infection. The establishment
of a Childhood Malaria Research Unit in partnership with
the College of Medicine University of Ibadan, Nigeria allows
us to sample the malaria disease process in great detail. 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 Fernandez-Reyes D (2008)
Estimation of relevant variables on high-dimensional biological patterns using iterated
weighted kernel functions.
PLoS ONE 3:e1806
Buxton, B. F., Abdallahi, H., Fernandez-Reyes, D. and Jarra, W. (2007)
Development of an Extension of the Otsu Algorithm for Multidimensional Image
Segmentation of Thin-Film Blood Slides
International Conference on Computing: Theory and Applications, 552-562.
Identification of urine hepcidin and its levels in childhood severe malaria.
Hepcidin is a hormone produced by the liver involved in iron homeostasis,
and its levels increase during an infection and immunological response. (Left)
Hepcidin levels (red line) in control and different malaria patients by SELDIToF analysis of urine with metal affinity chemistry represented as a virtual gel.
(Right) Representative spectra from one sample for each group revealing the
different relative intensity of hepcidin.
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
39
Sebastien Gagneux
Population genomics and ecology of Mycobacterium tuberculosis
Lab members: Inaki Comas, Thembela Huna, Graham Rose
Many human pathogens escape host immunity by varying their
antigenic genes. To test whether Mycobacterium tuberculosis
uses a similar strategy to evade the human immune responses,
we generated the nearly complete genome sequences of 21
M. tuberculosis’ complex (MTBC) strains representative of the
organism’s global diversity (top figure). We then compared the
genetic diversity and evolutionary conservation across three
experimentally confirmed sets of genes, including essential genes,
non-essential genes, and genes encoding known T cell epitopes.
We found, as expected, that essential genes in MTBC were less
diverse than non-essential genes. Essential genes were also more
evolutionarily conserved than non-essential genes, as indicated
by a lower ratio of non-synonymous to synonymous nucleotide
changes. Surprisingly, however, we found that the known T
cell epitopes were the least diverse and most evolutionarily
conserved regions of the MTBC genome. This observation
suggests MTBC might benefit from host immune recognition of
these T cell epitopes, perhaps because the associated immunepathological processes (e.g. lung cavitation) increase disease
transmission. Our findings have important implications for the
development of new tuberculosis vaccines.
Global phylogeny of M. tuberculosis complex based on 21 genome
sequences
Ratio of non-synonymous to synonymous nucleotide changes in different
gene classes of M. tuberculosis complex.
Publications
Comas I, Chakravartti J, Small PM, Galagan J, Niemann S, Kremer K, Ernst JD and Gagneux S (2010)
Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved.
Nature Genetics 42:498-503
Coscolla M and Gagneux S (2010)
Does M. tuberculosis genomic diversity explain disease diversity?
Drug Discovery Today: Disease Mechanisms 7: e43-e59
de Jong BC, Antonio M and Gagneux S (2010)
Mycobacterium africanum-review of an important cause of human tuberculosis in West Africa.
PLoS Neglected Tropical Diseases 4:e744
40
Parasitology
Tony Holder
Malaria parasites and red blood cells
Lab members: Eilidh Carrington, 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 fresh red cells. This cycle is
responsible for the disease. Understanding the interaction
between the parasite and the host immune system
contributes to the development of a malaria vaccine.
The identification of new targets for drugs to kill the
parasite and interrupt the cycle of multiplication offers the
potential of new therapeutic interventions.
In one project, we focus on the interaction between the
parasite and the surface of the host red cell that it invades.
Invasion is a multistep process driven by the parasite’s
actomyosin-based motor. At the parasite surface during
invasion there is a complex but ordered series of events
involving protein complex formation and modification,
export of protein from intracellular organelles and
transfer of proteins to the host cell. We are defining the
role of parasite components essential for invasion using a
range of genetic, molecular and cell biological techniques.
Understanding the importance of specific interactions will
inform the development of therapeutic strategies to block
them.
Publications
Kadekoppala M, Ogun SA, Howell S, Gunaratne RS and Holder AA
(2010)
Systematic genetic analysis of the Plasmodium falciparum MSP7-like
family reveals differences in protein expression, location and
importance in asexual growth of the blood stage parasite.
Eukaryotic Cell 9:1064-1074
Hinds L, Green JL, Knuepfer E, Grainger M and Holder AA (2009)
A novel putative GPI-anchored micronemal antigen of Plasmodium
falciparum that binds to erythrocytes.
Holder AA (2009)
Malaria vaccines: where next?
Malaria can lead to severe anaemia. One mechanism may involve the destruction of uninfected red
blood cells by immune mechanisms recognising antibody bound to parasite antigens coating these
cells. The parasite antigens may be released as soluble proteins during invasion, which then stick to
uninfected cells (A), or be transferred to the surface of cells during an aborted invasion (B).
See references 41, 66, 100, 124, 125, 183, 222, 239, 244, 251, in the
bibliography at the back for publications from this group in 2010.
41
Immunoregulation
George Kassiotis
Antiviral immunity
Lab members: Urszula Eksmond, Dorothy Ng, 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, for example influenza A and smallpox viruses.
In contrast, other viruses are able to persist chronically in infected
individuals, despite induction of an immune reaction (e.g. HIV, hepatitis
and herpes viruses) and almost all humans are chronically infected by
one or more persistent viruses. Our understanding of the pathogenic
processes of viral infection remains incomplete.
Viral infection elicits potent innate and adaptive host immunity.
However, an excessive or inappropriate immune response may also
lead to host pathology, often more severe than the direct effects of
viral replication. We found that, without affecting virus replication,
regulatory T (Treg) cells delayed the appearance of clinical signs and
prolonged survival of mice following influenza A virus infection. This
correlated with reduced expression of the monocyte chemoattractant
CCL8 and recruitment of monocytes into the infected lungs. The
finding that part of the pathology following Influenza A virus infection
is amenable to immune regulation suggests a causal involvement of the
immune response.
Treg cells suppress the induction of monocyte chemoattractant CCL8 by Influenza A
virus infection in the lungs.
Publications
Antunes I and Kassiotis G (2010)
Suppression of innate immune pathology by regulatory T cells during Influenza A virus infection of immunodeficient mice.
Influenza A virus-induced pathology (body weight loss) is
delayed by regulatory T cells (Treg 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
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
42
See references 8, 181 in the bibliography at the back for publications from this
group in 2010.
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
Karamitris, Trisha Norton, Keith Williams
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
Menzel U, Ktistaki E, Tolaini M, Veiga-Fernandes H and Kioussis D (2010)
Replication allows inactivation of a knocked-in locus control region in inappropriate cell lineages.
Image of mouse chromosome 6. Multi-colour chromosome banding
(MCB) with CD8a and CD4 gene probes.
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 37, 38, 83, 127, 128, 137, 172, 256, 257, 274 in the bibliography at the back for
publications from this group in 2010.
43
Parasitology
Jean Langhorne
Immunity and immunopathogenesis in malaria infections
Lab members: Deirdre Cunningham, Ana Paula Freitas do Rosario, William Jarra, Jennifer Lawton, Wiebke Nahrendorf, Dorothy Ng,
Philip Spence, Anne-Marit Sponaas, Sophie Roetynck, Christine Tshitenge, Bettina Wagner
CD4 T cells are crucial for development of protective
immunity to blood-stage malaria, but may also contribute
to the pathology of severe disease. A major focus of our
laboratory is to understand how memory CD4 T cells
develop, which can protect against re-infection but cause
minimal pathology. Protective immunity against malaria
develops only after several infections and can be lost on
leaving an area in which malaria is transmitted. This suggests
that the chronic infection may maintain the protective immune
response. We have used a mouse model of a blood-stage
malaria infection to examine the memory response of CD4 T
cells during chronic infection. Understanding what constitutes
a protective CD4 T cell may help us design more protective
vaccines. We show that protective memory CD4 T cells
persist in an activated state following a first infection, produce
the inflammatory cytokines TNFα and IFNγ, and are more
protective than “resting” memory CD4 T cells obtained from
mice in which the infection has been eliminated. This may
explain why people are better protected against malaria when
they are infected frequently.
Publications
Stephens R and Langhorne J (2010)
Effector memory Th1 CD4 T cells are maintained in a mouse model of
chronic malaria.
Nduati EW, Ng DHL, Ndungu FM, Gardner P, Urban BC and Langhorne
J (2010)
Distinct kinetics of memory B-cell and plasma-cell responses in
peripheral blood following a blood-stage Plasmodium chabaudi infection
in mice.
PLoS ONE 5:e15007
Belyaev NN, Brown DE, Diaz AIG, Rae A, Jarra W, Thompson J, Langhorne
J and Potocnik AJ (2010)
Induction of an IL7-R+c-Kithi myelolymphoid progenitor critically
dependent on IFN-γ signaling during acute malaria.
Nature Immunology 11:477-85
See references16, 50, 71, 85, 182, 206, 211, 237, 262 in the bibliography at
the back for publications from this group in 2010.
44
CD4 T cells remain in an activated state following a Plasmodium chabaudi infection.
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 specialised receptors
on the surface and in the cytoplasm of cells called neutrophils
and macrophages. This triggers an immediate ‘innate’ immune
response involving the production of specialised 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.
We study a signalling pathway that regulates the activation
of TPL-2, a protein kinase that is critical for the induction of
the cytokines tumor necrosis factor and interleukin-1b in
inflammatory responses. Our current experiments aim to
investigate the role of TPL-2 in autoimmunity, allergy and
immune responses to pathogens, and are important in the
evaluation of TPL-2 as a potential anti-inflammatory drug target.
TPL-2 is required for induction of TNF by macrophages.
Publications
Gantke, T., Sriskantharajah, S. and Ley S. C. (2011)
Regulation and function of TPL-2, an IκB-regulated MAP kinase kinase kinase.
Cell. Research 21:131-45
Sriskantharajah S and Ley SC (2010)
Turning off inflammation signaling.
Science 327:1093-4
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.
Schematic diagram of TPL-2 / ERK signalling pathway.
45
Virology
John McCauley
Host specificity of influenza viruses
Lab members: Haixia Xiao, Nicole Runkler, Ana Luisa Reis, Michael Bennett, Steve Wharton, Saira Hussain
Influenza A viruses infect a variety of species, with humans (also
the host for influenza B viruses), horses and pigs representing the
main mammalian hosts of the virus in which infection is sustained.
Avian species, particularly water-fowl and gulls, harbour a wide
variety of influenza A viruses defined by their haemagglutinin
(H1-16) and neuraminidase (N1-9) glycoprotein subtypes in a
variety of H/N combinations. New pandemic strains of human
influenza virus arise from an animal reservoir either directly, as
for the 2009 pandemic A(H1N1) virus, or as a result of gene
reassortment, 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. 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. Our research programme is closely integrated with
the surveillance activities of the WHO Collaborating Centre (WIC) in the Division. Recent human H3N2 viruses that have been
examined in the WIC show unexpected receptor binding activities. For many of these viruses the neuraminidase glycoprotein
rather than the haemagglutinin mediates attachment to red cells. The characteristics of this binding are being examined in
collaboration with colleagues in the Divisions of Physical Biochemistry and Molecular Structure, and with Prof. Ten Feizi, Imperial
College London.
Publications
Lin, Y.P., Gregory, V., Collins, P., Kloess, J., Wharton, S., Cattle, N.,
Lackenby, A., Daniels, R., and Hay, A. (2010).
Neuraminidase receptor binding variants of human influenza
A(H3N2) viruses due to substitution of aspartic acid 151 in the
catalytic site - role in virus attachment?
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
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
See references 12, 89, 178, 218, 250 in the bibliography at the back
for publications from this group in 2010.
46
Agglutination of turkey erythrocytes by recent seasonal H3N2 viruses can be
mediated by the Neuraminidase. This agglutination correlates with the presence
of a glycine at position 151 of the neuraminidase and utilises the catalytic site of
the enzyme. The figure shows turkey erythrocytes incubated with recombinant
virus carrying the haemagglutinin and neuraminidase glycoproteins of the A/Hong
Kong/4443/2005 (H3N2) virus in the absence (A) or presence (B) of a neuraminidase
inhibitor which binds to the catalytic site thereby preventing agglutination.
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, Fotini Rozakeas, Vangelis Stavropoulos, Xuemei Wu
Immune cells can produce different soluble factors called cytokines to control
infection, but they can mediate host damage if uncontrolled. We are researching
the molecular mechanisms for the development and function of discrete subsets
of immune cells producing different cytokines protective against pathogens, and
the induction and function of a regulatory cytokine, IL-10. We use diverse tools to
study the molecular mechanisms of IL-10 gene regulation in macrophages, dendritic
cells and T cells, and the consequences of IL-10 action in mouse models of bacterial
infections, with strong emphasis on tuberculosis (TB) caused by Mycobacterium
tuberculosis.
TB is a major global cause of morbidity and mortality. Using a systems biology
approach we identified a robust blood transcriptional interferon-inducible
neutrophil-driven signature in human TB, which disappears during successful
treatment. Based on these findings and continued studies in human disease and
in cellular and in vivo experimental models, we are continuing to identify immune
mechanisms of protection or pathogenesis important for disease control in
tuberculosis and other bacterial infections.
Publications
Berry MPR, Graham CM, McNab FW, Xu Z, Bloch SAA, Oni T,
Wilkinson KA, Banchereau R, Skinner J, Wilkinson RJ, Quinn C,
Blankenship D, Dhawan R, Cush JJ, Mejias A, Ramilo O, Kon OM,
Pascual V, Banchereau J, Chaussabel D and O’Garra A (2010)
An interferon-inducible neutrophil-driven blood transcriptional
signature in human tuberculosis.
Nature 466:973-977
Redford PS, Boonstra A, Read S, Pitt J, Graham C, Stavropoulos E,
Bancroft GJ and O’Garra A (2010)
Enhanced protection to Mycobacterium tuberculosis infection in
IL-10-deficient mice is accompanied by early and enhanced Th1
responses in the lung.
European Journal of Immunology 40:2200–2210
Transcriptome analysis of human TB to enhance mouse models of MTb infection for in-depth
mechanistic studies.
Saraiva M and O’Garra A (2010)
The regulation of IL-10 production by immune cells.
Nature Reviews Immunology 10:170-81
See references 18, 166, 208, 221 in the bibliography at the back for
47
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
Belyaev NN, Brown DE, Diaz AIG, Rae A, Jarra W, Thompson J,
Langhorne J and Potocnik AJ (2010)
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
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.
48
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.
Both the numbers and types of T cells found in the immune system are
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, causing them to malfunction.
Abnormal responses by T cells can result in autoimmune diseases like diabetes
or the development of leukaemia. Cellular signals transduced by the T cell
antigen receptor (TCR) and from cytokines such as IL-7 play a central role in
regulating homeostasis of T cells.
We have developed two novel in vivo models in which we can specifically
control expression of IL-7Rα, the receptor for the cytokine interleukin-7, and
the Syk family kinase Zap70, which is an essential signalling component down
stream of the TCR. Using these models, we are investigating the role of IL-7
and TCR signals in controlling T cell survival.
T cell development and maturation depends on TCR signalling and IL-7.
Mature naïve T cells cannot develop in the absence of either TCR signalling
or IL-7. Our conditional expression models permit us to manipulate these
signalling pathways on a temporal basis, after T cells have first developed in
the thymus.
Publications
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.
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
IL-7R and Zap70 expression in TetIL-7R and TetZap70 mice
are induced by administration of the inducing antibiotic,
doxycycline (dox). The graphs show the death of F5 TCR
transgenic T cells after loss either of IL-7R (left) or Zap70
(right) by withdrawing dox (-dox lines) from mice.
49
Gitta Stockinger EMBO member, FMedSci
Development, maintenance and regulation of peripheral T cell compartments and immune
responses
Lab members: Judit Biro, Keiji Hirota, Joao Duarte, Ceri Wiggins, Helena Ahlfors, Christoph Wilhelm, Ying Li
Our current focus is on the development and function of
innate and adaptive IL-17 producing T 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. We developed an IL-17A fate reporter model,
which allows us to study development of IL-17 producing
T cells and their behaviour during infection in vivo. We
furthermore study the role of the aryl hydrocarbon
receptor in the immune system, trying to unravel its impact
on the function of different immune cells in the defense
against pathogens.
Publications
Hirota K, Duarte J.H, Veldhoen M, Hornsby E, Li Y, Cua D.J, Ahlfors H, Wilhelm C, Tolaini M, Menzel U,
Garefalaki A, Potocknik A.J and Stockinger B (2011)
Fate mapping of interleukin-17 producing T cells in inflammatory responses.
Nature Immunology 12:255–263
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, 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 24, 118, 179, 248, 258, 259, 260 in the bibliography
at the back for publications from this group in 2010.
Accumulation of eYFP+ cells from IL-17A fate reporter mouse in
skin following infection with Candida albicans.
50
Virology
Jonathan Stoye
Retrovirus-host interactions
Lab members: Vicky Felton, Seti Grambas, Kate Holden-Dye,Wilson Li, 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 co-evolution
has taken place resulting in the development of specific
defence mechanisms by the host and of means to
overcome such defences by the virus. Understanding
such natural anti-viral genes might suggest novel means
of combating retroviral infection. We anticipate that
these studies will shed new light on the early stages of
retrovirus replication and the control of cross-species
infection.
The host proteins TRIM5α and Fv1 typify such defence
factors. They interact with incoming viruses, shortly
after viral entry into the cell cytoplasm, binding to
the viral core and inhibiting reverse transcription or
nuclear transport. Study of the binding assay has been
complicated by a requirement for polymerised capsid as
found in virions and difficult to isolate experimentally. We
have now devised a method for polymerising retrovirus
capsids on lipid nanotubes producing assemblies closely
resembling those found in retroviruses. We are using
these tubes for studying both retroviral assembly and
mode of Fv1 binding.
Publications
Goldstone DC, Yap MW, Robertson LE, Haire LF, Taylor WR, Katzourakis A, Stoye JP and Taylor
IA (2010)
Structural and functional analysis of prehistoric lentiviruses uncovers an ancient molecular
interface.
Cell Host & Microbe 8:248-259
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.
See references 98, 106, 107, 166, 238 in the bibliography at the back for publications from this
group in 2010.
Electron microscope analysis of lipid nanotubes decorated with assembled
retrovirus capsid protein : Left: cross-section of tube. Middle: surface of tube.
Right: filtered image showing lattice. Collaboration with Peter Rosenthal
(Division of Physical Biochemistry).
51
Immune Cell Biology
Pavel Tolar
Activation of immune receptors
Lab members: Jason Lee, Elizabeth Natkanski, Antonio Casal
Antibodies are critical for human immunity and their
induction has been instrumental for the success of many
vaccines. However, some of the most dangerous pathogens
of today’s world, such as HIV, influenza or malaria, evade
antibody responses, both natural and vaccine-induced. A
better understanding of the mechanisms by which these
pathogens trigger antibody responses will be necessary for the
development of more effective vaccines.
Antibody responses are initiated by B lymphocytes that detect
pathogens by surface antibodies in the form of B cell antigen
receptors. Pathogen binding to the membrane antibody of the
B cell receptor transduces signals to the intracellular signaling
components. We are elucidating the structure of the parts
of the B cell receptor that underly this process. We are also
developing new ways to visualise the activation of individual
B cell receptor molecules in the plasma membrane and their
trafficking within B cells.
Domain architecture of the B-cell antigen
receptor.
Publications
Tolar P and Pierce SK (2010)
A conformation-induced oligomerization model for B cell receptor microclustering and signaling.
Current Topics in Microbiology and Immunology 340:155-69
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 (2005)
The initiation of antigen-induced B cell antigen receptor signaling viewed in living cells by fluorescence resonance
energy transfer.
See references 149, 150 in the bibliography at the back for publications from this group in 2010.
52
A scheme of B cell receptor clustering during
formation of the immunological synapse.
Immune Cell Biology
Victor Tybulewicz EMBO member, FMedSci
Signal transduction in B and T cells
Lab members: Alexander Saveliev, Agnieszka Zachacz, Amy Slender, Lesley Vanes, Robert Köchl, Karen McGee, Sheona Watson,
Eva Lana Elola, Edina Schweighoffer, Harald Hartweger
B and T lymphocytes are white blood cells that are critical mediators of the immune
response against a variety of pathogens. Inappropriate activation of these cells can
result in autoimmune diseases such as rheumatoid arthritis. We are interested in
understanding the biochemical signalling pathways within lymphocytes that control
the activation, survival and migration of the cells. 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 (Hsa21) occurs in around 1 in 750 live births
and the resulting gene dosage imbalance gives rise to Down Syndrome, the most
common form of mental retardation. In collaboration with Prof E. Fisher (UCL), we
are interested in identifying genes on this chromosome, which, when present in three
copies, cause the many different phenotypes of Down Syndrome. We have created
a novel mouse strain carrying a freely segregating copy of Hsa21, which displays
many of the features of Down Syndrome, including learning difficulties and cardiac
abnormalities. In a recent study, we showed that the reduced incidence of solid
tumours in Down Syndrome may be caused by decreased tumour angiogenesis.
Publications
Faroudi M, Hons M, Zachacz A, Dumont C, Lyck R, Stein JV and
Tybulewicz VLJ (2010)
Critical roles for Rac GTPases in T cell migration to and within
lymph nodes.
Blood 116:5536-47
Henderson RB, Grys K, Vehlow A, de Bettignies C, Zachacz A,
Henley T, Turner M, Batista F and Tybulewicz VLJ (2010)
A novel Rac-dependent checkpoint in B cell development
controls entry into the splenic white pulp and cell survival.
Journal of Experimental Medicine 207:837-853
Reynolds LE, Watson AR, Baker M, Jones TA, D’Amico G, Robinson
SD, Joffre C, Garrido-Urbani S, Rodriguez-Manzaneque JC, MartinoEcharri E, Aurrand-Lions M, Sheer D, Dagna-Bricarelli F, Nizetic D,
McCabe CJ, Turnell AS, Kermorgant S, Imhof BA, Adams R, Fisher
EMC, Tybulewicz VLJ, Hart IR and Hodivala-Dilke KM (2010)
Tumour angiogenesis is reduced in the Tc1 mouse model of
Down’s syndrome.
Nature 465:813-7
See references 6, 7, 52, 56, 62, 72, 116, 175, 209, 271 in the
bibliography at the back for publications from this group in 2010.
3D quantitative immunohistology shows
that T cells deficient in Rac GTPases (red)
are mostly stuck on the endothelium of the
lymph node (gold), whereas wild-type T cells
(green) are able to penetrate the interstitial
tissue.
Sections of spleen from the Tc1 model of
Down Syndrome show increased numbers
of megakaryocytes compared to wild-type
spleens. Megakaryocytes are visible as large
red cells in the hematoxylin and eosin stained
images, and brown in slides stained with
antibodies to CD41.
53
Immunoregulation
Andreas Wack
Immune response to influenza
Lab members: Stefania Crotta, Sophia Davidson, Annita Gjoka, Gregory Ellis
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 also contributes to lung
pathology. In addition to direct damage, influenza infection also
increases dramatically the susceptibility to bacterial co-infections,
as evidenced by epidemiological and microbiological data from
seasonal and pandemic influenza waves. Both for single and
co-infections, it is unclear which factors tip the balance between
pathology or death versus successful clearance of the pathogen
without 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 innate 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.
These studies are complemented by in vivo studies to understand
how airway epithelia contribute to the anti-influenza immune
response. In addition, we are interested in the roles of natural
killer cells and granulocytes in influenza infection and co-infection.
These approaches will allow us the identification of early events
and players 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
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.
Piccioli D, Sammicheli C, Tavarini S, Nuti S, Frigimelica E, Manetti AGO, Nuccitelli A, Aprea S, Valentini S,
Borgogni E, Wack A and Valiante NM (2009)
Human plasmacytoid dendritic cells are unresponsive to bacterial stimulation and require a novel type of
cooperation with myeloid dendritic cells for maturation.
Blood 113:4232-4239
54
Influenza virus propagates in mouse airway epithelia.
Cultures were infected with low amounts of influenza
virus and stained for the tight junction protein ZO-1
(green) and influenza nucleoprotein (magenta) at the
indicated time points after infection.
Immune Cell Biology
Robert Wilkinson FRCP
Victor Tybulewicz
Understanding and intervening in HIV-associated tuberculosis
Lab members: Katalin Wilkinson, Anna Coussens, Adrian Martineau, Shepherd Nhamoyebonde
The programme derives its research questions from the clinical care
of tuberculosis (TB) and HIV-TB co-infected persons in South Africa
and London. Through clinically based studies we aim to improve
knowledge of pathogenesis and thereby prevention and treatment.
We have contributed to the description of a distinct transcriptomic
signature of active TB and studies of interferon gamma release assays
in the diagnosis of tuberculosis. We have investigated the effects and
mechanisms of preventive therapies against tuberculosis. We have
determined that protective antiretroviral-mediated immune recovery
in HIV-TB is associated with expansion of central memory T cells
rather than the commonly determined effector response. Conversely,
pathological immune restoration, as exemplified by the HIV-TB
immune reconstitution inflammatory syndrome, is contributed to by
dysregulated Th1 expansions and by exaggerated cytokine release.
We have determined that the steroid hormone, vitamin D, augments
protective immunity to TB and that corticosteroids help suppress
pathological immunity via downregulation of IL-6 and TNF. We have
also uncovered evidence that an antigen absent from most BCG
vaccine strains is a major target of the protective immune response.
Publications
Martineau, A.R., Timms, P.M., Bothamley, G.H., Claxton, A.P., Hanifa, Y., Islam, K., Packe,
G.E., Moore-Gillon, J.C., Darmalingam, M., Davidson, R.N., Millburn, H.J., Baker,
L.V., Barker, R.D., Woodward, N.J., Venton, T.R., Barnes, K.E., Mullett, C.J., Coussens,
A.K., Rutterford, C.M., Mein, C.A., Davies, G.R., Wilkinson, R.J., Nikolayevskyy, V.,
Drobniewski, F.A., Eldridge, S.M., Griffiths, C.G. (2011)
High-dose vitamin D3 during intensive phase treatment of pulmonary tuberculosis:
a double-blind randomised controlled trial.
Lancet 377: 242-250
Gideon, H.P., Wilkinson, K.A., Rustad, T.R., Oni, T., Guio, H., Kozak, R.A., Sherman, D.R.,
Meintjes, G., Behr, M.A., Vordermeier, H.M., Young, D.B., Wilkinson, R.J. (2010)
Hypoxia induces an immunodominant target of tuberculosis specific T cells absent
from common BCG vaccines.
Implication of TNF and IL-6 in the pathogenesis of TB-IRIS. Whilst many
pro- and anti-inflammatory cytokine transcript and protein levels were
elevated in TB-IRIS patients according to experimental circumstances, only
IL-6 and TNF were elevated in all circumstances. Thus blockade of IL-6 or
TNF may be a rational approach to immunomodulation in this condition.
Berry MPR, Graham CM, McNab FW, Xu Z, Bloch SAA, Oni T, Wilkinson KA,
Banchereau R, Skinner J, Wilkinson RJ, Quinn C, Blankenship D, Dhawan R, Cush JJ,
Mejias A, Ramilo O, Kon OM, Pascual V, Banchereau J, Chaussabel D and O’Garra
A (2010)
An interferon-inducible neutrophil-driven blood transcriptional signature in
human tuberculosis.
Nature 466:973-977
See references 10, 13, 18, 19, 30, 34, 40, 95, 141, 144, 145, 157, 158, 160, 168, 169,
170, 190, 201, 223, 242, 249, 270, 273, in the bibliography at the back for publications
55
Mark Wilson
Regulation of Th2 cells during allergic inflammation and anti-helminth immunity
Lab members: Stephanie Czieso, Eleni Ktistaki, Nicholas Mathioudakis, Isobel Okoye, Kathleen Roderick
More than a quarter of the world’s population are infected by
one of four parasitic helminth’s (filarial worms, schistosomes,
whipworms or roundworms) making them the most common
infectious agents of humans in developing countries. Efficient
expulsion of parasitic helminth’s from mammalian hosts requires
a well-orchestrated immune response to activate innate immune
cells and stimulate local tissue responses. CD4+ T helper 2 (Th2)
lymphocytes coordinate the expulsion mechanism, placing them
front and centre of anti-helminth immunity. One major aim of
our work is to develop ways to promote Th2 cell responses and
enhance anti-helminth immunity. An additional and complementary
aim is to investigate ways to inhibit Th2 cell responses to remedy
allergic disease. Allergic diseases plague hundreds of millions
of people worldwide and are the result of dysregulated and
hyperactive Th2 responses.
These aims are being investigated using in vivo helminth infection
and allergy models. Using next-generation sequencing and gene
manipulation techniques the role of regulatory RNA species in Th2
cells and associated responses are being studied. De novo immune
responses develop, often in tandem, with other ongoing immune
responses. Therefore, in collaboration with other NIMR labs, we are
investigating the mechanisms of Th2 cell development and function
in the context of other immune responses. Together these aims will
extend our knowledge of Th2 immunobiology, facilitate helminth
elimination strategies, and identify novel allergy intervention.
Hallmarks of allergic asthma using a murine model of
Th2-mediated airway inflammation. Allergen-induced
airway eosinophilia (A), goblet cell hyperplasia and
mucus hypersecretion (B), peri-bronchial and perivascular inflammation (C).
Publications
Wilson MS, Pesce JT, Ramalingam TR, Thompson RW, Cheever A and Wynn TA (2008)
Suppression of murine allergic airway disease by IL-2:anti-IL-2 monoclonal antibody-induced
regulatory T cells.
Wilson MS, Elnekave E, Mentink-Kane MM, Hodges MG, Pesce JT, Ramalingam TR, Thompson RW,
Kamanaka M, Flavell RA, Keane-Myers A, Cheever AW and Wynn TA (2007)
IL-13Rα2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and
fibrosis in mice.
Journal of Clinical Investigation 117:2941-2951
Wilson MS, Taylor MD, Balic A, Finney CAM, Lamb JR and Maizels RM (2005)
Suppression of allergic airway inflammation by helminth-induced regulatory T cells.
56
Helminth parasites of mammalian hosts.
Schistosoma mansoni (A; adult male and female), Heligmosomoides polygyrus
(B), Trichuris muris (C) in situ.
Douglas Young FMedSci
Mycobacterial pathogenesis: gene expression and innate immune response
Lab members: Kristine Arnvig, John Brennan, Stephen Coade, Teresa Cortes, Joanna Dillury, Damien Portevin, Graham Rose, 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 in a persistent asymptomatic, latent
infection. We are studying the way that M. tuberculosis evades
host immunity by misdirecting innate immune recognition
and by adapting to a form that resists killing by phagocytes.
Ultimately, we aim to develop drugs that rapidly eliminate
persisting bacteria and vaccines that elicit more effective
immunity.
Evolutionarily diverse strains of M. tuberculosis vary widely in
their induction of the host inflammatory response. Suppression
of innate immune recognition by modern lineages promotes
early progression to disease, while the pro-inflammatory
phenotype of ancient lineages favours latent infection and
reactivation. RNA sequencing has allowed us to identify an
extensive network of post-transcriptional regulation that we
think will be critical in adaptation of mycobacteria to survival
in infected tissues. We are studying this as part of SysteMTb, a
European systems biology consortium.
We have identified a large number of regulatory small RNA molecules
in M. tuberculosis. We are currently characterising the role of sRNAs in
mycobacterial gene regulation.
Publications
Kirschner DE, Young D and Flynn JL (2010)
Tuberculosis: global approaches to a global disease.
Current Opinion in Biotechnology 21:524-531
Arnvig KB and Young DB (2009)
Identification of small RNAs in Mycobacterium tuberculosis.
Molecular Microbiology 73:397-408
Clinical isolates of M. tuberculosis show consistent differences in cytokine
induction during infection of human monocyte-derived macrophages.
We are studying the genetic basis for this variation.
Barry CE, 3rd, Boshoff HI, Dartois V, Dick T, Ehrt S, Flynn J, Schnappinger D, Wilkinson RJ and Young D
(2009)
The spectrum of latent tuberculosis: rethinking the biology and intervention strategies.
Nature Reviews Microbiology 7:845-855
See references13, 46, 133, 231, 236 in the bibliography at the back for publications from
this group in 2010.
57
Microarray laboratory
Molecular pathogenicity of mycobacteria
Lab members: Roger Buxton, Debbie Hunt, Christina Kahramanoglou, Nishad Matange, Vicky Spivey
To grow within a host, some pathogens manipulate their
environment for their own advantage. Mycobacterium
tuberculosis is a master of this ecological niche management,
allowing it to grow within macrophages, cells that kill most
pathogens. We are studying two signalling systems that the
bacterium uses to achieve this, serine-threonine protein
kinases (in collaboration with Steve Smerdon, Molecular
Structure), and the global transcriptional regulator, cyclic AMP
receptor protein.
One of the genes that the cAMP receptor protein (CRP) controls is espA,
required for secretion of the virulence factor, the protein ESAT-6. In this
western blot of cell-free extracts of M. tuberculosis, the accumulation of
ESAT-6 can be seen in an espA mutant (lanes 2 and 3) whereas in the
wild-type virtually all of the protein is secreted (lanes 1 and 6).
Complementation with the wild-type espA allele restores ESAT-6 secretion
(lanes 4 and 5).
The metabolic changes that the bacterium causes means,
however, that gene regulation also has evolved to cope
with these novel conditions. For example, mycobacteria
synthesise very high levels of the small nucleotide cyclic AMP,
which increase after macrophage infection. In collaboration
with Jeff Green (University of Sheffield) we have examined
how M. tuberculosis manages to control gene expression at
these high levels of cAMP, identifying novel mechanisms of
transcriptional initiation control via the cyclic AMP receptor
protein. Knowing how M. tuberculosis copes with its peculiar
lifestyle enables us to identify novel features that may be drug
targets, and in collaboration with MRC Technology we have
carried out screens for new inhibitors against these targets.
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, DNA-binding and transcription activation properties.
Journal of Biological Chemistry 285:7016-7027
Hunt DM, Saldanha JW, Brennan JF, Benjamin P, Strom M, Cole JA, Spreadbury CL and Buxton RS
(2008)
Single nucleotide polymorphisms causing structural changes in the CRP transcriptional regulator
of the TB vaccine strain Mycobacterium bovis BCG alter global gene expression without attenuating
growth.
Infection and Immunity 76:2227-2234
Signalling mediated by a serine-threonine protein kinase. Autoradiogram
showing phosphorylation of the ABC transporter Rv1747 in vitro by the kinase
PknF on residues T150 and T208. Mutation of both these residues results in
significant loss of phosphorylation.
58
Rickman L, Scott C, Hunt DM, Hutchinson T, Menendez MC, Whalan R, Hinds J, Colston MJ, Green J
and Buxton RS (2005)
A member of the cAMP receptor protein family of transcription regulators in Mycobacterium
tuberculosis is required for virulence in mice and controls transcription of the rpfA gene coding for
a resuscitation promoting factor.
Molecular Microbiology 56:1274-1286
Parasitology
Tony Holder, Olugbemiro Sodeinde, Delmiro Fernandez-Reyes
This clinical research unit is a partnership between the NIMR Division of Parasitology and the College of Medicine University of
Ibadan, University College Hospital (COMUI-UCH), in Ibadan, Nigeria.
Nigeria, the most populous African country, accounts for an estimated one-quarter of all malaria cases worldwide. Malaria in
Ibadan is holoendemic with transmission occurring all year round. Ibadan is a densely populated city of at least three million
people where malaria is ranked amongst the most common causes of death in children under the age of five years.
The CMRG at COMUI-UCH is placed within the major clinical referral centre for severe malaria cases and provides the
framework for our research on the molecular basis of the pathogenesis of cerebral malaria and severe malarial anaemia. Among
its several functions the CMRG builds malaria research capability closer to the point of care, which allows more precise sampling
and alignment of the clinical and molecular aspects of severe disease.
The CMRG is overseen by a group of seven academics from both institutions and its infrastructure consists of a Malaria Research
Laboratory situated at the Department of Paediatrics, closely coupled with the Paediatrics Emergency Ward and the Children’s
Outpatient Clinics where recruitment of patients take place.
For information or submitting research enquires for collaborative work please email Dr. Fernandez-Reyes at [email protected]
The CMRG academic panel:
• Prof. K. Osinusi. Head of Department of Paediatrics COMUI-UCH
• Dr. B.J. Brown. Department of Paediatrics
COMUI-UCH.
• Dr. F.O. Akinbami. Department of Paediatrics,
COMUI-UCH
• Prof. W.A. Shokunbi. Department of Haematology,
COMUI-UCH
• Dr A. Holder. Head of Division of Parasitology,
NIMR
• Dr. D. Fernandez-Reyes. Division of Parasitology, NIMR
• Prof. O. Sodeinde. Division of Parasitology, NIMR
59
Virology
WHO Collaborating Centre for
Reference and Research on Influenza (WIC)
Director: John McCauley
Lab members: Rod Daniels (Deputy Director), Yi Pu Lin (Assistant Director), Zheng Xiang, Vicki Gregory, Lynn Whittaker,
Nick Cattle, Karen Cross, Chandrika Halai, Johannes Kloess
The WHO Influenza centre at NIMR is one of five WHO Collaborating Centres for Reference and Research on Influenza. These
Centres, together with some 130 National Influenza Centres, comprise the WHO Global Surveillance Network which tracks
influenza viruses as they circulate around the world.
Viruses are characterised antigenically and genetically in the laboratories and their susceptibility to antiviral drugs is determined.
Results of these analyses from Collaborating and National Influenza Centres are used to develop recommendations for the most
appropriate type A and type B influenza viruses for use in seasonal influenza vaccines and provide advice to national authorities on
both global and regional influenza circulation.
Recent work in the WIC has highlighted the emergence of a variant of the pandemic H1N1 virus that shows distinct receptor
binding characteristics and cell tropism in model systems. In addition recent H3N2 viruses show distinct alterations in their ability
to bind to sialic acid receptors; these alterations in receptor binding can have marked implications on the antigenic analysis of the
virus. For both the pandemic H1N1 and H3N2 viruses, recently emerged genetic groups of viruses have been detected.
All studies are carried out on a collaborative basis with the various National Influenza Centres that supply specimens, the other
WHO Collaborating Centres, the UK Health Protection Agency Centre for Infection (Colindale) and National Institute for
Biological Standards and Control, members of the European Community Network of Reference Laboratories for human influenza
and the Wellcome Trust Sanger Institute.
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 (2010)
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 28:1156-67
Lin YP, Gregory V, Collins P, Kloess J, Wharton S, Cattle N, Lackenby
A, Daniels R and Hay A (2010)
Neuraminidase receptor binding variants of human influenza
A(H3N2) viruses due to substitution of aspartic acid 151 in the
catalytic site - role in virus attachment?
A model of the structure of the H3
haemagglutinin glycoprotein illustrating the
location of amino acid substitutions seen in three
emerging genetic groups of the A(H3N2) virus.
Positions of substitutions are colour-coded by
genetic group/subgroup as represented by A/
Hong Kong/2121/2010 (D53N, I230V, E280A/
Y94H, R208K), A/Johannesburg/310/2010 (S45N)
and A/Sri Lanka/3/2010 (T48A, K92R, N312S).
60
A model of the structure of the H1 haemagglutinin
glycoprotein illustrating the location of amino
acid substitutions seen in two emerging genetic
groups of the pandemic A(H1N1) 2009 virus.
Positions of substitutions are colour-coded by
genetic group/subgroup as represented by A/
Christchurch/16/2010 (N125D/D94N,V250A) and
A/Hong Kong/2213/2010 (S128P,V199A, I295V/
K163T, P271S).
Liu Y, Childs RA, Matrosovich T, Wharton S, Palma AS, Chai W,
Daniels R, Gregory V, Uhlendorff J, Kiso M, Klenk H-D, Hay A, Feizi
T and Matrosovich M (2010)
Altered receptor specificity and cell tropism of D222G
haemagglutinin mutants from fatal cases of pandemic A(H1N1)
2009 influenza.
See references 12, 31, 148, 151, 177, 185, 277 in the bibliography
at the back for publications from this group in 2010.
Structural Biology
Mathematical Biology
Willie Taylor (Head of Division)
Richard Goldstein
Molecular Structure
Steve Gamblin (Joint Head of Division)
Steve Smerdon (Joint Head of Division)
Paul Driscoll
Annalisa Pastore
Andres Ramos
Katrin Rittinger
Ian Taylor
Physical Biochemistry
Justin Molloy (Head of Division)
Ed Hulme
John Offer
Peter Rosenthal
Martin Webb
See also the following groups:
Mike Blackman (Infections and Immunity)
Tom Carter (Neurosciences)
Matthew Hannah (Neurosciences)
Jonathan Stoye (Infections and Immunity)
61
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,
Gemma Wildsmith, Lucy Murfitt
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 include the activation of death receptor
signalling cascades, limb regeneration in the adult newt, the regulation
of phospholipase C isozymes, and the interaction of VEGF with its
receptors.
Recently we have developed a system to enable structural and
biophysical investigation of the core of the so-called death-inducing
signalling complex (DISC) comprised of the ‘death domains’ of the cell
surface receptor CD95/Fas and its immediate adaptor protein FADD.
We find that the 120 kD particle comprises ten protein chains in a 5+5
arrangement, and that the complexity of the NMR spectra derives from
intrinsic asymmetry of the structure. These data are reminiscent of the
asymmetric structure of the PIDDosome, an unrelated death domain
complex; NMR spectra for the PIDDosome yield similar characteristics.
This work provides an excellent platform for further analysis of the intact
DISC.
Cartoon representation of death inducing signalling complex
(DISC) formation.
Publications
Esposito D, Sankar A, Morgner N, Robinson CV, Rittinger K and Driscoll PC (2010)
Solution NMR investigation of the CD95/FADD homotypic death domain complex suggests
lack of engagement of the CD95 C terminus.
Structure 18:1378-90
Jarvis A, Allerston CK, Jia H, Herzog B, Garza-Garcia A, Winfield N, Ellard K, Aqil R, Lynch R,
Chapman C, Hartzoulakis B, Nally J, Stewart M, Cheng L, Menon M, Tickner M, Djordjevic S,
Driscoll PC, Zachary I and Selwood DL (2010)
Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A)
interaction.
Journal of Medicinal Chemistry 53:2215-26
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
62
Detail from ILV-methyl TROSY NMR spectra of free (black) and complexed (red)
DISC death domains.
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, Elizabeth Underwood, Peter Coombs, Sebastien Vachieri,
Rein Aasland, Steve Martin
We study the structure and function of molecules involved in
disease processes such as influenza, diabetes and cancer. We
use X-ray crystallography and NMR to determine the threedimensional structures and dynamics of these molecules. In
combination with other biophysical, biochemical and biological
techniques, the data help us elucidate the function of the
proteins of interest and provide information that may be useful
for the development of therapeutic approaches.
We have a long-term interest in how cellular energy levels
are sensed and regulated by the heterotrimeric AMP
activated protein kinase (AMPK). In response to increased
energy utilisation AMPK activates energy producing pathways
and inhibits energy consuming processes. As such it has
been implicated in a number of diseases related to energy
metabolism including type 2 diabetes, obesity and, most recently,
cancer. In a long-term collaboration with David Carling’s
laboratory we have recently shown that ADP, as well as AMP,
binding to regulatory domain protects the enzyme from
dephosphorylation. Our studies have shown that AMPK displays
significantly tighter binding to ADP than to Mg.ATP, explaining
how the enzyme is regulated under physiological conditions
where the concentration of Mg.ATP is higher than that of ADP
and much higher than that of AMP. We have determined the
crystal structure of an active AMPK complex that shows how
the binding of ADP to the regulatory subunit protects the
kinase domain from dephosphorylation and have developed
a model for how the energy status of a cell regulates AMPK
activity.
Publications
Xiao B, Sanders M, Underwood E, Heath R, Mayer F, Carmena D, Jing C, Walker P, Eccleston J, Haire L,
Howell S, Saiu P, Aasland R, Martin SR, Carling D & Gamblin SJ. (2011)
Structure of mammalian AMPK and its regulation by ADP.
Nature 472:230-3
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
Ribbons representation of two orthogonal views of active AMPK. The
kinase domain is coloured in yellow with its activation loop in pink. The
regulatory gamma subunit which binds AMP/ADP/ATP competitively is
coloured in red.
63
STRUCTURAL BIOLOGY
Richard Goldstein
Modelling of evolution
Lab members: Martin Godany, Kyriakos Kentzoglanakis, Asif Tamuri
All biology is the result of evolution. In order
to understand life, we need to investigate the
evolutionary process that determines its form and
function. Because living things encode this evolutionary
heritage, studies of their properties can provide
insights into the evolutionary process. Following the
evolutionary path of specific components can provide
important information about the characteristics of
living organisms. Combining insights from physical
chemistry, condensed matter physics, artificial
intelligence, complexity theory, and mathematical
biology, we are developing computational and
theoretical methods to explore these areas.
We are investigating 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 are also studying how horizontal
gene transfer affects the evolution of bacteria,
espeically in cases where the interests of the genes
and the organisms conflict.
Publications
Shah SD, Doorbar J and Goldstein RA (2010)
Analysis of host-parasite incongruence in Papillomavirus evolution using importance sampling.
Molecular Biology and Evolution 27:1301-14
Structure of NS1 protein from influenza, interacting with Human Cellular
Factor CPSF30 (PDB 2RHK), showing in orange the locations identified as
involved with the adaptation of influenza from birds to humans. Many of the
locations so identified (such as locations 104 and 105 in this protein) interact
with host factors, in this case, one processing celluar pre-mRNAs involved in
the host imune response.
See references 61, 76, 77, 78, 79, 97, 228 in the bibliography at the back for publications from this group in 2010.
64
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
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
STRUCTURAL BIOLOGY
Ed Hulme
Structure and function of G protein-coupled receptors
Lab members: Carol Curtis
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.
M1 muscarinic acetylcholine receptors (M1 mAChRs) regulate
the activity of important neurons in the forebrain. They are
major mediators of cortical attention mechanisms. Drugs
that selectively activate M1 mAChRs may help to alleviate
the cognitive defects in Alzheimer’s and schizophrenia. We
are making stable ligand complexes of M1 mAChRs, using
pharmacological and mutational methods. Recently, we
have focused on a high affinity peptide toxin, MT7. We are
working towards an atomic resolution structure by X-ray
crystallography. Such complexes will provide a starting point
for structure-based drug design.
Publications
Hulme EC and Trevethick MA (2010)
Ligand binding assays at equilibrium: validation and interpretation.
British Journal of Pharmacology 161:1219-37
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
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.
Molecular Pharmacology 72:1484-1496
The high affinity peptide toxin MT7 may emulate the “plug” domain of the
photoreceptor, rhodopsin. The tips of the three “fingers” of the disulphidestabilised β-sheet of the toxin insert themselves into the extracellular loops of
the M1 mAChR to yield a stable complex .
See reference 119 in the bibliography at the back for publications from this group in 2010.
65
STRUCTURAL BIOLOGY
Justin Molloy
Single molecule studies of cell motility and cell signalling
Lab members : Suleman Bawumia, Rachel Farrow, Stephen Martin, Gregory Mashanov, Paul Moody
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.
Laser-based optical methods like optical tweezers and total
internal reflection fluorescence microscopy (TIRFM) 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; dual-colour fluorescence
imaging has allowed us to image individual G-protein
coupled receptors at the cell membrane and a reagentless
biosensor has enabled us to visualise DNA unwinding by
helicases.
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.
(A) Dual colour imaging to visualise the formation and dissociation of
individual muscarinic acetylcholine receptors at the cell membrane of a living
cell. (B) Single (upper) and dual (lower) colour imaging was used. The red (R)
and green (G) dots (in the lower panel) are individual receptors. Dimers have
either “RR”, “RG” or “GG” dyes. (C) By tracking individual molecules as they
diffuse, we observe two-step photobleaching (upper) and see
differentially-labelled dimers (RG) form and then dissociate (lower panel).
Fili N, Mashanov GI, Toseland CP, Batters C, Wallace MI, Yeeles JTP, Dillingham MS, Webb MR and
Molloy JE (2010)
Visualizing helicases unwinding DNA at the single molecule level.
Nucleic Acids Research 38:4448-4457
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.
See references 15, 25, 80, 117, 162 in the bibliography at the back for publications from this group
in 2010.
66
STRUCTURAL BIOLOGY
John Offer
Synthetic protein laboratory: acyl transfer for chemical biology and synthesis
Lab members: Lotta Holm, Caroline Morris, George Papageorgiou
Post translationally-modified proteins can now be synthesised with a combination
of ligation and optimised peptide synthesis. Emerging methods of ligation enable
expressed proteins and synthetic peptides to be selectively coupled and our
main goal is to increase the synthetic flexibility of these techniques, 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 ligation 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. The demand for site-specifically modified proteins for
structural studies or fluorescent labelling of proteins in cells is driving the further
development of these techniques. We are also applying chemical ligation to the
synthesis of chemically defined peptide-oligosaccharide glycoconjugates as HIV
vaccines.
Publications
Offer J (2010)
Native chemical ligation with Nα acyl transfer auxiliaries.
Biopolymers 94:530-541
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
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
67
STRUCTURAL BIOLOGY
STRUCTURAL BIOLOGY
Molecular Structure
Molecular Structure
Annalisa Pastore EMBO member
Understanding the molecular bases of neurodegeneration
Lab members: Salvatore Adinolfi, Cesira de Chiara, Serena Faggiano, John McCormick, Laura Masino, Kris Pauwels, Raj Menon,
Robert Yan
We are interested in studying the structure and function of proteins
linked to neurodegenerative diseases in order to understand the
events which lead to pathology and design suitable therapeutic
strategies. We focus on two distinct but converging families of
diseases. We study proteins involved in diseases caused by protein
aggregation and misfolding, such as Huntington’s chorea, MachadoJoseph disease and other types of spinocerebellar ataxias. We are
interested in mitochondrial pathologies linked to misfunctioning of
iron metabolism, such as Friedreich’s ataxia.
Our approach uses different complementary biophysical,
biochemical and bioinformatics techniques which range from
various spectroscopies, to AFM, EM and ITC calorimetry. During the
last few years, we have identified the molecular bases which explain
the onset of spinocerebellar ataxia type 1and 3. In both cases, we
have shown that it is essential to understand the normal functions
of the proteins responsible for disease in order to understand
pathology as the two aspects are intimately linked. We have also
described the interactions between frataxin and the IscS/IscU
complex, central to the highly conserved machinery devoted to
iron sulphur cluster assembly. This knowledge will be used for drug
design for the treatment of Friedreich’s ataxia.
Publications
Adrover M, Esposito V, Martorell G, Pastore A and Temussi PA (2010)
Understanding cold denaturation: the case study of Yfh1.
Journal of the American Chemical Society 135:16240–16246
Prischi F, Konarev PV, Iannuzzi C, Pastore C, Adinolfi S, Martin SR,
Svergun DI and Pastore A (2010)
Structural bases for the interaction of frataxin with the central
components of iron-sulphur cluster assembly.
Nature Communications 1:95
Adinolfi S, Iannuzzi C, Prischi F, Pastore C, Iametti S, Martin SR,
Bonomi F and Pastore A (2009)
Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster
formation catalyzed by IscS.
Nature Structural & Molecular Biology 16:390-6
See references 2, 3, 55, 58, 68, 69, 184, 196, 198, 204, 205, 214, 243,
252 in the bibliography at the back for publications from this group
in 2010.
Model of the ternary complex of bacterial frataxin, IscS and IscU as obtained from a combination of
NMR, small angle X-ray scattering and mutagenesis data.
68
STRUCTURAL BIOLOGY
Molecular Structure
Andres Ramos
Molecular recognition in post-transcriptional regulation
Lab members: Adela Candel, Katherine Collins, David Hollingworth, Vijayalaxmi Manoharan, Giuseppe Nicastro
Post-transcriptional control plays a key role in expanding
genomic diversity in complex organisms, and de-regulation of
the metabolism of specific mRNAs lies at the basis of common
genetic diseases, cancer, autoimmune pathologies and viral
infection. Our goal is to explain how RNA-binding proteins
achieve and regulate target selectivity and how they control
the expression of subsets of genes. We combine information
obtained from NMR experiments with that obtained by other
biophysical/structural techniques and by in cell/in vivo assays.
Our recent work on the FUSE element of the c-myc
oncogene indicates that single stranded nucleic acid
binding proteins use common strategies in transcriptional
and post-transcriptional regulation. We show that an
unfolded linker in the activator FUSE Binding Protein (FBP)
decreases the cooperativity between DNA binding and
repressor recruitment, allowing a substantial surge in c-Myc
concentration. This is reminiscent of the intramolecular interdomain decoupling existing in numerous proteins regulating
mRNA metabolism, such as KSRP/FBP2, which facilitates
reversible interactions. Our data on the FUSE system suggest a
way to control the changes in c-Myc concentration associated
with cell replication and human cancers.
Publications
The structure and nucleobase specificity of the four KH domains of the
KSRP protein indicate alternative binding modes to the AU-rich Element
(ARE) and miRNA precursor target RNAs
Cukier CD, Hollingworth D, Martin SR, Kelly G, Díaz-Moreno I and
Ramos A (2010)
Molecular basis of FIR-mediated c-myc transcriptional control.
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
See references 9, 48, 49, 59, 193 in the bibliography at the back for
The interaction between FBP Interaction Repressor (FIR) RRM1/RRM2 (grey) and the N-box
recruiting element of FIR (blue) (left) indicates that an unfolded 50-amino acid linker partially
decouples activator-DNA interaction from repressor recruitment (right).
69
STRUCTURAL BIOLOGY
Molecular Structure
Katrin Rittinger
Structural biology of signalling networks that regulate innate and adaptive immunity
Lab members: Frank Ivins, Aylin Morris-Davies, Kovilen Sawmynaden, Ben Stieglitz, Edmond Wong
Pattern recognition receptors are key sensors of microbial infection
and responsible for initiating a pro-inflammatory response. The
signalling pathways regulating these events need to be tightly
controlled as misregulation can lead to chronic inflammation and
autoimmune disease. Innate immune responses can also trigger
adaptive immunity and the two systems are linked through complex
signalling networks.
Our research is focused on the structural and mechanistic
characterisation of protein complexes that regulate innate and
adaptive immunity. We are particularly interested in understanding
the function of the NLR (NOD-like receptor) family of intracellular
pattern recognition receptors on a molecular level.
Post-translational modification of proteins with ubiquitin acts as a key
signal in immune signalling pathways. Unlike K48-linked polyubiquitin
chains, which target a protein for proteasomal degradation, K63linked and the recently discovered M1-linked (“linear”) ubiquitin
chains have emerged as key components of pathways mediating
immune and inflammatory responses. We want to understand how
poly-ubiquitin chains regulate the activation of NF-kB. In parallel we
aim to elucidate the mechanism by which E3 ligases catalyse the
formation of specific ubiquitin chains.
Signalling through NLRs.
Publications
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
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.
See references 11, 63, 67, 108 in the bibliography at the back for publications from this
group in 2010.
70
Overview of the ubiquitination cascade. The covalent
attachment of ubiquitin to a protein substrate proceeds via a
3-step reaction involving an E1 ubiquitin-activating enzyme, E2
ubiquitin-conjugating enzyme and an E3 ubiquitin ligase.
STRUCTURAL BIOLOGY
Peter Rosenthal
Cryomicroscopy of proteins, viruses and cells
Lab members: Lesley Calder, Tim Grant, Saira Hussain, Rishi Matadeen, Kasim Sader, James Streetley, 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 during 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.
Publications
Calder LJ, Wasilewski S, Berriman JA and Rosenthal PB (2010)
America 107:10685-10690
Schmitz S, Schaap IAT, Kleinjung J, Harder S, Grainger M, Calder L,
Rosenthal PB, Holder AA and Veigel C (2010)
Malaria parasite actin polymerisation and filament structure.
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
See references 25, 26, 222 in the bibliography at the back for
Map of the pyruvate dehydrogenase E2
complex by cryomicroscopy and image analysis.
Structural model for a Weibel-Palade body
containing von Willebrand factor tubules.
71
STRUCTURAL BIOLOGY
Molecular Structure
Steve Smerdon EMBO member
Structural biology of phosphorylation-dependent signalling in the cell cycle and DNA
damage response
Lab members: Julie Clapperton, Richard Li, Simon Pennell, Grace Yu, Otto Kyrieleis, Lasse Stach, Mohamed Ismail, Jan Lloyd, Oliver de Peyer
The dynamic nature of cellular signalling processes requires them
to be rapidly reversible, a characteristic that is generally achieved
through protein phosphorylation. The response to DNA damage
is mediated by a cascade of phosphorylation that originates at the
lesion and is transduced to effector molecules and complexes.
Defects in the precision of phosphorylation are a primary cause of
many cancers and other diseases. By understanding the molecular
basis of specificity within a web of regulatory interactions, we can
determine why these processes run amok, and may be able to
design drugs to combat these effects. To this end, we focus on an
emerging group of proteins and modules such as 14-3-3, Forkheadassociated (FHA), Brca1-C-terminus (BRCT) and Polo-box domains
that function as phosphorylation-dependent adaptors or scaffolding
molecules in Ser/Thr kinase pathways.
Our recent work has shown how FHA and BRCT-repeat domains
of Nbs1 - a component of the MRN DNA damage complex - work
in concert to orchestrate DNA break processing and signalling to
the rest of the repair machinery. In a study of kinase signalling in M.
tuberculosis, we have revealed a role for phospho-independent FHA
interactions and a novel, intra-molecular binding mechanism in the
control of core metabolic processes that likely have significance for
bacterial virulence.
The FHA-domain protein Rv1827 regulates three enzymes of the TCA
cycle in Mycobacterium tuberculosis to control glutamate flux and nitrogen
assimilation (left). It does so by phospho-independent interactions
with three distinct enzyme complexes mediated through a surface on
the core FHA domain.This is occluded by a novel ‘bind-back’ switch
activated by threonine phosphorylation within a regulatory N-terminal
region as revealed by nuclear magnetic resonance spectroscopy (right).
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 double-strand breaks. (See also erratum:Vol 124,
pg 1299, 2006).
Cell 123:1213-26
72
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: David Goldstone, Joe Hedden, Tom Flower, Laura Robertson, 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. In recent studies we
have determined the structure of a complex of the capsid from a fossil
lentivirus (RELIK) with the host cell protein cyclophilin A. This study has
been critical to understanding the molecular details of this fundamental
host-virus interaction.
Details of the RELIK-CypA molecular interface. Residues 91-96 of
RELIK CA-NtD are shown in stick representation (blue) located
in the CypA binding groove, the isomeric Pro94 is indicated. CypA
is shown in green cartoon, residues that make hydrogen-bonding
interactions (dashed lines) are labelled and displayed as sticks.
Publications
Goldstone DC, Yap MW, Robertson LE, Haire LF, Taylor WR, Katzourakis A, Stoye JP and Taylor IA (2010)
Structural and functional analysis of prehistoric lentiviruses uncovers an ancient molecular interface.
Crystal structure of the RELIK-CypA complex. The
structures are shown in cartoon representation, RELIK
in blue, CypA in green. Secondary structure elements
are labelled sequentially from the N-terminals.
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.
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.
Journal of Molecular Biology 376:1493-1508
73
STRUCTURAL BIOLOGY
Willie Taylor
Protein structure analysis and design
Lab members: Katarzyna Maksimiak, Michael Sadowski
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 threedimensional structure. It is the aim of my group to try to
understand the relationship between the protein sequence
and its structure and hence its function.
To test our ideas on how the protein chain can adopt
different folds, we are using idealised models of small
proteins, each of which has a different fold (see figure).
From an abstract representation of the fold, comprising a
few letters, we construct a 2D diagram of the secondary
structure positions (alpha-helices and beta-strands) then
make a 3D stick model which is then elaborated into
amino acid (residue) positions. These are refined to
make realistic all-atom models that can be used to design
the best sequence to adopt the fold of each model. In
collaboration with the Driscoll group, we are now making
some of these proteins.
Publications
Grainger B, Sadowski MI and Taylor WR (2010)
Re-evaluating the “rules” of protein topology.
Journal of Computational Biology 17:1253-66
Hollup SM, Fuglebakk E, Taylor WR and Reuter N (2011)
Exploring the factors determining the dynamics of different protein folds.
Protein Science 20:197-209
Macdonald JT, Maksimiak K, Sadowski MI and Taylor WR (2010)
De novo backbone scaffolds for protein design.
Proteins 78:1311-25
A zoo of novel folds for a small protein, some of which will be made.
74
See references 75, 98, 103, 129, 155, 194, 216, 217, 246, 247, in the bibliography at the back for
STRUCTURAL BIOLOGY
Martin Webb
The molecular mechanisms of motor proteins
Lab members: Claudia Arbore, Lori Callum, Liisa Chisty, Colin Davis, Katy Hedgethorne, Simone Kunzelmann, Gordon Reid
Movement within the cell is often driven by motor proteins
that move along linear tracks. The tracks may be filaments
of proteins or nucleic acid. We are interested in the way
in which helicases move along double-stranded DNA,
separating the two strands. Such a process is essential as
part of DNA replication and repair. We are developing
new optical approaches, such as reagentless biosensors, to
study the proteins and nucleic acids during this process of
movement along DNA.
In order to develop our understanding of how helicases
work as part of a complete system, we are investigating
the replication of certain plasmids that contain antibiotic
resistance and that 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
working on building up this system in vitro to study the role
and mechanism of each component in this system.
The development of biosensors has included one for ADP
or GDP, which has a high specificity and has properties that
make it suitable for real-time assays and for high-throughput
approaches.
Scheme for asymmetric replication of a plasmid, showing
the role of PcrA helicase.
Rhodamine-ParM as biosensor for ADP, showing titration of ADP and ATP
and schematic of its use in assaying a kinase.
Publications
Fili N, Mashanov GI, Toseland CP, Batters C, Wallace MI, Yeeles JTP, Dillingham MS, Webb MR and Molloy
JE (2010)
Kunzelmann S and Webb MR (2010)
A fluorescent, reagentless biosensor for ADP based on tetramethylrhodamine-labeled ParM.
ACS Chemical Biology 5:415-25
See references 80, 138, 139, 253, 265, 278 in the bibliography at the back for
Toseland CP, Martinez-Senac MM, Slatter AF and Webb MR (2009)
The ATPase cycle of PcrA helicase and its coupling to translocation on DNA.
75
Neurosciences
Developmental Neurobiology
David Wilkinson (Head of Division)
Siew-Lan Ang
James Briscoe
Alex Gould
Nobue Itasaki
Jean-Paul Vincent
Molecular Neurobiology
François Guillemot (Head of Division)
Vassilis Pachnis
Iris Salecker
Molecular Neuroendocrinology
Tom Carter (Acting Head of Division)
Matthew Hannah
Paul Le Tissier
Neurophysiology
Troy Margrie (Acting Head of Division)
76
NEUROSCIENCES
Siew-Lan Ang
Neuronal subtype specification in the midbrain and hypothalamus
Lab members: Neal Anthwal, Suzanne Claxton, Lan Chen, Emmanouil Metzakopian, Wei Lin, Martin Levesque, Simon Stott,
Annabel Walsh
The mammalian midbrain and hypothalamus contain many types of
neurons that regulate voluntary movement and energy homeostasis,
respectively. How the different types of neurons are generated
and are wired into functional circuits 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 involved in regulating feeding. 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 arcuate proopiomelanocortin and neuropeptide Y. Our studies employ a
combination of embryological, genetic, molecular, genomic and
proteomic approaches, including genetic fate mapping studies, null
and conditional mutant mice, brain slice culture, time-lapse imaging,
chromatin immunoprecipitation, biochemical and transcriptome
analyses. These studies provide important insights into how
embryonic gene expression leads to mature neuronal phenotypes.
Novel obese mouse model
Publications
Peling M, Anthwal N, McNay D, Gradwohl G, Leiter, AB, Guillemot F and Ang SL (2011)
Differential requirements for neurogenin 3 in the development of POMC and NPY neurons in
the hypothalamus.
Developmental Biology 349: 406-416
Corin enhancer-lacZ transgenic mouse embryo (10.5 days)showing expression
of b-galactosidase (blue) in midbrain dopaminergic progenitors and floor plate.
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
77
NEUROSCIENCES
James Briscoe EMBO member
Pattern formation in the vertebrate nervous system
Lab members: Nikos Balaskas, Natascha Bushati, Rachel Chung, Michael Cohen, John Jacob, Anna Kicheva, Eva Kutejova, Steven
Moore, Ana Ribeiro, Vanessa Ribes, Noriaki Sasai, Samuel Tozer
We study how the central nervous system (CNS) is formed
in embryos. Despite its complexity, the CNS is assembled in a
remarkably reliable and accurate manner. This precision is necessary
for the wiring of nerves into the functional neural circuits that gives
the CNS its function. Our research focuses on the spinal cord,
which is the part of the CNS that contains the nerves that allow
us to sense our environment and respond to it by moving muscles.
The findings will contribute to understanding of the development
of the spinal cord as well as shed light on diseased and damaged
nervous systems. In turn, we hope this will help in the development
of therapies for these conditions.
Specifically, we are interested in the signalling mechanisms and
transcriptional programme responsible for pattern formation in
the neural tube. In ventral regions of the caudal neural tube, the
secreted molecule Sonic Hedgehog (Shh) forms an extracellular
gradient that governs pattern formation and tissue growth. We use
a range of molecular, imaging and modelling approaches to identify
Shh regulated genes that control the identity and proliferation of
neural progenitors.
Expression of the transcription factors Arx (blue), FoxA2 (red) and
Nkx2.2 (green) is dynamic in the neural tube of mouse embryos.
Publications
An adaptation mechanism for Shh
signalling involving Gli induced negative
feedback via Ptch. Fixed concentrations
of Shh are converted into temporally
varying profiles of Gli activity.
Dessaud E, Ribes V, Balaskas N, Yang LL, Pierani A, Kicheva A, Novitch BG, Briscoe J and Sasai N (2010)
Dynamic assignment and maintenance of positional identity in the ventral neural tube by the morphogen Sonic hedgehog.
PLoS Biology 8:e1000382
Ribes V, Balaskas N, Sasai N, Cruz C, Dessaud E, Cayuso J, Tozer S, Yang LL, Novitch B, Marti E and Briscoe J (2010)
Distinct Sonic Hedgehog signaling dynamics specify floor plate and ventral neuronal progenitors in the vertebrate neural tube.
Kutejova E, Briscoe J and Kicheva A (2009)
Temporal dynamics of patterning by morphogen gradients.
Current Opinion in Genetics & Development 19:315-322
See references 23, 45, 47, 57, 132, 210, 224, 279 in the bibliography at the back for publications from this group in 2010.
78
MRC
MRCNational
NationalInstitute
Institutefor
forMedical
MedicalResearch
Research
NEUROSCIENCES
Tom Carter
Secretory organelle formation, trafficking and exocytosis
Lab members: Nikolai Kiskin, Nicola Hellen, Laura Knipe, Emma Cookson, Jennifer Frampton
One of the ways in which cells sense and respond to their environment is through
the cell surface expression of integral membrane proteins (e.g. hormone receptors,
ion channels, adhesion molecules, etc.) and the secretion of soluble proteins into
the external environment (e.g. hormones, transmitters, morphogens). The correct
delivery of such proteins to the cell surface or extracellular space involves a complex
intracellular machine called the secretory pathway. We study the secretory pathway
using molecular, biochemical and live cell optical imaging techniques in order to
understand the processes that underlie the formation, trafficking and exocytosis of
regulated secretory organelles, the post-Golgi membrane bound containers that
store and deliver proteins to the cell surface/exterior in response to external signals.
We use endothelial cells and the Weibel-Palade body as our model system.
Examination of the intra-organelle properties, cargo composition and exocytosis of
regulated secretory organelles responsible for the trafficking and secretion of procoagulants (e.g. von Willebrand factor), anti-coagulants (e.g. tPA) or inflammatory
molecules (e.g. MCP-1, P-selectin) has led to new insights into the storage and
secretion of such molecules from cultured endothelial cells.
Publications
Kiskin NI, Hellen N, Babich V, Hewlett L, Knipe L, Hannah MJ and
Carter T (2010)
Protein mobilities and P-selectin storage in Weibel-Palade bodies.
Journal of Cell Science 123:2964-2975
Knipe L, Meli A, Hewlett L, Bierings R, Dempster J, Skehel P, Hannah
MJ and Carter T (2010)
A revised model for the secretion of tPA and cytokines from
cultured endothelial cells.
Blood 116:2183-2191
Weibel Palade bodies (WPBs)
are rod shaped secretory
organelles containing the procoagulant von Willebrand factor (VWF, green in top panel)
and, under certain conditions, a
cocktail of small inflammatory
molecules (red and blue in top
panel).VWF, the main core
component of WPBs forms
large polymers that condense
into flexible helical tubules
that pack tightly to produce
a ridged paracrystal (lower
panel).
Berriman JA, Li S, Hewlett LJ, Wasilewski S, Kiskin FN, Carter T,
Hannah MJ and Rosenthal PB (2009)
America 106:17407-17412
See references 134, 135 in the bibliography at the back for
79
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
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 dietary nutrients regulate embryonic and
foetal growth. Much of our research in this area uses the fruit fly Drosophila, a model
organism that shares many genes with mammals. We recently utilised Drosophila to
develop a model for studying the role, during brain growth, of the mitochondrial lipid
Coenzyme Q10 (sold over-the-counter as the dietary supplement Q10). We have
also identified an organ-to-organ relay mechanism in Drosophila whereby aminoacid sensing by adipose tissue triggers neural stem cells to enter the cell cycle. This
constitutes an important nutritional checkpoint that is active during an early phase of
brain growth.
Protein structural models of the catalytic domain of wild-type Qless (Qless,
left panel) and an inactive mutant form of Qless (Qless109, right panel). Note
that the serine at position 215 is changed to asparagine in the mutant protein
(arrows).
Data from J. Grant et al., 2010
A Drosophila central nervous system containing clones, marked
with nuclear GFP (green), that are mutant for the Coenzyme Q10
biosynthetic gene, Qless. Neural stem cell-like progenitors are also
shown (red).
Data from J. Grant et al., 2010
Publications
Sousa-Nunes R, Yee LL and Gould AP (2011)
Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila.
Nature 471: 508–512
Grant J, Saldanha JW and Gould AP (2010)
A Drosophila model for primary Coenzyme Q deficiency and dietary rescue in the developing nervous system.
Disease Models and Mechanisms 3:799-806
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
80
NEUROSCIENCES
François Guillemot FMedSci, EMBO member
Genomic and functional analysis of neurogenesis
Lab members: Roberta Azzari, Lan Chen, Daniela Dreschel, Laura Galinanes-Garcia, Patricia Garcez, Sebastien Gillotin, Matilda
Haas, Mélanie Lebel, Ben Martynoga, Cristina Minieri, Emilie Pacary, Vidya Ramesh, Noelia Urban
Neural stem cells in the embryo produce a vast array of neurons
that reach specific positions in the developing brain where they
integrate into functional circuits. This process of neurogenesis
involves the progression of neuronal precursors through a
succession of cellular steps of proliferation, migration and
differentiation. We study the genetic programmes that regulate
and coordinate these different steps, using genomic approaches
to identify the genetic pathways involved, and functional assays
to determine the contribution of individual genes to the different
steps of neurogenesis.
We recently found that the transcription factors Neurog2
and Ascl1, which initiate the programme of neurogenesis in
stem cells, also promote the migration of postmitotic neurons.
Moreover, they control different steps of neuronal migration in
the cerebral cortex, through induction of two distinct small GTPbinding proteins, Rnd2 and Rnd3, respectively. These proneural
factors thus regulate the responsiveness of newborn neurons to
multiple migratory signals, which we are currently characterising.
By gaining insight into mechanisms driving the differentiation
of stem cells into neurons, we are helping devise strategies to
replace lost cells in diseased brains.
Silencing of the small GTP-binding protein Rnd3 in a dissociated
cortical neuron promotes polymerisation of actin filaments (visualised
with a utrophin-GFP construct) in neuronal processes.
Publications
Pacary,E., Heng, J., Azzarelli,R., Riou, P., Castro, D., Lebel-Potter, M., Parras, C., Bell, D.M. Ridley, A.J., Parsons,
M., Guillemot, F. (2011)
Proneural transcription factors regulate different steps of cortical neuron migration through Rndmediated inhibition of RhoA signalling.
Neuron 69:1069-84
Zimmer C, Lee J, Griveau A, Arber S, Pierani A, Garel S and Guillemot F (2010)
Role of Fgf8 signalling in the specification of rostral Cajal-Retzius cells.
The proneural transcription factors Neurog2 and Ascl1 control two distinct
steps of neuronal migration: the transition from multipolar to bipolar stages
in the intermediate zone (IZ) and locomotion along radial glia fibers in the
cortical plate (CP), respectively. They act by inducing the small GTP binding
proteins Rnd2 and Rnd3, which, together with hypothetical extrinsic signals
A and B, promote respectively the extension of the leading process and
translocation of the nucleus during these two phases of migration.
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
See references 42. 96. 109, 159, 191, 199, 227, 229, 280 in the bibliography at the back
81
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 stimulation-dependent 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
Kiskin NI, Hellen N, Babich V, Hewlett L, Knipe L, Hannah MJ and
Carter T (2010)
Berriman JA, Li S, Hewlett LJ, Wasilewski S, Kiskin FN, Carter T, Hannah
MJ and Rosenthal PB (2009)
America 106:17407-17412
Giblin JP, Hewlett LJ and Hannah MJ (2008)
Basal secretion of von Willebrand factor from human endothelial
cells.
Blood 112:957-964
Weibel-Palade bodies (green), Golgi apparatus (white) and nucleus (blue)
visualised in a cultured human endothelial cell.
82
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
Amirthalingam GS, Howard S, Alvarez S, de Lera AR and Itasaki N
(2009)
Regulation of Hoxb4 induction after neurulation by somite signal
and neural competence.
BMC Developmental Biology 9:17
Franch-Marro X, Wendler F, Guidato S, Griffith J, Baena-Lopez A,
Itasaki N, Maurice MM and Vincent J-P (2008)
Wingless secretion requires endosome-to-Golgi retrieval of
Wntless/Evi/Sprinter by the retromer complex.
Nature Cell Biology 10:170-7
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
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.
83
NEUROSCIENCES
Paul Le Tissier
Control of prolactin and growth hormone cell differentiation and function
Lab members: Leonard Cheung, Molly Strom
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 inter-relationship 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 cell death induced by
the drug doxycycline and used these to kill prolactin cells before
and after puberty - when the number of cells normally increases
- and determine how quickly the pituitary gland recovers.
When cells are killed before puberty, the gland rapidly recovers,
whereas there is only a very slow recovery if cells are killed after
puberty. This suggests that there is a limited capacity of the gland
to regenerate after damage in adult animals.
Induction of M2 protein expression (green) leads to loss of prolactin cells
(red) in animals treated with doxycycline (right panel) compared with
animals without any induction (left panel).
Publications
Castrique E, Fernandez-Fuente M, Le Tissier P, Herman A and Levy A (2010)
Use of a prolactin-Cre/ROSA-YFP transgenic mouse provides no evidence for lactotroph
transdifferentiation after weaning, or increase in lactotroph/somatotroph proportion in lactation.
Journal of Endocrinology 205:49-60
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.
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
See references 28, 114, 140, 220, 263 in the bibliography at the back for publications from this
group in 2010.
84
Sequencing of the POU1F1 gene of a patient with short stature (subsequenty confirmed as combined pituitary hormone deficiency) shows
two independent mutations (top sequencing traces) of the normal
sequence (lower traces). Each mutation is inherited from one parent,
who are both unaffected (lower panel shows the inheritance of the
mutant alleles).
NEUROSCIENCES
Neurophysiology
Troy Margrie
Sensory processing in single cells, circuits and behaviour
Lab members: Ed Bracey, Alex Brown, Ninja Grewe, Ede Rancz, Bruno Pichler, Mateo Velez-Fort
The goal of our lab 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, multidisciplinary
approach to understanding sensory representation that
allows us to explore this fundamental issue from the systems
to the cellular level. Specifically, we are investigating several
key questions: 1) To what extent is sensory representation
distributed across primary and secondary or multimodal
brain areas? 2) What is the relationship between neuronal
connectivity and sensory function? 3) How is sensory
information encoded and integrated by individual cells and
synapses?
To address this question we use a variety of in vivo techniques
including behavioral experiments, fMRI, population calcium
imaging and electrophysiology. By complementing this with
genetic tools such as transgenic mouse lines and viral tracing
and in vitro electrophysiological recordings we can explore
such questions ranging from single synapses and cells to
circuits and behavior.
Horizontal images
taken from an
anaesthetised rat
recorded using
fMRI highlighting
brain regions that
respond to electrical
stimulation of the
vestibular nerve.
Whole-cell recordings from cortical pyramidal cells in anaesthetized
and awake head-restrained preparations. The
histogram of membrane potential reveals a positively skewed
distribution (right). In the awake case (red), the slow oscillatory
activity is replaced by more high frequency fluctuations in membrane
potential. Such recordings will allow us to explore the activity within
individual cells while a sensory task is being performed.
Publications
Rancz EA, Franks KM, Schwartz M, Pichler B, Schaefer AT and Margrie TW (2011)
Transfection via whole-cell recordings in vivo. Bridging single-cell physiology, genetics and connectomics.
Nature Neuroscience 14(4):527-32
A three-dimensional stack of calcium dye-loaded cells in the cortex
of an anaesthetised mouse imaged using a two-photon microscope.
This allows us to monitor the activity of large numbers of cells during
sensory stimulation. Scale bar is 50 µm.
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
85
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:
Heanue TA and Pachnis V (2011)
Prospective identification and isolation of enteric nervous system progenitors using Sox2.
Stem Cells 29:128-140
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.
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.
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Institute for
for Medical
Medical Research
Research
MRC
Kioussis D and Pachnis V (2009)
Immune and nervous systems: more than just a superficial similarity?
Immunity 31:705-710
See references 127, 128 in the bibliography at the back for publications from
this group in 2010.
NEUROSCIENCES
Iris Salecker
Visual circuit assembly in Drosophila
Lab members: Holger Apitz, Dafni Hadjieconomou, Emily Richardson, Benjamin Richier, Nana Shimosako, Katarina Timofeev
In the third instar larval optic lobe of Drosophila, progenitors in the
outer and inner proliferation centers (OPC, IPC; blue) give rise to
post-mitotic neurons in the medulla and lobula complex (green).
The ability of animals to interpret sensory information and to
produce complex behaviors relies on the perfect functioning of their
nervous system, which consists of a large diversity of neurons and
glia. This raises the central questions: how the generation of neurons
and glia is regulated, and what enables neurons to recognise each
other and to eventually form precise synaptic contacts between them
during development.
We use the visual system of the fruit fly Drosophila as model to
investigate the mechanisms that control the formation of glia and
higher-order neurons. Furthermore, we seek to determine how the
axons of one color-sensitive photoreceptor neuron subtype know
where to stop in a temporary layer and to correctly proceed to, as
well as to recognise their final target layer and connect with their
partner neurons in a series of interdependent cellular interactions. To
facilitate these studies we recently have generated a multicolour cell
labelling approach for Drosophila, called Flybow. We anticipate that
our studies will help to advance our understanding of normal brain
development, as well as related neurological disorders.
Publications
In the adult visual system, photoreceptor neurons (R1-R8, blue)
extend axons from the retina into two areas of the optic lobe,
the lamina and medulla, where they connect with target neurons
in an intricate neural network characterised by a highly regular
organisation of columns and layers. Using the Flybow approach,
target neurons were stochastically labelled with three different
fluorescent proteins (EGFP, mCitrine, mCherry).
Hadjieconomou D, Rotkopf S, Alexandre C, Bell DM, Dickson BJ and Salecker I. (2011)
Flybow: genetic multicolor cell labeling for neural circuit analysis in Drosophila melanogaster.
Nat Methods doi:10.1038/nmeth.1567.
Hadjieconomou D, Timofeev K, and Salecker I. (2010)
A step-by-step guide to visual circuit assembly in Drosophila.
Current Opinion in Neurobiology doi:10.1016/j.conb.2010.07.012.
Bazigou E, Apitz H, Johansson J, Lorén CE, Hirst EMA, Chen PL, Palmer RH, and Salecker I. (2007)
Anterograde Jelly Belly and Alk receptor tyrosine kinase signaling mediates retinal axon targeting in Drosophila.
Cell 128: 961-975.
See reference 110 in the bibliography at the back for publications from this group in 2010.
87
NEUROSCIENCES
Jean-Paul Vincent EMBO member, FMedSci
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 small number of signalling molecules orchestrate growth
and cell fate decisions during development. We investigate the
mechanisms that control the production, spread and activity
of one such signal, Wingless (a member of the Wnt family of
secreted proteins, which are implicated in numerous cancers).
In addition, we study the regulatory mechanisms that allow cells
to compute their position within the Wingless gradient.
Epithelia behave like ecosystems with weak or defective cells
being eliminated by a process called apoptosis (cell suicide).
As Wnt signalling affects cell fitness, we have begun a research
programme aimed at understanding the processes that
triggers death in weak or defective cells within developing
epithelia. We have uncovered a novel feedback mechanism that
modulates the interpretation of the Wg gradient in responding
tissue. Specifically, we showed that cells influence each other’s
response to Wingless through at least two modes of lateral
inhibition, one acting at short range and the other over several
cell diameters. We have been able to show that medium
range inhibition is mediated by Notum, a secreted GPI-specific
phospholipase.
High resolution distribution of Wingless. Electron micrograph
of a Drosophila wing imaginal discs expressing Wingless fused to
Horseradish Peroxidase. An enzyme reaction reveals the distribution
of the fusion protein as a dark stain. Note the presence of Wingless on
membranous structures (arrowhead).
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 23, 240, 266 in the bibliography at the back for publications from
this group in 2010.
88
Uniform Wingless signalling promotes proliferation in Drosophila wing imaginal discs. Uniform signalling (indicated by the uniform expression of the
target gene vestigial) was experimentally induced in the green territory,
whereas in the non-green territory (left hand side of the disc) Wingless
forms its normal gradient. There is an increased density of PH3, a marker
of mitosis, in the green territory.
NEUROSCIENCES
David Wilkinson EMBO member, FMedSci
Regulation of boundary formation and neurogenesis
Lab members: Marie Breau, Sean Constable, Sebastian Gerety, Andrew Georgiou, Lauren Gregory, Mohamed Ismail, Rosie Morley,
Alexei Poliakov, Javier Terriente, Qiling Xu
During early stages of nervous system development in
vertebrates, neural tissue is subdivided into regions, each with
a distinct identity. Within these subdivisions, the differentiation
of progenitor cells is regulated in time and space to form the
correct organisation of specific neuronal and glial cell types. In
order for such precise patterns to form and be maintained, it is
essential that cells do not move to inappropriate locations.
Our studies aim to elucidate molecular mechanisms of boundary
formation and cell differentiation, and the links between these
processes in nervous system development. We analyse how
signalling through Eph receptors and ephrins segregates distinct
cell populations, leading to formation of sharp boundaries. In
related work, we study how boundaries, together with signalling
from specific neurons, organise discrete zones of progenitor
cells and neuronal differentation in the hindbrain. Finally, we
are dissecting the mechanisms of action of a transcriptional
repressor and targetted protein degradation in neural stem
cell maintenance and differentiation. These studies utilise the
powerful genetic and transgenic tools available in the zebrafish
model for analysis of gene function and imaging.
Feedback loop required for the onset of primary neurogenesis.
Expression of the proneural gene Neurog1 is inhibited in progenitor
cells due to Notch activation and the transcriptional repressor,
Plzf. Neuronal differentiation requires proneural upregulation of a
ubiquitination adaptor protein, Btbd6a, that targets the degradation
of Plzf.
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
Hindbrain segments and neurons in zebrafish. Immunocytochemistry was
carried out to reveal segments 3 and 5 (blue signal) and neurons (red) in
an embryo that has been microinjected to generate mosaic expression of
green fluorescent protein.
A feedback loop mediated by degradation of an inhibitor is required to initiate neuronal
differentiation.
Genes and 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
89
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
Peter Thorpe
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
90
GENETICS AND DEVELOPMENT
Paul Burgoyne FMedSci
The Y chromosome and infertility
Lab members: Áine Rattigan, Obah Ojarikre, Shantha Mahadevaiah, Julie Cocquet, Nadege Vernet, Teruko Taketo
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-targetting 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 targetting 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 severely impaired sperm function and associated sperm DNA
damage. We have now disrupted the function of a related multi-copy X gene (Slx)
which also plays an essential role in sperm development.
Publications
Cocquet J, Ellis PJI, Yamauchi Y, Riel JM, Karacs TPS, Rattigan Á,
Ojarikre OA, Affara NA, Ward MA and Burgoyne PS (2010)
Deficiency in the multicopy Sycp3-like X-linked genes Slx and Slxl1
causes major defects in spermatid differentiation.
Molecular Biology of the Cell 21:3497-3505
Deficiency in the Sycp3-like X-linked genes Slx and Slxl1 leads to impaired sperm development. A) Testis
tubules of a Slx/Slxl1-deficient mouse. Groups of apoptotic elongating spermatids (green) are visible
in various tubular stages. Blue signal marks the nuclei and red signal the acrosomes. B-G) Electron
microscopy of normal (B-C) and Slx/Slxl1-deficient (D-G) sperm show that the deficiency causes sperm
abnormalities such as partial detachment of the tail, parallel alignment of the head and tail, and curved
or looped tail. H) Slx/Slxl1 deficiency alters metabolic processes during sperm development. The bar
graph represents the number of genes found differentially expressed in round spermatids from Slx/Slxl1deficient males compared with wild-type males. Differentially expressed genes are shown according to
their likely biological function.
Wijchers PJ, Yandim C, Panousopoulou E, Ahmad M, Harker N,
Saveliev A, Burgoyne PS and Festenstein R (2010)
Sexual dimorphism in mammalian autosomal gene regulation is
determined not only by Sry but by sex chromosome complement
as well.
Yamauchi Y, Riel JM, Stoytcheva Z, Burgoyne PS and Ward MA (2010)
Deficiency in mouse Y chromosome long arm gene complement is
associated with sperm DNA damage.
Genome Biology 11:R66
See references 36, 153, 215, 269, 276 in the bibliography at the back
91
Rita Cha
Regulation of eukaryotic chromosome metabolism
Lab members: Jesus Carballo, Tony Johnston, Ana Penedos, and Alexander Widger
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 Telangiectasia and Seckle syndrome.
We use genetically tractable S. cerevisiae to study the molecular
basis for the functions of ATR/ATM. 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.
Publications
Hashash N, Johnson AL, Cha RS. (2011)
Regulation of chromosome breakage at replication slow zones, a
Mec1/ATR sensitive fragile site.
Mec1/Tel1 (A) and ATR/ATM (B) targets during yeast and mouse meiosis. (A) Spatial and temporal
distribution of phosphorylated Mec1/Tel1 targets during meiotic prophase I is visualised using a-p[S/T]Q
(red), Zip1-GFP (green), and DAPI (blue). Foci are observed initially coinciding with DSBs during
leptotene. a-p[S/T]Q foci number is reduced as Zip1 polymerises during zygotene. At pachytene, only
few strong foci localise at the synapsed chromosomes and telomeric regions. The a-p[S/T]Q patches
become more intense and thicker as chromosomes condense and Zip1 staining disappears during
diplotene. (B) Immuno-signals from a-p[S/T]Q were visualised in mouse spermatocytes. Green signals
from a-SCP3. (Mouse data from J. Turner)
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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
See reference 112 in the bibliography at the back
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, Callaway HA, Cerda GA, Lewis KE and Elgar G (2011)
Minor change, major difference: divergent functions of highly
conserved cis-regulatory elements subsequent to whole genome
duplication events
Development. Jan 19. [Epub ahead of print]
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
Developmental enhancers containing pbx-hox bipartite binding sites drive restricted patterns of reporter
expression in zebrafish and lamprey embryos. A) Graphical representation of an alignment of lamprey,
Fugu and human genomic sequences adjacent to the meis2 gene. Pink peaks represent non-coding
sequence conservation. B-Q) GFP reporter assays in zebrafish (B-M, Q) and lamprey (N-P) embryos
demonstrating strong hindbrain expression, with some elements driving segment-restricted patterns.
93
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 will be focusing on the period in the development of the early embryo
when control passes from maternal gene products, deposited in the egg
before fertilisation, to those derived from activation of gene transcription
in the growing embryo. This maternal-zygotic transition marks a profound
watershed in the growth of the embryo as it becomes reliant on the integrity
of its own genetic material, and physically marks the onset of asynchronous cell division and the development of physiologically
distinct structures. Using the Xenopus model system, we have taken a high resolution time series of whole embryo mRNA
samples through this transition period for transcriptome analysis using massively parallel sequencing technology, and are now
inspecting the data looking for signatures of gene activation. Further experimental work will involve selective knock-down and
chromatin immunoprecipitation assays of early activated genes to establish their likely downstream targets, and hence construct
the regulatory networks established at this time.
Publications
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
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.
Developmental Dynamics 238:1379-1388
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
94
Study of gene activation at the maternal-zygotic transition in early embryogenesis. Whole genome
transcript profiling will allow us to establish the validity of our model of gene activation at this
developmental transition point. Families of bold and dashed coloured lines in the model represent
initial activation of ‘master regulator’ transcription factors, followed by activation of their respective
downstream targets.
Malcolm Logan
Understanding vertebrate limb development
Lab members: Anna Kucharska, Sue Miller, Natalie Bufferfield, Veronique Duboc, Satoko Nishimoto, 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 origins 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
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.
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.
A 3D rendering of the mouse hindlimb (left) and forelimb(right) at
embryonic day(E) 14.5. The images were produced by Seth Ruffins
(UCLA) using datasets produced in our lab using Optical Projection
Tomography and computer-assisted segmentation.
95
Robin Lovell-Badge FRS, EMBO member, FMedSci
Sex, stem cells and decisions of cell fate
Lab members: Sarah Booth, Christophe Galichet, Sam Goldsmith, Silvana Guioli, Albie Mackintosh, Ander Matheu, Adam Nunn,
Helen O’Neill, 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.
Cells expressing GFAP (yellow), which marks neural stem cells and their
astrocyte progeny in the adult brain, are no longer found in the absence
of SOX9.
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
Scott CE, Wynn SL, Cruz C, Cheung M, Gomez-Gaviro MV, Gao B, Cheah, KSE, Lovell_Badge R and Briscoe
J (2010)
SOX9, acting downstream of Sonic hedgehog signalling, is required for the initiation and maintenance of
neural stem cell properties.
Nature Neuroscience 13, 1181-1189
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
FOXL2 is required to maintain adult ovaries in mice (left), because,
when mutant for the gene, follicle cells transdifferentiate into SOX9positive Sertoli cells, typical of testes (right).
96
Sekido, R. and Lovell-Badge, R (2008).
SRY and SF1 act on a specific enhancer of SRY in sex determination.
Nature 453, 930-4.
See references 29, 87, 154, 203, 212, 224, 225, 241 in the bibliography at the back for publications from this
group in 2010.
Tim Mohun
Heart development in vertebrates
Lab members: Mike Bennett, Laurent Dupays, Surendra Kotecha, Marianne Neary, Stuart Smith, Norma Towers, Robert Wilson
Formation of the heart is a complex process that begins
very early in the vertebrate embryo, remodelling a simple
peristaltic tube into a complex multi-chambered organ capable
of supporting embryo growth. This transformation requires
exquisite coordination of cell differentiation and growth to
produce the dramatic changes in organ shape. Abnormalities
affecting any step will have profound consequences on the
foetal heart and heart defects are the most common birth
defect. By studying the roles of individual genes and cell
populations in normal heart development, 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.
We are using transgenic and genomic methods to examine
how gene expression is regulated in the developing heart of
frog and mouse embryos. 3D imaging and computer modelling
procedures allow us to examine the embryonic heart and
identify changes in heart morphology resulting from changes
in cardiac gene expression. Most recently, this approach
has established that mice carrying human chromosome 21
provide an accurate model of the congenital heart defects
characteristic of human Down Syndrome.
The heart of a tadpole. A single muscular ventricle pumps blood to the body
via a single large outflow vessel which splits symmetrically into three major
vessels (pigmented) supplying each side of the body. 3D reconstruction
(orange) allows the internal structure of the heart to be studied.
Publications
Dunlevy L, Bennett M, Slender A, Lana-Elola E, Tybulewicz VL, Fisher EMC and Mohun T (2010)
Down’s syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1
mouse.
Cardiovascular Research 88:287-295
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
See references 21, 22, 62, 113, 163, 167 in the bibliography at the back for publications from this
group in 2010.
Although very different in structure, the ventricles of the frog and mouse
hearts both contain a complex, interlaced web of muscle fibres (trabeculae),
modelled here from images of a mouse embryo heart.
97
Elke Ober
Liver development in zebrafish
Lab members: Jordi Cayuso Mas, Johanna Fischer, Katarzyna Koltowska, Despina Stamataki, Heidi Miu
During development, the liver, gall bladder and pancreas arise from neighbouring
domains within the foregut. Highly regulated interactions between instructive
signals and tissue competence are required for the specification and
differentiation of each organ. Our understanding of these signals and interactions
is still limited.
We combine genetic and imaging approaches in zebrafish to elucidate the
molecular network and cellular mechanisms underlying vertebrate liver
formation. Our studies focus on identifying the genetic programmes governing
the specification of liver progenitors within the ventral foregut endoderm.
Furthermore, we examine the intricate cellular and molecular mechanisms
that enable these newly specified progenitors to grow into an organ bud of
appropriate shape and size. We recently isolated group specific component (gc) as
the only homologue of the Albumin and α-Fetoprotein family of plasma proteins.
Analysis of spatiotemporal expression in wild-type and selected mutants, such
as the chromatin remodelling factor histone deacetylase1, indicates that onset of
gc expression is indicative of progressive hepatic differentiation and represents
a specific landmark of liver development. Unravelling the genetic programme
of liver formation will provide insights into embryonic development, tissue
homeostasis in adults, regeneration following tissue damage, as well as the
development of hepatic stem cells for therapeutic purposes.
Publications
Cayuso Mas J, Noël ES, and Ober EA (2010)
Chromatin modification in zebrafish development
Methods in Cell Biology (in press)
Noël ES, dos Reis M, Arain Z and Ober EA (2010)
Analysis of the albumin/α-fetoprotein/afamin/group
specific component gene family in the context of
zebrafish liver differentiation.
Gene Expression Patterns 10:237-243
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.
The newly established liver and pancreas are
connected via the extrahepatopancreatic
ductal system (blue) to the digestive tract in 2
day old zebrafish.
98
Hepatocytes (green) and biliary ducts (red) in the
differentiating liver.
Systems Biology
Jim Smith FRS, EMBO member, FMedSci
The molecular basis of mesoderm formation
Lab members: Camille Bouissou, John Cannon, Clara Collart, Kevin Dingwell, Tiago Faial, George Gentsch, Helle Jørgensen,
Anna Strobl, Alex Watson, Mary Wu
The different cell types of the body are formed in the right
place and at the right time in response to signals produced
by special organiser regions of the embryo. These signals,
or 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
causes the formation of organs and cell types such as
muscle, kidney and bone, as well as the heart and vascular
system.
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, and biochemical and mathematical approaches
to ask how cells distinguish between different morphogen
concentrations. We also use sophisticated molecular
techniques to elucidate the genetic regulatory networks that
drive the formation of specific cell types. As well as helping
understand development, we hope our work will assist in
efforts to direct stem cells down the desired developmental
pathways.
Visualising cranial blood
vessels in a Fli1-GFP
zebrafish embryo
Chromatin immunoprecipitation followed by high-throughput sequencing
identifies a new target of the Xenopus tropicalis T box protein Brachyury. Nine
Brachyury binding sites are present in the 5’ region of the gene, which encodes
a previously-unknown helix-loop-helix protein.
Publications
Callery EM, Thomsen GH and Smith JC (2010)
A divergent Tbx6-related gene and Tbx6 are both required for neural crest and intermediate
mesoderm development in Xenopus.
Cannon JE, Upton PD, Smith JC and Morrell NW (2010)
Intersegmental vessel formation in zebrafish: requirement for VEGF but not BMP signalling
revealed by selective and non-selective BMP antagonists.
Harvey SA, Tümpel S, Dubrulle J, Schier AF and Smith JC (2010)
no tail integrates two modes of mesoderm induction.
Immunostaining of transgenic zebrafish embryos carrying a bacterial artificial
chromosome in which the ntl protein is marked with a ‘Flag tag’. Expression
of the tagged protein occurs in the margin of the embryo at 6 hours after
fertilisation (A) and in the notochord at 11 hours after fertilisation (B).
99
Peter Thorpe
Systems microscopy studies of cell fate determination
Asymmetric cell division is the process by which one cell
divides to give two cells with different fates. Repeated
asymmetric divisions allow a fertilised egg to generate
diverse cell types during development, and in adult
stem cells such divisions maintain the population while
simultaneously generating new, differentiated cells. The
goal of our lab is to determine how cellular asymmetry
is established and maintained over multiple divisions to
create cell lineages. Specifically, we focus on understanding
how asymmetry of the mitotic spindle - the machinery
that segregates chromosomes during division - affects how
genetic information is accurately passed down to daughter
cells.
Our model system is the budding yeast, Saccharomyces
cerevisiae, which shows patterns of asymmetric division
like those of more complex organisms. We employ highthroughput fluorescence microscopy techniques that allow
us to rapidly screen the localisation, levels and dynamics of
all yeast proteins and integrate them into a visual dataset.
Using these tools, we aim to identify the conserved
mechanisms controlling asymmetric division, lineage
specification and mitotic spindle function.
1st
division
DIC
m
enhanced
b
Mtw1YFP
mm
2nd mother
division
bm
mb
2nd bud
division
bb
Publications
Thorpe, PH; Bruno, J and Rothstein, R (2009)
Kinetochore asymmetry defines a single yeast lineage.
Proceedings of the National Academy of Sciences of the United States
of America 106, 6673-6678.
Thorpe, PH; Bruno, J and Rothstein, R (2008)
Modeling stem cell asymmetry in yeast.
Cold Spring Harbor Symposia on Quantitative Biology 73, 81-88
Cagney, G; Alvaro, D; Reid, RJD; Thorpe, PH; Rothstein, R and Krogan,
NJ (2006)
Functional genomics of the yeast DNA-damage response.
Genome Biology 7, 233.
100
mmm
mmb
3rd mother division
mbm
mbb
bmm
3rd division
bbm
bbb
bmb
3rd division
3rd division
As a yeast spore undergoes successive cell divisions, the fluorescently-labelled kinetochore
proteins
to both
daughters
or protein is
preferentially
As
a yeasteither
sporesegregate
undergoes equally
successive
cell divisions,
the(symmetry)
fluorescently-labelled
kinetochore
proteins
retained
in the mother
(asymmetry).
restricted
either segregate
equallycell
to both
daughtersAsymmetric
(symmetry) kinetochore
or protein issegregation
preferentiallyisretained
in to
thea
singlecell
lineage
of cells (left
side of figure)
descended
from the
spore.
mother
(asymmetry).
Asymmetric
kinetochore
segregation
is restricted
to a single lineage of cells
(left side of figure) descended from the spore.
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.
In XYY males, the two Y chromosomes (blue) fully pair and escape
the silencing mark gH2AX (red).
Publications
Royo H, Polikiewicz G, Mahadevaiah SK, Prosser H, Mitchell M, Bradley A, de Rooij DG, Burgoyne
PS and Turner JMA (2010)
Evidence that meiotic sex chromosome inactivation is essential for male fertility.
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.
Escape from sex chromosome silencing causes germ cell death (arrow).
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.
101
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
tasks specific genes perform in living organisms. Our group studies gene functions
important for initial formation of organs and subsequent disease processes, by
identifying and characterising genetic mutations that profoundly affect tissue
development. Since most gene functions are shared among all vertebrates, we
use the easily-studied externally-developing embryos of a frog with a simple
chromosomal structure, Xenopus tropicalis.
We have identified a number of mutations that model important human disease
processes including cancer. One striking mutation, xenopus de milo (xdm), results
in specific failure of forelimb initiation upstream of tbx5 expression during
metamorphosis, and arises from disruption of the small secreted integrin ligand
nephronectin. Nephronectin has previously been associated with cancer metastasis
as well as kidney function. Another mutation, white hart, is being characterised for
its effects on blood formation in the embryo. White hart has been mapped to the
smad4 gene, an important mediator of intercellular signalling which is frequently
mutated in human pancreatic and colorectal cancers.
Publications
Abu-Daya A, Nishimoto S, Fairclough L, Mohun TJ, Logan MPO and
Zimmerman LB (2010)
The secreted integrin ligand nephronectin is necessary for forelimb
formation in Xenopus tropicalis.
smad4 mutant shows deficits in blood formation. Left: muzak mutants which have wild-type blood
formation (in situ hybridisation for the blood marker globin) but defective heartbeat; Right: white hart
tadpoles show deficits in ventroposterior tissues including decreased blood formation.
Geach TJ and Zimmerman LB (2010)
Paralysis and delayed Z-disc formation in the Xenopus tropicalis
unc45b mutant dicky ticker.
Hellsten U, Harland RM, Gilchrist MJ, Hendrix D, Jurka J, Kapitonov
V, Ovcharenko I, Putnam NH, Shu S, Taher L, Blitz IL, Blumberg B,
Dichmann DS, Dubchak I, Amaya E, Detter JC, Fletcher R, Gerhard
DS, Goodstein D, Graves T, Grigoriev IV, Grimwood J, Kawashima T,
Lindquist E, Lucas SM, Mead PE, Mitros T, Ogino H, Ohta Y, Poliakov
AV, Pollet N, Robert J, Salamov A, Sater AK, Schmutz J, Terry A,
Vize PD, Warren WC, Wells D, Wills A, Wilson RK, Zimmerman LB,
Zorn AM, Grainger R, Grammer T, Khokha MK, Richardson PM and
Rokhsar DS (2010)
The genome of the Western clawed frog Xenopus tropicalis.
Science 328:633-6
See references 1, 92, 115 in the bibliography at the back for
102
nephronectin is required for
forelimb formation. Left: skeleton
of a wild-type metamorphosing
tadpole showing scapula (sc),
humerus (hu), ulna (ul), and digits
(dit). Right: forelimb skeletal
elements are missing in xdm
froglets, but ribs are unaffected
(r1,r2,r3).
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.
David Trentham, FRS
In 1983 David Trentham moved from a position in the USA to head the new Division of
Physical Biochemistry at NIMR, where he remained until retiring in 2003. He developed a truly
interdisciplinary Division that encompassed chemistry, physiology, physics, biochemistry and
molecular biology.
Early in his career David’s research moved into areas of chemistry that were relevant to
biology, when he worked on nucleotide chemistry at Cambridge. After periods at the Salk
Institute and the Massachussets Institute of Technology, David continued postdoctoral work
with Freddie Gutfreund at the University of Bristol. He mastered techniques of rapid reaction
kinetics that had been recently developed and also began his interest in myosin and muscle
that continued throughout his career. He became a Reader in Biochemistry at Bristol and in
1977 moved to become Chairman of the Department of Biochemistry and Biophysics at the
University of Pennsylvania.
David’s research involves rigorous quantitative analysis, bringing physical methods to bear on biological problems. At Bristol he
produced a series of highly cited publications using rapid-reaction techniques to delineate the reaction mechanism for ATP
hydrolysis by skeletal muscle myosin. Myosin became a paradigm for understanding the wide range of motor proteins that
are known today. The mechanism showed that protein conformation changes could be linked both to biochemical steps and
potentially also to the motor function: a concept considered as commonplace today. In the muscle field there was considerable
effort for various disciplines (biochemists, structural biologists, physiologists etc) to interact. Such an interdisciplinary focus was
a crucial aspect of David’s research, and was part of the attraction of moving to NIMR. It was important to take the research
methods of isolated proteins to organised systems and the cell, and David saw the potential of caged compounds for timeresolved measurements in such systems. For example, caged ATP is an inert derivative that on photolysis produces ATP. This
work exemplifies David’s curiosity for new areas of research and his enthusiasm for applying chemistry to biological problems. He
worked with physiologists, chemists and physicists to establish that high-power lasers enabled rapid release of ATP in muscle fibres
and so initiate contraction, as well as to understand the “uncaging” itself. This led to a series of other caged compounds that could
release biologically important triggers, such as IP3.
As more measurements on organised systems became possible and protein crystal structures became widely available, there
remained a significant gap between dynamic measurements on milliseconds scale and those static structures. David focused
his more recent work on this problem. By placing fluorophores at specific locations on the cross-bridge of muscle fibres, their
movement could be monitored on the millisecond time scale, so showing which parts of the cross-bridges moved and when. As
well as his work on muscle in increasing organisational complexity, David maintained several long-term collaborations in which
physical methods were applied to a variety of biological preparations, including chemotaxis and neural signalling.
David was elected a Fellow of the Royal Society in 1977 and received the Colworth Medal of the Biochemical Society and the
Feldberg Prize. Since retirement he has continued as an active scientist at NIMR and King’s College London, both with his own
research programme and by encouraging and advising younger scientists.
103
Emeritus scientists
Robert G. Edwards, CBE, FRS
Robert Edwards completed his PhD at the University of Edinburgh and then spent
one year at the California Institute of Technology at Pasadena before coming to
NIMR. Alan Parkes interviewed him at NIMR in 1957 and was much impressed,
describing him as “a young man of great promise”, who had “already done some
extremely good research work”.
Edwards worked at NIMR from 1958-1962, in the Division of Experimental Biology
headed by Alan Parkes. Other prominent members of the Division at the time were
the cryobiology pioneer Audrey Smith, Chris Polge and Colin (Bunny) Austin. Polge,
Smith and Parkes had earlier published a landmark paper on the freezing and revival
of spermatozoa. Austin had previously discovered sperm capacitation.
At NIMR Edwards was chiefly interested in the immunology of reproduction and
gained an excellent reputation in this field. During his time at NIMR his interests
shifted from pure science to biomedicine, and his emphasis on immunology gradually
decreased. Increasingly his main ambition was to work with human gametes and
embryos, and to do something about human infertility. Whenever he could, he pursued his investigations on oocyte
maturation, looking at a range of species. Edwards also carried out a lot of work on induced ovulation and superovulation in
mice, looking at the effects on eggs, the embryos, the mothers, parturition and offspring. Techniques to induce ovulation are
relevant to IVF in humans as it is very difficult to use natural ovulation.
Others had shown that egg cells from rabbits could be fertilised in test tubes when sperm was added, giving rise to
offspring. Edwards decided to investigate if similar methods could be used to fertilise human egg cells, and started to obtain
human samples from a nearby hospital.
Edwards left NIMR in 1962 and joined John Paul’s group at the University of Glasgow. He then accepted an invitation by
Alan Parkes, recently appointed as the Mary Marshall Professor of the Physiology of Reproduction at Cambridge University,
to join him there. Austin also moved to the same department in Cambridge.
Robert Edwards was awarded the Lasker prize in 2001 for his work on IVF, and in 2010 was awarded the Nobel Prize in
physiology or medicine for his pioneering work in the development of human in vitro fertilization (IVF) therapy.
104
Research facilities
Biological and Procedural Services
Structural biology facilities
MRC Biomedical NMR Centre
X-ray crystallography
Mass spectrometry
Other structural biology facilities
Protein sequence analysis and structure modelling
Analytical ultracentrifugation
Imaging
Confocal Imaging and Analysis Laboratory
Histology
Electron microscopy
OPT and HREM imaging
Single molecule techniques
Total internal reflection fluorescence microscopy
Optical tweezers
Atomic force microscopy
Cryo electron microscopy
Other scientific facilities
Genomics facility
High throughput sequencing
Microarray
Bioresources
Large-scale laboratory
Media production
Freezer archive
Flow cytometry facility
Level 4 high-containment virus laboratory
Engineering workshop
Electronic instrument prototyping and support
Other support services
PhotoGraphics
Computing
Library
Web Team
General services
Occupational Health
Safety and security
Human Resources
Finance and purchasing
105
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. The size, scope and efficiency
of Biological Services provide an extraordinary service to nearly all aspects of the
Institute’s science as well as to many scientists elsewhere.
Xenopus laevis
Individually ventilated cages
106
Laboratory opossum with litter
We aim to meet all the needs of the scientific Divisions whilst ensuring the highest possible standards of health and welfare for all
species. The Division is active in the field of laboratory animal science, conducting and promoting research and uptake of the 3Rs
(replacement, reduction, refinement) and presents its work at national and international meetings. The animal care and technical
staff are trained in the production, care and use of animals for research purposes to the highest standards of animal husbandry.
Additionally they provide a range of centralised procedural support. A full-time veterinary surgeon and microbiologist offer advice
on the health and welfare of our animals. The Division also provides services for the incubation of fertile chicken eggs and the
production of antibodies. In addition, administration and licence control under the Animals (Scientific Procedures) Act 1986, and
coordination of the Institute’s Local Ethical Review Process, is managed by Biological Services.
Procedural Service Section
The Procedural Service Section provides a range of services and facilities for the production,
maintenance and preservation of genetically altered rodents. The service produces approximately
200 new genetically altered rodent lines each year by both transgenic and gene-targetted
technologies. A full range of techniques is employed to provide a comprehensive service for the
cryopreservation of rodent germplasm, and more recently the service has expanded to include
cryopreservation of frog and fish spermatozoa. In addition, the section is responsible for the
rederivation of new lines imported into the Institute. Every year, together with Biological Services,
the Section coordinates over 150 shipments of live animals and frozen germplasm to collaborators
all over the world. The staff are also skilled in a number of assisted reproductive techniques,
including in vitro fertilisation and intracytoplasmic sperm injection, which are useful for maintenance
of lines with poor breeding performance or to provide age-matched cohorts for experiments. The
section is also committed to investigating and implementing the 3Rs by researching and developing
new refinements such as non-surgical methods of embryo transfer.
Microinjection of ES cells
Procedural Services Manager:
Sarah Johnson
Micromanipulation
107
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 1979 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 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 research groups from NIMR and 16 external groups at
universities and institutes from around the UK. Within NIMR our closest
links are with the Division of Molecular Structure.
1
NMR structure of the two central KH domains of the KSRP protein, showing (in yellow
and green) the regions of the molecule involved in recognition of AU-rich elements in
mRNA. The two domains form a single structural element; each domain has an RNA
binding site, but these are non-contiguous and orientated at 90 degrees to one another.
These results show that the RNA molecule must be bound in a bent conformation.
Publications
Cukier CD, Hollingworth D, Martin SR, Kelly G, Díaz-Moreno I and Ramos A (2010)
Magnet of the 800 MHz spectrometer.
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
peptidyl-prolyl isomerase activity.
FEBS Journal 276:4529-4544
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.
108
X-ray crystallography
Protein X-ray crystallography is a technique that produces a 3-dimensional model of the structure of a protein at atomic
resolution. The X-ray crystallography facilities within the Division of Molecular Structure at the Institute are state-of-theart and include a high intensity X-ray source coupled with an automated robotic sample mounting system which allows the
unattended screening of 80 crystals in a single experiment. Diffracting protein crystals are the culmination of an extensive series
of experimental procedures which include protein purification and protein crystallisation. A range of sophisticated techniques are
employed to help explore the largest number of conditions within each of the projects under investigation. These include those
techniques being developed in the Protein Expression Lab together with a wide range of robotic procedures to set up multi-well
dishes and to automatically screen for protein crystals.
X-ray generator and automated sample mounting robot insert
shows the loop used to hold the protein crystal.
The Protein Expression Lab was established in 2009
to provide dedicated support to members of the Division of
Molecular Structure. The facility provides a comprehensive
resource for the production of recombinant proteins.
Currently we offer a choice of two expression systems:
bacteria and insect cells. A high-throughput pipeline for cloning
DNA fragments and small-scale expression tests in E. coli has
been established, allowing the generation and screening of
96 expression constructs in a week. In parallel, protein is also
expressed in insect cells using a baculovirus expression vector
system. Services include the generation and amplification
of high-titre baculovirus stocks, analytical scale productions
for optimisation of protein expression, and preparative scale
productions. In addition, the facility maintains a vector DNA
repository, provides in-house vector design, troubleshooting
and training. In the 20 months of operation we have produced
and tested more than 1000 constructs in E. coli and have
generated over 50 high-titre baculoviruses in insect cells.
3D structure of an influenza virus protein.
Small scale protein test SDS-PAGE gel.
Insect cell expression in a Wave Bioreactor™..
109
Mass Spectrometry
A tandem mass spectrum of an in-gel digested protein.
The Institute currently has two mass spectrometers which
are used in a range of biochemical applications. A research
grade MALDI-TOF 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-offlight (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.
In the last year, the Institute has invested further in this
important area and a new mass spectrometry suite is under
construction. This will house the existing machines alongside a
state-of-the-art LTQ Orbitrap Velos spectrometer capable of
110
Other structural biology facilities
Protein sequence analysis and structure modelling
Computational tools for prediction, analysis and visualisation can
provide inspirational new ways to look at data, no matter which
protein family is the main focus of research.
From high-level predictions of protein topology by template-free
methods (sometimes called ‘ab initio’), through three-dimensional
all-atom models of protein structure, to detailed protein-ligand
docking studies; theoretical methods developed both at NIMR
and in the wider academic community can suggest new insights
and new hypotheses leading to the design of fruitful experiments.
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.
The Division of Mathematical Biology contains a support
service for protein sequence analysis and structure modelling.
It draws on state-of-the-art algorithms being developed by
experts in the Division as well as the many computer programs
freely available from the scientific community. There is also an
in-house, commercial, computer graphics package for detailed
three-dimensional modelling. The service is available to all NIMR
scientists and external collaborators.
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.
111
Confocal Imaging and Analysis Laboratory (CIAL)
Yan Gu
Co-workers: Kate Sullivan, Donald Bell, Chen Qian
CIAL provides an imaging core facility available to everyone at NIMR.
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 supports 170 researchers from 15 NIMR
Divisions. Users operate the system, but the complexity of imaging
makes support an extremely important aspect of the facility. Routinely,
we provide users with training, troubleshooting, consultation and
microscope maintenance. We also support special techniques such as
thick tissue imaging, live experiments, 2nd harmonic generation imaging,
quantitative imaging, deconvolution imaging, and automatic cell counting.
Research activities in CIAL are focused on techniques of super
resolution imaging, correlative microscopy, high-throughput imaging,
automatic cell segmentation and tracking, and others relevant to NIMR
research. The lab has expertise in sample preparation and labelling, live/
fixed sample imaging, and hardware/software development required by
NIMR researchers.
2nd harmonic generation image (grey level) of the nonlabelling muscle/tendon cells, and the GFP/Alexa 488
labelled limb tissue (green) in a mouse embryo.
Courtesy of Malcolm Logan
High-throughput quantification of virus-infected cell population and plaque
formation.
Courtesy of Yipu Lin
Publications
Ktistaki E, Garefalaki A, Williams A, Andrews SR, Bell DM, Foster KE, Spilianakis CG, Flavell RA, Kosyakova N, Trifonov V, Liehr T and Kioussis D (2010)
CD8 locus nuclear dynamics during thymocyte development.
Journal of Immunology 184:5686 -5695
McIntosh PB, Laskey P, Sullivan K, Davy C, Wang Q, Jackson DJ, Griffin HM and Doorbar J (2010)
E1Ê4-mediated keratin phosphorylation and ubiquitylation: a mechanism for keratin depletion in HPV16-infected epithelium.
Zhu D, Jarmin S, Ribeiro A, Prin F, Xie SQ, Sullivan K, Briscoe J, Gould AP, Marelli-Berg FM and Gu Y (2010)
Applying an adaptive watershed to the tissue cell quantification during T-cell migration and embryonic development.
Methods in Molecular Biology 616:207-28
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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 is 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 service
also provides training, protocols, and assistance for investigators on
all aspects of histology, including tissue fixation, tissue processing, and
immunohistochemical techniques.
Bone stained with Mallory’s Trichrome (E. Grigorieva)
Kidney stained with Periodic Acid Schiff stain(PAS) (E. Grigorieva)
Colon stained with Hematoxylin and Eosin (E. Grigorieva)
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Electron microscopy
Liz Hirst
The facility has both Transmission (Jeol 1200 EX set up for
conventional scattering optics) and Scanning (Jeol 35CF)
Electron Microscopes which have both been upgraded to
CCD photography. There is also a dedicated EM processing
laboratory. Staff from NIMR may request TEM or SEM
investigations for their scientific studies.
TEM techniques available include ultra-thin sectioning and
ultra-structural analysis of experimental tissues, cell cultures
or pellets. Immuno-EM techniques can be post-embedding
immuno-gold labelling of antigens upon ultra-thin 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 facility. Technical advice, training and
support is also provided.
SEM of spinal cord of 1.5 day chick embryo, electroporated to
overexpress Sox9 and slug genes
Publications
Ermakov A, Stevens JL, Whitehill E, Robson JE, Pieles G, Brooker D, Goggolidou P, Powles-Glover N, Hacker T, Young SR,
Dear N, Hirst E, Tymowska-Lalanne Z, Briscoe J, Bhattacharya S and Norris DP (2009)
Mouse mutagenesis identifies novel roles for left-right patterning genes in pulmonary, craniofacial, ocular, and limb
development.
Polyakova O, Dear D, Stern I, Martin S, Hirst E, Bawumia S, Nash A, Dodson G, Bronstein I and Bayley PM (2009)
Proteolysis of prion protein by cathepsin S generates a soluble β-structured intermediate oligomeric form, with
potential implications for neurotoxic mechanisms.
European Biophysics Journal 38:209-218
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
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Immuno-EM of Escherichia coli showing that Suf B and Suf C are
localised to the bacterial membrane (10 nm gold particles).
OPT and HREM imaging
Imaging methods play an increasingly central role in enabling gene or protein activity to be linked to function and phenotype, from
subcellular to whole organism levels. Within the Division of Developmental Biology, the Institute has developed dedicated facilities
for imaging complex morphology and gene expression of embryonic and adult tissue in 3D using Optical Projection Tomography
(OPT) and High Resolution Episcopic Microscopy (HREM). This complements existing facilities at NIMR provided by Confocal
Imaging and Histology. Automated HREM developed at NIMR forms the basis of an ongoing project funded by the Wellcome
Trust and supported by the Medical Research Council to provide comprehensive imaging of normal and mutant mouse embryos
at unprecedented resolution. The freely available data (www.embryoimaging.org) complement standard anatomical texts and can
form the basis for systematic analysis of mutant morphological phenotypes.
OPT imaging of the transcription factor Hnf3β (red) in the mouse
embryo.
HREM imaging of mouse embryo tissue structure and 3D
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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 molecules. Some of these techniques provide high resolution images
of the molecules, and others give dynamic information about the interactions between proteins, DNA, lipid membranes and small
ligand molecules.
TIRF (left) and Optical Tweezers (right) 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 every
millisecond.
Atomic Force Microscopy (AFM) enables us to analyse the
structure of biological molecules by scanning their surface
topology using a microfabricated mechanical probe or “tip”.
The AFM used at NIMR (JPK NanoWizard) is ideally suited
to studying biological materials in aqueous solution at room
temperature. The AFM tip is scanned over the sample. As it rides
over molecules fixed to the surface, deflections of the tip 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 NanoWizard 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 yield very
high resolution pictures. CryoEM is well-suited to high-resolution
studies of both the structure and dynamics of large proteins and
protein complexes, such as cytoskeletal proteins or viral capsids.
Our latest methods also enable structures within rapidly frozen
mammalian cells to be visualised. By recording many digital
images of a specimen held at different orientations (tomography),
a three-dimensional view of the molecule or cell is obtained.
Individual molecules, whole virus particles or living mammalian cells
embedded in ice can be imaged in three dimensions. Averaging of
proteins can reveal near-atomic resolution structural information.
Slice of a three-dimensional tomogram showing the edge of a frozen hydrated cell
and a computational model for membrane organelles.
Image courtesy of Sebastian Wasilewski
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Genomics facility
Abdul Karim Sesay
Co-workers: Bob Butler, Harsha Jani
The Genomics facility makes state-of-the-art, next-generation sequencing and microarray
services available to NIMR research scientists. Services include sample preparation, highthroughput sequencing and microarray hybridisation. Support is also provided for data
analysis. Situated within the Division of Systems Biology, the Genomics facility is equipped
with state-of-the-art instrumentation for genomic sequencing, genotyping and gene
expression studies, including Illumina GAIIx and HiSeq2000 sequencers, the Affymetrix
Gene Chip hybridisation and Illumina iScan Systems.
High-throughput sequencing
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
core facility. The facility currently supports DNA/RNA sequencing using the Illumina
Genome Analyzer IIx (commonly referred to as “Solexa”) for reads up to 150 bases for
both single and paired-end runs. 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. The facility now includes the Illumina HiSeq 2000 sequencer. With innovative design features,
the HiSeq 2000 provides output of up to 200 Gb per run (2 x 100 bp read length), up to 25 Gb per day and two billion pairedend reads/run.
DNA shearing
The Genomics Facility has a Covaris system (based
on Covaris Adaptive Focused Acoustics™ (AFA)) for
DNA shearing for next-generation sequencing and for
conventional molecular biology applications and chromatin
shearing for chromatin immuno-precipitation.
Quality control
We offer an extensive platform for quality control and
quantification of DNA, RNA and proteins. The following
equipment is available for QC analysis:
Whole-genome chromatin IP sequencing (ChIP-Seq) to identify targets of the
Brachyury transcription factor that regulates mesoderm formation, which include
members of the HES gene family. The figure shows multiple binding of Xenopus
• Nanodrop spectrophotometer and two Agilent 2100
Brachyury in the vicinity of hes9.1 and two novel HES genes. RNAPII (ChIP-Seq) and
Bioanalyser, for quality control and quantification of DNA, RNA-Seq profiles were superimposed with Xbra ChIP-Seq. Members of the HES
family are involved in the segmentation of mesodermal tissue.
RNA and proteins.
Courtesy of G Gentsch and J Smith.
•Two Life Technology Qubit systems, for the quantification
of DNA, RNA and proteins.
•Life Technology E-Gel systems for size selection of
sequencing libraries
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Microarray
Whilst the most common use of microarrays is examining the
level of expression of many different genes or mRNA species in
a sample simultaneously, there are now chips available for other
protocols. These include SNP analyses, resequencing – including
a human mitochondrial genome chip - exon arrays for analysis
of alternative splicing, arrays for ChIP on chip experiments for
investigation of gene promoters, and miRNA and snoRNA
analysis with coverage of multiple organisms on a single array
(human, mouse, rat, canine, and monkey). Arrays are available for
many different organisms; we have used those for Mycobacterium
tuberculosis, Drosophila, Xenopus, zebrafish, chicken, dog, mouse,
rat and human. The microarray facility offers full technical
support in the preparation and running of RNA or DNA
samples prepared by the scientists. It also offers access to and
training in use of the Gene Spring software package from Agilent
for preliminary analysis of microarray data.
The facility now includes the Illumina iScan System with
Universal Starter Kit. Based around the iScan Reader, which
incorporates high-performance lasers, optics, and detection
systems, the iScan System offers sub-micron resolution, higher
throughput rates and very economical BeadChips available for
human, rat and mouse. Even the highest density BeadChips can
be scanned in minutes, allowing processing of up to 96 multisample BeadChips per day. Applications include gene expression
Transcriptional profiling, using Affymetrix GeneChips, identifies Foxj1 as
analysis; array-based transcriptome analysis; FFPE sample analysis; differentially regulated by Shh signalling in the neural tube. (A) Hierarchical
clustering of genes up- and downregulated by Shh. Normalised expression
SNP genotyping and CNV analysis; whole genome, custom or
values are shown for for downregulated genes (Cluster 1; B) and upregulated
focused genotyping; cytogenetic analysis; linkage analysis; copy
genes (Cluster4, C). (D-K) In situ hybridisation of Foxj1 in chick (D, E) and
number analysis; gene regulation and epigenetic analysis, and arraymouse (F-K) embryos.
Courtesy of James Briscoe.
based methylation analysis.
The Genomics facility team
The new HiSeq 2000
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Bioresources
Joachim Payne
Co-workers: Wioletta Berg, Brian Trinnaman, Jackie Wilson, Ian Oliver, Charlotte Austin, 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 10 research Divisions
at NIMR, as well as collaborating with
other MRC units, the Marie Curie
Research Institute, NIBSC and the
Wellcome Trust.
Last year we grew 1300 litres of
hybridoma cells and 3200 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 1,200 types of
product, and last year processed 3,500
orders, totalling around 36,000 litres of
media and associated solutions including
a quarter of a million tubes of Drosophila
food and 45,000 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
the MRC’s Prion and Clinical Trials Units
and researchers as far away as the MRC
SPHSU in Glasgow.
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Wioletta inspects a hybridoma culture.
Brian sets up one of our bioreactors.
Flow cytometry facility
Graham Preece
The flow cytometry facility provides state-of-the-art technology
for high speed, sterile sorting of multiple types of cell
populations for molecular, signalling and in vivo studies, 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, training
is also provided for research staff, including PhD students and
postdoctoral researchers. The facility is well equipped, with five
cell sorters that range from 4-colour to 13-colour machines
(Beckman Coulter MoFlo; Becton Dickinson FACS Aria II;
Automacs Pro Bead Sorting), and eight FACS Analysers that
include 4- and 9-colour machines (Becton Dickinson FACS
Calibur, Canto and LSRII; Beckman Coulter Cyan ADP).
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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 WHO Influenza Centre (WIC) at NIMR
that involves the handling of influenza viruses from all over the world, such as the novel H1N1 virus, prior to its emergence as a
full-blown pandemic virus. In addition, poorly characterised viruses are also received. Some of these viruses, notably viruses from
zoonotic H5N1 infections, have considerable pathogenic potential in both birds and humans. Work with poorly characterised
viruses and viruses that might, or do, have pandemic potential requires a high degree of containment to prevent the spread of
influenza viruses into birds or the environment, as well as operator protection to minimise the risk of handling viruses potentially
harmful to man.
The facility is built to Health and Safety Executive requirements and DEFRA regulations under the Specified Animals Pathogen
Order. It was used for the growth and characterisation of samples of the pandemic H1N1 virus, at the early stages of its global
spread, sent from around the world, and to generate reference ferret antisera to the emerging pandemic viruses for virus antigenic
analyses. It has also been used for the isolation and characterisation of human isolates of H5N1 avian influenza virus, for example
from the Turkish outbreak in humans in 2006. The laboratory capacity has been extended to have two standard high containment
laboratory areas and two laboratories equipped to handle infected small animals under high level containment. With the enhanced
capacity, in addition to the virus surveillance and characterisation studies of the WIC, simultaneous studies of the mechanisms of
disease causation by avian or other influenza viruses can be carried out.
Features of the laboratory include:
• A negative pressure air regime with HEPA filtered input and double HEPA filtered extract.
• Waste treatment with heating of liquid waste and autoclave sterilisation of solid waste within the body of the laboratory.
• Class III and Class I/III microbiological safety cabinets for handling samples.
• Class III cabinets for handling infected small animals.
• Sealable, so as to permit fumigation.
• Strict codes of practice including the requirement for all workers to undergo a complete change of clothing before.
entering the laboratory and to shower when leaving.
In addition to the Level 4 laboratory, there are 11 Level
3 laboratories scattered among the main buildings and
biological research facilities at NIMR. These laboratories
allow the safe handling of a number of pathogenic
organisms, permitting studies of the microbiology and
immunology of Mycobacterium tuberculosis, the invasion
of blood cells by the malaria parasite and the growth of
the retroviruses that cause AIDS.
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Engineering workshop
Alan Ling
Co-workers: Derek Brewer, Peter Cookson, Ray Herriot, Derek Rumley
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
diverse range of projects can be worked on, including:
• micromanipulators
• microscope set-ups
• custom-made parts
• temperature controlled chambers
• drug infusers and nebulisers
• blood flow measurement devices
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Electronic instrument prototyping and support
Martyn Stopps
In collaboration with Programme Leaders, instruments are
designed and manufactured for applications in physiology and
single molecule research. Work conducted in cutting-edge
science often requires new instrumentation that is not available
commercially. Examples of this over the past year include:
• An optical trap with a PC interface for single molecule
research.
• A high speed closed-loop thermal controller for live cell
imaging studies of secretary pathways.
• Behavioural neuroscience apparatus enabling subtly different
odours to be rapidly switched and delivered along
independent odor lines.
Utilising current technologies, the resource in collaboration
with researchers and Mechanical Engineering, enables
comprehensive system development from initial specification to
proof of concept and the final solution.
Alternating two-colour fluorescence imaging a custom-built control unit synchronises an EMCCD digital
camera and two lasers together with a computer data acquisition
programme.
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An Electronics and Programming Workshop a two-day practical workshop providing basic electronics and
programming techniques enabling exploration of novel research beyond
what commercial apparatus may provide.
PhotoGraphics
Joe Brock
Co-workers: Neal Cramphorn, Wai Han Yau, Hayley Wood, Jamie Brock
The PhotoGraphics service provides a professional design,
illustration and imaging facility to visualise the innovative
research carried out at NIMR. Our fully trained team provides
a wide range of specialist skills using state-of-the-art equipment,
software and techniques. These include digital manipulation,
illustration, Flash™ animation, film making and editing, 3D
modelling, scanning and photography as well as providing a
printing, copying and binding service.
This facility is open to all researchers wishing to relate their
science visually through publication, digital presentation and
posters. Novel methods developed by us for presenting science
using interactive animations provide more dynamic in-depth
explanations and we regularly receive requests for copies by
researchers and companies world-wide who recognise this
media as a powerful informative tool.
The PhotoGraphic team design and publish NIMR publications such as this report, the Mill Hill Essays
and other in-house publications. We also present training courses throughout the year for researchers
who wish to use applications such as Adobe Photoshop™ and Microscoft Powerpoint™ to professional
level. Photographics also maintain the seminar and meeting room facilities and provide the audio-visual
Composite image showing 3D modelling, illustration and embedded
movies within a single animation describing the role of myosin in
merozoite infection of red blood cells.
Typical illustration produced by PhotoGraphics to visualise scientific and
biological processes.
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Computing
Clive Lunny
Co-workers: Aomar Ayad, Jose Ayala, Darsheni Fatania, John Green, Debra Harper, Ben Kesel, Graeme Millar, Harsha Sheth,
Nathan Smith
Computing and Telecommunications provides secure access to
the Internet, via a firewall, over a 100Mb JANET (Joint Academic
Network) connection. They provide a range of services including
email with web-based access, secure remote access, web servers
for intranet and public websites, IT security, including anti-virus
and spam filters, data encryption, FTP server/web-based export
server, database and related services, support services for both
Windows and Macintosh computers and other mobile devices,
secure wireless networks and an internal telephone system.
Recently they have introduced Webex video collaboration
services, a new 100TB data storage system and are adopting
virtualisation to increase energy and space efficiency.
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Library
Frank Norman
Co-workers: Patti Biggs, Nicola Weston, Lynsey Eames
The Library is dedicated to serving the information needs of
scientific staff and students at NIMR. It provides access to a broad
range of electronic journals (2000 plus titles) and searching tools.
Extensive printed journal backfiles and a print book collection
supplement these. Easy access to document delivery completes
the picture.
Library staff provide individualised help for scientists in the
lab or at their desktop. Expert assistance with information
searching is available, including help with systematic literature
reviews, difficult-to-answer questions and search alerts for easier
literature scanning. Support for publishing includes assistance with
bibliographic management (e.g. Endnote, Reference Manager,
Mendeley, Zotero) and advice on Open Access compliance. A
daily news service keeps staff informed of current science policy
developments.
Desk space in the Library includes dedicated study desks for
write-up, a cluster of computer desks with PCs and Macs, and
casual reading space. There is a wifi network in the main reading
room so that laptops and other mobile devices can be used.
The Library records the Institute’s major research outputs and
achievements, ensuring that these are listed on the NIMR website
and in the Annual Report. It also maintains the Institute’s historical
archives and repository of publications.
The main reading room.
Casual seating area with new book and journal displays.
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Web Team
Christina McGuire
Co-worker: Mark Houghton
The Web Team is responsible for the day-to-day
management of the NIMR website, intranet and online
presence, and longer-term strategic projects such as the
recent redevelopment and implementation of a content
management system on the external website.
Our aims are to ensure that the external website reflects the
excellence of science at NIMR, meets user and organisational
needs, and promotes the research and outreach work
at NIMR. Internally, we want to provide easy access to
information and resources to enable staff to work efficiently
and effectively.
We produce microsites for NIMR sponsored initiatives such
as conference websites; develop innovative solutions such as
our online weekly newsletter for staff; and are always willing
to provide advice and expertise.
The Web Team provides not only technical infrastructure, but
also training and support (including tools for easy updating).
We develop cross-platform, user-friendly, visually appealing
websites and applications, and ensure compliance with
relevant standards and legislation.
We work with and for staff throughout NIMR, and proactively
engage at all levels through one-to-one meetings, focus
groups, surveys, feedback forms, instant polls, and user testing
and evaluation. We also have an open door policy, something
we have in common with other support sections at NIMR.
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General services
Occupational Health
Occupational Health (OH) is concerned with the effects of health on work and work on health with consideration for the
working environment. Occupational services include health protection, health promotion and lost time management. The OH
team assist the Institute in striving towards enhancing productivity and excellence through a fit, healthy and effective workforce.
Our professional service observes Health and Safety regulations and helps to support the overall needs of NIMR. We offer
impartial advice to all employees on health matters related to the working environment. We provide specific health surveillance
to staff members exposed to hazards, thereby promoting their wellbeing at work.
Safety and security
The Safety section provides a safe working environment at the Institute. All staff are provided with 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.
Human Resources
The Human Resources section works in partnership across the Institute to support its objectives and a diverse group of science
and support staff. A team of specialists work to embed shared principles and a culture that support great science, and provide
expert advice on employment matters such as recruitment, development, performance, reward and recognition.
Finance and Purchasing
The Finance team provides advice and support to staff in the costing of grant applications, full economic costing, expenses and
sales invoices. They are also responsible for the management, reporting and forecasting of the Institute’s budgets. The Purchasing
team assists staff with all aspects of procurement including tendering for capital equipment, service contracts, and consumables.
They also liaise closely with the RCUK Shared Service Centre to ensure that we get best value for money in pricing.
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A history of chemistry research at NIMR
The International Year of Chemistry 2011 (IYC 2011) is a worldwide celebration of the achievements of chemistry and its contributions to
the well-being of humankind. We outline here the role that research in chemistry has played at NIMR.
Given the enormous importance of chemistry to our lives, and in particular to the development and production of medicines, it is
not surprising that it has been a central topic of research at NIMR almost from the inception of the Institute nearly 100 years ago.
It is notable that of five Nobel prizes awarded to scientists who have spent substantial parts of their careers at the Institute, two
were for chemistry. During the 1920s and 1930s a plethora of important chemical discoveries were made at the Institute, some of
which passed rapidly into clinical use while others were key wayposts of knowledge in particular areas.
Henry Dale was head of the Department of Biochemistry and
Pharmacology when the Institute was first established. He recruited several
chemists with whom he had worked at the Wellcome Laboratories:
George Barger and Arthur Ewins in 1914; Harold King and Harold Dudley
in 1919. Working with them Dale isolated acetylcholine, one of a family of
neurotransmitters that pass nerve impulses to other nerve or muscle cells.
Dale and Dudley continued to work together on acetylcholine, histamine
and the ergot alkaloids. Dudley isolated ergometrine from the ergot fungus
that infects rye, and it is still used as a drug in obstetrics to control postdelivery haemorrhage.
Harold Dudley
Henry Dale
After just a few years at the Institute, Ewins moved to become head
of research at May & Baker while Barger took a chair in medicinal chemistry at the University of
Edinburgh. Harold King, whose interests covered a wide field of organic chemistry, then became the Institute’s chief chemist. He
identified and isolated tubocurarine, a muscle relaxant, from the curare toxin used in hunting by Amazonian Indians. As a direct
consequence of this work, a series of synthetic compounds was developed by King and collaborators in the mid-1930s and these
are still used as muscle relaxants in surgery, permitting lighter and hence safer levels of anaesthesia than would otherwise be
required. One of these compounds, hexamethonium, was the first clinically-effective drug for treatment of high blood pressure.
King retired in 1950, a few months after the Institute’s move to Mill Hill.
King also contributed to major Institute findings in steroid chemistry. In
the early 1920s he revealed the complex architecture of the cholesterol
molecule and its relation to that of other sterols occurring naturally. Henry
Dale noted that this change in the structural conception of a molecule,
starting from purely theoretical considerations, had far-reaching effects on
biochemistry, pharmacology, endocrinology and therapeutics.
Separate steroid work, led by R.B. Bourdillon in Henry Dale’s Division,
was on calciferol, also known as Vitamin D2. In the mid-1930s, with crucial
input from Robert Callow who had joined NIMR in 1929, they prepared
Vitamin D2 as the first pure, chemically-identified vitamin. In due course
Robert Callow
Harold King
this work led to the effective elimination of rickets, previously a common
and debilitating disease in the UK and elsewhere. This work and the related studies of the molecular structure of cholesterol by
Rosenheim and King, carried out at about the same time, provide interesting insights into the dual competitive and collegiate
nature of scientific research. On the one hand, NIMR chemists competed with the long-established chemical laboratories of
German universities and industry, and on the other, like all the scientists mentioned above, they depended on close collaboration
with their in-house biomedical colleagues.
130
NIMR was the coordinating centre of the MRC Chemotherapy Committee, established in the years between the two World
Wars. It aimed to foster drug development in the public sector by supporting work in various chemical and biological laboratories.
Chemotherapy had effectively begun only in 1910 with the use of salvarsan as a treatment for syphilis and by the late 1920s there
were still very few effective drugs. Furthermore, those that were available were largely the products of the German chemical
industry and there was concern that another war would cut off supplies. It was also felt that Britain, then at the height of its
imperial power, should be making efforts to combat the tropical diseases prevalent in many of the territories over which it held
sway.
Following the MRC-sponsored breakthrough in 1937 with sulphonamide drugs, the MRC Council proposed an intensive
programme of research in chemotherapy. The Institute’s planned move to a larger building at Mill Hill helped provide room for this
expansion, though it was delayed until 1950. The MRC Annual Report of 1948-1950 reported that “The greatly improved facilities
in the new National Institute have made it possible to expand chemotherapeutic research in both the chemical and the equally
important biological aspects.”
Much work at NIMR was directed at anti-parasitic therapies, particularly malaria and sleeping sickness,
but effective drugs proved hard to find. One of the more enduring legacies is the drug pentamidine,
which was produced very soon after similar compounds were developed at the Institute by Harold
King in a search for drugs active against trypanosomes, the parasites responsible for African Sleeping
Sickness. Pentamidine was initially used to treat Sleeping Sickness but more recently has been
reintroduced as a therapy for Pneumocystis carinii pneumonia (PCP - now known as Pneumocystis
jirovecii) that frequently affects AIDS patients. King also discovered a series of diamidine compounds,
which led to development of a drug useful in treating leishmaniasis.
James Walker
Archer Martin
James Walker joined NIMR in 1939, later succeeding Harold King as head of Organic Chemistry
during his career of 30 years at the Institute. His synthesis of the anti-malarial drug pyrimethamine, led
to a method that was later adopted for commercial use.
During the post-World War II period very important developments were made by A.J.P. Martin
and R.L.M. Synge in separation techniques known as chromatography that allowed the analysis and
purification of complex mixtures of chemical substances. Martin moved to NIMR in 1948 and further
developed these techniques, notably by the invention of gas-liquid chromatography (GLC) which
is still an important analytical tool. Various modern methods based on this pioneering work are in
everyday use in applications such as synthetic chemistry, forensic science, industrial quality control,
environmental monitoring and the detection of illicit drugs in sport. Under Martin’s guidance, I.E.
Bush made related advances in another separation technique, paper chromatography. This played an
important role in work from the 1950s, particularly in the isolation and characterisation of the saltregulating steroid aldosterone. The invention of the electron capture detector by J.E. Lovelock in 1957
greatly increased the sensitivity of GLC and ultimately had significant influence on the developing
environmental movement in the 1960s through its ability to detect low levels of pesticide residues
and chlorofluorohydrocarbons. Lovelock left NIMR in 1961 and is now more widely known for his
Gaia theory of the Earth as a self-regulating system, but the ramifications of his invention of the
electron capture detector remain with us today.
131
A history of chemistry research at NIMR (contd.)
Sir John Cornforth
In the late 1940s Sir John Cornforth joined NIMR. He worked with Callow to show that hecogenin
could be obtained from the waste-product of sisal manufacture in East Africa, so providing a starting
material for the commercial manufacture of cortisone. Working with George Popjak, Cornforth
began an extensive and elegant series of studies that used radioisotopes to determine how
cholesterol is made in the body. This work, for which he was ultimately awarded a Nobel Prize in
1975, is directly relevant to the modern statin drugs. These reduce cholesterol levels and thereby
diminish fatty deposits that otherwise restrict blood flow. Statins act on an enzyme involved in
cholesterol synthesis, one of the many enzymes studied in Cornforth’s steroid work. In another area
of his work past and present research at NIMR are neatly linked, since Cornforth also published a
method for the synthesis of N-acetylneuraminic acid. This compound is a component of the sugars
that are attached to the outer membranes of animal cells and to which the influenza virus binds as
the first step in its invasion of cells that ultimately results in an attack of flu. The structural details of
this binding have been a major topic of recent and current research on influenza at NIMR.
Chemistry at NIMR from the 1960s was largely carried on by Roy Gigg,
who was initially a student of Cornforth’s. He spent his whole career
at NIMR, retiring in 1995, and did excellent work in carbohydrate
synthesis, not least in glycolipids of the tuberculosis bacterium. Toward
the end of his research, he developed elegant syntheses of inositol
phosphates. These molecules are used by cells as internal “messengers”
to control various functions in response to outside stimuli. At the time,
the actions of these compounds had only just been discovered and his
work greatly assisted studies of their biological function. Derek Smyth
joined NIMR in 1962 and later was appointed Head of the Laboratory
of Peptide Chemistry (1972 - 1992). In collaboration with Sayaki Utsumi
Roy Gigg
he unravelled the structure of the “hinge region” of rabbit antibody,
Derek Smyth
locating the bridge that links the two half molecules and revealing a
new oligosaccharide chain. With Gordon Bisset he prepared a novel form of oxytocin, the N,O - dicarbamyl derivative, which
proved to be a specific inhibitor of the hormone without intrinsic activity. He followed this by sequencing the C-peptide of
proinsulin, modelling its contribution to the 3D structure. The enzymatic processing of prohormones to generate their active
constituents was a dominant research interest. In a classic series of papers from 1975-1982 he and his collaborators showed that
the C-terminal fragment of b-lipotropin, first isolated in his laboratory from pituitary, was an endogenously expressed opiate.
They showed that this 31 amino acid peptide, now known as b-endorphin, is a neurohormone with potent analgesic activity and
produces profound behavioural effects on the brain. Later he elucidated the mechanism of the C-terminal amidation process
which is essential for activation of numerous peptide hormones. In the mid 1970s, Nigel Birdsall synthesised two “workhorse”
radioligands [3H]N-methyl scopolamine and [3H]oxotremorine M, both used globally in hundreds of studies of muscarinic
receptors to the present day.
In 1983, David Trentham came to the Institute as head of the Division of Physical Biochemistry, bringing with him the recently
developed chemistry of caged compounds. These are biological compounds made inactive by attachment of a chemical group
that prevents them from displaying their normal biological activity. The attached group is designed so that, when exposed to
light of the right wavelength and intensity, it splits off from the molecule in a process called photolysis, generating the active
biomolecule. The term “caged compounds” is used, since the biomolecules are locked-up until released by the flash of light.
132
The technique is used to study biological processes such as muscle
contraction and cell signalling that take place in a few thousandths of a
second or less.
John Corrie joined the Trentham group in 1988 with interests in
further development of caged compounds and of fluorescence probes.
Discussions with biological colleagues, especially David Ogden and
Martin Webb, revealed requirements for particular new chemical tools.
One focus was the rapid release of neurotransmitter molecules that
carry signals between nerve cells. By being able to release known
concentrations of neurotransmitter independently of any electrical
impulse, the transmission process can be analysed and manipulated
John Corrie
David Trentham
more readily. A range of caged compounds were prepared to optimise
the efficiency and speed of neurotransmitter release in a water-based environment, as required for studying live tissue. A new
photochemical reaction was discovered and led to compounds that have proved optimal for neurophysiological studies. Some of
these caged compounds have been licensed for commercial production and are very widely used tools for neurophysiology.
John Corrie was also involved in developments using fluorescence to open up a new method for tracking the metabolism
of the biological molecule adenosine 5’-triphosphate (ATP). Previous methods to do this were tedious and did not permit
measurements to be made in real time. To improve existing methods, a protein produced by the common bacterium Escherichia
coli was utilised. Each molecule of this protein binds one phosphate ion in a tight complex, and upon binding undergoes a large
change in shape, in a manner conceptually similar to the Venus Flytrap. When the protein was tagged with a fluorescent label,
designed for this purpose, the change of shape greatly increased the fluorescence intensity. This system has become widely used
to monitor many biological processes and the labelled protein is now being produced commercially to make it available to other
researchers.
Following John Corrie’s retirement in 2006, John Offer joined the Institute to continue the tradition of chemistry. The focus of
his laboratory is to use emerging ligation techniques to build biological macromolecules. Chemical ligation is a powerful enabling
technology for a broad range of applications. It involves the coupling of two or more biomolecules in aqueous buffers at low
concentration to give the product in its final form with no further modification. It can be considered as the next generation of
bioconjugation reactions, as ligation is much more defined and selective than previous methods. John Offer’s research is focused
on extending the applicability of this reaction to give greater flexibility to the synthesis of protein targets, to explore its biological
relevance and to develop applications that allow modification of proteins in their native setting with minimal genetic manipulation
as part of the expanding contemporary effort to apply organic chemistry to the cell.
The rich history of chemical work at NIMR demonstrates how important chemistry is in medical research and this can only
increase as our understanding of the mechanisms of biological activities grows. It is obvious that the continuing need for such
teams will create opportunities for interesting chemistry far into the future. The importance and central position of chemistry in
so many aspects of future science and industry demands the inspiration of education professionals and the chemistry community,
and the interest and support of our politicians.
Based on an essay written by John Corrie with contributions from several others.
133
In memoriam
Don Williamson (1930-2010)
Don Williamson died on Tuesday 2nd November 2010, aged eighty. He was a programme leader at NIMR for 28 years.
Don Williamson graduated from Edinburgh University in 1956 with a Ph.D. in bacteriology, and then worked in Alan Eddy’s group
at the Brewing Industry Research Foundation from 1956-1962. He acquired a taste for working on yeast and developed methods
for isolating protoplasts and for synchronizing cell division. After a spell at the John Innes Institute, from 1962-1965, his interest in
DNA replication in the yeast cell cycle led to a sabbatical as a Research Associate Professor in Herschel Roman’s Department
of Genetics in Seattle. He used that time to work on the molecular biology of Saccharomyces cerevisiae and initiated studies that
eventually established patterns of yeast mitochondrial DNA replication.
In 1967 he moved to NIMR’s Microbiology Division to continue his work on yeast. Although trained as a bacteriologist he saw
himself primarily as a cell biologist and his recruitment was seen as a good way to build links between the Microbiology Division
and other areas at NIMR. He was a gifted collaborator, forging links both within and beyond the Institute. Don was seen as a great
asset to the Institute; Howard Rogers, Head of the Microbiology Division, wrote in support of a promotion for Don:
“He is a leading authority on the behaviour of DNA during the cell cycle and has helped to
demonstrate the great power of microorganisms as models to unravel cell cycle events. For
some years Don has been concerned with the overall problem of regulation of mitochondrial
DNA synthesis and the relationship between the physical nature of the mitochondrial
genome and the genetic behaviour of the mitochondrial system. His major contributions
were the demonstration of extensive recombination of mitochondrial DNA in growing cells
and his studies on the packaging of mitochondrial DNA”.
When Howard Rogers retired in 1983 Don took over as acting Head of Division for
two years. The Division was disbanded in 1985 and Don became Head of the newlyformed Laboratory of Cell Propagation.
Don in 1969
In the mid-1980s Don switched interests to the molecular biology of malaria
parasites and, working with Iain (R.J.M.) Wilson in the Division of Parasitology, he was
instrumental in analysing replication mechanisms of organelles and transfected plasmids
in Plasmodium. This collaboration proved very fruitful and in 1991 Don transferred
to the Division of Parasitology. He retired in 1995 though he continued as a visiting
worker for several more years.
Jim Smith, NIMR Director, said:
“I’m so sad to hear about Don’s death. I met him in 1984, when I came to work at NIMR for the first time. He was always a terrific
colleague: approachable, kind, clever, considerate and collegial. Everyone liked him.”
134
Scientific seminars
Nearly 200 seminars and lectures by visiting speakers are given at the Institute each year. Each major area of science has its own
seminar series and the Mill Hill Lecture series is an annual series of about ten lectures given by eminent scientists from around
the world. A selection of highlights from the past year is shown.
David Barford
Frédéric Barras
Dennis Bray
Sally Camper
Anne Cooke
Carole Goble
Anne Cooke
Christian Dahmann
Hendrik Dietz
Catherine Dulac
Suzanne Eaton
James E. Ferrell, Jr
Antonio Freitas
Robin Irvine
Steve Jackson
Tom Jessell
Chaya Kalcheim
Dominic Kwiatkowski
Bart Lambrecht
Warren Leonard
Werner Muller
Paul Nurse
Luke O’Neil
Benedita Rocha
Alexander Rudensky
Evan Sadler
Philippe Sansonetti
Jim Sellers
Michael B.Yaffe
Department of Pathology, University of Cambridge
Trinity College, Dublin
NIH/National Heart Lung and Blood Institute
Pasteur Institute, Paris
University of Manchester
Department of Pathology, University of Cambridge
IRB Institute for Research in Biomedicine, Bellinzona, Switzerland
Necker Institute, Paris
Pasteur Institute, Paris
University of Ghent
Wellcome Trust Sanger Institute
Memorial Sloan-Kettering Cancer Center
University of Cambridge
Columbia University Medical Center
Harvard University
Washington University, St Louis
Massachusetts Institute of Technology
Gurdon Institute, Cambridge
University of Cambridge
Department of Medical Neurobiology, Hebrew University of Jerusalem
Department of Chemical & Systems Biology, Stanford School of Medicine
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden
Department of Human Genetics, University of Michigan Medical School
Rockefeller University, New York
NIH/National Heart Lung and Blood Institute
Institut Fédératif de Recherche, Biologie Structurale et Microbiologie, Centre National
de la Recherche Scientifique, Marseille
Institute of Cancer Research, London
Center for Nanotechnology and Nanomaterials, Technische Universität München,
Germany
135
]
Staff honours
Prizes and awards
Alex Gould
Robin Lovell-Badge
2011 Hooke Medal (awarded 2010)
Waddington Medal 2010
Editorial boards
Siew-Lan Ang
Mike Blackman
James Briscoe
John Doorbar
Paul Driscoll
Francois Guillemot
Tony Holder
Jean Langhorne
Paul Le Tissier
Malcolm Logan
Troy Margrie
Anne O’Garra
Annalisa Pastore
Katrin Rittinger
Jonathan Stoye
James Turner
Jean-Paul Vincent
Robert Wilkinson
David Wilkinson
Douglas Young
136
International Journal of Developmental Biology
PLoS Pathogens (associate editor)
Development
Developmental Dynamics
Neural Development
Journal of General Virology
Journal of Functional and Structural Genomics
BMC Developmental Biology
Neural Development
Molecular and Biochemical Parasitology
Eukaryotic Cell
International Journal of Parasitology (specialist editor)
PLoS Pathogens (associate editor)
Cell Biochemistry & Function
Journal of Neuroendocrinology
Developmental Dynamics
Development
Frontiers in Neural Circuits
Journal of Experimental Medicine
Prion
The Open Biochemistry Journal
The Open Spectroscopy Journal
Journal of Biological Chemistry (scientific editor)
PLoS One (scientific editor)
Biochemical Journal
Journal of Virology
Chromosome Research
Biology of Reproduction
Science Signalling
Tuberculosis (section editor)
PLoS One, and the International Journal of Tuberculosis and Lung Disease (associate editor)
Faculty of 1000
BMC Developmental Biology
Mechanisms of Development (editor in chief)
Gene Expression Patterns (editor in chief)
Tuberculosis (consulting editor)
Scientific committees
Mike Blackman
James Briscoe
John Doorbar
Alex Gould
François Guillemot
Ed Hulme
Jean Langhorne
Troy Margrie
Tim Mohun
Justin Molloy
Anne O’Garra
Steve Smerdon
Jim Smith
Gitta Stockinger
David Wilkinson
Douglas Young
Wellcome Trust Immunity and Infectious Diseases Funding Committee
Director, Company of Biologists
British Society for Developmental Biology (Meetings Secretary)
Society for General Microbiology Translational Virology Group
Wellcome Trust Molecules Genes and Cells Funding Committee
Patient Advisory Committee, Respiratory BRU Clinical Research Facility, Royal Brompton Hospital
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
Wellcome Trust Expert Review Panel on the Immune system in Health and Disease
Scientific Advisory Board of the Research Centre for Infectious Diseases, University of Wuerzburg
Grant Committee Membership: HFSP, European Union
MRC Molecular and Cellular Medicine Board
BBSRC Tools and Resources Development Fund (Chair);
EPSRC Peer Review College; Wellcome Trust Expert Review College
Scientific Advisory Boards:
Institute for Biomedical Sciences, Bellinzona, Switzerland
Baylor Institute for Immunology, Dallas, USA
Institute for Molecular Medicine, Lisbon
World Premier International Research Center (WPI) Initiative
Osaka University, Japan
Keystone Symposia Scientific Advisory Board
Research funding boards:
MRC Developmental Pathway Funding Scheme Grant Research Board
MRC/ABPI, Inflammation and Immunology Initiative - Steering Group
Grant Committees:
MRC Molecular & Cellular Medicine Board
NIH Structural Genomics Study Group
BBSRC IGF & Genomics Evaluation Panel
Diamond Peer Review Panel.
Advisory Boards:
Structural Genomics Consortium
MRC-Technology Governing Board
ASM Scientific/TwistDX Inc.
Wellcome Trust Investigator Awards Selection Panel
Scientific Advisory Council
Indian Institute of Science Education and Research
Scientific Advisory Board - TwistDx (ASM Scientific)
Scientific Advisory Board - Institute for Toxicology and Genetics, Karlsruhe
ERC Young Investigator panel
Multiple Sclerosis Society panel
Academy of Finland grant panel, Atip/Avenir panel
EMBO Long Term Fellowships committee, Welbio
Advisory committees:
GXD Advisory Board
EMAGE Advisory Board
Board of Directors, Aeras Global TB Vaccine Foundation
Chair of International Scientific Advisory Board, Malawi-Liverpool-Wellcome Trust Clinical Research Programme
Member of Governance Committee, European Tuberculosis Vaccine Initiative (TBVI)
137
PhD theses awarded in 2010
138
Name
Division
Title of thesis
Veronica Fridh
Molecular Structure
Biochemical and biophysical characterisation of a novel
CARD-CARD Interaction in NOD2
Peter Gardner Parasitology
Investigating the B Cell response to malaria: cloning a malariaspecific B Cell receptor and analysis of the antibody reponse
Eve Hornsby Molecular Immunology
The role of IL-17 in the development of autoimmunity
James Turton Molecular Neuroendocrinology
In vitro studies of dominant negative PIT1 mutant proteins
Izbel Yusuf Molecular Neuroendocrinology
Identifications of a new target tissue for growth hormone: the
placenta
Matthew Child Parasitology
Trafficking and function of a malarial sheddase
Cyprian Daniel Cukier
Molecular Structure
Transcription-responsive regulation of c-myc proto-oncogene
- structural and biophysical studies
Rachel Farrow
Single molecule characterisation of unconventional myosins
Laura Galinanes-Garcia Molecular Neurobiology
Molecular mechanisms underlying Mash1 function in
oligodendrogenesis
Katie Foster
The role of neural crest cells in the development, organisation
and migration of the thymus
Nicolaos Balaskas
The gene regulatory logic of Sonic hedgehog morphogen
interpretation in the ventral neural tube
Jameela Khan
Virology
Proteolytic cleavage of human papillomavirus type 16 E1Ê4
Catia Laranjeira
In vivo identification of neural stem cells in the enteric nervous
systems
Emmanouil Metzakopian
Genome wide identification of transcriptional targets of Foxa2
in midbrain dopaminergic cells by ChIP-Seq
Peter Saiu
Molecular Structure
Structural and functional studies on nucleotide binding to
AMP-activated protein kinase
Natalie Silmon de Monerri
Parasitology
Investigation into the role of PfSUB1 and two perforin-like
proteins in Plasmodium falciparum
Charles Sinclair
Immune Cell Biology
The role of Zap70 in thymocyte development
Jessica Borger
Visualising early signalling events in T cell activation
Current funding sources
The Medical Research Council (MRC) is the principal source of research funding. A total budget of £42m p.a. is set every five years
following an Institute-wide review of resources. This review takes place after the quinquennial peer review (conducted by MRC
Research Boards) of the programmes of the individual Divisions.
The Institute also attracts funding support from a wide range of different agencies, including medical research charities, international
sources, particularly the EU, and from industrial and commercial companies:
• Association for International Cancer Research (AICR)
• Biotechnology and Biological Sciences Research Council (BBSRC)
• European Molecular Biology Organization (EMBO)
• European Research Council (ERC)
• GlaxoSmithKline UK
• Health Protection Agency (HPA)
• Imperial College
• International Federation of Pharmaceutical Manufacturers & Associations (IFPMA)
• Lady Tata Memorial Trust
• Leukaemia & Lymphoma Research
• Leverhulme Trust
• Medical Research Council
• Medical Research Council Technology
• National Institutes of Health (US)
• Parkinson’s Disease Society
• The Royal Society
• University College London (UCL)
• Wellcome Trust
139
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152
5
Peter Medawar, OM, CBE, FRS
Peter Medawar was the Director of NIMR from 1962-1971. He was the foremost biologist of his
generation. Largely through his work a new branch of science was created – the immunology of
transplantation. He was also a philosopher, a humanist and humanitarian – in short, a rounded scholar –
and a gifted science communicator. The inaugural Medawar Lecture was held on 26 May 2010. NIMR’s
PhD students chose and hosted the speaker, Tom Jessell.
153
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
154
155
The Ridgeway
Mill Hill
London NW7 1AA
Tel +44 (0)20 8959 3666
Fax +44 (0)20 8816 2041
MRC NIMR location map
A1 North
to M25, Heathrow and Stansted Airports
od
Hi
London
La
ay
ew
ers
MRC National
Institute for Medical
Research
dg
Ri
rd
W
ay
The Ri
dgew
M25
A1
Bit t a
cy
ll
Hi
Mill Hill East
Dollis R
M1
J2
d
Lan
W
atfo
Hendon
rd W
ay
ll R
oa
H ale
N
La n
ass
B a r ne t B y p
Mill Hill Broadway ThamesLink
to Central London via King’s Cross
Daws
e
Mill Hill
Broadway
ay
A5100
e
M25
NIMR
ll
e
Th
W
at
fo
A41 to
Central London
e
ne
A5109
an
Marsh L
A1
M25
H a mm
B a r n e t Way
Hi
gh
wo
M1
A598
Finchley
Central
A5000 Northern Line
to Central London
e
rs
Hi
A1
oad
H
ol
d
Bus number 240 connects NIMR to both Mill Hill East and Mill Hill Broadway stations. Trains run from Mill Hill East station on the
Northern Line into central London. Main line trains run from Mill Hill Broadway station to Luton Airport, Gatwick Airport and St
Pancras station in central London.The M1, M25 and North Circular Road are within easy reach of NIMR. On-site parking is available
at NIMR.
156

pdfMRC NIMR Annual Report - The Francis Crick Institute

Transcription

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