MRC National Institute for Medical Research

Transcription

MRC National Institute for
Medical Research
2011/2012 Annual Report
and Prospectus
Edited by:Victor Tybulewicz
Designed by: Joe Brock
Photography by: Neal Cramphorn & James Brock
Production: Christina McGuire & Frank Norman
Editorial Assistant: Eileen Clark
© MRC National Institute for Medical Research
Enquiries about this report should be addressed to:
Assistant Director’s Office
+44 (0)20 8816 2281
enquiries@nimr.mrc.ac.uk
Further information is available on our website at:
http://www.nimr.mrc.ac.uk
Copies obtainable from the Librarian at NIMR
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Contents
Director’s foreword
The Francis Crick Institute
Science overview
Scientific highlights
NIMR history and milestones
Careers :
PhD students
Sandwich students and work experience
Postdoctoral scientists
Programme Leaders
Research support
Animal Technicians
Translational research
Support for translation
Commercial translation
Clinical translation
Public outreach
Research groups :
Infections and Immunity
Structural Biology
Neurosciences
Genetics and Development
Research facilities
Nobel Laureates
Five famous alumni
Scientific seminars
Staff honours 2011
PhD theses awarded
Indexes
Research groups
Research themes
Current funding sources
Bibliography
NIMROD social club
Map, location and travel
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Director’s foreword
This has been a very busy and successful year at NIMR. We have been doing more terrific science (see Scientific highlights, page
10), and we have completed a very successful quinquennial review. Current and former members of staff have received various
honours and awards, and we have welcomed new programme leaders to the Institute. We have also made a great deal of
progress towards establishing The Francis Crick Institute (see page 6).
The outcome of the Institute quinquennial review - confirmed by MRC Council in December - was very positive. The preparation
of the report, and its presentation to the visiting committee, showed the Institute at its best, with everyone pulling together for
a tremendous result. This is a good opportunity for me to highlight the importance to the Institute’s science of our world-class
support services: they were strongly commended by the visiting committee, and I would like to thank everyone involved for
their invaluable contributions to the life and work of the Institute. In particular, the work of Biological Services, under the expert
direction of Kathleen Mathers, was strongly praised by the review committee, confirming my own view that we have one of the
best-run facilities in the world.
My scientific proposals for the review focused on exciting new opportunities growing
from recent successes. Thus the review committee endorsed the creation of a
Division of Physiology and Metabolism, under Alex Gould, and a revitalised Division
of Neurophysiology. Together these will allow us to drive forward some critically
important emerging areas of biomedical science. Forthcoming new appointments
will help realise this vision. We also took the opportunity at the quinquennial review
to move James Briscoe and Jean-Paul Vincent to the Division of Developmental
Biology, where, as joint heads, they are bringing new approaches to understanding the
molecular and cellular mechanisms underlying embryonic development.
Institutes like NIMR thrive on turnover and the arrival of new colleagues, and we
were delighted to welcome two new Programme Leaders Track this year: Eva Frickel
and Luiz Pedro de Carvalho. Eva joins us from Hidde Ploegh’s lab at the Whitehead
Institute, where she looked at immune surveillance of Toxoplasma gondii and the
generation of parasite epitopes for recognition by CD8 T cells. Eva’s programme at
NIMR builds on these studies to identify novel pathways and mechanisms of host
resistance to Toxoplasma. Luiz Pedro de Carvalho worked as a postdoctoral fellow in
Carl Nathan’s laboratory at the Weill Cornell Medical College, where he studied host
interactions of Mycobacterium tuberculosis. In particular he contributed to LC-MSbased metabolomics methods for systems-level studies of M. tuberculosis, which forms
the basis of his new lab at NIMR.
Alex Gould
I was also delighted in the last year that my Assistant Director, John Wills, and my
Director of Research, Steve Gamblin, both received external recognition. John’s
outstanding contributions were recognised by the award of an MBE in the New Year
Honours List for services to Science, while Steve was elected to the Fellowship of the
Royal Society for his work on the structural and functional mechanisms of molecules
involved in disease processes.
Eva Frickel and Luiz Pedro de Carvalho
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The Royal Society also recognised two of our scientific alumni: Tim Bliss has been invited to deliver the 2012 Croonian Lecture,
the Society’s premier lecture in the biological sciences, and Robin Holliday has been awarded a Royal Medal. Tim’s award
recognised his work on synaptic plasticity and especially long-term potentiation and long-term depression; Robin’s medal
recognised his pioneering work on DNA-strand exchange that involved what is now known as the Holliday Junction.
We also congratulate three of our Programme Leaders who have been awarded major external grants: Troy Margrie
(Neurophysiology) has a Wellcome Trust New Investigator award, and Anne O’Garra (Immunoregulation) and Jean-Paul Vincent
(Developmental Biology) have both received grants from the European Research Council.
John Wills MBE
Royal Society Fellows Jim Smith, Steve Gamblin, Sir John Skehel, Sir Keith Peters and
Tim Bliss celebrate Steve Gamblin’s election.
Tim Bliss
Robin Holliday
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The Francis Crick Institute
This year has seen the former UK Centre for Medical Research and Innovation - now named The Francis Crick Institute - really
start to take shape, in terms of its people, its organisation and its building. Sir Paul Nurse, appointed as Director and Chief
Executive of The Crick, will need no introduction to the readers of this report. He took up this new leadership role at The Crick
after resigning in 2011 as President of the Rockefeller University and becoming President of the Royal Society. Through all of this,
he has never stopped working on the cell cycle and morphogenesis in fission yeast. It was for that work that he was awarded the
Nobel Prize in Physiology or Medicine in 2001.
Speakers at the time capsule ceremony.
The time capsule.
The name, The Francis Crick Institute, celebrates one of the country’s most distinguished scientists: the co-discoverer of the
structure of DNA, and someone whose work epitomised the multidisciplinary approach to be adopted by scientists at the
institute that bears his name. Francis’ daughter, Gabrielle, came to a ceremony at the site of the new Institute, along with David
Willetts MP, the Minister for Universities and Science, and Mayor Boris Johnson, to witness the burial of a time capsule. NIMR’s
contributions included many photographs of the building, our most recent Quinquennial Review, a copy of Mill Hill Essays 2010,
and a list of our collected publications, 1970–2011.
Computer-generated image of the interior of the new building.
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King’s College London and Imperial College London have formally joined The Francis Crick Institute, bringing their clinical and
scientific skills to the partnership. Representatives of the six partners (Imperial, King’s, UCL, the Wellcome Trust, CRUK’s London
Research Institute and NIMR) are now involved in all aspects of planning, and we are taking every opportunity to maximise our
scientific interactions to prepare for transfer into The Crick. In September 2011 we held a joint scientific retreat and we are
planning a series of joint academic ventures in the coming year.
Computer-generated image of the exterior of the new building.
The building itself will soon be taking shape. The planning application received its final approval early in 2011, and Laing O’Rourke
were selected to do the construction work, realising the design created by HOK and PLP Architecture. Building began in June
2011 and as I write, in December 2011, 100,000 tonnes of soil and concrete have been removed from the site. It is hard to
convey just how big the building will be: at 83,000 m2 its internal floor area will be 10% bigger than Brent Cross shopping centre
in North London and when it has been fully excavated, the waste material will be enough to fill the Albert Hall twice. Waste clay
soil is being used to help restore a bird sanctuary, while heavier material, which may contain concrete, is cleaned at a washing
plant and recycled. The building itself will be finished in the middle of 2013, and fitting-out is expected to take two years. There is
no doubt that The Francis Crick Institute will be a fantastic place to work. As we move closer to 2015 our pace of progress will
continue to accelerate: keep an eye on the NIMR and Crick websites for details.
www.crick.ac.uk
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Science overview
Research programmes at NIMR
NIMR is one of the world’s leading medical research institutes. It is dedicated to studying important questions about the life
processes that are relevant to all aspects of health. NIMR is the largest of the Medical Research Council’s institutes. 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. Research
is focused on four scientific areas: Infections and Immunity, Genetics and Development, Neurosciences and Structural Biology.
Collaborations underpin progress in these areas, e.g. on the structure and function of molecules involved in infectious diseases,
common mechanisms of nervous system and immune system development, and how the functioning of the brain arises during
embryonic development.
The immune system is a key part of the body’s defence against infections. Its importance is illustrated by the effects of a defective
immune system, as seen in people with AIDS, which results in overwhelming infections leading to death. While an effective
immune system is vital for health, an over-exuberant immune system can start to attack the body itself, a process known as
autoimmunity. Autoimmunity is the cause of allergies such as hay fever and more serious conditions such as asthma, rheumatoid
arthritis, and multiple sclerosis. We are analysing how the cells of the immune system are triggered to mount an immune response
when faced with an infectious agent, how the process can go awry in autoimmunity, and how complex checks and balances in the
system ensure activation of the immune system only when needed.
Infectious diseases result from the transmission of pathogenic micro-organisms. Examples studied at NIMR include malaria,
tuberculosis, AIDS and influenza which are responsible for the deaths of millions of people every year. This death toll is exerted
mainly in the poorer countries of the world, and is also a significant and increasing burden for the National Health Service. Our
research seeks to understand the fundamental biology of the causative micro-organisms and their interaction with hosts. We use
this understanding to promote the development of new drugs, vaccines and diagnostic reagents. The study of pathogenic agents is
also a rich source of important information on basic mechanisms of cell and molecular biology.
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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.
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.
Our work also examines the role of the nervous system and other tissues in energy balance and metabolism. These studies take
place in close collaboration with developmental biologists who are exploring the molecular and cellular basis of organogenesis
and body patterning. We also have fruitful collaborations with clinical colleagues to understand the genetic and developmental
processes that lead to defects in the central and the peripheral nervous system.
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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Scientific highlights
It gives me great pleasure to outline here a few of the Institute’s most exciting discoveries of the year. A major strength of NIMR
is the way in which structural biology informs our understanding of infectious disease. Influenza remains an important focus of the
Institute, and the significance of this work was emphasized by the news, at the end of 2011, that just five mutations in H5N1 bird
flu might allow it to be transmissible between humans through the air. This observation highlights the importance of the WHO
Influenza Centre at NIMR, which monitors genetic changes in circulating influenza viruses. And while it is very unlikely indeed
that such a virus should appear, the work also emphasises the need to develop therapeutic agents that will block all influenza
virus infections (including swine flu, bird flu and Spanish flu) and could be stockpiled for use in emergencies. One such reagent,
a neutralising monoclonal antibody that confers protection to mice and ferrets, has now been characterised by John Skehel
and Steve Gamblin together with colleagues from Switzerland. An understanding of the structural basis of protection will be
extraordinarily valuable in helping design broad-spectrum vaccines.
Another example of structural biology informing the struggle against infectious disease
comes from work by Ian Taylor, Luiz Pedro de Carvalho and Jonathan Stoye. They
characterised the structure of SAMHD1, a restriction factor which inhibits the growth
of HIV-1, the causative agent of AIDS. Normally expressed in dendritic and other
myeloid immune cells, SAMHD1 prevents reverse transcription of the HIV-1 genome
and inhibits its replication. Further study of SAMHDI will help develop new therapeutic
approaches to HIV-1 and even vaccine development.
Rob Wilkinson and colleagues have found that vitamin D deficiency is extremely
common in black Africans living in Cape Town, South Africa, and is associated
A trimer of haemagglutinin binding to three
with susceptibility to tuberculosis infection. The work suggests that vitamin D
molecules of antibody.
supplementation might be a cost-effective, safe and simple means to reduce the
incidence of TB in South Africa and elsewhere in the world. Work on malaria at NIMR has also continued apace, with new
insights into the way in which the malaria parasite invades red blood cells. Tony Holder and his colleagues have demonstrated that
the malaria parasite can select from a panel of ligands to bind to receptors on the surface of host red blood cells, and this will
probably confound attempts to block invasion that are based on any single ligand receptor.
Gitta Stockinger’s group, with her colleague Marc Veldhoen (now at the Babraham Institute), has discovered that nutrients found in
vegetables such as broccoli and Brussels sprouts activate the aryl hydrocarbon receptor, which helps maintain intestinal epithelial
cells and prevents adverse effects of pathogenic gut micro-organisms. Gitta has also studied the cytokine interleukin-9 (IL-9),
which has been implicated in lung inflammation. By making a mouse in which IL-9-expressing cells carry a stable genetic mark, she
has discovered that during an inflammatory response this cytokine is activated transiently by a subpopulation of innate lymphoid
cells. Those cells go on to express IL-13 and IL-5, cytokines that are normally expressed in the Th2 subset of T cells and which
are a major cause of allergic reactions. Blocking IL-9 reduced IL-13 and IL-5, suggesting that innate lymphoid cells represent an
important link in the regulation of Th2 responses.
Cell marking techniques have also proved important in the area of neuroscience and developmental biology, where Iris Salecker
has devised a genetic multi-colour cell labelling approach for Drosophila that she calls Flybow. Extending work by Josh Sanes
and Jeff Lichtman at Harvard University, this technique allows workers simultaneously to visualise neurons or other cell types, in
defined tissues and at defined times, through the stochastic expression of four membrane-tethered fluorescent reporters. This
will prove to be a remarkably powerful technique to follow the behaviour of cells as they divide, migrate and interact with each
other during development. Alex Gould’s group has investigated the mechanism by which the brain is spared in periods of nutrient
deprivation during human gestation. They also found that the Drosophila brain is protected from the effects of dietary restriction
and that this occurs because the receptor Anaplastic Lymphoma Kinase switches stem cells in the brain from a state where they
require nutrients to grow to one where they do not. This discovery establishes a new genetic model for human intra-uterine
growth restriction, and will shed light on how the mother’s diet influences health and disease in later life.
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Activity of Flybow 1.1 in the 3rd instar larval and adult visual system.
Brain sparing in the late-stage Drosophila larva
Important insights into how progenitor cell proliferation is regulated in the developing vertebrate brain have come from François
Guillemot and colleagues, who studied a proneural transcription factor, Ascl1, known to be essential for neuronal differentiation.
A genome-wide analysis of transcriptional targets of Ascl1 unexpectedly found that these include genes that control cell cycle
progression. Furthermore, since inactivation of Ascl1 was found to alter the proliferation of neural progenitor cells, this proneural
factor contributes to the expansion of progenitor cell number as well as to their differentiation.
Jean-Paul Vincent, with Eugenia Piddini (now at the Gurdon Institute in Cambridge), has studied how Wnt signalling determines
whether a cell will live or die. Previous work had indicated that cells require Wnt signalling in order to survive. Jean-Paul and
Eugenia found that what really matters is the relative level of Wnt signalling. For example, if a normal cell is surrounded by cells in
which the Wnt signalling pathway is hyperactive, that cell will die. This might be relevant to human cancers in which Wnt signalling
is overactive, perhaps due to mutations in genes such as APC (the most common mutation in colon cancer).
In another technical advance, this time in the mouse, Troy Margrie and his colleagues have shown that the whole-cell patch clamp
method can be used to transfect single cells with plasmids during neuronal recording in vivo. This allowed Troy to record the
synaptic input and sensory function of a neuron and then to trace the upstream brain circuits, but the potential of the method
goes beyond this to include genetic perturbation of intracellular signalling pathways, the introduction of light-activatable ion
channels, and many other possibilities. This approach represents a major step forward in our attempts to understand the functional
architecture of the brain.
Highlights 2007-2010
2010
2009
Wnt-induced cell competition and Notum
2008
2007
See references 35, 42, 82, 89, 125, 135, 160, 188, 244 and 249 in
the bibliography at the back for the publications mentioned.
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Immune signature for tuberculosis (Anne O´Garra and Robert Wilkinson)
Parasite invasion and replication (Mike Blackman)
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)
Depletion of activated CD4+T cells (George Kassiotis and Dimitris Kioussis)
Structure of Nbs1 protein (Steve Smerdon)
Morphogen gradients not needed for proliferation (Jean-Paul Vincent)
Evolution of vertebrate limbs (Malcolm Logan)
Neurogenin2 controls neuronal migration (François Guillemot)
A transcription factor linking environmental toxins to autoimmunity (Gitta Stockinger)
The adult pituitary gland contains stem/progenitor cells (Iain Robinson and Robin Lovell-Badge)
Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants (Steve Gamblin, Alan Hay and John Skehel)
Timer genes control brain size (Alex Gould)
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)
AMPK enzyme structure offers hope of effective diabetes treatment (Steve Gamblin)
Fruit fly’s fatty secrets shed light on liver disease (Alex Gould)
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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.
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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 2 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.
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CAREERS
PhD students
The training of students, of all levels, is integral to NIMR and through the programmes we offer we strive to train biomedical
leaders of the future.
PhD Programme
The NIMR four-year PhD programme has been designed to equip our students
with the scientific and transferable skills required to make them internationally
competitive. Fully integrated into the NIMR PhD programme are medical
undergraduate (MB BS) students who join us in January of each year via the UCL
MB PhD programme. All of our students benefit from access to the state-of-the
art facilities and extensive expertise available across the Institute. We encourage
innovation, interdisciplinarity and collaboration, and, indeed, many of our PhD
students have projects that span multiple research themes, providing them with
an excellent opportunity to broaden their general understanding of science and
acquire practical expertise. As a result of this, our 80 or so students significantly
contribute to the research output of NIMR.
On arrival at NIMR, students work closely with their supervisors to develop their
project proposal. They also choose a thesis committee, members of which have
expertise in a range of scientific areas and whose role is to advise the student for
the duration of their PhD studies. Initially registered for an MPhil degree, students
transfer to a PhD registration in Year 2 on the basis of an upgrade report. To
support the development of our students we offer a wide range of internal training
courses ranging from bioinformatics, statistics and microscopy to ethics, report
preparation and presentation skills. We also run a series of careers seminars and an
annual careers round table event, which reflect the broad range of careers that are
available to PhDs.
Donna Brown
Director of Studies
We encourage a good work-life balance and onsite you’ll find a range of social activities including football, fitness classes, squash,
badminton, a book club, quizzes and a licensed bar. Our student representatives (see page 15) organise a number of social events
including a Christmas dinner and summer barbecue attended by PhD, Sandwich, Summer and work experience students. Social
activities at NIMR contribute to the spirit of collaboration which pervades science at the Institute. For those looking for a short
commute, we offer on-site accommodation for 12 students.
Exciting times lie ahead with the opening of The Francis Crick Institute in 2015. The students we recruit from 2012 will move to
The Crick when it opens and plans are already in place to ensure a smooth transition. Until then NIMR students will benefit from
our close relationship with our partner in The Crick, the CRUK London Research Institute.
.
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CAREERS
The 2011 intake of PhD students
Student representatives
With a varied intake of PhD, MBPhD, Summer and Sandwich year students
throughout the year the student representatives aim to inspire a sense of
community amongst the student body through regular social activities. Weekly
student seminars and monthly journal clubs expose students to topics outside
of their primary field of interest, and allow students to receive informal
feedback on their presentations, to ask questions, and to establish potential
collaborations with other Divisions. Additionally a Student Seminar Day is
held each year in association with students based at UCL offering a further
opportunity for students to present their work. The student representatives
also sit on various committees within both the NIMR and UCL so that their
opinions can be voiced.
The 2011 student representatives:
Sam Goldsmith, Laura Robinson and Kat Collins.
The 2011 Travel Prize
Each year NIMR awards a £1000 Travel Prize for the best Upgrade Report.
This year the judges were so impressed by all of the reports they decided
to introduce a runner-up prize of a £100 Amazon voucher. The prizes
were presented by Steve Gamblin (Director of Research) to the winner,
Jeff Cloutier (Stem Cell Biology and Developmental Genetics) and the
runner up, Elizabeth Underwood (Molecular Structure).
15
CAREERS
PhD students – in their own words
Christine Tshitenge
“I’ve been at NIMR for almost three years as a Marie Curie PhD student. My research
project focuses on characterising the differences in immunopathology in virulent
and avirulent P. chabaudi infection. The ultimate aim is to identify differences in the
host immune responses that correlate with disease outcome. This could hopefully
provide useful information for vaccine development and also more insight into disease
pathogenesis. I came to do my PhD here for various reasons. Amongst these are
that NIMR has some of the top and most referenced labs in the world, national and
international collaborations, a culture of learning and carrying out challenging research,
the opportunity to be mentored by some of the world’s leading scientists and to
interact with them on a daily basis. I could say a mouthful of adjectives to describe my
experiences at NIMR, but what I will say is that NIMR has given me an edge in terms of
future career aspirations.”
Jeff Cloutier
“Over the past two years, I have been working with James Turner in the Division of Stem
Cell Biology and Developmental Genetics at NIMR. Before coming here, I undertook
my undergraduate education at Middlebury College, Vermont (USA), where I had my
first taste of meiosis research. After attending a Gordon Conference on Meiosis, where
I learned about James’ interesting research, I was inspired to pursue my PhD research
in the UK. My work in the Turner lab has been focused on understanding the molecular
mechanisms that lead to germ cell loss and infertility in mice.
NIMR is a unique place for research. The tightknit nature of the community encourages
frequent interactions, both in the laboratory and in the canteen, corridors and onsite
bar. As a PhD student, I have also had the opportunity to present my work at two big
international meetings. My PhD training at NIMR has been a stimulating and exciting
experience. Over the next two years, I will complete my PhD work at the National
Institutes of Health (USA), as part of a collaborative training programme funded by an
NIH Marshall Scholarship.”
16
CAREERS
Sandwich students and work experience
Sandwich placements
Now, more so than ever, having practical research experience
is essential for a scientific career at any level. Our Sandwich
placements provide students with the opportunity to fully
immerse themselves in a research lab for 12 months and to work
on an independent research project. Sandwich students also have
access to a wide range of lectures, seminars and training, and
thus fully benefit from all that NIMR has to offer. Many of our
Sandwich students go on to do a PhD at NIMR and other leading
research institutions.
Work experience for school students
The 2011 intake of sandwich students
We encourage students from an early age and each year local school students work alongside our researchers, quite often PhD
students, for periods of up to six weeks (also see Research Summer School on page 29). Many of these students come back as
undergraduate, Summer or Sandwich students.
Tom Flower
“I was based in Dr Ian Taylor’s lab within the Division of Molecular Structure. My project
focused on a retroviral protein known as Foamy Virus Gag. During the project I obtained
numerous skills including protein production, purification and crystallisation along with
other analytical techniques. I am happy to say that the project was very successful and
resulted in the determination of a Foamy Virus Gag crystal structure. I found the NIMR
a great place to socialise outside of the lab thanks to facilities such as the onsite bar,
monthly social events and weekly sporting activities. The subsidised canteen and Costa
coffee shop were very reasonably priced and made living in London much more affordable.
Overall this year at NIMR has strengthened my desire to work in research and as a result I
aim to study for a PhD after I graduate.”
Rebecca Campion
“This year I spent six months doing work experience at NIMR before going to Cambridge
University to study Natural Sciences (Biological). I spent three months each in two different
laboratories. In all honesty, I have not the words to express how much I learnt and
enjoyed my experience. Although I was exceedingly naive, lacking in both experience and
knowledge, everyone I met took time to answer any and all questions that I had (and there
were many of them). Not only were they incredibly patient, but also everyone I met at the
Institute made me feel welcome. For anyone who is willing and eager to learn I can think of
no better place for student research studies.”
17
CAREERS
Postdoctoral scientists
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 acquire key scientific and
complementary managerial skills.
NIMR hosts approximately 220 postdoctoral researchers, supported either by MRC core funding or externally funded fellowships.
The core funding promotes careers at the postdoctoral level through three year MRC Career Development Fellowships (CDFs).
In addition to the training and support offered to postdoctoral researchers by NIMR, the Postdoc Committee is very active
arranging seminars, retreats and careers sessions. In 2010 The Scientist ranked NIMR third in the UK among “Best Places to Work
for Postdocs”.
NIMR also has a vital role in providing research training for clinical scientists, and this is an important facilitator of translational
projects and national and international collaborations. NIMR hosts many visiting postdoctoral clinical scientists from the UK and
abroad carrying out research on, for example, infectious diseases and genetic disorders.
The Postdoc Committee
The Postdoc Committee is composed of postdocs working at NIMR in different fields and was created to organise, inform and
support the community of postdocs at NIMR. The Committee promotes communication between postdocs, runs a postdoc
website, and has organised a seminar series, exclusively dedicated to and attended by postdocs of the Institute, which has featured
high calibre presentations. The Committee has representation on a number of Institute committees. Finally, it organises the annual
Postdoc Retreat, which, this year, took place at the Natural History Museum. This was a resounding success with interesting
scientific speakers as well as career-focussed presentations and networking. In the coming year the Committee aims to continue
with current activities as well as increasing the communication between postdocs at NIMR and those at institutions that will also
move into The Francis Crick Institute.
The 2011 Postdoc committee:
Melanie Lebel, Otto Kyrieleis, Harriet Groom, Mohamed Ismail (Soly) and TJ Ragan
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CAREERS
Postdoctoral scientists – in their own words
Laurent Dupays, Division of Developmental Biology
“Working at NIMR has been a great experience over the past few years. The
large size of the Institute and the wide range of expertise available allow any
researcher to find what he or she needs in a matter of hours, whether it be
an unusual restriction enzyme or the answer to an obscure statistical problem.
One of the many assets is the incredibly well organised network of services.
As a developmental biologist working on mouse heart development it’s great
to have access to such a wonderful mouse facility. Our animal technicians
are dedicated to taking care of our mouse colonies, which allows us as
researchers to spend more time at the bench furthering our knowledge. And
the mouse facility is just one part of the many dedicated services provided for
scientists at the Institute.
Another benefit is the number of people working on so many different model
organisms. Maybe your speciality is mouse embryology, but you would like to perform some quick functional analyses in an alternative
model? Just go next door and ask about zebrafish or Xenopus embryos and you can expand your project into another organism
within the week. And colleagues are always happy to help you ‘see the light’ by using their preferred model! Without doubt the great
infrastructure combined with the sharing of knowledge and skills makes NIMR a wonderful place to work efficiently, and perform well.”
Otto Kyrieleis, Division of Molecular Structure
“I started at NIMR in November 2009. I am working in Steve Smerdon’s
group, on the structural biology of complexes involved in ubiquitin-regulated
signalling events following double-stranded DNA breaks. I have always enjoyed
the friendly, collegial atmosphere at the Institute and in particular in the
Division of Molecular Structure. In addition to the great working atmosphere
here, the Institute offers a great variety of facilities available for everyone in
the Institute. This allows you to learn many additional techniques and methods
to tackle biological questions. Each facility is run by competent and friendly
staff, who are willing to share their knowledge and expertise with you and to
support you. This makes the life of postdocs at NIMR a lot easier compared
to other institutions. And finally, I really appreciate the opportunities for social
networking at NIMR including the onsite bar, various sport pitches, squash
court and the seminar series such as the Mill Hill Lectures and the bi-monthly
postdoc seminar series with a beer session afterwards. Taking all these things
together this makes the NIMR a very inspiring and exciting place to work.”
19
CAREERS
Programme Leaders
Most Programme Leaders at NIMR are initially recruited on Programme Leader Track positions. This provides core support
for a five-year period, which, following external review, can lead to promotion to an open-ended MRC Programme Leader
appointment. This latter position provides long-term core support, subject to regular scientific review, that enables ambitious
research to be carried out. A number of scientists who have established their reputation at NIMR have gone on to head institutes
or university departments around the world.
Eva Frickel, Parasitology - joined NIMR in 2011
“The reason I am at NIMR is simple. I have always chosen scientific topics and projects
I found most interesting, in the places that I thought did them best. I wanted to start
my own small research group aiming to make a difference in my area of research with
a multi-disciplinary approach. I knew that this would only work in a highly collaborative
environment with research groups around me interested in similar aspects of infectious
diseases, others working with similar methods, all embedded in an institute with fantastic
core facilities and support staff. NIMR immediately stood out as a unique place that
provides all of this.
I applied for a Wellcome Trust Career Development Award to be able to take my research
to Mill Hill. I found an NIMR sponsor in Jean Langhorne, who was enthusiastic to recruit
me to the Institute. NIMR welcomed me with open arms and I am convinced I made the
right choice. I am looking forward to starting my independent career at this place of great
history and innovation.”
Peter Thorpe, Stem Cell Biology and Developmental Genetics joined NIMR in 2011
“I was looking to establish my own laboratory exploring how yeast can be used
to understand adult stem cell function. Many institutions focus their research into
narrowly-defined themes. Finding an environment that bridged basic science and
clinical research was difficult. Although some larger universities achieve this balance,
researchers are naturally divided into either clinical or basic research and often have
limited contact or appreciation of each other’s work. I had seen how the MRC brings
together scientists working at both ends of the basic–clinical science spectrum and so
when I saw an opportunity to work at NIMR, I applied immediately. NIMR’s research is
legendary and with so many great scientists launching their careers here, this was too
good an opportunity to miss.
At NIMR the MRC support means we can spend most of our time on research. We
are able to drive the research forward using new approaches to solve our scientific
questions. The friendly and welcoming atmosphere helps to make interdisciplinary
research a reality. I have already been working with both structural and developmental
biologists to exploit our yeast system in new ways. In the coming years I hope to be
able to make the most of this fantastic environment.”
20
CAREERS
Troy Margrie, Neurophysiology - joined NIMR in 2009
“As a graduate student in Australia I discovered NIMR through my reading
of several key studies on synaptic transmission and plasticity that were
carried out here. Later, one of my PhD advisors collaborated with Tim
Bliss who visited our lab to carry out in vivo experiments. This exposure
to whole animal electrophysiology seeded my long-standing interest in
systems neuroscience. When I later heard of positions opening up at
NIMR it immediately caught my interest as a very exciting, collegial and
interdisciplinary environment.
NIMR differs from the other institutes I have worked in in two ways.
Firstly, the Lab Managers make a genuine difference; they have all been
outstanding in their ability and attitude. From sorting out hand towels to
redesigning lab space, they work with minimal fuss and as efficiently as
possible. Secondly, the open-door policy and generosity that permeates the
Institute is apparent from the students and postdocs through to Programme Leaders and the Directors and their support teams. There is
genuine altruism and, most importantly, a sense that the science comes first. These two main points have stood out for me and underlie
the very positive psychology that exists here. I think this is also the main challenge for NIMR and its staff moving forward to The Crick.
It is really not about bricks and mortar or the logistics of moving mice and microscopes but rather how one creates such a unique and
positive scientific culture within a reincarnation of NIMR and its co-founding partners.”
Iris Salecker, Molecular Neurobiology - joined NIMR in 2001
“After completing my postdoctoral training in California at UCLA I came
to NIMR to set up my first independent research group. Over the years,
I experienced a truly supportive environment that allowed me to grow
into the role of a PI and develop a long-term research programme, first
as a career-track and then as a tenured Programme Leader. Within the
Developmental Biology/Neurosciences community and beyond, our shared
activities, such as internal seminar series, not only expose us continuously
to outstanding research in a wide range of different research areas, but
importantly also create a genuine spirit of collegiality. Thus, I found both real
mentorship and inspiring colleagues with whom to exchange advice and
expertise and to venture into new territories, such as imaging techniques,
which may not have felt reachable otherwise. I also value that by running
a relatively small group and because of core funding and solely voluntary
teaching, I can work even as a PI, whenever possible, at the bench or in
my case in the fly room or at the confocal microscope side-by-side with
my students and postdocs to test ideas and share the excitement of
advancing our research.”
21
CAREERS
Research support
NIMR offers career opportunities that can be broadly termed research support, covering many different types of jobs. Research
Technicians are located within specific programmes and are directly involved in research. Laboratory Managers look after all
the labs and equipment of one or more Divisions, ensuring that the science runs smoothly. Many individuals are involved in the
running of NIMR’s extensive facilities, for example the biggest of which, Biological Services, provides a fully integrated laboratory
animal and technical resource to the Institute. Finally, the Institute employs individuals in a range of non-scientific activities,
including Divisional Administrators, Personal Assistants, Human Resources, Accounts, Procurement, Stores and Security.
Alessandra Gaiba, Laboratory Manager
“I started my scientific career with a six-month placement at Glaxo Wellcome in
Stevenage straight after my degree from the University of Bologna in Italy. I decided
to stay in the UK where there were more possibilities to do research outside
academia than there were in Italy. I then spent 13 years working as a medicinal
chemist at SmithKline Beecham (which then became GSK).
A couple of years ago, I decided to change career and came to NIMR as a
Laboratory Manager. For 18 months I shadowed other Lab Managers and covered
for them while they were on holiday, which gave me the opportunity to get to know
all the different areas and all the key people in the Institute. From the beginning, I
was struck by how different the atmosphere was at NIMR compared to industry and
how much easier it was to talk to people. Since July 2011, I have taken on the role
of Lab Manager for the Divisions of Immune Cell Biology and Molecular Immunology,
following the retirement of Nick Clark. So far, I have really enjoyed my new role. I
love interacting with other support staff and my scientists, helping them sort out
problems with equipment, ordering from suppliers and coordinating lab refurbishments.”
Vangelis Christodoulou, Protein Expression Manager
“After successful stints at EMBL-Hamburg Outstation, University of Athens and the
Netherlands Cancer Institute, I came to NIMR (nearly three years ago) with the rather
daunting task to set-up the Protein Expression Lab within the Division of Molecular
Structure. When I arrived, there was a lab packed with equipment waiting for me.
And thanks to the help and support of my line manager and the members of the
Division I had my lab up and running within a few weeks of my arrival. Since being
at NIMR, I have benefited immensely from the freedom I was given to develop new
protein expression technologies, the close working relationship with the members of my
Division and the collaborative spirit amongst NIMR scientists.
So far, NIMR has been a fantastic place to work, giving me the opportunity to get
involved in challenging projects while generously offering all the necessary resources
and support, which makes the whole process very enjoyable.”
22
CAREERS
Graham Preece, Flow Cytometry Manager
“Following a decision not to pursue a teaching career I arrived at NIMR on
November 14th 1977 and only really expected to stay a couple of years.
However, NIMR’s invigorating and academically stimulating environment together
with its unique warm and friendly atmosphere, which can only be described as
mildly addictive, got in the way of moving further afield and I have thoroughly
enjoyed an exciting and interesting career spanning 34 years.
I first joined Dr Mike Parkhouse’s lab in the Immunology Division and became
an expert in monoclonal antibody production. Following Mike’s departure in
1990 I moved into Dr Ann Ager’s lab where I spent the next ten years working
on lymphocyte trafficking. When Ann moved to Cardiff in 2000 I was recruited
into the expanding Flow Cytometry labs. The research skills I had gained over
the previous 23 years and in particular the experience I had working with
antibodies, fluorochromes, and flow cytometric methods meant that I was easily able to slot into a very busy lab. In 2010 I successfully
applied for the post of Flow Cytometry Manager. Running the Flow Cytometry labs has given me the opportunity to develop the service
and we are now able to offer a cell sorting service at CL2 and have just taken delivery of a new state-of-the-art analyser.
In summary, NIMR offers a fantastic career opportunity for those who want it. Combining this with the exceptional uniqueness of the
NIMR environment means that my last 34 years here have been an incredible experience. I would recommend it to anyone and I hope
new staff experience the same at The Crick.”
Mike Reilly, Procurement Manager
“I began my career as a Research Technician at the Liverpool School of Tropical Medicine and
moved to NIMR in 2003, continuing as a Research Technician in the Division of Developmental
Biology. The position allowed me to gain experience in laboratory management and to successfully
undertake research projects. Three years ago the opportunity arose to become Procurement
Manager at the Institute after I expressed interest to move out of the laboratory. The transition
into purchasing has been an excellent move for me professionally and personally, with my scientific
background proving to be greatly beneficial. The change allowed me to remain at NIMR, as I wished,
as it is an outstanding place to work, evidenced by the length of service of current staff.
One of the major benefits of working at NIMR, within the MRC, is the commitment to professional
development of its staff. I have been fully supported which has allowed me to complete my first
Chartered Institute of Purchasing and Supply (CIPS) qualification in 2011. This is prominently
recognised in the procurement field and I continue these studies to the next qualification with
sustained support. Finally, another highlight of the year was my football team winning the NIMR
8-a-side league!”
23
CAREERS
Animal Technicians
NIMR is committed to ensuring a high standard of training and education for Animal Technicians and support staff at all stages of
their careers. Continuous Professional Development (CPD) for Animal Technicians at NIMR includes formal and informal learning,
training and experiences. Competency-based qualifications allow training specific to the individual and their work while Open
University and Institute of Animal Technology qualifications deliver a wide knowledge of laboratory animal science, the 3Rs and a
good background in biological sciences. Technicians are encouraged to spend time in NIMR research labs in order to gain handson experience of experimental procedures, and attend workshops and seminars held on a regular basis on subjects related to
laboratory animal science. Visits to other scientific establishments, symposia and international meetings are also organised which
enable technicians to gain experience in more varied aspects of laboratory animal husbandry and science, ensuring the 3Rs are
embedded in all work involving animals at the Institute.
Ola Puchalska-Oosorio, Animal Technician
“I joined NIMR Biological Services two years ago as an Animal Technician. Since the
beginning I was trained on how to take the best care of animals used for medical
research, their welfare and how to handle different species correctly. After a few
months at the Institute I had the opportunity to study the Level 3 CPD course in
Animal Technology, and decided to take it because I felt it could help me to improve
my knowledge in this field. This course has helped me to understand more deeply
the legal and ethical aspects of using animals in medical research, their needs,
welfare and environment. The course has been an important complement to my
practical skills gained at the Institute. Also, I found that the flexibility of the course
allows me to take more time in research and helps me to further analyse the topics
studied.”
Kim Demetriou, Animal Technician
“I initially chose to complete the level 2 CPD course in Animal Technology to
increase my vocational qualifications. As much as I enjoy my job as an Animal
Technician, since starting the course I have begun to view my work as a career
rather than just a job. I believe I have gained confidence in my abilities to control
and handle animals, and I have found that learning more about animal husbandry,
the scientific background and the roles of the support staff, has given me a deeper
understanding of research and the importance of providing a high standard of
animal welfare.”
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TRANSLATIONAL RESEARCH
Support for translation
Eileen Clark
Laboratory-based studies at NIMR underpin the MRC’s mission to improve human health through research. Discoveries of
how molecules, cells and organs are formed, regulated and function provide the knowledge that can lead to new therapies
and diagnostics. This ‘intellectual property’ and its translation into products such as useful novel drugs or vaccines feeds into
commercial projects that can build on this ‘know-how’, and Technology Transfer facilitates this exploitation.
Some studies are closely aligned to specific human diseases and this research benefits from close interactions with clinicians.
Productive exchange between basic scientists and clinicians allows model systems to be used to their greatest advantage in
scientific discovery, and provides insights into the disease process in patients as well as potential treatments and improved clinical
care.
Technology Transfer
NIMR scientists are supported by a local Technology Transfer office which
provides mechanisms and structure to allow basic technology transfer
activities such as material transfer agreements, collaboration agreements and
confidentiality agreements to be dealt with locally and speedily. The office
is also responsible for raising awareness of intellectual property issues and
encouraging scientists to be alert to potential exploitation opportunities.
MRC Technology (MRCT) is the exclusive technology transfer agent for
the Medical Research Council and is responsible for translating cutting edge
scientific discoveries into commercial products. In addition they have small
molecule drug discovery and therapeutic antibody facilities, providing lead
stage therapeutic assets to pharmaceutical and biotechnology companies.
MRC Technology adds value to cutting-edge scientific discoveries through
strategic patent protection and creative licensing of intellectual property (IP)
or through partnered research with industry. Examples of licensed technology
include transgenic mice and crystal structures. NIMR scientists have a variety of
industrial collaborations and also act as consultants to a range of companies.
A translation club for NIMR scientists promotes collaborations/networks
with MRCT, the pharmaceutical industry, clinician scientists and engineers. It
aims to achieve better translational exploitation of NIMR scientists’ findings,
reagents, methodologies and equipment. It meets two or three times a year
and, in addition to NIMR scientists, involves representatives from key partners
including MRCT and University College London Hospital to discuss new
opportunities for translation and to raise the overall awareness of potential
interesting opportunities. In addition, the club aims to bring in a cross-section of
experts from potential partners as guest speakers on an ad hoc basis to open
up new ideas and ways of thinking. Case studies of previous NIMR successes in
translation have been presented to Programme Leaders at the Institute. The club
aims to establish an informal network of contacts that is readily accessible to
NIMR scientists, in order to help exploit their findings.
25
Commercial translation
Phosphate biosensor
A basic research programme on motility proteins required
a rapid and sensitive way to measure inorganic phosphate,
one product of ATP hydrolysis. This led to a novel approach
- a fluorescent reagentless biosensor. The concept is
straightforward. A protein is used as the biosensor framework
to interact with the target molecule, in this case phosphate,
and is modified by attachment of a fluorescent reporter.
Binding of ligands often results in rapid conformational
changes, and these can be read out by changes in the
fluorescent reporter. A phosphate binding protein was chosen
and a fluorophore was attached to this framework to provide
the signal in response to phosphate binding. The resulting
adduct has a millisecond response time and can measure submicromolar concentrations of phosphate.
Although originally designed for a particular project, the
widespread study of phosphatases, ATPases and GTPases
mean that this is a general tool and led to patent protection
by the MRC, licensing to companies and eventually the
availability of the biosensor commercially. The experience and
design principles of this biosensor have also led to a number
of related developments. Several biosensors using similar
principles were developed at NIMR, including ones for ADP
and GDP, which have now been patented.
Structure of phosphate biosensor, solved at NIMR (coumarin fluorophore
in red, inorganic phosphate in blue).
Mouse House
NIMR Animal Technicians led the work to develop a proven
enrichment device that has significantly enhanced the
welfare of laboratory mice - the Mouse House - which was
patented by the MRC and is now marketed by Techniplast
UK. Over 200,000 Mouse Houses have been sold worldwide.
The transparent red is of a specific wavelength that the
mice see as dark grey. Thus when inside the Mouse House,
mice feel secure while Technicians can still see in to carry
out routine checks and husbandry. Studies have shown that
the mouse house helps to reduce aggression and improves
breeding performance, which is especially important in
transgenic mouse strains. The designers of the Mouse House
were awarded the 2002 ‘Animal Welfare Award’ by the
Swiss Society for Laboratory Animal Science, the first nonacademic recipients of this prestigious award.
The Mouse House.
26
Clinical Research
Infectious diseases continue to blight human health worldwide. Our laboratory-based research on diseases such as influenza,
malaria, and tuberculosis (TB) benefits from and informs clinical practice worldwide.
Influenza
The NIMR WHO Collaborating Centre for Reference and Research on Influenza is part of the global surveillance system and is
one of six collaborating centres that assesses the antigenic and genetic characteristics of influenza viruses from around the world.
These centres help to advise WHO and formulate the twice-yearly WHO recommendations for the composition of seasonal
influenza vaccines (see page 54). The six collaborating centres also advise WHO on the emergence of drug-resistant viruses and
on the pandemic potential of animal influenza viruses that can cause infections of humans. By harnessing the power of molecular
and structural biology with virology, the antigenic properties and drug susceptibility of circulating human influenza viruses can be
dissected and the pandemic potential of animal influenza viruses assessed.
Malaria
The Childhood Malaria Research Group (CMRG) has been established as a
partnership between the Division of Parasitology (Fernandez-Reyes and Holder
groups) and the College of Medicine, University of Ibadan, University College
Hospital (COMUI-UCH) in Ibadan, Nigeria. This collaboration brings together
superb clinical skills and hospital infrastructure for the management of severe
malaria with the molecular expertise of NIMR in the densely populated city of
Ibadan, where malaria is among the most common causes of death in children
under the age of five. Nigeria has an estimated one quarter of all malaria cases
worldwide. Our research on the molecular basis of cerebral malaria and severe
malaria anaemia benefits from the close alignment with clinical specialists and
provides a laboratory research capability close to patient point of care. Our
research has already defined molecular markers that predict disease progression
to severity and have the potential to be developed into clinically useful tools for
disease prognosis and clinical management.
Tuberculosis and HIV-TB coinfection
Waiting at the Children’s Outpatient Clinic, University
College Hospital, Ibadan, Nigeria.
Close clinical ties in South Africa (the Wilkinson group at the University of Cape Town) and London have allowed an international
team of basic researchers, clinicians and bioinformaticians, led by Anne O’Garra, to identify a transcriptional signature in the
blood of active TB patients that is missing in the majority of asymptomatic latent and healthy individuals. This signature of active
tuberculosis correlates with the extent of lung radiographic disease and is diminished upon treatment, thus offering potential
biomarkers for diagnosis and treatment monitoring. This is much needed in tuberculosis, which is difficult to diagnose and still
causes 1.7 million deaths per year.
27
Hirschsprung’s disease
The pathogenesis of Hirschsprung’s disease (the most frequent congenital abnormality of gut peristalsis) is studied by the Pachnis
group in collaboration with clinicians at the UCL Institute of Child Health, Great Ormond Street Hospital. Together the groups
are developing methods to isolate and characterise enteric neural stem cells from human gut tissue, and establishing experimental
systems to assess their ability to colonise aganglionic gut. Having shown in a model system at NIMR that enteric glial cells function
as facultative neural stem cells, the two groups are now studying how the neurogenic potential of human enteric glial cells can be
activated to generate functional enteric neurons in Hirschsprung’s disease patients.
The image depicts groups of enteric neurons and the network of their axonal processes. These neurons fail to develop in
parts of the colon of Hirschsprung’s disease patients.
Disorders of sexual development
The Lovell-Badge group, together with clinical collaborators, has found that chromosome rearrangements around the SOX3
gene are a frequent cause of human XX male sex reversal. This finding followed work in mice where they found that ectopic
expression of Sox3 in the early gonad gives XX males, with Sox3 mimicking the Y-linked testis determining gene, Sry. This work has
important implications for diagnosis in the clinic.
28
PUBLIC OUTREACH
Public engagement
Human Biology Essay Competition 2011
NIMR’s Essay Competition is now in its ninth 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 Abida Gani of Mill Hill County High School on Have we anything to fear from genetic screening? can be
found in the Mill Hill Essays 2011.
Research Summer School
In 2011 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.
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 year’s event
was Molecular biology for the future. We accommodated a capacity audience of 360 visitors over two days drawn from 23 local
schools. As usual there was a lively interrogation of the speakers on their subject, careers and topical issues. We also presented a
small demonstration on a developmental biology theme to provide a glimpse of real experimental material. There was a high level
of participation in our quiz based on posters relating to science in the news.
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PUBLIC OUTREACH
Professional development for teachers
In June 2011 we held a meeting for local teachers focused on recent developments in biomedical science. We had about 60
participants from 37 schools. Talks included:
• Meiosis: The crucial stage in chromosomal physiology that makes genetic re-assortment possible
• Recent progress in molecular biology
• How vertebrates make their limbs; new methods of studying gene function
• The origins of allergy and autoimmunity
• New ways of studying tuberculosis
Once again the speakers found exactly the right level with sufficient novel material to interest teachers but not too far removed
from the curriculum. The lively discussion and written responses afterwards suggest the event was a great success.
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 where NIMR staff answer questions and put students
on the right track.
The University of the Third Age (U3A) at NIMR
In November 2011 NIMR hosted the ninth 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 Curses and
benefits of parasites at which Tony Holder and Mark Wilson spoke. Once again, we had a capacity crowd of nearly 150 enthusiasts.
30
PUBLIC OUTREACH
NIMRart
a
NIMRart is an experimental and innovative arts programme creating opportunities for artists to make and think about art
in a non-art context. A series of residencies set up in collaboration with the Arts Council and coupled with short visits, talks,
exhibitions and publications has produced an ever-changing platform for ideas and creativity. By actively encouraging artists to
engage with scientists and other staff at the Institute an increased consideration and comprehension of the work of both the
artists and scientists involved has been achieved.
NIMR also subscribes to the Arts Council Collection’s Long Loan Scheme, allowing opportunities to exhibit works by famous and
established artists in our common public areas. This complements the examples obtained from the NIMRart programme and our
own rolling exhibition displayed in the corridors and stairwells of images taken from current scientific projects.
Recent loans from the Arts Council Collection include (left) Eduardo Paolozzi, Caprese, bronze 1975, (centre) Liz Pannett, 14.1.79 - 8.80, 1980,
(right) Victor Newsome, Corner of a bathroom, 1975.
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
31
Immune Cell Biology
Immunoregulation
Molecular Immunology
Mycobacterial Research
Parasitology
Virology
32
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)
Mark Wilson
Douglas Young (Head of Division)
Luiz Pedro de Carvalho
Robert Wilkinson
Tony Holder (Head of Division)
Michael Blackman
Delmiro Fernandez-Reyes
Eva Frickel
Jean Langhorne
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. The latest figures report that 33 million people
globally are living with HIV/AIDS. There has also been much
excitement and controversy recently over the association
of gammaretroviruses, particularly XMRV, with prostate
cancer and chronic fatigue syndrome. Innovative therapeutics
for retroviral diseases 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 defining the specific functions of viral
and cellular proteins during the early post-entry stages of
the retroviral life cycle, particularly reverse transcription, viral
trafficking and nuclear entry. We are using mutant viruses that
cannot complete these steps to identify the cellular proteins
involved in these processes and characterise the important
interactions between viral components. One focus of our
studies is the p12 protein from gammaretroviruses that has
an unknown but essential function during the early stages of
viral replication. We have identified multiple functional domains
within this 84 amino acid protein.
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
Bishop KN, Verma M, Kim E-Y, Wolinsky SM and Malim MH (2008)
APOBEC3G inhibits elongation of HIV-1 reverse transcripts.
PLoS Pathogens 4:e1000231
Murine leukaemia virus infection of a D17 cell during anaphase. The viral p12
(red) and nucleocapsid (green) proteins associate with condensed cellular
chromatin (blue). Scale bars are 2 μm.
33
Parasitology
Mike Blackman
Proteases in host cell exit and invasion by the malaria parasite
Lab members: Christine Collins, Sujaan Das, Fiona Hackett, Robert Moon, Maria Penzo, Andrea Ruecker, Robert Stallmach,
Malcolm Strath, Catherine Suarez, Chrislaine Withers-Martinez, Christiaan van Ooij
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.
Immunofluorescence images showing differences in the sub-cellular
localisation of two cysteine protease-like molecules, SERA5 and SERA6,
around intracellular malaria merozoites.
Publications
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
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
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
See references 196 and 204 in the bibliography at the back for publications from this group in 2011.
34
Molecular model of the active site of PfSUB1, a subtilisinlike protease involved in malaria parasite release from red
cells. A peptide substrate is shown docked into the active
site cleft.
Mycobacterium tuberculosis systems and chemical biology
Lab members: Flora Dix, Gerald Larrouy-Maumus, Gareth Prosser, Sonia Pedreno Lopez, Joao Pedro S. Pisco
The recent dissemination of strains of Mycobacterium
tuberculosis (Mtb) resistant to multiple drugs constitutes
a major health threat. Mankind might soon face the
first epidemic of untreatable tuberculosis. Multidrug
resistance arises and is selected for because of the
complex growth pattern of Mtb, its extreme adaptation
to the host, and because existing therapies are flawed.
Current mycobacterial and anti-mycobacterial research
programmes have clearly not been sufficiently effective at
providing novel therapies that could reverse this trend in
a timely fashion. New approaches and technologies are
urgently needed to avoid a global health catastrophe.
Our recent work has demonstrated that biochemistry
and bio-analytical chemistry can lead to better
understanding of phenotypes and targets, and to
the rational design and study of new small molecule
therapeutics. We will continue to apply metabolomic
approaches in combination with classic biochemical
and microbiological methods to discover new reactions
and pathways in Mtb that are essential for its survival
and successful infection of human macrophages. In
addition, we will continue our efforts on rational design,
characterisation and testing of new antibiotic candidates
that might be used in the near future as alternative
treatment options for multidrug resistant tuberculosis.
Publications
de Carvalho LPS, Fischer SM, Marrero J, Nathan C, Ehrt S and Rhee KY (2010)
Metabolomics of Mycobacterium tuberculosis reveals compartmentalized cocatabolism of carbon substrates.
Chemistry & Biology 17:1122-1131
de Carvalho LPS, Zhao H, Dickinson CE, Arango NM, Lima CD, Fischer SM,
Ouerfelli O, Nathan C and Rhee KY (2010)
Activity-based metabolomic profiling of enzymatic function: identification of
Rv1248c as a mycobacterial 2-hydroxy-3-oxoadipate synthase.
Chemistry & Biology 17:323-332
de Carvalho LPS, Lin G, Jiang X and Nathan C (2009)
Nitazoxanide kills replicating and nonreplicating Mycobacterium tuberculosis and
evades resistance.
Journal of Medicinal Chemistry 52:5789-5792
Schematic representation of Activity-based Metabolomic Profiling. This method is
used for functional annotation of enzymes and pathway discovery in Mycobacterium
tuberculosis.
See reference 82 in the bibliography at the back for publication from this group in 2011.
35
Virology
John Doorbar
Human papillomavirus biology and disease
Lab members: Cinzia Borgogna, Clare Davy, Heather Griffin, Deborah Jackson, Pauline McIntosh, Emilio Pagliarulo, Yasmina Soneji,
Christina Untersperger, Qian Wang, Zhonglin Wu.
Human papillomaviruses (HPV) cause a range of significant
human diseases, including laryngeal papillomatosis, genital warts
and cervical neoplasia. Certain HPV types, known as highrisk types, cause cervical lesions that can progress to cancer.
Cervical cancer is a major female cancer worldwide, and is
almost always caused by HPV. These viruses can also cause
a significant proportion of head and neck tumours, and have
been implicated in the development of some non-melanoma
skin cancers. How the body controls infection is poorly
understood, and currently there is no antiviral therapy that can
reliably clear infection.
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.
Publications
Maglennon GA, McIntosh P and Doorbar J (2011)
Persistence of viral DNA in the epithelial basal layer
suggests a model for papillomavirus latency following
immune regression.
Virology 414:153-163
Nicolaides L, Davy C, Raj K, Kranjec C, Banks L and Doorbar
J (2011)
Stabilization of HPV16 E6 protein by PDZ proteins, and
potential implications for genome maintenance.
Virology 414:137-145
Khan J, Davy CE, McIntosh PB, Jackson DJ, Hinz S, Wang Q
and Doorbar J (2011)
The role of calpain in the formation of HPV16 E1^E4
amyloid fibers and reorganization of the keratin network.
Journal of Virology 85:9984–9997
See references 23, 114, 130, 158, 184 and 203 in the
bibliography at the back for publications from this group
in 2011.
36
During active infection the virus drives cell proliferation in the lower epithelial layers and virion
assembly towards the surface. The immune system can suppress viral gene expression, but cannot
always clear viral genomes from the basal layer, allowing the potential for reactivation.
Parasitology
Pathogenesis of childhood severe malaria
Lab members: Samuel Abah, Dimitrios Athanasakis, Florence Burte, Ianina Conte, 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 around one million deaths. Cerebral malaria
and severe malarial anaemia are both major complications
with significant mortality and morbidity in children under
five years of age in Sub-Saharan Africa. We are focused on
the study of severe malaria syndromes in children attending
tertiary hospitals in densely populated holoendemic malaria
areas. Malaria pathogenesis caused by the parasite’s asexual
erythrocytic cycle largely occurs in the vascular compartment.
We are interested in both the role of endothelial cell activation
and the plasma proteome changes that occur during distinct
severe malaria presentations.
We carried out a large case-control plasma proteome
study of childhood severe malaria, including discovery and
validation cohorts, at the main tertiary hospital of the city of
Ibadan, Nigeria under the auspices of the Childhood Malaria
Research Group. Our clinical proteomics study shows that
plasma proteome profiles accurately discriminate severe
childhood malaria from uncomplicated cases as well as from
ill and healthy malaria-negative children. The defined plasma
proteome patterns are composed of a combination of several
differentially-expressed proteins that act as biomarkers of the
severe malaria disease process.
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
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
Visualisation of community control (CC, non-parasitaemic) children
versus other study groups. Each sphere represents an individual
child proteome profile plotted in 3D space defined by the first three
principal components. CM = Cerebral Malaria (red); SMA = Severe
Malarial Anaemia (purple); UM = Uncomplicated Malaria (yellow); DC
= Disease Controls (blue); CC = Community Controls (green).
(a) CC vs. CM; (b) CC vs. SMA; (c) CC vs UM and (d) CC vs. DC.
37
Parasitology
Eva Frickel
A new perspective on anti-Toxoplasma gondii immunity
Lab members: Clemence Foltz, Anna Sanecka-Duin, Nadia Shabbir
The protozoan parasite Toxoplasma gondii infects a broad range of hosts, with a
seroprevalence in man of about 30%. Toxoplasma maintains the intricate balance
between survival and host defence. IFNγ, the main cytokine responsible for its
control, activates cells to restrict intracellular parasite replication or to kill intracellular
Toxoplasma. Cell-mediated immunity, driven mostly by CD8 T cells, confers resistance
to the chronic phase of the parasite. The outcome of an infection with Toxoplasma
is determined not only by the host’s immune status, but also by the genotype of the
infecting strain. Toxoplasma pathogenesis results from parasite burden, concurrent with
an over-stimulation of the immune system in the form of high levels of T helper cell
type 1 cytokines.
Our long-term goal is to identify novel pathways and mechanisms of host resistance
to Toxoplasma. We are studying how the parasitophorous vacuole (PV) is remodelled
within host cells to limit parasite replication, as well as how antigen processing
is facilitated for presentation to CD8 T cells. We are specifically interested in the
functional consequences of vacuolar recognition by IFNγ-upregulated p65 GTPases
(GBPs), a yet understudied class of regulatory proteins. Additionally, we are defining
the requirements for recognition and functional consequences of Toxoplasma antigenspecific CD8 T cells in the chronic phase of infection in the brain.
Publications
Winter SV, Niedelman W, Jensen KD, Rosowski EE, Julien L,
Spooner E, Caradonna K, Burleigh BA, Saeij JPJ, Ploegh HL
and Frickel E-M (2011)
Determinants of GBP recruitment to Toxoplasma gondii
vacuoles and the parasitic factors that control it.
PLoS ONE 6:e24434
IFNγ-induced wild-type mouse embryonic fibroblasts infected with type I, II or III Toxoplasma show that
mGBP1 (in green) is preferentially recruited to nonvirulent type II and III vacuoles. The right panel shows
the frequencies of mGBP1-positive vacuoles.
Kirak O, Frickel E-M, Grotenbreg GM, Suh H, Jaenisch R and
Ploegh HL (2010)
Transnuclear mice with predefined T cell receptor
specificities against Toxoplasma gondii obtained via SCNT.
Science 328:243-248
Frickel E-M, Sahoo N, Hopp J, Gubbels M-J, Craver MPJ, Knoll
LJ, Ploegh HL and Grotenbreg GM (2008)
Parasite stage-specific recognition of endogenous
Toxoplasma gondii-derived CD8+ T cell epitopes.
Journal of Infectious Diseases 198:1625-1633
(A) Optical imaging of luciferase-expressing Toxoplasma either without or in the presence of antigenspecific CD8 T cells (T57) and quantification of signal (B).
Parasitology
Tony Holder
Malaria parasites and red blood cells
Lab members: Barbara Clough, Suraya Diaz, Muni Grainger, Judith Green, Claire Hastings, Madhu Kadekoppala, Ellen Knuepfer,
Robert Moon, Sola Ogun, Kaveri Rangachari, Ridzuan Razak, Shigeharu Sato, 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 area of research, we have focused on the posttranslational modification of proteins associated with
the parasite’s actomyosin-based motor that drives the
invasion of erythrocytes. Some of these proteins are
positioned at the right place in the cell by attaching
them to membranes, for example by N-myristoylation
or S-palmitoylation, which adds a C14-fatty acid to the
N-terminal glycine or a C16-fatty acid to a cysteine
residue, respectively. These and other proteins are
also modified by phosphorylation, a process that may
provide a way to regulate the motor. Together with
colleagues in MRC Technology and elsewhere we are
developing inhibitors of the enzymes that carry out these
modifications, to investigate their role in parasite biology
and their potential for therapeutic development.
Expression of a green fluorescent protein-tagged component of the
malaria parasite motor complex within an infected red blood cell.
Publications
Ogun SA, Tewari R, Otto TD, Howell SA, Knuepfer E, Cunningham DA, Xu Z, Pain A and
Holder AA (2011)
Targeted disruption of py235ebp-1: Invasion of erythrocytes by Plasmodium yoelii using
an alternative Py235 erythrocyte binding protein.
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.
Journal of Biological Chemistry 285:36577-36585
Mapping the binding sites for protective monoclonal antibodies that bind to
merozoite surface protein 1: amino acid changes shown on the structure
abolish the binding of individual antibodies.
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
See references 18, 19, 62, 83, 153, 160, 197, 202 and 232 in the bibliography at the back for
publications from this group in 2011.
39
Immunoregulation
George Kassiotis
Antiviral immunity
Lab members: : Urszula Eksmond, Micol Ferro, Dorothy Ng, Mickaël Ploquin, Lara Sellés, Georgina Thorborn, 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). Almost all humans are chronically infected by one or
more persistent viruses. Our understanding of the pathogenic processes of viral
infection remains incomplete.
Production of antiviral antibodies relies on cognate interaction between B cells and
CD4+ T helper (Th) cells. However, in addition to providing help to B cells, Th cells
are assigned with a range of additional tasks, including direct antiviral activity, and may
also mediate immune pathology. Using a model for retrovirus-induced leukaemia, we
found that interaction with B cells dramatically inhibits the function of virus-specific
Th cells. Ultimately, provision of help to B cells protects hosts from Th cell-mediated
immune pathology, at the detriment of Th cell-mediated protective immunity. Our
findings suggest that B cell presentation of vaccine antigens could be manipulated to
direct the appropriate Th cell response.
Publications
Ploquin MJ-Y, Eksmond U and Kassiotis G (2011)
B cells and TCR avidity determine distinct functions of CD4+
T cells in retroviral infection.
Journal of Immunology 187:3321-3330
Pike R, Filby A, Ploquin MJ-Y, Eksmond U, Marques R, Antunes I,
Hasenkrug K and Kassiotis G (2009)
Race between retroviral spread and CD4+ T cell response
determines the outcome of acute Friend virus infection.
Journal of Virology 83 11211-11222
Antunes I, Tolaini M, Kissenpfennig A, Iwashiro M, Kuribayashi K,
Malissen B, Hasenkrug K and Kassiotis G (2008)
Retrovirus-specificity of regulatory T cells is neither present
nor required in preventing retrovirus-induced bone marrow
immune pathology.
Immunity 29:782-794
See reference 180 in the bibliography at the back for
publication from this group in 2011.
40
Virus-induced leukaemia according to lymphocyte composition. Mice bearing B cells progress to
leukaemia, whereas mice bearing T cells resist leukaemia. The presence of
B cells negates the protective effect of T cells.
Parasitology
Jean Langhorne
Immunity and immunopathogenesis in malaria infections
Lab members: Nikolai Belyaev, Thibaut Brugat, Deirdre Cunningham, Ana Paula Freitas do Rosario, William Jarra, Jennifer Lawton,
Wiebke Nahrendorf, Dorothy Ng, Sophie Roetynck, Philip Spence, Anne-Marit Sponaas, Christine Tshitenge, Irene Tumwine
The major focus of our group is to understand the immune
response to the malaria parasite and the role it plays in the
development of severe malaria disease. Part of this work
is the identification of the key components of innate and
adaptive immunity that control and eliminate parasites, and
regulate immunopathology. Another aspect of our work is
to identify parasite molecules on the surface of the infected
erythrocytes that may be responsible for antigenic variation
and for binding of the parasite to host endothelium, and in this
way contribute to pathology.
We have identified a multigene family, cir, in the rodent malaria,
Plasmodium chabaudi, that codes for antigens expressed on
infected erythrocytes. These proteins are recognised by the
immune system and many different CIRs can be expressed
during infection suggesting a role in antigenic variation. Since
variant antigens of the human pathogen Plasmodium falciparum
also adhere to host endothelium, and thus contribute to
pathology of severe malaria, we are investigating whether CIRs
have a similar function. P. chabaudi erythrocytes do sequester in
different organs, and we are now evaluating the role of CIR in
cytoadherence.
Publications
Spence PJ, Cunningham D, Jarra W, Lawton J, Langhorne J and Thompson J (2011)
Transformation of the rodent malaria parasite Plasmodium chabaudi.
Nature Protocols 6:553-61
Stephens R and Langhorne J (2010)
Effector memory Th1 CD4 T cells are maintained in a mouse model of chronic malaria.
Ndungu FM, Cadman ET, Coulcher J, Nduati E, Couper E, Macdonald DW, Ng D and Langhorne
J (2009)
Functional memory B cells and long-lived plasma cells are generated after a single Plasmodium
chabaudi infection in mice.
See references 3, 46, 49, 73, 121, 155, 216, 220 and 239 in the bibliography at the back for
Expression of CIR proteins in the cytoplasm and on the surface
of P. chabaudi-infected RBC. (Green, CIR; Red, MSP1; Blue, parasite
nucleus)
41
Immune Cell Biology
Steve Ley
Regulation of immune responses by NF-κB and MAP kinases
Lab members: Hakem Ben-Addi, Thorsten Gantke, Eva Gueckel, Emilie Jacque, Julia Janzen, Agnes Mambole, Olivia Mitchell,
Matoula Papoutsopoulou, Karine Roget, Huei-Ting Yang, Rachel Zillwood
The innate immune response of mammals is the first line of
defence to infection by pathogenic micro-organisms, such
as viruses, bacteria, fungi and parasites. This is triggered by
pathogen interaction with receptors on the surface and in the
cytoplasm of neutrophils and macrophages. These specialised
immune cells then produce proteins called chemokines and
cytokines, which attract other immune cells to the site of
infection, including T lymphocytes. Together, these stimulate
the adaptive immune response, which eliminates the invading
pathogen by generation of antibodies and cytotoxic cells.
We study a signalling pathway that regulates the production
of cytokines by macrophages in innate immune responses,
which is regulated by TPL-2, a protein kinase. Our current
experiments are investigating the mechanism by which TPL-2
is activated, and evaluating the potential of TPL-2 as an antiinflammatory drug target in autoimmune diseases.
NF-κB1 negatively regulates interferon-β induction and STAT1 activation in
macrophages.
Publications
Gantke, T., Sriskantharajah, S. and Ley, S. C. (2011)
IκB kinase regulation of the TPL-2 / ERK MAP kinase pathway.
Immunological Reviews (in press)
Yang H-T, Wang Y, Zhao X, Demissie E, Papoutsopoulou S,
Mambole A, O’Garra A, Tomczak MF, Erdman SE, Fox JG, Ley SC
and Horwitz BH (2011)
NF-κB1 inhibits TLR-induced IFN-β production in
macrophages through TPL-2—dependent ERK activation.
Sriskantharajah S, Belich MP, Papoutsopoulou S, Janzen J,
Tybulewicz V, Seddon B and Ley SC (2009)
Proteolysis of NF-κB1 p105 is essential for T cell antigen
receptor-induced proliferation.
Nature Immunology 10:38-47
See references 16, 75, 76, and 256 in the bibliography at the
back for publications from this group in 2011.
42
Regulation of TPL-2 activation by NF-κB1 p105 and IκB kinase.
Virology
John McCauley
Host specificity of influenza viruses
Lab members: Michael Bennett, Donald Benton, Nicole Friedrich, Saira Hussain, Ana Luisa Reis, Steve Wharton, Haixia Xiao
Influenza A viruses infect a variety of species, with humans,
horses and pigs representing the main mammalian hosts
of the virus in which infection is sustained. Avian species,
particularly water-fowl and gulls, harbour a wide variety of
influenza A viruses defined by their haemagglutinin (H1-16) and
neuraminidase (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
between a human and an animal influenza virus, as in the 1957
and 1968 pandemics.
We are investigating the determinants of host range restriction
of avian and swine influenza viruses that limit their ability to
infect and propagate in human cells. The interaction between a
virus particle and its receptor on a host cell is a key feature that
limits the host range of influenza viruses, but additional factors following entry of virus into the cell also control the outcome of
infection. Recent human H3N2 viruses show unexpected receptor-binding activities. The characteristics of this binding are being
examined in collaboration with colleagues in the Divisions of Physical Biochemistry and Molecular Structure, and with Professor
Ten Feizi, Imperial College London.
Publications
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?
Journal of Virology 84:6769-6781
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
In culture, seasonal H3N2 influenza viruses readily mutate their neuraminidase glycoprotein to be
able to bind turkey erythrocytes (left plaque). On the right is a plaque of an unchanged virus.
43
Immunoregulation
Anne O’Garra FRS, AAAS Fellow, EMBO member, FMedSci
Regulation of the immune response in infectious disease
Lab members: Chloe Bloom, Jillian Christensen, John Ewbank, Leona Gabrysova, Christine Graham, Ashleigh Howes, Finlay McNab,
Jonathan Pitt, Paul Redford, Fotini Rozakeas, Vangelis Stavropoulos, Charlotte Whicher, Xuemei Wu
The immune system is effective in eradicating pathogens via many mechanisms,
including soluble mediators called cytokines. Immune cells can produce different
cytokines to control infection, but can also 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 produced
by many cell types. We will build on our past results, using biochemical methods
and genome-wide, high-throughput approaches and bioinformatics, to elucidate the
molecular mechanisms for induction of IL-10 production and function in different
immune cell types.
We continue to examine mechanisms of IL-10 production and function in chronic
MTb infection. Leading on from our findings in human TB, where we identified
a robust blood transcriptional interferon-inducible signature, we will investigate
potential factors in TB pathogenesis, such as Type I IFNs and Type I IFN-inducible
genes, using molecular methods and improved mouse models of TB, to identify
immune mechanisms of protection or pathogenesis important for disease control in
tuberculosis and other bacterial infections.
Publications
Berry MPR, 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
Saraiva M and O’Garra A (2010)
The regulation of IL-10 production by immune cells.
Nature Reviews Immunology 10:170-81
See references 73, 74, 128, 147, 148, 149, 159, 189, 246 and
256 in the bibliography at the back for publications from this
group in 2011.
44
Mechanisms of protection and pathogenesis. From experimental models to human disease: an iterative
process.
Immune Cell Biology
Benedict Seddon
Regulation of T cell homeostasis by antigen receptor signals and cytokines
Lab members: Thea Hogan, Daniel Marshall, Ina Schim van der Loeff, Ana Silva, Charles Sinclair, Sim Tung, Louise Webb
T lymphocytes are immune cells that play a central role in regulating immune
responses. There are several different T cell types, all with different functions. Having
the right number and composition of T cells is therefore essential for a normal
immune system. The production and maintenance of these cells is strictly controlled
by mechanisms regulating cell survival and proliferation. 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.
TCR and IL-7 signalling are both essential for regulating survival and homeostatic
proliferation of T cells. Whether there is any interaction between these signals is
controversial. We have recently uncovered a novel mechanism by which TCR and IL-7
signalling interact to control T cell homeostasis. We found that IL-7R expression by
mature T cells critically depends on TCR signals received during their development
in the thymus. This TCR signal dependent mechanism ensures that the best T cells
generated during positive selection have a survival advantage that preferentially
maintains them in the peripheral repertoire.
Induction of a tetracycline-inducible Zap70 transgene restores thymocyte
development in Zap70-deficient mice.
Controlling Zap70
expression in vivo reveals
how TCR signalling tunes
IL-7R expression during
development and maturation
of newly generated CD4 T
cell in the thymus.
A single dose of inducer results in a pulse of Zap70
protein expression in thymocytes that is sufficient to
start development of CD4 T cells.
Publications
Charles Sinclair, Manoj Saini, Ina Schim van der Loeff, Shimon
Sakaguchi3 and Benedict Seddon (2011)
Positive selection links T cell antigen receptor and IL-7 survival
signaling in the homeostatic control of naive T cells.
Science Signaling 4:ra77
Pearson C, Silva A, Saini M and Seddon B (2011)
IL-7 determines homeostatic fitness of T cells by distinct
mechanisms at different signalling thresholds in vivo.
European Journal of Immunology Epub ahead of print
Sinclair CGM, Saini M and Seddon BP (2008)
The role of ZAP-70 in the CD4/CD8 lineage decision.
Immunology 125:28
See references 175, 205, 207 and 220 in the bibliography
at the back for publications from this group in 2011.
45
Gitta Stockinger EMBO member, FMedSci
Development, maintenance and regulation of peripheral T cell compartments and immune
responses
Lab members: Helena Ahlfors, Judit Biro, Paola diMeglio, Joao Duarte, Keiji Hirota, Ying Li, Heike Müller, Matteo Villa,
Christoph Wilhelm
Our current focus is on the development and function
of innate and adaptive IL-17 producing T cells (Th17
cells), and modulation of effector functions by exogenous
and endogenous environmental factors. Th17 cells are
important for defence against fungal pathogens and
many extracellular bacteria, and are causally involved
in autoimmune diseases such as rheumatoid arthritis,
myocarditis, multiple sclerosis and psoriasis.
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 (AhR) in the immune system, trying to unravel
its impact on the function of different immune cells in the
defence against pathogens.
Publications
Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ,
Ahlfors H, Wilhelm C, Tolaini M, Menzel U, Garefalaki A,
Potocnik AJ and Stockinger B (2011)
Fate mapping of IL-17-producing T cells in inflammatory
responses.
Wilhelm C, Hirota K, Stieglitz B, Van Snick J, Tolaini M, Lahl K,
Sparwasser T, Helmby H and Stockinger B (2011)
An IL-9 fate reporter demonstrates the induction of an
innate IL-9 response in lung inflammation.
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
See references 98, 99, 125, 221 and 249 in the bibliography
46
Skin sample from a wildtype B6 mouse (left) or an AhR-deficient B6 mouse (right) stained with Oil
Red indicates substantial accumulation of neutral lipids in skin in the absence of AhR.
Virology
Jonathan Stoye
Retrovirus-host interactions
Lab members: Vicky Felton, Seti Grambas, Wilson Li, Sadayuki Okura, Martha Sanz-Ramos, 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 TRIM5a 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. To help study this interaction we
have isolated a number of viral mutants that escape from restriction
by the different factors and used them to delineate the region of
capsid recognised by Fv1 and TRIM5α. These studies implicate the
whole surface of the viral core in factor binding.
Publications
Hilditch L, Matadeen R, Goldstone DC, Rosenthal PB, Taylor
IA and Stoye JP (2011)
Ordered assembly of murine leukemia virus capsid protein
on lipid nanotubes directs specific binding by the restriction
factor, Fv1.
Proceedings of the National Academy of Sciences of the United
States of America 108:5771–5776
Ohkura S, Goldstone DC, Yap MW, Holden-Dye K, Taylor IA
and Stoye JP (2011)
Novel escape mutants suggest an extensive TRIM5α
binding site spanning the entire outer surface of the murine
leukemia virus capsid protein.
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
See references 82, 86, 97, 148, 161,186 and 238 in the
bibliography at the back for publications from this group in
2011.
Surface structure of the MLV CA protein showing positions of amino
acid changes associated with escape from rhesus monkey TRIM5α.
Collaboration with Ian Taylor (Molecular Structure)
47
Immune Cell Biology
Pavel Tolar
Activation of immune receptors
Lab members: Antonio Casal, Jason Lee, Elizabeth Natkanski
Antibodies are critical for human immunity and their
induction has been instrumental for the success of many
vaccines. However, some of the most dangerous pathogens
of today’s world, such as HIV, influenza or malaria, evade
antibody responses, both natural and vaccine-induced. A
better understanding of the mechanisms by which these
pathogens trigger antibody responses will be necessary for the
development of more effective vaccines.
We are interested in activation of B cells that detect pathogens
by their B cell antigen receptors (BCRs). The BCR is a protein
complex containing the membrane form of antibody and two
signalling components; we are characterising the structure of this
complex to gain insights into the mechanisms by which antigen
binding activates the BCR. We are also developing new ways
to visualise the activation and endocytosis of BCR molecules in
living B cells.
Publications
Tolar P (2011)
Inside the microcluster: antigen receptor signalling
viewed with molecular imaging tools.
Immunology 133:271-277
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.
48
Schematic structure of the BCR. The membrane proximal domains of the antibody pair with signalling
components, Igα, Igβ. HSQC spectrum and NMR structure of the critical Cμ4 domain are shown.
Immune Cell Biology
Victor Tybulewicz EMBO member, FMedSci
Signal transduction in B and T cells
Lab members: : Jochen Ackermann, Tiago Brazao, Natalia Dinischiotu, Harald Hartweger, Robert Köchl, Eva Lana Elola,
Karen McGee, Alexander Saveliev, Edina Schweighoffer, Amy Slender, Lesley Vanes, Sheona Watson-Scales
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. Currently we are studying signals that control B cell
homeostasis.
Mouse models of Down syndrome
Trisomy of human chromosome 21 (Hsa21) occurs in around 1 in 750 live births
and the resulting gene dosage imbalance gives rise to Down syndrome, the most
common form of mental retardation. In collaboration with Prof E. Fisher (UCL), we
are interested in identifying genes on this chromosome, which, when present in three
copies, cause the many different phenotypes of Down syndrome. We have created
a novel mouse strain carrying a freely segregating copy of Hsa21, which displays
many of the features of Down syndrome, including learning difficulties and cardiac
abnormalities. We are mapping the location of dosage-sensitive genes that cause
Down syndrome phenotypes using chromosome engineering techniques.
In the absence of Rac GTPases
B cell development is blocked
in the red pulp of the spleen
with the cells unable to enter
the white pulp.
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 116:5536-5547
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, RodriguezManzaneque JC, Martino-Echarri E, Aurrand-Lions M, Sheer D, Dagna-Bricarelli F, Nizetic D, McCabe CJ, Turnell AS,
Kermorgant S, Imhof BA, Adams R, Fisher EMC, Tybulewicz VLJ, Hart IR and Hodivala-Dilke KM (2010)
Tumour angiogenesis is reduced in the Tc1 mouse model of Down’s syndrome.
Nature 465:813-7
See references 37, 46, 56, 69, 120, 201, 208 and 243 in the bibliography at the back for publications from this group in 2011.
Chromosome engineering to create duplications and deletions
of megabase regions of mouse chromosomes to model Down
syndrome.
49
Immunoregulation
Andreas Wack
Immune response to influenza
Lab members: Stefania Crotta, Sophia Davidson, Gregory Ellis, Annita Gjoka
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 that 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 coinfections, as evidenced by epidemiological and microbiological data from
seasonal and pandemic influenza waves. Both for single infections and coinfections, it is unclear which factors tip the balance between pathology
and/or death, versus successful clearance of the pathogen without long
term damage.
Our work aims to identify virus and host determinants of disease
outcome. We focus on early events after infection, in particular on the
interface between infected epithelium and the innate immune system. We
use primary airway epithelial cells to determine which recognition systems
are used to detect viral infection and how this information is transmitted
to the immune system. The role of interferon-driven feedback systems
in infection is studied in this system and in vivo, to understand the role
of interferons in anti-influenza immune responses. We also investigate
the roles of natural killer cells and granulocytes in influenza infection and
co-infection. These studies will allow us to link early events to subsequent
immune-mediated pathology or protection.
Schematic illustration
of the primary murine
airway epithelial cell (AEC)
culture system.
Publications
Wack, A., Openshaw, P., O’Garra, A. (2011)
Contribution of cytokines to pathology and protection in
virus infection.
Current Opinion in Virology 1: 184-195
Seubert A, Calabro S, Santini L, Galli B, Genovese A, Valentini
S, Aprea S, Colaprico A, D’Oro U, Giuliani MM, Pallaoro M,
Pizza M, O’Hagan DT, Wack A, Rappuoli R and De Gregorio
E (2011)
Adjuvanticity of the oil-in-water emulsion MF59 is
independent of Nlrp3 inflammasome but requires the
adaptor protein MyD88.
Proceedings of the National Academy of Sciences of the United
States of America 108:11169-11174
Calabro S, Tortoli M, Baudner BC, Pacitto A, Cortese M,
O’Hagan DT, De Gregorio E, Seubert A and Wack A (2011)
Vaccine adjuvants alum and MF59 induce rapid recruitment
of neutrophils and monocytes that participate in antigen
transport to draining lymph nodes.
Vaccine 29:1812-1823
See references 28, 200 and 246 in the bibliography at the back
for publications from this group in 2011.
50
At the indicated time after air
exposure, mouse AEC were fixed,
permeabilised and stained for
the tight junction protein Z0-1,
for β tubulin IV to detect ciliated
cells, and for CCSP and the mucin
MUC5A to detect Clara cells and
Goblet cells respectively.
Robert Wilkinson FRCP
Understanding and intervening in HIV-associated tuberculosis
Lab members: Anna Coussens, Adrian Martineau, Katalin Wilkinson
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 plan further studies to validate this and extend
to the study of HIV associated tuberculosis. We have determined that
vitamin D deficiency is highly prevalent amongst black Africans in Cape
Town, and associates with susceptibility to active tuberculosis both in
the presence and absence of HIV infection. In a randomised controlled
trial, administration of four doses of 2.5 mg vitamin D3 reduced time to
sputum culture conversion in participants with the tt genotype of the TaqI
VDR polymorphism.
Publications
Martineau AR, Nhamoyebonde S, Oni T, Rangaka MX, Marais S,
Bangani N, Tsekela R, Bashe L, de Azevedo V, Caldwell J, Venton TR,
Timms PM, Wilkinson KA and Wilkinson RJ (2011)
Reciprocal seasonal variation in vitamin D status and
tuberculosis notifications in Cape Town, South Africa.
Proceedings of the National Academy of Sciences 108:19013-7
Martineau AR, Timms PM, Bothamley GH, Hanifa Y, Islam K, Claxton
AP, Packe GE, Moore-Gillon JC, Darmalingam M, Davidson RN,
Milburn HJ, Baker LV, Barker RD, Woodward NJ, Venton TR, Barnes
KE, Mullett CJ, Coussens AK, Rutterford CM, Mein CA, Davies GR,
Wilkinson RJ, Nikolayevskyy V, Drobniewski FA, Eldridge SM and
Griffiths CJ (2011)
High-dose vitamin D3 during intensive-phase antimicrobial
treatment of pulmonary tuberculosis: a double-blind randomised
controlled trial.
Lancet 377:242-50
Serum 25-hydroxyvitamin D (25[OH]D) concentration by HIV and TB status. Bars
represent means. Dashed line represents limit of detection (10 nmol/L)
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 51, 59, 109, 128, 132, 135, 136, 142, 143, 147, 163,
177 and 224 in the bibliography at the back for publications from this
group in 2011.
51
Mark Wilson
Regulation of Th2 cells during allergic inflammation and anti-helminth immunity
Lab members: : Stephanie Coomes, Stephanie Czieso, Nicholas Mathioudakis, Isobel Okoye, Victoria Pelly
More than a quarter of the world’s population are infected by one of
four parasitic helminths (filarial worms, schistosomes, whipworms and
roundworms) making them the most common infectious agents of
humans in developing countries. Efficient expulsion of parasitic helminths
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 hyper-active Th2 responses.
These aims are being investigated using in vivo helminth infection and
allergy models. Using next-generation sequencing and gene manipulation
techniques the roles 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 programmes, 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 interventions for allergic disease.
Goblet cell hyperplasia in allergic lung.
Publications
Wilson MS, Cheever AW, White SD, Thompson RW and Wynn TA (2011)
IL-10 blocks the development of resistance to re-infection with Schistosoma mansoni.
Wilson MS, Ramalingam TR, Rivollier A, Shenderov K, Mentink-Kane MM, Madala SK, Cheever AW,
Artis D, Kelsall BL and Wynn TA (2011)
Colitis and intestinal inflammation in IL10-/- Mice Results From IL-13Rα2-mediated
attenuation of IL-13 activity.
Gastroenterology 140:254-264
Okoye IS and Wilson MS (2011)
CD4+ T helper 2 cells - microbial triggers, differentiation requirements and effector functions.
52
T. muris associated intestinal inflammation.
Immune Cell Biology
Douglas Young FMedSci
Victor Tybulewicz
Understanding and intervening in HIV-associated tuberculosis
Lab members: Kristine Arnvig, John Brennan, Roger Buxton, Stephen Coade, Teresa Cortes, Joanna Dillury, Deborah Hunt,
Christina Kahramanoglou, Damien Portevin, Angela Rodgers, Graham Rose, Dorothee Schuessler, 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.
We are using high-throughput sequencing technologies to
define the genetic diversity of M. tuberculosis and to study gene
regulation at transcriptional and post-transcriptional levels. We
have discovered an extensive repertoire of non-coding RNAs
and are exploring their function, in part through participation
in SysteMTb, a European consortium using a systems biology
approach to characterise the fundamental biology of TB. Our
work demonstrates that genetic variation amongst clinical
isolates of M. tuberculosis results in phenotypic differences in their
interaction with the host innate immune system. We propose that
differences in innate immune recognition drive the epidemiology
of this complex disease.
Publications
Arnvig KB, Comas I, Thomson NR, Boshoff HI, Dillury J,
Croucher NJ, Rose G, Perkins TT, Parkhill J, Dougan G, Young
DB. 2011.
Sequence-based analysis uncovers an abundance of noncoding RNA in the total transcriptome of Mycobacterium
tuberculosis.
PLoS Pathogens In press
Portevin D, Gagneux S, Comas I and Young D (2011)
Human macrophage responses to clinical isolates from the
Mycobacterium tuberculosis complex discriminate between
ancient and modern lineages.
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
sRNA mapping by RNA sequencing. The
sRNA is shown in green; the red trace shows
divergent expression of an adjacent phage
integrase gene (top, transcription start sites;
bottom, total transcripts).
Immunohistochemical staining provides the first
demonstration of NK cells within mature TB
granulomatous lesions.
See references 9, 33, 118, 126, 181 and 217 in the bibliography
53
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), Nick Cattle, Karen Cross,Vicki Gregory, Chandrika
Halai, Lynn Whittaker, Zheng Xiang
The WHO Collaborating Centre for Influenza is one of six Collaborating Centres that along with 136 WHO National Influenza
Centres (NICs) form the WHO Global Influenza Surveillance and Response System (GISRS) to track influenza viruses as
they circulate around the world. Viruses are characterised antigenically (genetically) in the laboratories and their resistance to
antiviral drugs is determined. Results of these analyses from each collaborating centre and the national centres are used to
develop recommendations for the most appropriate strains for use in seasonal influenza vaccines and provide advice to national
authorities on the global and regional influenza circulation.
Research has focused on recent H3N2 viruses that show alterations in their ability to bind to sialic acid receptors. Many H3N2
virus strains agglutinate red blood cells through their neuraminidase glycoprotein, which has marked implications for the antigenic
analysis of these viruses. All our studies are carried out with the NICs from around the world, with other WHO Collaborating
Centres, the UK Health Protection Agency, the National Institute for Biological Standards and Control, and members of the
European Community Network of Reference Laboratories for human influenza, and the Wellcome Trust Sanger Institute.
A model of the structure of the H1 haemagglutinin glycoprotein illustrating the location of amino acid substitutions seen in three emerging genetic groups
of the A(H1N1)pdm2009 influenza virus.
Publications
Sullivan K, Kloess J, Qian C, Bell D, Hay A, Lin YP and Gu Y (2011)
High throughput virus plaque quantitation using a flatbed scanner.
Journal of Virological Methods Epub ahead of print
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?
See references 12, 52, 154, 191 and 210 in the bibliography at the back for publications from this group in 2011.
54
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)
Tom Carter
Ed Hulme
John Offer
Peter Rosenthal
Martin Webb
55
STRUCTURAL BIOLOGY
Tom Carter
Secretory organelle formation, trafficking and exocytosis
Lab members: Emma Cookson, Jennifer Frampton, Nicola Hellen, Nikolai Kiskin, Laura Knipe
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 molecules into the
external environment (e.g. hormones, transmitters, morphogens). The correct delivery
of such molecules to the cell surface or extracellular space involves the secretory
pathway. We study the secretory pathway 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 (ECs) and
the Weibel-Palade body (WPB) as our model system.
P-selectin is stored in WPBs and delivered to the EC surface following WPB
exocytosis where it functions to facilitate leukocyte attachment and rolling. FRAP
analysis of P-selectin in individual WPBs revealed that its enrichment within the
organelle arises from its immobilisation within the WPB membrane through an
interaction between its extracellular domain and the paracrystalline assembly of
Proregion-VWF tubules within the WPB lumen. Dissolution of Proregion-VWF
tubules during WPB exocytosis releases P-selectin allowing its diffusive delivery into
the plasma membrane.
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 are rod-shaped
secretory organelles containing the
haemostatic protein Von Willebrand
factor (VWF). Multimeric VWF forms
flexible helical tubules that pack tightly
into a ridged paracrystalline matrix.
56
Single granule FRAP studies show that P-selectin is immobile
within the membrane of WPBs. Immobilisation requires
the P-selectin extracellular domain and the paracrystalline
arrangement of VWF tubules.
Babich V, Meli A, Knipe L, Dempster JE, Skehel P,
Hannah MJ and Carter T (2008)
Selective release of molecules from Weibel Palade
bodies during a lingering kiss.
Blood 111:5282-5290
STRUCTURAL BIOLOGY
Molecular Structure
Paul Driscoll
Structural and functional analysis of signalling proteins
Lab members: Diego Esposito, Acely Garza-Garcia, Lily Nematollahi, Timothy Ragan, Masooma Rasheed, Christine Richter,
Gemma Wildsmith
Nuclear magnetic resonance (NMR) spectroscopy provides a valuable
means to probe the three-dimensional structure, dynamic characteristics
and binding properties of biological molecules, large and small. Our group
employs state-of-the-art methods in NMR to investigate 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 model, the
regulation of phospholipase C isozymes, the role of β2-glycoprotein 1
in antiphospholipid syndrome and the interaction of vascular endothelial
growth factor (VEGF) with its receptors.
Recently we have applied a combination of heteronuclear NMR,
microcalorimetry and small-angle X-ray scattering (SAXS) to dissect
the overall 3D structure and impact of phosphotyrosine peptide ligandbinding on the multi-domain ‘specific array’ component of the second
messenger enzyme phospholipase C γ1 (PLCγ1). With these data we
have developed a model of the mechanism for the enzyme’s activation.
In other work we have established a method to analyse small molecule
metabolites in Drosophila fruitfly samples by NMR. We used this approach
to contribute accurate measurements of larval hemolymph amino acid
concentrations in a study of brain sparing under conditions of nutrient
withdrawal.
Quantification by 1H NMR line shape analysis of methyl
group-containing amino acids in a sample of Drosophila larva
hemolymph.
Publications
Cheng LY, Bailey AP, Leevers SJ, Ragan TJ, Driscoll PC and Gould AP (2011)
Anaplastic lymphoma kinase spares organ growth during nutrient restriction in
Drosophila.
Cell 146:435-47
Best-fit superposition of independent models for the PLCγ1 ‘specific array’
construct based upon rigid-body simulated annealing of the component domain
structures to fit both experimentally derived NMR restraints and SAXS data.
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
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
See references 20, 35, 53 and 178 in the bibliography at the back for publications from
this group in 2011.
57
STRUCTURAL BIOLOGY
Molecular Structure
Steve Gamblin FRS, EMBO member, FMedSci
Structural biology of influenza, energy metabolism and cancer
Lab members: Patrick Collins, Peter Coombs, Valeria De Marco, Chun Jing, Neil Justin, Matthew Sanders, John Skehel,
Elizabeth Underwood, Sebastien Vachieri, Bing Xiao, Alex Xiong,
We study the structure
and function of molecules
involved in disease processes
such as influenza, diabetes
and cancer. We use X-ray
crystallography and NMR
to determine the three
dimensional structures
and dynamics of these
molecules. In combination
with other biophysical,
biochemical and biological
techniques, the data help
us elucidate the function of
the proteins of interest and
provide information that may be useful for the development of
therapeutic approaches.
We are interested in the structure and function of the two
major surface glycoproteins of influenza virus (hemagglutinin
and neuraminidase). This work has been conducted as a longstanding collaboration with John Skehel and now also involves
John McCauley’s lab in Virology as well as essential contacts
with NIMR’s WIC. As part of this effort, working with Antonio
Lanzavecchia and his colleagues, we have found that an antibody
called FI6 can combat all influenza A viruses that commonly
cause disease in humans and in animals. The finding represents a
potential turning point in the development of flu treatments and
in time may help to pave the way for a universal flu vaccine.
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.
Ribbons representation of the crystal structure of the crossreactive FI6 antibody binding to an HA trimer.
Publications
Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, Jing C, Walker PA, Eccleston JF, Haire LF, Saiu P, Howell SA, Aasland R, Martin SR,
Carling D and Gamblin SJ (2011)
Structure of mammalian AMPK and its regulation by ADP.
Nature 472:230-233
Corti D,Voss J, Gamblin SJ, Codoni G, Macagno A, Jarrossay D,Vachieri SG, Pinna D, Minola A,Vanzetta F, Silacci C, Fernandez-Rodriguez BM, Agatic G,
Bianchi S, Giacchetto-Sasselli I, Calder L, Sallusto F, Collins P, Haire LF,Temperton N, Langedijk JPM, Skehel JJ and Lanzavecchia A (2011)
A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins.
Science 333:850-856
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
58
STRUCTURAL BIOLOGY
Richard Goldstein
Modelling the evolution of molecular components, systems, and behaviours
Lab members: Martin Godany, Kyriakos Kentzoglanakis, Bhavin Khatri, Asif Tamuri, Grant Thiltgen
All biology is the result of evolution. In order to
understand life, we need to investigate the evolutionary
process that determines its form and function. Because
living things encode this evolutionary heritage, studies of
their properties can provide insights into the evolutionary
process. Following the evolutionary path of specific
components can provide important information about
the characteristics of living organisms. Combining insights
from physical chemistry, condensed matter physics, artificial
intelligence, complexity theory, and mathematical biology,
we are developing computational and theoretical methods
to explore these areas.
We are investigating protein evolution, exploring what
the evolutionary record can tell us about the effect of
mutations. We also use more theoretical models to better
understand how the evolution of proteins determined
their observed properties. We study the evolution of
viruses such as influenza in order to better understand the
way they act now, how they might change in the future,
and how they are able to shift from one host to another.
We model the evolution of chemotaxis, the process that
allows bacteria to find nutrients, providing insight into the
evolution of biochemical networks. We are also studying
how horizontal gene transfer affects the evolution of
bacteria, especially where the interests of the genes and
the organisms conflict, and where the transferred genes
encode social behaviour.
Two representations of Butyrylcholinesterase (PDB 2WSL), colour-coded by
evolutionary rate.
Publications
Soyer OS and Goldstein RA (2011)
Evolution of response dynamics underlying bacterial chemotaxis.
BMC Evolutionary Biology 11:240
Goldstein RA (2011)
The evolution and evolutionary consequences of marginal
thermostability in proteins.
Proteins 79:1396-1407
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
See references 52, 65, 66, 81, 214 and 227 in the bibliography
Adaptation of the haemagglutinin protein (H1) to humans (“Humanicity”)
following the host shift from birds to mammals in approximately 1900. The
degree of adaptiveness in H1 isolated from other hosts is shown.
59
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 to underpin
programs of selective drug development.
M1 muscarinic acetylcholine receptors (M1 mAChRs)
regulate the activity of many output neurons in the
forebrain. They are important mediators of cue detection
and memory. Drugs that selectively activate M1 mAChRs
are targeted at the cognitive defects in Alzheimer’s disease
and schizophrenia. We can isolate stable ligand complexes
of M1 mAChRs, combining pharmacological and protein
engineering methods. We are focusing on a highly-selective
peptide toxin, MT7, which binds to M1 with very high
affinity, working towards an atomic resolution structure by
X-ray crystallography. Such structures provide a firm basis
for the resurgent area of rational drug design.
Publications
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
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.
Kaye RG, Saldanha JW, Lu Z-L and Hulme EC (2011)
Helix 8 of the M1 muscarinic acetylcholine receptor: scanning mutagenesis delineates a G
protein recognition site.
Some thermostabilising mutations (yellow) in the M1
muscarinic receptor.
60
STRUCTURAL BIOLOGY
Justin Molloy
Single molecule studies of cell motility and cell signalling
Lab members: Suleman Bawumia, Rachel Farrow, Andrew Howe, Stephen Martin, Gregory Mashanov, Paul Moody, Martyn Stopps
The principal goal of the group 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
(see below). We are interested in diverse aspects of human
health, including how the malarial parasite gains entry into
human blood cells, how acetylcholine receptors transduce
signals in the heart, and how the two strands of DNA are
separated and copied.
Recently, we have used Atomic Force Microscopy (AFM)
to visualise ataxin-3 fibrils, which are the causative agent of
spinocerebellar ataxia. Thermal energy causes the fibrils to
bend and analysis of the different shapes that they adopt gives
an estimate of their mechanical rigidity. We found the fibrils
are unexpectedly flexible; consistent with their structure
being composed of “beads on a string”. Using a simple in vitro
assay consisting of just actin, myosin and ATP, we found that
actin filaments become aligned and form ordered domains.
We are now using a combination of mathematical modelling
and experiment to understand this simple system and test
Publications
Masino L, Nicastro G, De Simone A, Calder L, Molloy J and
Pastore A (2011)
The Josephin domain determines the morphological and
mechanical properties of ataxin-3 fibrils.
Biophysical Journal 100:2033-42
Mashanov GI, Nobles M, Harmer SC, Molloy JE and Tinker
A (2010)
Direct observation of individual KCNQ1 potassium
channels reveals their distinctive diffusive behaviour.
Padgett, M, Molloy, JE, McGloin, D, (editors)
Optical Tweezers: Methods and Applications
Chapman & Hall, 2009
Subunit counting by TIRFM. Coloured dots represent GFP tag intensity. (A) Potassium channels
(4xGFP) (B) Adenosine Receptors (2xGFP).
See references 62, 68, 152 and 156 in the bibliography at the
back for publications from this group in 2011.
61
STRUCTURAL BIOLOGY
STRUCTURAL BIOLOGY
Molecular Structure
John Offer
Synthetic protein laboratory: acyl transfer for chemical biology and synthesis
Lab members: Lotta Holm, Geoffrey Knight, Caroline Morris, George Papageorgiou
One of the most important recent developments in chemistry has been the
emergence of biologically compatible ligation reactions. These reactions can be used
to synthesize small proteins and introduce non-natural modifications to label proteins.
Chemical ligation is usually dependent on the presence of cysteine at the ligation
junction. However by simple modification of the terminus of a peptide we can modify
it into a mimic of cysteine. This expands the flexibility of the synthesis so that we can
cut and paste proteins and reassemble them from their component peptides.
The focus of the group is to expand the utility of ligation reactions and to look
for possible existing biological roles for these elegant chemical reactions. 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 applying chemical ligation to the synthesis of chemically defined peptideoligosaccharide vaccines and to activity based proteomics as well as the total
synthesis of homogenous post-translationally modified proteins and self-assembling
systems.
Publications
Holm L, Ackland GL, Edwards MR, Breckenridge RA, Sim RB and
Offer J (2011)
Chemical labelling of active serum thioester proteins for
quantification.
Immunobiology Epub ahead of print
Offer J (2010)
Native chemical ligation with Nα acyl transfer auxiliaries.
Biopolymers 94:530-541
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
See references 102 and 248 in the bibliography at the back for
62
Scheme 1 Peptide ligation with an
N-acylsulfonamide component. Pep 1 and 2
correspond to unprotected peptides.
Procedure for labelling, pull-down and
quantification of thioester containing proteins
from blood.
STRUCTURAL BIOLOGY
Molecular Structure
Annalisa Pastore
Understanding the molecular bases of neurodegeneration
Lab members: Salvatore Adinolfi, Cesira de Chiara, Serena Faggiano, Clara Iannuzzi, John McCormick, Laura Masino, Raj Menon, Kris
Pauwels, Domenico Sanfelice, Robert Yan
We are interested in a molecular understanding of
neurodegenerative diseases. To achieve this, we study the structure,
fold stability, and function of proteins involved in diseases using
different but complementary biophysical, biochemical and systems
biology approaches. We mainly focus on neurodegenerative
processes caused by misfolding and/or mitochondrial dysfunction.
Over the last year we made substantial advances in elucidating
the primary function of frataxin, the protein associated with
Friedreich’s ataxia. We conclusively showed that frataxin binds
to NFS1/IscS, the desulphurase central to iron-sulphur cluster
formation. As a result, frataxin enhances the affinity of NFS1/IscS
with the ISU/IscU scaffold protein and regulates rates of cluster
formation. By identifying the regions that determine fibrillogenesis
of ataxin-3, the protein responsible for Machado-Joseph disease,
we have also shown that normal function and aberrant protein
aggregation, as observed in several neurodegenerative diseases,
are competing pathways. This result is of primary importance
for understanding misfolding diseases and suggests that specific
therapeutic interventions can only be achieved by studying normal
function and pathology in parallel.
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
Masino L, Nicastro G, Calder L, Vendruscolo M and Pastore
A (2011)
Functional interactions as a survival strategy against
abnormal aggregation.
FASEB Journal 25:45-54
See references 25, 26, 60, 105, 134, 138, 140, 141, 168, 173,
174, 198, 209, 231 and 254 in the bibliography at the back for
Ternary complex of CyaY/IscS/IscU obtained by combining SAXS and NMR information: in blue and
cyan, the IscS protomers; in red and orange-red, IscU; and in gold and yellow, CyaY.
63
STRUCTURAL BIOLOGY
Molecular Structure
Andres Ramos
Molecular recognition in post-transcriptional regulation
Lab members: Adela Candel, Katherine Collins, Belinda Faust, Christopher Gallagher, David Hollingworth, Nessim Kichik,
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 RBM38-p21 system has connected
the RNA recognition properties of the RBM38 protein with
its capability to counteract the miRNA binding activity on
a subset of p53 targets. RBM38 is expressed under cellular
stress and binds selected miRNAs in the proximity of the
miRNA seed sequence, hindering miRNA activity. We show
that the RRM domain of RBM38 selects U/G rich sequences
and explain how this domain discriminates between two
pools of p53 targets creating a further level of downstream
regulation. Our data on the RBM38 system suggest a conduit
to control the activity of a subset of p53 targets associated
with cell replication and human cancers.
Interaction between the activator FBP and the repressor FIR in c-myc
transcriptional regulation.
Publications
Léveillé N, Elkon R, Davalos V, Manoharan V, Hollingworth D, Vrielink JO, le Sage C, Melo CA, Horlings
HM, Wesseling J, Ule J, Esteller M, Ramos A and Agami R (2011)
Selective inhibition of microRNA accessibility by RBM38 is required for p53 activity.
Cukier CD, Hollingworth D, Martin SR, Kelly G, Díaz-Moreno I and Ramos A (2010)
Molecular basis of FIR-mediated c-myc transcriptional control.
Nature Structural & Molecular Biology 17:1058-64
Trabucchi M, Briata P, Garcia-Mayoral M, Haase AD, Filipowicz W, Ramos A, Gherzi R and Rosenfeld
MG (2009)
The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs.
Nature 459:1010-1014
See references 24, 45, and 124 in the bibliography at the back for publications from this group
in 2011.
64
Role of RBM38 protein in p53 response to cellular stress.
STRUCTURAL BIOLOGY
Molecular Structure
Katrin Rittinger
Structural biology of signalling networks that regulate innate and adaptive immunity
Lab members: Nicholas Brown, Manuela Hess, Marios Koliopoulos, Aylin Morris-Davies, Rohini Rana, Kovilen Sawmynaden,
Ben Stieglitz, Edmond Wong
Pattern recognition receptors are key components of the innate
immune system that sense microbial and viral infections and
initiate a pro-inflammatory response. The signalling pathways
activated by these receptors need to be tightly controlled as
misregulation can lead to chronic inflammation and autoimmune
disease. Innate immune responses also trigger adaptive immunity
and the two systems are linked through complex signalling
networks.
Our research is focused on the structural characterisation of
protein complexes that regulate innate immunity. In particular,
we are interested in understanding how members of the NLR
(NOD-like receptor) family of intracellular PRRs recognise a
target and relay the signal to elicit a specific cellular response.
The post-translational modification of a protein with ubiquitin
chains is often used as a regulatory signal in immunity. The type
of ubiquitin chain attached to a target protein determines the
physiological outcome of the modification, with K48-linked chains
targeting a protein for degradation while K63 and M1-linked
(“linear”) chains play an important role in signalling. We aim to
elucidate, on a structural and functional level, the mechanism
by which a specific type of ubiquitin chain is synthesised
and attached to a target by a catalytic cascade involving the
sequential action of three enzymes.
Domain structure of LUBAC, an E3 ligase consisting of three subunits
that catalyses the synthesis of linear ubiquitin chains. Indicated are
domains that mediate complex formation and recognition of ubiquitin.
Publications
Ikeda F, Deribe YL, Skånland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk SJL, Goswami P, Nagy V, Terzic J, Tokunaga
F, Androulidaki A, Nakagawa T, Pasparakis M, Iwai K, Sundberg JP, Schaefer L, Rittinger K, Macek B and Dikic I (2011)
SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis.
Nature 471:637-41
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
In vitro synthesis of linear ubiquitin chains
by the HOIL-1L and HOIP subunits of
the LUBAC complex.
Rapley J, Tybulewicz VLJ and Rittinger K (2008)
Crucial structural role for the PH and C1 domains of the Vav1 exchange factor.
EMBO Reports 9:655-661
65
STRUCTURAL BIOLOGY
Peter Rosenthal
Cryomicroscopy of proteins, viruses and cells
Lab members: Lesley Calder, Tim Grant, Saira Hussain, Rishi Matadeen, Kasim Sader, Michael Shannon, 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 in virus
infection. We apply electron cryomicroscopy and image
analysis to study the structure of purified protein complexes
in frozen solution, and electron cryotomography to directly
image cells in a frozen-hydrated state providing high resolution
images of cell architecture as well as structural information
on protein complexes in vivo. We are also working to improve
experimental methods for high resolution imaging of proteins
and to develop new computational procedures for image
analysis.
We have performed high resolution studies of influenza virus
ultrastructure by cryomicroscopy that have shown us both the
structure of the virus envelope and the internal architecture
of the virus. We are extending these studies to directly image
how viruses enter cells by membrane fusion and how new
particles are assembled and released by budding through the
host membrane. As part of our studies of organelle formation
and transformation, we build structural models for WeibelPalade bodies, which are storage granules for the adhesive
blood glycoprotein von Willebrand factor, and study their
structural changes during exocytosis.
Cryoimage of influenza virus.
Publications
Berriman JA, Li S, Hewlett LJ, Wasilewski S, Kiskin FN, Carter T, Hannah MJ and Rosenthal PB (2009)
Structural organization of Weibel-Palade bodies revealed by cryo-EM of vitrified endothelial cells.
Calder LJ, Wasilewski S, Berriman JA and Rosenthal PB (2010)
Structural organization of a filamentous influenza A virus.
Hilditch L, Matadeen R, Goldstone DC, Rosenthal PB, Taylor IA and Stoye JP (2011)
Ordered assembly of murine leukemia virus capsid protein on lipid nanotubes directs specific
binding by the restriction factor, Fv1.
Proceedings of the National Academy of Sciences of the United States of America 108:5771–5776
66
Periphery of a frozen-hydrated endothelial cell.
STRUCTURAL BIOLOGY
Molecular Structure
Steve Smerdon EMBO member
Structural biology of phosphorylation-dependent signalling in the cell cycle and DNA
Lab members: Julie Clapperton, Oliver de Peyer, Mohamed Ismail, Otto Kyrieleis, Richard Li, Jan Lloyd, Simon Pennell, Lasse Stach, Grace Yu
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 phosphoindependent FHA interactions and a novel, intra-molecular binding
mechanism in the control of core metabolic processes that likely
have significance for bacterial virulence. Finally, we have resolved
long-standing questions about FHA domain specificity using X-ray
crystallography and molecular dynamics modelling methods.
Publications
Pennell S, Westcott S, Ortiz-Lombardía M, Patel D, Li J, Nott TJ, Mohammed D, Buxton RS, Yaffe MB, Verma
C and Smerdon SJ (2010)
Structural and functional analysis of phosphothreonine-dependent FHA domain interactions.
Structure 18:1587-95
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.
See references 4, 44, 126, 137 and 217 in the bibliography at the back for publications from this group in
2011.
The origin of FHA domain specificity. A pocket on the FHA surface
interacts with the extra methyl group of phosphothreonine, stabilising
a network of h-bonds (dashes) that are crucial for tight binding.
67
STRUCTURAL BIOLOGY
Molecular Sructure
Ian Taylor
Macromolecular assemblies
Lab members: Laurence Arnold, Neil Ball, Valerie Ennis-Adeniran, Joe Hedden, Dominic Pollard, Laura Robertson, David Schwefel.
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 proteins
that mediate retroviral restriction in host cells. Recently, we have
determined the structure of the HIV-1 restriction factor SAMHD1.
This study has revealed the molecular details of the mechanism of
SAMHD1 catalysis and provides an explanation for how this protein
can inhibit HIV-1 infection of myeloid-derived cells.
SAMHD1 structure A ribbons representation of the SAMHD1 dimer
with the major lobe (Blue), minor lobe (Grey) and C-terminal region
(Red). Guanosine is shown in the nucleotide-binding site at the dimer
interface.
Publications
Goldstone DC, Ennis-Adeniran V, Hedden JJ, Groom HC, Rice GI, Christodoulou E, Walker PA, Kelly
G, Haire LF, Yap MW, de Carvalho LP, Stoye JP, Crow YJ, Taylor IA and Webb M (2011)
HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase.
Nature 480:379-82
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.
Pancevac C, Goldstone DC, Ramos A and Taylor IA (2010)
Structure of the Rna15 RRM-RNA complex reveals the molecular basis of GU specificity in
transcriptional 3’-end processing factors.
Nucleic Acids Research 38:3119-3132
this group in 2011.
68
SAMHD1 active site. The active site contains zinc and
phosphate together with histidine, aspartic acid and arginine
residues that coordinate the ions.
STRUCTURAL BIOLOGY
Willie Taylor
Protein structure analysis and design
Lab members: Michael Doran, 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 defines
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.
With the rapid increase in the volume of sequence data,
we have re-examined residue contacts predicted from
correlated positions in a multiple sequence alignment.
In collaboration with colleagues in computer science at
UCL, we have developed new methods to extract these
contacts and applied them to protein structure prediction.
The contacts are often sparse and uncertain but, to some
extent, these limitations in the data can be overcome by
grouping the contacts by secondary structure elements and
enumerating the possible packing arrangements of these
elements in a combinatorial manner. Strong interactions
appear frequently but inconsistent interactions are downweighted and missing interactions up-weighted. The
resulting improved consistency in the predicted interactions
has allowed the method to be successfully applied to
proteins up to 200 residues in length, which is larger than
any structure previously predicted using sequence data
alone.
Publications
Sadowski MI, Maksimiak K and Taylor WR (2011)
Direct correlation analysis improves fold recognition.
Computational Biology and Chemistry 35:323-32
Taylor WR and Sadowski MI
Structural Constraints on the Covariance Matrix Derived from
Multiple Aligned Protein Sequences
PLoS ONE 6:e28265
Taylor WR, Jones DT and Sadowski MI
Protein topology from predicted residue contacts
Protein Science epub ahead of print
Residue contacts are shown in a ‘dot-plot’ with observed contacts in
green and predicted contacts in red. These are sufficient to identify the
fold of the protein (PDB code: 2gj8A).
See references 48, 100, 101, 112, 113, 167, 194, 229 and 230
in the bibliography at the back for publications from this group
in 2011.
69
STRUCTURAL BIOLOGY
Martin Webb
The molecular mechanisms of motor proteins
Lab members: Claudia Arbore, Lori Callum, Liisa Chisty, Colin Davis, Simone Kunzelmann, Gordon Reid, Lesley Southerden
Movement of proteins along DNA is an essential feature of cells: it
occurs during DNA replication and repair, for example. Helicases are
enzymes responsible for separating the two strands of DNA, making
them available for processing by other enzymes. We are interested
in both the mechanism and control of such processes. 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 addition such reagentless biosensors provide a way to
assay a wide range of enzymatic activities.
Our work on helicases is focussed on developing a complete
system in which the helicase interacts with other proteins as well as
moving through DNA. We are investigating the replication of certain
plasmids that contain antibiotic resistance genes and that are readily
transferred between bacteria. Such replicating plasmids contain a
specific double-stranded origin of replication, and are bound with a
replication initiation factor (RepD), 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.
Publications
Saikrishnan K, Powell B, Cook NJ, Webb MR and Wigley DB
(2009)
Mechanistic basis of 5’-3’ translocation in SF1B helicases.
Cell 137:849-59
Slatter AF, Thomas CD and Webb MR (2009)
PcrA helicase tightly couples ATP hydrolysis to unwinding
double-stranded DNA, modulated by the initiator protein for
plasmid replication, RepD.
Biochemistry 48:6326-6334
Nucleotide exchange on Ras at different
concentrations of the exchange factor, SOS.
This was measured using a GDP biosensor,
rhodamine-ParM : the cartoon illustrates
changes in structure producing the fluorescence
response.
70
Kinetics of nicking of supercoiled plasmid
by RepD measured by quench-flow. AFM of
plasmid before and after nicking and when
partially unwound by the helicase, PcrA.
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 17, 68, 82, 119, 235, 258 and 259 in the
bibliography at the back for publications from this group in
2011.
Neurosciences
Developmental Neurobiology
David Wilkinson (Head of Division)
Siew-Lan Ang
Molecular Neurobiology
François Guillemot (Head of Division)
Vassilis Pachnis
Iris Salecker
Neurophysiology
Troy Margrie (Acting Head of Division)
Physiology and Metabolism
Alex Gould (Head of Division)
71
NEUROSCIENCES
Siew-Lan Ang
Neuronal subtype specification in the midbrain and hypothalamus
Lab members: Neal Anthwal, Lan Chen, Suzanne Claxton, Martin Levesque, Wei Lin, Emmanouil Metzakopian, Anna Truckenbrodt
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 the
hallmark of 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, proliferation and differentiation of mDA, arcuate
proopiomelanocortin and neuropeptide Y neurons. Our studies
employ a combination of embryological, genetic, molecular, genomic
and proteomic approaches, including genetic fate mapping studies,
phenotyping null and conditional mutant mice, brain explants, timelapse imaging, chromatin immunoprecipitation, biochemical and
transcriptome analyses. These studies provide important insights
into how embryonic gene expression leads to mature neuronal
phenotypes. We are also interested in the role of transcription
factors in maintaining neurotransmitter phenotypes and function in
adult neurons.
In vitro differentiated midbrain dopaminergic progenitors.
Dopaminergic progenitors expressing Lmx1a and Nestin that were
generated by in vitro differentiation of mouse embryonic stem cells.
Publications
Mavromatakis YE, Lin W, Metzakopian E, Ferri ALM, Yan CH, Sasaki H, Whisett J and Ang S-L
(2011)
Foxa1 and Foxa2 positively and negatively regulate Shh signalling to specify ventral midbrain
progenitor identity.
Mechanisms of Development 128:90-103
Pelling 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
Yan CH, Levesque M, Claxton S, Johnson RL and Ang S-L (2011)
Lmx1a and Lmx1b function cooperatively to regulate proliferation, specification, and
differentiation of midbrain dopaminergic progenitors.
Journal of Neuroscience 31:12413-12425
See references 144, 176 ,and 255 in the bibliography at the back for publications from this
group in 2011.
72
Adult midbrain tyrosine hydroxylase positive neurons.
Genetic fate mapping studies identify floor plate descendants in tyrosine
hydroxylase positive (TH+) midbrain nuclei including the ventral tegmental area
(VTA), substantia nigra pars compacta (SN) and interfascicular nucleus (IFN).
NEUROSCIENCES
Physiology and Metabolism
Alex Gould EMBO member
Regulation of growth and metabolism
Lab members: Andrew Bailey, Louise Cheng, Einat Cinnamon, 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.
Currently, we are investigating how dietary nutrients regulate the embryonic and
foetal growth of each body organ. Much of our research in this area uses the fruit
fly Drosophila, a model organism that shares many genes with mammals. We recently
showed that neural stem cells in the Drosophila brain need to be kick started by
amino acids early on in development but, thereafter, they can grow and divide without
dietary nutrients. This reflects a switch in neural stem cells from Insulin-like Receptor
to Anaplastic Lymphoma Kinase signalling. Anaplastic Lymphoma Kinase lies at the
heart of a molecular network ensuring that the growth of the developing brain is
spared over that of the body when nutrients become limiting.
The Drosophila CNS escapes growth shutdown during nutrient restriction.
Publications
Cheng LY, Bailey AP, Leevers SJ, Ragan TJ, Driscoll PC and Gould AP (2011)
Anaplastic lymphoma kinase spares organ growth during nutrient restriction in Drosophila.
Cell 146:435-47
Neural stem cell clones growing in the developing
Drosophila CNS. A representative clone, marked
with GFP (green) and containing a single neural
stem cell (large red cell) is outlined.
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
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
See references 35, 38, and 213 in the bibliography at the back for publications from this group in 2011.
73
NEUROSCIENCES
François Guillemot FMedSci, EMBO member
Genomic and functional analysis of neurogenesis
Lab members: Jimena Andersen, Roberta Azzarelli, Lan Chen, Daniela Dreschel, Patricia Garcez, Sebastien Gillotin, Ben Martynoga,
Cristina Minieri, Emilie Pacary, Noelia Urban, Debbie Van Den Berg, Benny Yang
Neural stem cells in the developing brain produce a vast array
of neurons that reach specific positions 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 in the embryonic and adult mouse brain,
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 proneural transcription factor
Ascl1, well known for its role of promoting neurogenesis in the
embryo, also controls the division of neural stem cells during
development and in the adult brain. We are now studying the
molecular pathways that regulate the transcription and protein
stability of Ascl1 during adult neurogenesis, as disruption of
these pathways in the ageing brain might be responsible for
the reduction of neurogenesis and the accompanying cognitive
decline observed in old animals.
FRET analysis of differentiating cortical neurons in culture showing
that down-regulation of the proneural factor targets Rnd2 and Rnd3
stimulates RhoA signalling.
Publications
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
Pacary E, Heng J, Azzarelli R, Riou P, Castro D, Lebel-Potter M, Parras C, Bell DM, Ridley AJ, Parsons
M and Guillemot F (2011)
Proneural transcription factors regulate different steps of cortical neuron migration through
Rnd-mediated inhibition of RhoA signaling.
Neuron 69:1069-84
Castro DS, Martynoga B, Parras C, Ramesh V, Pacary E, Johnston C, Drechsel D, Lebel-Potter M,
Garcia LG, Hunt C, Dolle D, Bithell A, Ettwiller L, Buckley N and Guillemot F (2011)
A novel function of the proneural factor Ascl1 in progenitor proliferation identified by
genome-wide characterization of its targets.
Genes & Development 25:930-945
See references 5, 6, 31, 50, 67, 87, 90, 133, 164, 165, 176, 215, 223, 251 and 253 in the
bibliography at the back for publications from this group in 2011.
74
Circular representation of the neural stem cell genome showing that
clusters of binding sites for transcription factors regulating neural stem cell
self-renewal associate with the expression of target genes.
NEUROSCIENCES
Neurophysiology
Troy Margrie
Sensory processing in single cells, circuits and behaviour
Lab members: Ed Bracey, Alex Brown, Ninja Grewe, Bruno Pichler, Ede Rancz, Mateo Velez-Fort
The benefit of detecting and recognising information in the
external world has been a key driver of the evolution of
the central nervous system. The neuronal basis of sensory
representation in our brains therefore underpins how we
make sense of the world around us, our ability to solve
problems and remember past experiences. Our lab is focused
on understanding the fundamental cellular and network-based
mechanisms that underlie these processes.
The goal of our lab is to understand how the brain uses the
activity of individual neurons and collections of neurons to
encode sensory stimuli. To achieve this we use a top-down,
multidisciplinary approach that allows us to explore this key
issue from the systems to the cellular level. Specifically, we are
investigating several questions: (i) To what extent is sensory
representation distributed across primary and secondary or
multimodal brain areas? (ii) What, if any, is the relationship
between local neuronal connectivity and sensory function?
(iii) How is sensory information encoded and integrated by
individual cells and synapses?
Publications
Rancz EA, Franks KM, Schwarz MK, Pichler B, Schaefer AT and Margrie TW (2011)
Transfection via whole-cell recording in vivo: bridging single-cell physiology, genetics and
connectomics.
Nature Neuroscience 14:527-532
Angelo K, Margrie TW (2011)
Population diversity and function of hyperpolarization-activated current in olfactory bulb mitral
cells.
Scientific Reports 1: 50
Chadderton P, Agapiou JP, McAlpine D, Margrie TW (2009)
The synaptic representation of sound source location in auditory cortex.
Classical neuronal staining approaches (such as Golgi staining, left) have
revealed the brain’s complexity. The new method (right) allows scientists
to record the function of a single cell (red) and identify its presynaptic
connectivity (white).
75
NEUROSCIENCES
Neurophysiology
Vassilis Pachnis EMBO member, FMedSci
Development of the nervous system
Lab members: Werend Boesmans, Myrto Denaxa, Tiffany Heanue, Melanie Kalaitzidou, Chryssa Konstantinidou, Catia Laranjeira,
Reena Lasrado, Rita Lopes, Guillerme Neves, Valentina Sasseli
The nervous system mediates the interaction of organisms
with their environment, contributes to the maintenance of
internal homeostasis and is the anatomical substrate of cognitive
activity. Normal function of the nervous system depends
on the generation, at the right time and place, of integrated
cellular networks made up of a large number of diverse
neurons. Understanding the mechanisms that control the
generation of distinct neuronal subtypes and their migration to
the appropriate location is critical for comprehending normal
neuronal development and for treating neuronal deficiencies.
Our studies explore the mechanisms that control the
development of the enteric nervous system in the gut:
how enteric neurons and their progenitors migrate during
embryogenesis and how they differentiate to form complex
networks that regulate gut motility and secretions. We also
study the mechanisms that control neuronal differentiation
in the forebrain. We have identified signals that mediate
cellular interactions, molecules that underlie the functional
interconnection of neurons and transcription factors underlying
neuronal cell fate decisions. Our studies provide novel insight
into the development and function of the nervous system in
normal and disease conditions.
Publications
Laranjeira C, Sandgren K, Kessaris N, Richardson W, Potocnik A, Vanden Berghe P and Pachnis V
(2011)
Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury.
The Journal of Clinical Investigation 121:3412-3424
Heanue TA, Pachnis V (2011)
Prospective identification and isolation of enteric nervous system progenitors using Sox2
Stem Cells 29:128-40
Kioussis D, Pachnis V (2009)
Immune and nervous systems: more than just a superficial similarity?
Immunity 31:705-10
this group in 2011.
Confocal microscope image of a myenteric ganglion from the gut of
adult mice. Preparations of the myenteric plexus were immunostained
for neuronal and glial markers indicating the diversity of enteric ganglia.
76
MRC National
National Institute
Institute for
for Medical
Medical Research
Research
MRC
NEUROSCIENCES
Iris Salecker
Visual circuit assembly in Drosophila
Lab members: Holger Apitz, Dafni Hadjieconomou, Emily Richardson, Benjamin Richier, Nana Shimosako, Katarina Timofeev
The ability of animals to perform the many tasks of their
everyday lives relies on the perfect functioning of their
nervous systems. These consist of a large number of
neuronal and glial subtypes with strikingly diverse shapes.
Our understanding of the molecular mechanisms that
control the formation of these cell types and coordinate
their assembly into functional neural networks during
development is still limited. To address this issue, we use the
visual system of the fruit fly Drosophila as a genetic model,
because it enables us to study the stepwise development of
a complex neural circuit with single cell resolution.
In particular, we are investigating the mechanisms that
control (i) the development of specific neuronal and glial
cell subtypes in higher visual information processing areas,
(ii) the targeting of one colour-sensitive photoreceptor axon
subtype to its temporary and final synaptic layers, and (iii)
layer-specific targeting of dendritic and axonal branches of
partner neurons. To facilitate the imaging of the underlying
interdependent cellular interactions, we recently generated
a multicolour cell-labelling approach for Drosophila, called
Flybow. By studying the mechanisms underlying normal
brain development, we hope in the long term to contribute
to the understanding of neurological disorders that may be
linked to early connectivity defects.
In the larval optic lobe of Drosophila, progenitors (blue) in the outer and
inner proliferation centres (OPC, IPC; green) generate neurons in the
medulla and lobula complex (green).
Publications
Hadjieconomou D, Rotkopf S, Alexandre C, Bell DM, Dickson BJ and Salecker I (2011)
Flybow: genetic multicolor cell labeling for neural circuit analysis in Drosophila melanogaster.
Nature Methods 8:260-268
Hadjieconomou D, Timofeev K and Salecker I (2010)
A step-by-step guide to visual circuit assembly in Drosophila.
Current Opinion in Neurobiology 21:76-84
In the adult visual system, R1-R8 photoreceptor neurons (blue)
extend axons from the retina into the lamina and medulla. Neurons
in the target area were labelled with the Flybow approach.
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
77
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, Masanori Takahashi, Javier Terriente, Qiling Xu
During the 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 precise patterns to form and be maintained, it is
essential that sharp borders form at the interface of the distinct
regions.
Our studies aim to elucidate molecular mechanisms of boundary
formation and neuronal cell differentiation, and the links between
these processes in the formation of the segmented pattern
of the vertebrate hindbrain. We are using a combination of in
vitro assays, in vivo functional studies and computer modelling to
understand how signalling through Eph receptors and ephrins
leads to the formation of sharp borders. In related work, we
study how hindbrain boundaries, together with signalling from
specific neurons, organise discrete zones of progenitor cells and
neuronal differentiation. Finally, we are dissecting the mechanisms
of action of an intracellular network that regulates 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 in vivo imaging of cell
migration and lineage.
In vitro cell segregation assay. Cell lines expressing ephrinB1 (green)
or EphB2 (unlabelled) are mixed and plated in cell culture. They
segregate to form sharp borders.
Publications
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 ephrinexpressing cells.
Science 326:1502-9
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.
Gonzalez-Quevedo R, Lee Y, Poss KD and Wilkinson DG (2010)
Neuronal regulation of the spatial patterning of neurogenesis.
Developmental Cell 18:136-147
78
Neurons (green label), segments (two labelled in blue), and segment
boundaries (red) in the zebrafish hindbrain.
Systems Biology
Jim Smith (Head of Division)
Greg Elgar
Mike Gilchrist
Developmental Biology
James Briscoe (Joint Head of Division)
Jean-Paul Vincent (Joint Head of Division)
Malcolm Logan
Tim Mohun
Elke Ober
Lyle Zimmerman
Stem Cell Biology and Developmental Genetics
Robin Lovell-Badge (Head of Division)
Paul Burgoyne
Rita Cha
Peter Thorpe
James Turner
79
GENETICS AND DEVELOPMENT
James Briscoe EMBO member
Pattern formation in the vertebrate nervous system
Lab members: Fahad Al Saud, Natascha Bushati, Rachel Chung, Michael Cohen, Katrina Griffin, John Jacob, Anna Kicheva, Eva Kutejova, Steven Moore, Noriaki Sasai
We study how the central nervous system (CNS) is formed in embryos. Despite
its complexity, the CNS is assembled in a remarkably reliable and accurate manner.
This precision is necessary for the wiring of nerves into the functional neural circuits
that give the CNS its function. Our research focuses on the spinal cord, which is the
part of the CNS that contains the nerves that allow us to sense our environment
and respond to it by moving muscles. Our studies contribute to understanding
the development of the spinal cord as well as shed light on diseased and damaged
nervous systems. We hope this will help in the development of therapies for these
conditions.
Specifically, we are interested in the cellular and molecular mechanisms responsible
for 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 and reconstruct the regulatory network that
controls the growth and development of the ventral neural tube.
A reporter of Shh signalling (top panels; green in bottom panels) provides a
readout of intracellular signalling in vivo.
A gradient of Shh (green) controls the expression of genes
(red, orange, blue) in neural progenitors.
Publications
Cruz C, Ribes V, Kutejova E, Cayuso J, Lawson V, Norris D, Stevens J, Davey M, Blight K, Bangs F, Mynett A, Hirst E, Chung R, Balaskas N, Brody SL,
Marti E and Briscoe J (2010)
Foxj1 regulates floor plate cilia architecture and modifies the response of cells to sonic hedgehog signalling.
Development 137:4271-4282
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.
80
See references 13, 27, 34, 58, 85 and 185 in the bibliography at
the back for publications from this group in 2011.
Paul Burgoyne FMedSci
The Y chromosome and infertility
Lab members: Fanny Decarpentrie, Shantha Mahadevaiah, Obah Ojarikre, Áine Rattigan, Nadege Vernet
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.
We have been using sex chromosomally variant mouse models in combination with the
selective addition of Y genes by transgenesis to elucidate the role of specific Y genes in male
and female fertility. Using this approach we, together with the Turner group, have identified
important quality control functions during spermatogenesis for the Y-encoded genes Zfy1
and Zfy2. These genes encode zinc finger transcription factors that proved to be necessary
for the apoptotic elimination of sex chromosomally aberrant pachytene spermatocytes in
response to a failure of Y chromosome silencing, and during the first meiotic metaphase in
response to the presence of an unpaired X chromosome.
Sxra encompasses18 genes from the mouse Y chromosome, including the testis
determinant Sry. XO carrier males (XSxraO) are sterile because spermatocytes
are eliminated by apoptosis during the first meiotic division.
With the reduced Y gene complement of Sxrb plus Eif2s3y
(spermatogonial proliferation factor), or Sry and Eif2s3y, there is no
apoptotic response; this is reinstated by the addition of Zfy2.
Publications
Vernet N, Mahadevaiah SK, Ojarikre OA, Longepied G, Prosser HM, Bradley A, Mitchell MJ and Burgoyne PS (2011)
The Y-encoded gene Zfy2 acts to remove cells with unpaired chromosomes at the first meiotic metaphase in male mice.
Current Biology 21:787-793
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, Bourc’his D, de Rooij DG, Bestor TH, Turner JMA and Burgoyne PS (2008)
Extensive meiotic asynapsis in mice antagonises meiotic silencing of unsynapsed chromatin and consequently disrupts meiotic sex chromosome inactivation.
Journal of Cell Biology 182:263-76
81
Rita Cha
Regulation of eukaryotic chromosome metabolism
Lab members: Jesus Carballo and Ana Penedos
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
kinases. These evolutionarily conserved signal transduction proteins
play a key role in many fundamental DNA/chromosomal processes
such as genome duplication, recombination, and checkpoint
regulation. Inactivation of ATR/ATM in humans 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 ATR/ATM function. 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. Our research focuses on
elucidating the molecular mechanism(s) by which the loss of Mec1/
Tel1 function leads to these defects.
Cytological visualisation of Hop1, a Mec1/Tel1 target. Hop1 (green) is phosphorylated by Mec1/Tel1
following the initiation of meiotic recombination (red) at specific loci along the chromosome axis. Blue
(DNA).
Publications
Hashash N, Johnson AL and Cha RS (2010)
Regulation of fragile sites expression in budding yeast by
MEC1, RRM3 and hydroxyurea.
Carballo JA, Johnson AL, Sedgwick SG and Cha RS (2008)
Phosphorylation of the axial element protein Hop1 by
Mec1/Tel1 ensures meiotic interhomolog recombination.
Cell 132:758-70
Carballo JA and Cha RS (2007)
Meiotic roles of Mec1, a budding yeast homolog of
mammalian ATR/ATM.
Chromosome Research 15:539-50
ChIP-CHIP analysis of Rec114 reveals the impact of Mec1/Tel1 phosphorylation on its chromosome
localisation. Green (WT Rec114); red (non-phosphorylatable Rec114); blue (phospho-mimetic Rec114).
Black (meiotic double strand break hotspots).
82
MRC
MRCNational
NationalInstitute
InstituteforforMedical
MedicalResearch
Research
Systems Biology
Greg Elgar
Regulation of early vertebrate development
Lab members: Dilrini DeSilva, Joseph Grice, Stefan Pauls, Paul Piccinelli, Hannah Stanforth
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.
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
Woolfe A and Elgar G (2007)
Comparative genomics using Fugu reveals insights
into regulatory subfunctionalization.
Genome Biology 8:R53
See references 84 and 171 in the bibliography at the back
for publications from this group in 2011.
Comparative sequence analysis identifies conserved regulatory signatures in genomic DNA that drive
specific patterns of hindbrain expression in developing zebrafish (a-m) and lamprey (n-q) embryos.
83
Systems Biology
Mike Gilchrist
Gene regulatory networks in early development
Lab members: Brook Cooper, Nick Owens
Embryonic 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 through complex gene regulatory networks. Our aim is
to elucidate these networks using molecular and computational tools that
enable a systematic and large-scale approach.
We are focusing on the period in the development of the early embryo
when control passes from maternal gene products, 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. Using the
Xenopus model system, we have taken a high resolution time series of whole
embryo mRNA samples through this transition period and analysed these
for gene expression levels using high-throughput Illumina RNA-seq technology. In order to understand our data better, we have
been taking a close look at intrinsic variation in gene activity, by studying biological replicates. This has enabled us to build a robust
method for detecting signatures of gene activation, and this is a first step in the process of reconstructing the gene regulatory
networks involved in early development.
Publications
Parain K, Mazurier N, Bronchain O, Borday C, Cabochette P,
Chesneau A, Colozza G, El Yakoubi W, Hamdache J, Morgane
L, Gilchrist MJ, Pollet N, Perron M. (2011)
A large scale screen for neural stem cell markers in
Xenopus retina
Developmental Neurobiology (in press)
Simeoni I, Gilchrist MJ, Garrett N, Armisen J and Gurdon JB
(2011)
Widespread transcription in an amphibian oocyte relates to
its reprogramming activity on transplanted somatic nuclei.
Stem Cells and Development Epub ahead of print
Visualisation methods are important for assessing reproducibility, and here we are comparing gene
expression levels between two biological replicates. The quasi-volcano plot (right) gives a much better
sense of the variation in the data than the traditional scatter plot (left).
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
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Intrinsic variation can make real effects hard to see. Compare the gene expression variation between
two biological replicate controls (left) and between a control and an effective gene knock-down (right).
Malcolm Logan
Understanding vertebrate limb development
Lab members: Sorrel Bickley, Natalie Bufferfield, Martin Carkett, Veronique Duboc, Anna Kucharska, Sue Miller, Satoko Nishimoto
Limb defects are the second most common congenital
abnormality present in human live births and diseases affecting
the musculoskeletal system are a significant clinical problem in
the older population. The goal of our work is to understand
how the limbs normally form during embryogenesis, the genesis
of limb abnormalities and disease in humans and to provide
potential therapeutic approaches to block degeneration or trigger
regeneration of the musculoskeletal system.
At early stages of embryonic development, the forelimb and
hindlimb buds are a similarly shaped mass of cells. During
subsequent steps of development the progenitors are
transformed into a complex of interconnected bones, muscles
and tendons. These limb tissues are exquisitely sculpted to
become the correct size and shape and must also form the
appropriate interconnections so that each muscle group attaches
to the skeletal scaffold via the correct tendon. How this complex
is elaborated is poorly understood.
We are using animal models to understand the mechanisms that
control limb bud formation and the subsequent construction of
the individual limb elements.
Publications
Abu-Daya A, Nishimoto S, Fairclough L, Mohun TJ, Logan MPO and Zimmerman LB (2011)
The secreted integrin ligand nephronectin is necessary for forelimb formation in Xenopus tropicalis.
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.
Section of a mouse forepaw approximately 3/4 the way through
the gestation period. Forming digits (red) and muscles (green)
have been identified using antibodies that recognise tissue-specific
proteins combined with fluorescent labels. Blood cells (yellow), that
autofluoresce, are also visible.
85
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, 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 sex determination, cells of
the early gonad have an additional choice to make: to become cells typical of
testes or ovaries. In mammals this usually depends on the presence or absence of
the Y chromosome (males are XY, females XX); more precisely to a single gene
on the Y, termed Sry. This encodes a transcription factor with an HMG box type
of DNA binding domain, also present in proteins encoded by the Sox gene family.
We use many techniques to explore how SRY and other factors act to initiate
and maintain testis or ovary differentiation, with mice as our main experimental
model. Because male birds lack Sry, evolutionary comparisons use chick
embryos, and our work informs the human situation, where disorders affecting
sex determination can have devastating physiological and social consequences. We also study pluripotent stem cells from early
embryos (ES cells) or after reprogramming from adult cells (iPS cells), and multipotent stem cells from the brain and pituitary.
Certain Sox genes are critical for self-renewal and stem cell potential. We therefore explore how these impact on cell fate
choices, and how they might be exploited to aid treatments for clinical problems, such as stroke and cancer.
Publications
Acloque H, Ocana OH, Matheu A, Rizzoti K, Wise C, LovellBadge R and Nieto MA (2011)
Reciprocal repression between Sox3 and Snail
transcription factors defines embryonic territories at
gastrulation.
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
Sutton E, Hughes J, White S, Sekido R, Tan J, Arboleda V,
Rogers N, Knower K, Rowley L, Eyre H, Rizzoti K, McAninch
D, Goncalves J, Slee J, Turbitt E, Bruno D, Bengtsson H, Harley
V, Vilain E, Sinclair A, Lovell-Badge R and Thomas P (2010)
Identification of SOX3 as an XX male sex reversal gene in
mice and humans.
Journal of Clinical Investigation 4:328-41
See references 2, 10, 107, 116, 190, 192 and 226 in the
bibliography at the back for publications from this group in 2011.
86
Reducing SoxB1 (Sox2 and Sox3) gene activity
leads to increased expression of Snail and to more
cells in the primitive streak of a gastrulating mouse
embryo. The two types of transcription factor
mutually repress each other to control the extent
and rate of epithelial to mesenchymal transition.
A sex-reversing Sox3 transgene mimics Sry
and not Sox9. This explains how Sry could have
evolved from Sox3 via a regulatory mutation, and
why rearrangements of the X chromosome near
SOX3 are associated with human XX male sex
reversal.
Tim Mohun
Heart development in vertebrates
Lab members: Mike Bennett, Laurent Dupays, Surendra Kotecha, Marianne Neary, Izabela Piotrowska, Stuart Smith,
Norma Towers, Robert Wilson
Formation of the heart is a complex process that begins
very early in the vertebrate embryo, remodelling a simple
peristaltic tube into a complex multi-chambered organ capable
of supporting embryo growth. This transformation requires
exquisite coordination of cell differentiation and growth to
produce the dramatic changes in organ shape. Abnormalities
affecting any step will have profound consequences on the
foetal heart and heart defects are the most common birth
defect. By studying the roles of individual genes and cell
populations in normal heart development, 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 techniques and genome-wide analysis
to investigate how cardiac gene expression is regulated in the
developing vertebrate embryo. Novel imaging and computer
modelling procedures that we have developed allow us
to examine the precise three-dimensional structure of the
embryonic heart and identify changes in morphology resulting
from altered gene expression. This approach not only helps us
to understand normal gene function in the developing heart,
but also to investigate possible causes of congenital heart
disease and genetic conditions (such as Down syndrome)
which often result in heart malformations.
In this tadpole, muscle cells of the heart, head and body can be readily
visualised through expression of a fluorescent reporter, providing a simple
way to monitor heart development.
Publications
Smith SJ and Mohun TJ (2011)
Early cardiac morphogenesis defects caused by loss of embryonic macrophage function in
Xenopus.
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
3D models of the mouse embryo heart (left) or the lumens of the heart
chambers (right) reveal the complex mesh of muscle fibres characteristic of
the embryonic heart.
Dupays L, Kotecha S and Mohun TJ (2009)
Tbx2 misexpression impairs deployment of second heart field derived progenitor cells to the
arterial pole of the embryonic heart.
See references 1, 43, 47, 127, 151 and 211 in the bibliography at the back for publications from this
group in 2011.
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Elke Ober
Liver development in zebrafish
Lab members: Johanna Fischer, Jordi Cayuso Mas, Despina Stamataki
The liver represents the largest internal organ, performing a
plethora of essential functions to maintain body homeostasis.
During embryogenesis, the liver, pancreas and lung originate from
adjacent domains of the foregut. A well-orchestrated programme
of developmental steps ensures the functional differentiation of each
organ, starting with the precise allocation of multipotent foregutendoderm to a particular organ fate. Central aims of our research
are to understand how liver progenitors are specified from the
foregut endoderm and how these committed precursors rearrange
to shape the functional liver. We investigate these questions using
the experimental advantages of zebrafish.
Using genetic approaches, we found that two Wnt ligands regulate
specification and subsequent proliferation of liver progenitors.
Importantly, Wnt levels need to be tightly controlled within the
embryo, since excess expression of either ligand promotes liver
formation at the expense of the pancreas. Our current work
aims to determine the interactions of Wnt signalling with other
pathways controlling liver formation to unravel the molecular
network directing underlying liver specification from the pool of
multipotential progenitors. The identification of organ-specific
genetic programmes will provide insights into not only the
mechanisms regulating embryonic development, but also tissue
homeostasis and regeneration following injury in adults.
Publications
Poulain M and Ober EA (2011)
Interplay between Wnt2 and Wnt2bb controls multiple
steps of early foregut-derived organ development.
Noël ES, Casal-Sueiro A, Busch-Nentwich E, Verkade H, Dong
PDS, Stemple DL and Ober EA (2008)
Organ-specific requirements for Hdac1 in liver and
pancreas formation.
Ober EA, Verkade H, Field HA and Stainier DY (2006)
Mesodermal Wnt2b signalling positively regulates liver
specification.
Nature 442:688-691
Impaired Wnt2/Wnt2bb signalling disrupts liver (red) specification from multipotent foregut endoderm,
while excess Wnt2bb promotes liver formation at the expense of the pancreas (green).
88
Systems Biology
Jim Smith FRS, EMBO member, FMedSci
The molecular basis of mesoderm formation
Lab members: Camille Bouissou, Clara Collart, Kevin Dingwell, Alex Eve, Tiago Faial, George Gentsch, Elsie Place, Thom Spruce,
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 cell types such as muscle, kidney
and bone, as well as the heart and vascular system. We
study the formation of the mesoderm as well as that of the
neural crest.
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 in mesoderm
(including vascular cells) and neural crest. As well as helping
understand development, we hope our work will assist in
efforts to direct stem cells down desired developmental
pathways.
Top: searching for targets of the transcription factor Xbra in the Xenopus
embryo by ChIP-Seq. Bottom: loss of function of Xbra and Xbra3 causes
severe posterior defects in tailbud embryos.
Publications
Collart C, Christov CP, Smith JC and Krude T. (2011).
An essential Y RNA-dependent pathway for the initiation of DNA replication is activated at the
mid-blastula transition in Xenopus laevis.
Molecular Cell Biology 31, 3857-70.
Harvey SA, Tümpel S, Dubrulle J, Schier AF and Smith JC (2010)
no tail integrates two modes of mesoderm induction.
Tmem88a was identified in an RNA-Seq screen for genes expressed in
endothelial and haematopoietic cells. Loss of Tmem88a function by means
of antisense morpholino oligonucleotides causes loss of erythrocytes
(brown).
Harvey SA and Smith JC (2009)
Visualisation and quantification of morphogen gradient formation in the zebrafish.
See references 15, 39 and 187 in the bibliography at the back for publications from this group in 2011.
89
Peter Thorpe
Systems microscopy studies of cell fate determination
Lab members: Erika Aquino, Eva Herrero, Elena Ledesma and Guðjón Ólafsson
Asymmetric cell division is the process by which one cell
divides to give two cells with different fates. Repeated
asymmetric divisions allow a fertilised egg to generate
diverse cell types during development, and in adult
stem cells such divisions maintain the population while
simultaneously generating new, differentiated cells. The
goal of our group is to determine how cellular asymmetry
is established and maintained over multiple divisions to
create cell lineages. Specifically, we focus on understanding
how asymmetry of the mitotic spindle - the machinery
that segregates chromosomes during division - affects how
genetic information is accurately passed down to daughter
cells.
Our model system is the budding yeast, Saccharomyces
cerevisiae, which shows patterns of asymmetric division
like those of more complex organisms. We employ highthroughput fluorescence microscopy techniques that allow
us to rapidly screen the localisation, levels and dynamics of
all yeast proteins and integrate them into a visual dataset.
Using these tools, we aim to identify the conserved
mechanisms controlling asymmetric division, lineage
specification and mitotic spindle function.
Yeast arrayed at high-density allow large-scale screening of mutants for their
effect upon the kinetochore. This reverse genetics approach identifies genes
that regulate kinetochore function, particularly asymmetry of cell division.
Publications
Thorpe PH, Alvaro D, Lisby M and Rothstein R (2011)
Bringing Rad52 foci into focus.
Thorpe PH, Bruno J and Rothstein R (2009)
Kinetochore asymmetry defines a single yeast lineage.
Thorpe PH, Bruno J and Rothstein R (2008)
Modeling stem cell asymmetry in yeast.
Cold Spring Harbor Symposia on Quantitative Biology 73:81-88
Analysis of images of fluorescently-tagged yeast kinetochore proteins
allows relative quantitation of their concentration. The isosurface
fluorescence image (right) corresponds to the yeast shown (left).
James Turner
X chromosome inactivation, meiotic silencing and infertility
Lab members: Jeff Cloutier, Jennifer Grant, Grzegorz Polikiewicz, Helene Royo, Mahesh Sangrithi
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. The role of XCI in
male germ cells is unclear. 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 male germ cells is essential for fertility.
This study has also allowed us to ascertain that misexpression of
the gene pair, Zfy1/2, is the underlying cause of sterility in XYY
males. We have found that the X chromosome is highly enriched
in genes involved in sperm differentiation, with around 20% of all
genes on the X chromosome being expressed only in male germ
cells. Many of these genes are likely to be important for normal
male fertility. In female eutherian, or ‘placental’ mammals, XCI is
mediated by the non-coding RNA Xist, but how XCI is controlled
in the other major class of mammals, the metatherians, is
unknown. We have now discovered that the epigenetics of XCI in
metatherians is similar to that of eutherians, raising the possibility
that XCI in metatherians is mediated by an as yet unidentified
non-coding RNA.
In XYY males, pairing allows the two Y chromosomes to escape
inactivation by gH2AX and to express Y-genes; the resulting
expression of the toxic Zfy1/2 genes leads to germ cell arrest.
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, Van de Berg JL, McCarrey JR, Mackay S, Turner JM (2009)
Key features of the X inactivation process are conserved between marsupials and
eutherians.
Mueller JL, Mahadevaiah SK, Park PJ, Warburton PE, Page DC and Turner JMA (2008)
The mouse X chromosome is enriched for multicopy testis genes showing
postmeiotic expression.
Nature Genetics 40:794-9
Identification of Rsx, a non-coding RNA that coats the female metatherian X
chromosome.
See references 36, 94 and 225 in the bibliography at the back for publications from this group
in 2011.
91
Developmental Bioiogy
Jean-Paul Vincent EMBO member, FMedSci
Patterning and homeostasis in developing epithelia
Lab members: Cyrille Alexandre, Luis Alberto Baena-Lopez, Karen Beckett, Maria Gagliardi, Satoshi Kakugawa, Paul Langton, Hisashi
Nojima, Lucy Palmer, Alice Mitchell, Rohan Bundell
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 signal,
Wingless (a member of the Wnt family). We also study the regulatory
mechanisms that allow cells to compute their position within the
Wingless gradient. This led us to find that cells with overactive Wnt
signalling eliminate their normal neighbours, a finding that may be
relevant to tumour biology. In a separate, but related strand of
research, we aim to understand the mechanisms that trigger the
elimination of cells following epithelial disruption.
Disruption of epithelial cell adhesion leads to widespread apoptosis,
a phenomenon that likely reflects the need to eliminate cells that
detach from the epithelium, thus preventing them from causing
havoc. As we found recently, Jun kinase (JNK) is a key mediator of this
process. However, how epithelial disruption activates JNK remains to
be discovered. It will also be important to understand why in other
cellular contexts, this pathway does not necessarily trigger apoptosis.
We are using transcriptional profiling, confocal imaging and genetic
analysis to investigate the links between epithelial disruption, JNK
signalling and apoptosis.
A model for Wingless transcytosis and loading onto exosomes.
This working model accounts for the role of Evi (red squiggles) in
Wingless (blue dots) secretion and provides a possible explanation
for the transport of Wingless from the apical to basal surface.
Publications
Vincent JP, Kolahgar G, Gagliardi M and Piddini E (2011)
Steep differences in wingless signaling trigger Myc-independent competitive cell
interactions.
Piddini E and Vincent J-P (2009)
Interpretation of the Wingless gradient requires signaling-induced self-inhibition.
Cell 136:296-307
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
See references 117, 166, 244 and 245 in the bibliography at the back for publications
from this group in 2011.
92
APC mutant cells grow at the expense of normal cells. Wild type cells (green and
non-green) contribute equal amount of tissues (left). By contrast, normal cells
(green) are eliminated by APC mutant cells (non-green), which overactivate Wnt
signalling.
Lyle Zimmerman
Using frog genetics to understand vertebrate development and disease
Lab members: Anita Abu-Daya, Tosikazu Amano, Tim Geach, Holly Ironfield, Joachim Kurth
Harvesting medical benefits from the human genome depends on understanding
the tasks that 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 used positionally mapped genes underlying a number of mutations,
including several resulting in abnormalities of otoconia, inner ear crystal structures
essential for vestibular/balance function. Study of these mutations may help
understand a common human balance disorder, benign positional vertigo.
Together with collaborators, we have also used solution-hybridisation wholeexome enrichment technology to isolate and sequence the protein-coding space
of X. tropicalis genomes derived from chemically mutagenised stocks. This strategy
has rapidly yielded more than 100 new mutations for further study, and includes
genes that are important for a variety of processes including ciliogenesis, left-right
asymmetry and erythropoiesis.
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.
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
Abnormal large otoconia from komimi (otoconin90) mutant tadpoles compared to wild type. (I, J)
Sections showing komimi otoconia with reduced contact with inner ear sensory epithelium.
Goda T, Abu-Daya A, Carruthers S, Clark MD, Stemple DL
and Zimmerman LB (2006)
Genetic screens for mutations affecting development of
Xenopus tropicalis.
PLoS Genetics 2:e91, 811-825
See references 1, 78, and 157 in the bibliography at the back for
93
Genetically induced green fluorescent protein expression in the neural crest population of a mid gestation mouse embryo. Optical
sections were captured as a confocal stack which was then colour coded according to the depth within the sample.
J Tabler (sample), Donald Bell (imaging), Chen Qian (software).
94
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
Histology
Electron microscopy
OPT and HREM imaging
Single molecule techniques
Total internal reflection fluorescence microscopy
Optical tweezers
Atomic force microscopy
Electron cryomicroscopy
Other scientific facilities
Genomics
High throughput sequencing
Microarray
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PhotoGraphics
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Finance and purchasing
95
RESEARCH FACILITIES
Biological and Procedural Services
Kathleen Mathers
The Division of Biological Services provides a fully integrated laboratory animal and
technical resource to the Institute. The multidisciplinary research of the Institute
requires a range of species and models, and to meet these needs we operate and
manage a number of complex animal facilities. These include an isolation/quarantine
unit, containment facilities at Levels 2, 3 and 4 for animals infected with organisms
potentially harmful to man and/or the environment, specialist procedural, behavioural
and surgical suites, imaging and irradiation facilities, and extensive aquatic facilities. The
vast majority of animals in the facility are rodents, with large numbers of genetically
altered lines of mice and rats. In addition, our facilities house ferrets, rabbits, the
laboratory opossum, zebrafish and Xenopus species. 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
96
Laboratory opossum with litter
RESEARCH FACILITIES
We aim to meet all the needs of the scientific Divisions whilst ensuring the highest possible standards of health and welfare for all
species. The Division is active in the field of laboratory animal science, conducting and promoting research and uptake of the 3Rs
(replacement, reduction, refinement) and presents its work at national and international meetings. The animal care and technical
staff are trained in the production, care and use of animals for research purposes to the highest standards of animal husbandry.
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-targeted
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
97
RESEARCH FACILITIES
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 18 external groups at
universities and institutes from around the UK. Within NIMR our closest
links are with the Division of Molecular Structure.
NMR spectroscopy used to monitor the reaction of the HIV restriction factor SamHD1
with dGTP. Successive 31P NMR spectra were recorded at hourly intervals, and reveal
that SamHD1 possesses triphosphohydrolase activity, in this instance converting dGTP to
guanosine and inorganic triphosphate. (In collaboration with Dr Ian Taylor, NIMR.)
For more information see Taylor, Webb et al, Nature (2011).
Magnet of the 800 MHz spectrometer.
98
Representative publications are listed on the Centre’s website, www.nmrcentre.mrc.ac.uk
RESEARCH FACILITIES
X-ray crystallography
Protein X-ray crystallography is a technique that produces a three-dimensional model of the structure of a protein at atomic
resolution. The X-ray crystallography facilities within the Division of Molecular Structure at the Institute are state-of-the art
and include a high intensity X-ray source coupled with an automated robotic sample mounting system 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, proteins are
also expressed in insect cells using the baculovirus expression
vector system (BEVS). Services include the generation and
amplification of high-titre baculovirus stocks, analytical scale
productions for optimisation of protein expression, and
preparative scale productions. In addition, the facility maintains
a vector DNA repository, provides in-house vector design,
troubleshooting and training.
The crystal structure of the RELIK CA-NtD-CypA complex. The Relik
CA-NtD (blue) and cyclophilin (gold) molecules are displayed in cartoon
representation. The solvent accessible surface of the bound cyclophilin is
shown in grey.
Insect cell expression in a Wave Bioreactor™.
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RESEARCH FACILITIES
Mass spectrometry
The proteomics and mass spectrometry facility is housed
in a purpose-built suite. It currently houses three mass
spectrometers and ancillary equipment, which are used in a
range of biochemical analyses. A state-of-the-art LTQ Velos
Orbitrap high resolution tandem MS coupled to a nano-HPLC
is utilised in proteomics studies and is capable of identifying
hundreds of proteins from a single run. Protein quantification
is performed using standard techniques such as SILAC or
iTRAQ labelling. Identification of the sites of post-translational
modifications, such as phosphorylation and ubiquitination, is also
achieved on this instrument.
A quadrupole time-of-flight tandem mass spectrometer,
equipped with an electrospray source, is utilised for protein and
peptide characterisation. A GC-MS has recently been added to
the facility and is currently used in metabolomics research, such
as the quantification of fatty acids.
Phosphorylation site localisation by LC MS/MS.
100
The nano-electrospray source of the Orbitrap Velos.
RESEARCH FACILITIES
Other structural biology facilities
Protein sequence analysis and structure modelling
José Saldanha
Computational tools for prediction, analysis and visualisation
can provide inspirational new ways to look at data, no matter
which protein family is the main focus of research. From highlevel 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.
Ribbon visualisation of a protein model with helices in red, strands in
yellow and loops in green. The ribbons are surrounded by a protein
surface mesh in blue.
A support service for protein sequence analysis and structure
modelling is provided. It draws on state-of-the-art algorithms
being developed by experts in the Division of Mathematical
Biology as well as the many computer programs freely available
from the scientific community. There is also an in-house,
commercial, computer graphics package for detailed threedimensional 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 panel. A fringe displacement pattern produced by a moving
concentration boundary measured by the Rayleigh interference optics of the
XL-I is shown above.
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RESEARCH FACILITIES
Confocal imaging and analysis
Yan Gu
Co-workers: Donald Bell, Chen Qian, Kate Sullivan
The Confocal Imaging and Analysis Laboratory (CIAL) provides an
imaging core facility at NIMR. The facility has six confocal microscopes,
three wide-field fluorescence microscopes, a multiphoton microscope,
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 16 NIMR Divisions.
Users operate the system, but the complexity of imaging makes support
an extremely important aspect of the facility. We routinely provide users
with training, troubleshooting, consultation and microscope maintenance.
We also support special techniques such as thick tissue imaging, live cell
experiments, 2nd harmonic generation imaging, quantitative imaging,
deconvolution imaging, and automatic cell counting.
Research activities in CIAL are focused on techniques of 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.
GFP-labelled mouse neuron showing the dendritic
tree and spine formation. The image is post
processed with a depth-coded pseudo-colour
projection.
Multiphoton microscopy examining the development of retinal nerve connections
in Drosophilia. The left panel shows the two colour raw image whilst the right panel
represents the GFP signal with a depth-coded pseudo-colour projection.
Publications
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.
Pacary E, Heng J, Azzarelli R, Riou P, Castro D, Lebel-Potter M, Parras C, Bell DM, Ridley AJ, Parsons M and
Guillemot F (2011)
Proneural transcription factors regulate different steps of cortical neuron migration through Rnd-mediated
inhibition of RhoA signaling.
Neuron 69:1069-84
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
102
RESEARCH FACILITIES
Histology
Radma Mahmood
The Histology service provides a range of sectioning techniques for
visualisation of tissue structure and gene expression in animal research
models. By making paraffin blocks of animal tissues, we produce thin
sections that when stained allow for analysis of tissues at a cellular level.
Tissues are automatically processed, embedded into paraffin blocks and
sectioned manually by facility histologists. Slides generated are stained
for cell and nuclear structure or left unstained for the researcher’s
own use. Newly acquired equipment includes the Leica automated
tissue processor (ASP300) and automated slide stainer (Autostainer
XL) as well as two new rotary microtomes and cryostats. The ASP300
processor utilises ten different processing programs designed to
optimally maintain morphology of all tissues from mouse embryos and
neonates, rats, frogs and fish, as well as human research samples. Paraffin
tissue blocks are sectioned manually and the automated stainer is used
for hematoxylin and eosin (HE) 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.
Periodic acid Schiff stained mouse gut with nematode.
HE and Giemsa stained bone marrow showing malaria organisms.
In situ hybridisation of Xenopus embryo hearts counter-stained
with nuclear fast red.
HE stained mouse embryo day 16.5, sagittal section.
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RESEARCH FACILITIES
Electron microscopy
Liz Hirst
The EM facility has both a Transmission Electron Microscope
(TEM, Jeol 1200 EX set up for conventional scattering optics)
and a Scanning Electron Microscope (SEM, Jeol 35CF), both
of which have been recently upgraded to digital photography
(Gatan Orius 1000 and SemAfore respectively). There is
also a dedicated EM processing laboratory. Staff from any
department at NIMR may request TEM or SEM investigations
in support of their scientific studies. 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.
Technical advice, training and support is also provided for
staff wishing to learn EM techniques.
TEM techniques available include ultra-thin sectioning and
ultra-structural analysis of experimental tissues, cell cultures
or sub-cellular pellets. Immuno-EM techniques provided are
post-embedding immuno-gold labelling of antigens upon
ultra-thin sections or pre-embedding by HRP labelling. SEM
techniques available include internal anatomy by dry fracture
or dissection as well as external topology. Elsewhere within
the Institute, a second Jeol 1200EX is set up for low dose
phase contrast EM for molecules.
SEM Loss and rescue (above) of a gene function in Drosophila eye (Molecular
Neurobiology).
Publications
Cruz C, Ribes V, Kutejova E, Cayuso J, Lawson V, Norris D, Stevens J, Davey M, Blight K, Bangs F,
Mynett A, Hirst E, Chung R, Balaskas N, Brody SL, Marti E and Briscoe J (2010)
Foxj1 regulates floor plate cilia architecture and modifies the response of cells to sonic hedgehog
signalling.
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.
Developmental Dynamics 238:581-94
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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TEM Mouse heart mitochondrial morphology changes before, during
(above) and after birth.
Post-embedding Immuno EM.
Gold-conjugated antibodies
demonstrate that SufB and
SufC are located at the
bacterial membrane of E.coli.
RESEARCH FACILITIES
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 the Confocal
Imaging and Analysis Lab (page 102) and Histology (page 103). 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 morphology.
105
RESEARCH FACILITIES
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 (right) and Optical Tweezers (left) are powerful tools that assist studies of motor proteins which are the
molecular machines contained in every cell of the body (images by Gregory Mashanov and Justin Molloy).
We have developed methods to visualise and manipulate single molecules, with high time resolution, using two laser-based
techniques; Total Internal Reflection Fluorescence (TIRF) microscopy and Optical Tweezers (OT). TIRF microscopy uses the
evanescent field associated with a totally internally-reflected laser beam to excite fluorophores at the surface of a microscope
coverslip. Sensitive camera systems are used to detect light emitted by the fluorophores. These measurements have a resolution
of around five nanometres within 50 milliseconds. Optical Tweezers make use of radiation pressure to pick-up and manipulate
individual molecules. Using fast detectors, the position of optically trapped particles are measured with nanometre precision
so that forces and movements produced by single molecules can be measured. The resolution is around one nanometre every
millisecond.
Atomic Force Microscopy (AFM) enables us to analyse the
structure of biological molecules by scanning their surface
topology using a microfabricated mechanical probe or “tip”.
The AFM used at NIMR (JPK NanoWizard) is ideally suited
to studying biological materials in aqueous solution at room
temperature. As the AFM tip is scanned over the sample it
rides over molecules fixed to the surface. Deflections of the tip
are measured using a laser-based position sensor producing a
three-dimensional topological map of the surface. The technique
is ideally suited to studies of material for which high-resolution
dynamic information is required. The ultimate resolution depends
on the sharpness and stiffness of the silicon tip, the mechanical
properties of the specimen and also upon the mechanical
stability of the laboratory and microscope system. For soft
biological molecules, the resolution is around five nanometres.
Upper panel shows a single actin filament and a single microtubule (MT) (by
Iwan Schaap); Lower panels show different phases of bacterial Plasmid DNA
replication (by Claudia Arbore).
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RESEARCH FACILITIES
Electron cryomicroscopy
High resolution cryo electron microscopy (cryoEM) enables
the structure of biological molecules and larger materials to be
visualised in a frozen hydrated state without fixation or staining.
An aqueous solution containing the specimen is frozen very
rapidly to liquid nitrogen temperatures. When cooled rapidly,
water forms a glass (rather than forming ice crystals) and the
embedded biological material, locked in this transparent medium,
can be viewed by electron microscopy. Because the electron
beam has a much shorter wavelength than visible light, individual
protein molecules can be visualised. Although the image contrast
of each individual molecule is low, signal averaging can yield very
high resolution pictures. CryoEM is well-suited to high-resolution
studies of both the structure and dynamics of large proteins and
protein complexes, such as cytoskeletal proteins or viral capsids.
Our latest methods also enable structures within rapidly frozen
mammalian cells to be visualised. By recording many digital
images of a specimen held at different orientations (tomography),
a three-dimensional view of the molecule or cell is obtained.
Individual molecules, whole virus particles or living mammalian cells
embedded in ice can be imaged in three dimensions.
Slice of a three-dimensional tomogram showing the edge of a frozen hydrated cell
and a computational model for membrane organelles.
Image courtesy of Sebastian Wasilewski
107
RESEARCH FACILITIES
Genomics
Abdul Karim Sesay
Co-workers: Leena Bhaw-Rosun, Harsha Jani
The Genomics facility provides next-generation sequencing and microarray services
to NIMR scientists. Services include sample preparation, high-throughput sequencing
and microarray hybridisation. Support is also provided for data analysis. Situated
within the Division of Systems Biology, the Genomics facility is equipped with stateof-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 bioinformatics
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 paired
end 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 immunoprecipitation.
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:
• Nanodrop spectrophotometer and two Agilent 2100
Bioanalyser, for quality control and quantification of DNA,
RNA and proteins.
• Two Life Technology Qubit systems, for the quantification
of DNA, RNA and proteins.
• Life Technology E-Gel systems for size selection of
sequencing libraries.
.
108
The Genomics facility team.
RESEARCH FACILITIES
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 such as Mycobacterium tuberculosis, Drosophila,
Xenopus, zebrafish, chicken, dog, mouse, rat and human. The microarray facility offers full technical support in the preparation and
running of RNA or DNA samples prepared by the scientists. It also offers access to and training in the 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 analysis; array-based
transcriptome analysis; FFPE sample analysis; SNP genotyping and CNV analysis; whole genome, custom or focused genotyping;
cytogenetic analysis; linkage analysis; copy number analysis; gene regulation and epigenetic analysis, and array-based methylation
analysis.
Global analysis of the
haematopoietic and endothelial
transcriptome during zebrafish
Development. Data from RNASeq
experiment,
courtesy of John Cannon, Systems
Biology, Smith’s Lab.
The biological functions of the 754 enriched genes using
the Panther Ontology.
RNA-Seq read alignment to Zv8
zebrafish genome on UCSC
genome browser. Illustrative
alignments of reads from the first
biological replicate of gfp+ and gfplibraries.
Tmem88a and trim2a morphants have reduced erythrocytes shown by Odianisidine
staining at 48 hours post-fertilisation.
109
RESEARCH FACILITIES
Bioresources
Joachim Payne
Co-workers: Charlotte Austin, Wioletta Berg, Viktoria Janusova, Ian Oliver, Brian Trinnaman, Jackie Wilson
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 mammalian,
insect, yeast and bacterial cells for ten
research Divisions at NIMR, as well
as collaborating with other MRC and
academic units. Last year we grew
around 1000 litres of hybridoma and
insect cells and 3900 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 products,
and last year processed 3,500 orders,
totalling around 36,000 litres of liquid
reagents, 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.
Wioletta inspects a hybridoma culture.
110
Brian sets up one of our bioreactors.
RESEARCH FACILITIES
Flow cytometry
Graham Preece
Co-workers: Bhavik Patel, Wayne Turnbull
The flow cytometry facility provides a state-of-the-art, high
speed, sterile cell sorting service. We sort multiple types of cell
populations for both in vitro and in vivo studies, single cell sorting
and cloning. In addition, it offers multiparameter fluorochrome
analysis of cell markers and measurement of calcium fluxes,
apoptosis and cell cycle.
The facility serves a large number of NIMR researchers from
the Infections and Immunity, Genetics and Development and
Neurosciences groups. Training is also provided for research staff,
including PhD students and postdoctoral researchers.
The facility is well equipped, with four cell sorters including two
7-colour Beckman Coulter MoFlo sorters, a 13-colour Becton
Dickinson FACS Aria II and a 10-colour Becton Dickinson Influx.
The Influx is situated inside a containment level 2 (CL2) bio-safety
cabinet for sorting samples classified at CL2. Additionally there are
eight flow cytometric Analysers that include a 4-colour Becton
Dickinson FACSCalibur, a 6-colour Becton Dickinson FACSVerse,
an 8-colour FACSCanto, a 14-colour Becton Dickinson LSRII and
a 9-colour Beckman Coulter Cyan ADP. The facility also houses
an Automacs Cell separator.
111
RESEARCH FACILITIES
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, sent from around the world at
the early stages of its global spread, and to generate reference ferret antisera to the emerging pandemic viruses for virus antigenic
analyses. It has also been used for the isolation and characterisation of human isolates of H5N1 avian influenza virus, for example
from the Turkish outbreak in humans in 2006. The laboratory capacity has been extended to have two standard high containment
laboratory areas and two laboratories equipped to handle infected small animals under high level containment. With the enhanced
capacity, in addition to the virus surveillance and characterisation studies of the WIC, simultaneous studies of the mechanisms of
disease causation by avian or other influenza viruses can be carried out.
Features of the laboratory include:
• A negative pressure air regime with HEPA filtered input and double HEPA filtered extract.
• Waste treatment with heating of liquid waste and autoclave sterilisation of solid waste within the body of the laboratory.
• Class III and Class I/III microbiological safety cabinets for handling samples.
• Class III cabinets for handling infected small animals.
• Sealable, so as to permit fumigation.
• Strict codes of practice including the requirement for all workers to undergo a complete change of clothing before
entering the laboratory and to shower when leaving.
In addition to the Level 4 laboratory, there are 11 Level
3 laboratories scattered among the main buildings and
biological research facilities at NIMR. These laboratories
allow the safe handling of a number of pathogenic
organisms, permitting studies of the microbiology and
immunology of Mycobacterium tuberculosis, the invasion
of blood cells by the malaria parasite and the growth of
the retroviruses that cause AIDS.
112
RESEARCH FACILITIES
Engineering workshop
Alan Ling
Co-workers: Derek Brewer, Peter Cookson, Ray Herriott, Richard Jones
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
The experienced staff can manufacture quick one-off prototypes,
followed by continued development and modification to produce
the desired item or apparatus.
Onsite repair and maintenance of laboratory equipment is also
carried out in the workshop. The varied facilities mean that a
diverse range of projects can be worked on, including:
• micromanipulators
• microscope stage modifications
• custom-made parts
• temperature controlled chambers
• drug infusers and nebulisers
• blood flow measurement devices
113
RESEARCH FACILITIES
Electronic instrument prototyping and support
Martyn Stopps
Instruments are designed and manufactured for applications in
physiology and single molecule research. Work conducted in
cutting-edge science often requires new instrumentation which
is not available commercially. Examples of this over the past
year include:
• A multi-channel rate-controlled perfusion flow system
for studying shear-dependent interactions between blood
components and endothelial cells.
• A high brightness LED light source integrated with an
optical trap microscope enabling automatic intensity control
during the study of single myosin molecules.
• A malarial parasite counting device that enables
determination of parasitemia.
Utilising current technologies, the resource in collaboration
with researchers enables comprehensive system development
from initial specification, through proof of concept to the final
application.
A multi-channel perfusion flow system.
114
Prototype counter assisting determination of parasitemia in blood
samples.
RESEARCH FACILITIES
PhotoGraphics
Joe Brock
Co-workers: Jamie Brock, Neal Cramphorn, Hayley Wood, Wai Han Yau
The PhotoGraphics service provides a professional design,
illustration and imaging facility to visualise the innovative research
carried out at NIMR. Our fully trained team provides a wide
range of specialist skills using state-of-the-art equipment, software
and techniques. These include digital manipulation, illustration,
Flash™ animation, film making and editing, 3D modelling,
scanning and photography as well as providing a printing, copying
and binding service.
This facility is open to all researchers wishing to relate their
science visually through publication, digital presentation and
posters. Novel methods developed by us for presenting science
using interactive animations provide more dynamic in-depth
explanations and we regularly receive requests for copies by
researchers and companies world-wide who recognise this
media as a powerful informative tool.
The 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 support to the Institute, ensuring smooth running for both in-house and visiting speakers.
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 visualising scientific and
biological processes.
115
RESEARCH FACILITIES
Computing and Telecommunications
Clive Lunny
Co-workers: Aomar Ayad, Jose Ayala, Darsheni Fatania, John Green, Debra Harper, Ben Kesel, Kevin McInerney, 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. We 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.
We also provide and maintain the internal telephone system and
are currently testing a new secure wireless networking solution
for both staff and visitors.
We provide a Cisco Webex system for live collaboration and
web conferencing. We are currently developing a custom filesharing system which is secure and user-friendly, and will facilitate
internal and external collaboration. We recently expanded
our data storage/archival system from 100TB to 180TB, added
replication and are adopting a strategy of providing backup to all
desktop, laptop and scientific facilities users with a server-based
system which is now in the testing phase.
116
RESEARCH FACILITIES
Library
Frank Norman
Co-workers: Patti Biggs, Lynsey Eames, Nicola Weston
The Library serves the information needs of scientific staff and
students at NIMR. It provides access to more than 2000 electronic
journals and to literature searching tools like Scopus and Metalib.
We have extensive printed journal backfiles and a printed book
collection as well as easy access to a document delivery service.
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. We offer assistance with citation manager software (e.g.
Endnote, Reference Manager, Mendeley, Pages, Zotero) and advice
on Open Access compliance. A daily news service keeps staff
informed of current science policy developments.
Casual reading space and dedicated study desks for write-up are
available plus some computer desks with PCs and Macs. There is
a WiFi network in the Library. 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 students study suite.
Casual seating area with new book and journal displays.
117
RESEARCH FACILITIES
Web Team
Christina McGuire
The Web Team is responsible for the day-to-day
management of the NIMR website, intranet and online
presence, and longer-term strategic projects such as the
recent redevelopment and implementation of a content
management system on the external website. Our aims are
to ensure that the external website reflects the excellence
of science at NIMR, meets user and organisational needs, and
promotes the research and outreach work at NIMR. Internally,
we aim to provide easy access to information and resources
through online systems which support effective and efficient
working.
We produce microsites for NIMR-sponsored initiatives such
as conference websites; develop innovative solutions such as
our online weekly newsletter for staff; and are always willing
to provide advice and expertise. The Web Team provides not only technical infrastructure, but also training and support (including
tools for easy updating). We develop cross-platform, user-friendly, visually appealing websites and applications, and ensure
compliance with relevant standards and legislation. We work with staff throughout NIMR, and use one-to-one meetings, focus
groups, surveys, feedback forms, instant polls, and user testing and evaluation to help inform future developments. We also have an
open door policy, in common with others at NIMR.
Online weekly newsletter for staff
118
Customisable intranet homepage
RESEARCH FACILITIES
General services
Occupational Health
Occupational Health (OH) is concerned with the effects of
health on work and of work on health with consideration for
the working environment. Occupational services include health
protection, health promotion and lost time management. Our
professional service observes Health and Safety regulations
and helps to support the overall needs of NIMR. We offer
impartial advice to all employees on health matters related to
the working environment. The OH team also provide specific
health surveillance to staff members exposed to hazards.
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 scientific and support staff. A team of specialists work to
embed shared principles and a culture that support science,
and provide expert advice on employment matters such
as recruitment, development, performance, reward and
recognition.
Finance and Purchasing
The Finance team provides advice and support to staff
in the costing of grant applications, full economic costing,
expenses and sales invoices. They are also responsible for
the management, reporting and forecasting of the Institute’s
budgets. The Purchasing team assists staff with all aspects of
procurement including tendering for capital equipment, service
contracts, and consumables. They also liaise closely with the
RCUK Shared Service Centre to ensure that we get best value
for money in pricing.
119
Nobel Laureates
Five scientists from NIMR have been awarded Nobel Prizes for their scientific research.
Henry Dale, OM, FRS (1875-1968)
Henry Dale worked at NIMR from its inception in 1914 and was the first Director, serving from
1928-1942. His research on the functions of nerve cells led to the discovery of acetylcholine as a
neurotransmitter and to the chemical basis of neurotransmission. For this work he received the Nobel
Prize for Physiology or Medicine in 1936.
Henry Dale
Archer Martin, CBE, FRS (1910-2002)
Archer Martin worked at NIMR from 1948-1956. Before arriving at NIMR he worked on amino acid
analysis and the development of partition chromatography for the purification of biological molecules. He
received the Nobel Prize for Chemistry for this work in 1952. At NIMR he developed the method of gasliquid chromatography, which has had far-reaching impact on the study of biochemistry.
Archer Martin
Rodney Porter, FRS (1917-1985)
Rodney Porter worked at NIMR from 1949-1960. His research on the many specificities of antibodies
led to the separation of antigen binding (Fab) and crystalline (Fc) proteolytic fragments of antibodies,
an essential step for the determination of their complete sequences of amino acids. For this work he
received the 1972 Nobel Prize in Physiology or Medicine.
Rodney Porter
John Cornforth, FRS (1914-)
John Cornforth worked at NIMR from 1946-1962. He completed the first total synthesis of the nonaromatic steroids and in collaboration with George Popjak he identified the chemical structure of
cholesterol. He received the Nobel Prize for Chemistry in 1975.
John Cornforth
Peter Medawar, OBE, OM, FRS (1915-1987)
Peter Medawar was Director of NIMR from 1962-1971. He was one of the foremost biologists of his
generation, and also a hugely gifted populariser of science. Earlier in his career he studied how the
immune system rejects foreign tissue grafts and discovered the phenomenon of immune tolerance. For
this work he was awarded the Nobel Prize for Physiology or Medicine in 1960.
Peter Medawar
120
Five famous alumni
Brigitte Askonas, FRS (1923-)
Brigitte (Ita) Askonas worked at NIMR from 1952-1989. She was Head of the Division of Immunology
from 1976. She made seminal contributions to our understanding of the molecular basis of lymphocyte
responses to proteins, and especially to infectious agents.
Brigitte Askonas
Philip D’Arcy Hart, CBE (1900-2006)
Philip D’Arcy Hart joined the MRC in 1937, working on dust diseases in coal miners, then moved to the
MRC Tuberculosis Research Unit until he retired in 1965. In 1948 he ran the first controlled clinical trial,
to show the efficacy of streptomycin against tuberculosis. A later trial led to the introduction of BCG
vaccination in the UK. After he retired he moved to NIMR with an MRC research grant, working until 2002.
Philip D’Arcy Hart
Robert Edwards, CBE, FRS (1925-)
Robert Edwards worked at NIMR from 1958-1962. During this 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 later work at Cambridge, with Patrick Steptoe, in which
they applied such approaches to humans, thus bringing about the revolution in in vitro fertilisation. For this
later work he received the Nobel Prize for Physiology or Medicine in 2010.
Robert Edwards
Charles Harington, FRS (1897-1972)
Charles Harington was Director of NIMR from 1942-1962, and oversaw the Institute’s move from
Hampstead to Mill Hill. He was an outstanding biochemist who contributed to our understanding of the
thyroid gland and of the hormones it produces, particularly thyroxine. Another achievement was the
synthesis of glutathione, and he undertook pioneering work in immunochemistry. As Director he strongly
encouraged cooperation between scientists working in different departments.
Charles Harington
James Lovelock, CBE, FRS (1919-)
James Lovelock worked at NIMR from 1941-1961. His most important invention
while at the Institute was the electron capture detector, which was able to detect minute amounts of
chemicals. Originally designed for analytical purposes it was also able to detect industrial pollutants in the
atmosphere, alerting the world to the dangers of unchecked pollution. After leaving NIMR he became an
independent scientist and developed the Gaia Hypothesis.
James Lovelock
121
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.
CharlesBangham
Yves-Alain Barde David Barondeau
Zhijian ‘James’ Chen
Peter Cherepanov
Claude Desplan
Chen Dong
WitoldFilipowicz
Richard Flavell
Paul Freemont
Siamon Gordon
John Gurdon
Thierry Heidmann
Brigid Hogan
Michael K Rosen
Sam Li
Mike Malim
Pascal Meier
Christien Merrifield
Ken Murphy
Onora O’Neill
MassimoPalmarini
MicheleParrinello
Susan Pierce
Orly Reiner
Helen Saibil
Yoshiki Sasai
David Tarlinton
KennethZaret
122
Imperial College London
University of Basel, Switzerland
Texas A&M University, USA
University of Texas Southwestern Medical Center, USA
New York University, USA
University of Texas MD Anderson Cancer Center, USA
Friedrich Miescher Institute for Biomedical Research, Switzerland
Yale University, USA
University of Oxford
Gurdon Institute
Institut Gustave Roussy, France
Duke University Medical Center, USA
University of Texas Southwestern Medical Center, USA
University of California San Francisco, USA
King’s College London
Institute of Cancer Research
MRC Laboratory of Molecular Biology, Cambridge
Washington University School of Medicine, USA
Cambridge University and House of Lords
MRC Centre for Virus Research, Glasgow
ETH Zurich, Switzerland
National Institutes of Health, USA
Weizmann Institute of Science, Israel
Birkbeck, University of London
RIKEN Center for Developmental Biology, Japan
Walter and Eliza Hall Institute, Australia
University of Pennsylvania School of Medicine, USA
Staff honours 2011
Prizes and awards
Tim Bliss
Steve Gamblin Steve Gamblin Alex Gould
Robin Holliday Robin Lovell-Badge
Royal Society Croonian Lecturer 2012
Feldberg Prize 2012
Fellow of the Royal Society
Hooke Medal 2011
Royal Society Royal Medal
Fellow of the Society of Biology
Editorial boards
Siew-Lan Ang
Mike Blackman
James Briscoe
John Doorbar
Paul Driscoll
Greg Elgar
RichardGoldstein
Francois Guillemot
Tony Holder
George Kassiotis
Jean Langhorne
Steve Ley
Malcolm Logan
Robin Lovell-Badge
John McCauley
Elke Ober
Anne O’Garra
AnnalisaPastore
AndresRamos
Katrin Rittinger
Ben Seddon
International Journal of Developmental Biology
PLoS Pathogens
Development
Neural Development
Journal of General Virology
Journal of Structural and Functional Genomics
PLoS ONE
Genome Biology and Evolution
Briefings in Functional Genomics
BMC Evolutionary Biology
Journal of Chemical Biology
Protein Engineering, Design and Selection
Genes & Development
Neural Development
BMC Developmental Biology
Eukaryotic Cell
Molecular and Biochemical Parasitology
PLoS ONE
PLoS Pathogens
International Journal of Parasitology
Cell Research
Development
Developmental Dynamics
Biology of Sex Differences
Organogenesis
Sexual Development
Virus Research
Journal of Experimental Medicine
Open Biology
Prion
Journal of Biological Chemistry
PloS ONE
Open Magnetic Resonance Journal
Encyclopaedia of Biophysics
Biochemical Journal
Frontiers in Immunological Memory
123
Staff honours 2011 (cont.)
Jim Smith
Gitta Stockinger
Jonathan Stoye
James Turner
Victor Tybulewicz
Jean-Paul Vincent
Robert Wilkinson
David Wilkinson
Mark Wilson
Douglas Young
Lyle Zimmerman
Open Biology
Biology Image Library
Frontiers in Immunology
Journal of Virology
Biology of Reproduction
Chromosome Research
Immunology
Frontiers in B cell Biology
Frontiers in T cell Biology
Science Signalling
International Journal of Tuberculosis and Lung Disease
Tuberculosis
PLoS One
Mechanisms of Development (Editor in Chief)
Gene Expression Patterns (Editor in Chief)
Faculty of 1000
BMC Developmental Biology
Journal Clinical and Developmental Immunology
Journal of Tropical Diseases
Tuberculosis
genesis: The Journal of Genetics and Development
Scientific Committees and Scientific Advistory Boards (SAB)
Mike Blackman
James Briscoe
Paul Driscoll
Alex Gould
Francois Guillemot
Tony Holder
Ed Hulme
Jean Langhorne
Steve Ley
124
Microbiology, Immunology and Infection Grant Evaluation Panel, Agence Nationale
de la Recherche, France
Company of Biologists
Wellcome Trust Expert Review Group
TB Community Annotation Project Steering Committee (NIH/NIAID)
Henry Wellcome NMR Laboratories, Birmingham University SAB
Wellcome Trust Investigator Awards Selection Panel
UK Metabolic Discussion Group
ERC Advanced Investigator Grants Panel
Peter and Patricia Gruber International Research Award in Neuroscience, selection committee
Heptares Therapeutics SAB
European Virtual Institute for Malaria Research
Hartmut Hoffmann-Berling International Graduate School of Molecular & Cellular Biology,
Heidelberg, Germany SAB
Institut fuer Molekulare Infektionsbiologie, Wuerzburg, Germany SAB
Scientific Subject Matter Expert attached to Laboratory of Malaria Immunology and Vaccines,
NIAID/NIH, USA
MRC Infections & Immunity Board
Robin Lovell-Badge
John McCauley
Justin Molloy
John Offer
Anne O’Garra
AnnalisaPastore
Katrin Rittinger
Steve Smerdon
Jim Smith
Gitta Stockinger
Victor Tybulewicz
Jean-Paul Vincent
Robert Wilkinson
David Wilkinson
BBVA Foundation, Frontiers of Knowledge Award, Jury
Feldberg Prize Committee
Human Fertility and Embryo Authority, Scientific and Clinical Advances Advisory Committee
Royal Society, GSK Prize Committee
Royal Society, Member of Council
Understanding Animal Research, Member of Council
International Committee on Taxonomy of Viruses, Orthomyxovirus study group, Chair
Royal Society & Academy of Medical Sciences, Committee on pandemic influenza
Royal Society of Chemistry, Proteins Group
Keystone Symposia SAB
Baylor Institute for Immunology, Dallas, USA, SAB
Institute for Biomedical Sciences, Bellinzona, Switzerland, SAB
Institute for Molecular Medicine, Lisbon, SAB
World Premier International Research Center, Osaka University, Japan, SAB
MRC/ABPI, UK Inflammation and Immunology Initiative - Steering Group
Biotechnology Institute, Helsinki, Finland, SAB
Deutsche Forschungs Gemeinschaft
TwistDX, SAB
MRC Technology Governing Body
MRC Molecular & Cellular Medicine Board
Diamond Light Source Peer Review Panel
Oxford Protein Production Facility UK, Management Committee
Wellcome Trust/Royal Society Henry Dale Fellowship Committee, Chair
TwistDX, SAB
Wellcome Trust Investigator Awards Selection Panel
Indian Institute of Science Education and Research, SAB
Academy of Finland Grants Panel
ERC Young Investigator Grants Panel
Multiple Sclerosis Society
CRUK Biological Sciences Committee
Atip Grant Panel, Chair
British Society for Cell Biology, Committee Member
Academy of Medical Sciences, Chair Sectional Committee
Wellcome Trust and NIH PhD Programme interview panel
Africa Centre for Health and Population studies, Mtubatuba, Kwa Zulu Natal, South Africa
South African Centre for Epidemiological Modeling and Analysis, Cape Town, South Africa
TB-PANNET European Union
EMBO Long Term Fellowships committee
Welbio Scientific Council
Gene Expression Database Advisory Board
EMAGE Advisory Board
125
PhD theses awarded in 2011
Name
Division
Title of thesis
Alison Gaudion
Lauren Gregory
Dafni Hajieconomou
Samantha Hiew
Virology
Holly Ironfield
Katarzyna Koltowska
Jennifer Lawton
RebeccaLeyland
Parasitology
Gareth Maglennon
Lietta Nicolaides
Virology
Virology
RebeccaPike
Masooma Rasheed
Immunoregulation
Molecular Structure
Ana Ribeiro
Robert Rowlands
Molecular Neuroendocrinology
Valentina Sasselli
The role of the ECF sigma factor SigG in Mycobacterium
tuberculosis
Eph-ephrin signalling in cell sorting and directional migration
Development of a genetic multicolor cell labeling approach
for neural circuit analysis in Drosophila
Examining the biological consequences of DNA damage
caused by irradiated 3T3-J2 fibroblast feeder cells and HPV16
Genetic studies of inner ear development in Xenopus
tropicalis
Molecular and morphological analysis of organ growth and
differentiation during zebrafish embryogenesis
Investigation of the cir gene family in Plasmodium chabaudi
Lineage relationship analysis of lymphoid progenitor subsets in
the bone marrow of naïve mice and during inflammation
Study of latent papillomavirus infection in an animal model
Interactions of the human papillomavirus E6 protein and their
role in the persistence of viral episomes
The role of CD4 T cells in Friend virus infection
NMR characterisation of apo- and ligand-bound states of
bacterial DDAH
Shh signaling and the dynamic pattern of the vertebrate
neural tube
The effects of statin treatment on the synthesis, processing,
storage and exocytosis of von Willebrand factor in cultured
human endothelial cells
The potential role of the Rac signalling and planar vell polarity
pathway in writing of the enteric nervous system
Investigation into the role of PfSUB1 and two perforin-like
proteins in Plasmodium falciparum
The role of Zap70 in thymocyte development
Functional analysis of the serine-threonine protein kinase PknF
and its substrate, the ABC transporter Rv1747, in
Mycobacterium tuberculosis
The roles of Tbx5 and Tbx4 in the symmetrical initiation of
the left and right limb
Computation of protein and cellular architecture from
cryomicroscopy image
Origin and destination of Interleukin-9 producing cells
Natalie Silmon de Monerri Parasitology
126
Charles Sinclair
VictoriaSpivey
Immune Cell Biology
Fatima Sulaiman
Sebastian Wasilewski
Christoph Wilhelm
A – Z list of group leaders
Siew-Lan Ang
Kate Bishop
Mike Blackman
James Briscoe
Paul Burgoyne
Tom Carter
Rita Cha
John Doorbar
Paul Driscoll
Greg Elgar
Eva Frickel
Steve Gamblin
Mike Gilchrist
Richard Goldstein
Alex Gould
Francois Guillemot
Tony Holder
Ed Hulme
George Kassiotis
Jean Langhorne
Steve Ley
Malcolm Logan
Robin Lovell-Badge
John McCauley
Troy Margrie
Tim Mohun
Justin Molloy
72
33
34
80
81
56
82
35
36
57
83
37
38
58
84
59
73
74
39
60
40
41
42
85
86
43
75
87
61
Elke Ober
John Offer
Anne O’Garra
Vassilis Pachnis
Annalisa Pastore
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
88
62
44
76
63
64
65
66
77
45
67
89
46
47
68
69
90
48
91
49
92
50
70
78
51
52
53
93
For current list visit the NIMR website: http://www.nimr.mrc.ac.uk/research/a-z
127
Research themes
Biochemistry
Eva Frickel
Justin Molloy
John Offer
Martin Webb
35
38
61
62
70
56
60
61
66
68
70
Cancer
Rita Cha
Steve Gamblin
Andres Ramos
Steve Smerdon
Jean-Paul Vincent
Martin Webb
82
58
64
67
92
70
Cell biology
Kate Bishop
Mike Blackman
Tom Carter
Rita Cha
Eva Frickel
Tony Holder
Steve Ley
Tim Mohun
Justin Molloy
Elke Ober
Katrin Rittinger
BenedictSeddon
Jim Smith
128
47
90
48
49
92
78
Chromosome biology
Biophysics
Tom Carter
Ed Hulme
Justin Molloy
Peter Rosenthal
Ian Taylor
Martin Webb
Jonathan Stoye
Peter Thorpe
Pavel Tolar
Victor Tybulewicz
Jean-PaulVincent
David Wilkinson
33
34
56
82
38
39
42
87
61
88
65
45
89
Rita Cha
Peter Thorpe
James Turner
82
90
91
Developmental biology
Siew-LanAng
James Briscoe
Paul Burgoyne
Greg Elgar
Mike Gilchrist
Alex Gould
François Guillemot
MalcolmLogan
Robin Lovell-Badge
Tim Mohun
Elke Ober
Vassilis Pachnis
Andres Ramos
Iris Salecker
Jim Smith
Jean-PaulVincent
David Wilkinson
Lyle Zimmerman
72
80
81
83
84
73
74
85
86
87
88
76
64
77
89
92
78
93
Evolutionary biology
Paul Driscoll
Richard Goldstein
MalcolmLogan
Robin Lovell-Badge
57
59
85
86
Genetics and genomics
Siew-LanAng
Paul Burgoyne
Rita Cha
Mike Gilchrist
François Guillemot
MalcolmLogan
Robin Lovell-Badge
Tim Mohun
Elke Ober
Iris Salecker
Jim Smith
Peter Thorpe
James Turner
Victor Tybulewicz
Jean-Paul Vincent
Robert Wilkinson
Mark Wilson
Lyle Zimmerman
72
81
82
84
74
85
86
87
88
77
89
90
91
49
92
51
52
93
Immunity
John Doorbar
Eva Frickel
George Kassiotis
Jean Langhorne
Steve Ley
Anne O’Garra
Andres Ramos
Katrin Rittinger
Benedict Seddon
Gitta Stockinger
Pavel Tolar
Victor Tybulewicz
Andreas Wack
Robert Wilkinson
Mark Wilson
Douglas Young
36
38
40
41
42
44
64
65
45
46
48
49
50
51
52
53
Infectious disease
Kate Bishop
Mike Blackman
John Doorbar
Eva Frickel
Steve Gamblin
Richard Goldstein
Tony Holder
George Kassiotis
Jean Langhorne
John McCauley
Anne O’Garra
Peter Rosenthal
Steve Smerdon
Gitta Stockinger
JonathanStoye
Ian Taylor
Pavel Tolar
Andreas Wack
Robert Wilkinson
Mark Wilson
Douglas Young
33
34
35
36
37
38
58
59
39
40
41
43
44
66
67
46
47
68
48
50
51
52
53
Mathematical biology
Mike Gilchrist
Richard Goldstein
Willie Taylor
84
59
69
Neurosciences
Siew-Lan Ang
James Briscoe
Alex Gould
François Guillemot
Ed Hulme
Troy Margrie
72
80
73
74
60
75
Vassilis Pachnis
Annalisa Pastore
Iris Salecker
David Wilkinson
76
63
77
78
Physiology and metabolism
Siew-LanAng
Tom Carter
Paul Driscoll
Steve Gamblin
Alex Gould
Troy Margrie
Steve Smerdon
Gitta Stockinger
Mark Wilson
72
56
35
57
58
73
75
67
46
52
Willie Taylor
Martin Webb
69
70
Systems biology
James Briscoe
Greg Elgar
Mike Gilchrist
Malcolm Logan
Annalisa Pastore
Douglas Young
80
35
83
37
84
85
63
53
Stem cell biology
Alex Gould
François Guillemot
Robin Lovell-Badge
Vassilis Pachnis
Peter Thorpe
James Turner
David Wilkinson
73
74
86
76
90
91
78
Structural biology
Mike Blackman
Paul Driscoll
Steve Gamblin
Ed Hulme
Annalisa Pastore
Andres Ramos
Katrin Rittinger
Steve Smerdon
JonathanStoye
Ian Taylor
34
57
58
60
63
64
65
67
47
68
129
Current funding sources
The Medical Research Council (MRC) is the principal source of research funding. The budget - currently £42m p.a.- is set every five
years following an Institute-wide review of resources. This review takes place after the five-yearly peer review (conducted by MRC
Research Boards) of the programmes of the individual Divisions.
The Institute also attracts funding support from a wide range of different agencies, including medical research charities, international
sources, particularly the EU, and from industrial and commercial companies:
• A* Singapore
• Academy of Medical Sciences
• Alzheimer Research Trust
• Arthritis Research UK
• Ataxia UK
• Biotechnology and Biological Sciences Research Council
• British Heart Foundation
• Dana Foundation Grant
• Diabetes UK
• Discovery Foundation (South Africa)
• European Molecular Biology Organization
• Engineering and Physical Sciences Research Council
• European Research Council
• European Union, including Marie Curie Fellowships
• Federation of European Microbiological Societies
• Fondation Leducq
• Health Protection Agency
• HIV Research Trust
• International Federation of Pharmaceutical Manufacturers Association
• Imperial College London
• Lady TATA memorial fund
• Leverhulme Trust
• Marshall Foundation
• Medical Research Council
• Medical Research Council Technology
• National Research Foundation of South Africa
• National Institutes of Health, USA
• Parkinsons UK
• Queen Mary University of London
• Royal Society
• Sanofi Pasteur MSD
• Swiss National Science Fund
• The German National Academic Foundation
• University College London
• Wellcome Trust
130
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Nucleic Acids Research 39:2271-85
259. Zhou R, Kunzelmann S, Webb MR and Ha T (2011)
Detecting intramolecular conformational dynamics of single molecules in
short distance range with subnanometer sensitivity.
Nano Letters 11:5482-8
141
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
142
143
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
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London
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MRC National
Institute for Medical
Research
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ay
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M25
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Mill Hill East
Dollis R
M1
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Lan
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Hendon
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ay
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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
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B a r n e t Way
Hi
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M1
A598
Finchley
Central
A5000 Northern Line
to Central London
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Bus number 240 connects NIMR to both Mill Hill East and Mill Hill Broadway stations. Trains run from Mill Hill East station on the
Northern Line into central London. Main line trains run from Mill Hill Broadway station to Luton Airport, Gatwick Airport and St
Pancras station in central London. The M1, M25 and North Circular Road (A406) are within easy reach of NIMR. Onsite parking
is available at NIMR.
144
2011/2012 Annual Report and Prospectus
2011/2012 Annual Report and Prospectus
MRC National Institute
for Medical Research
Science for health

MRC National Institute for Medical Research

Transcription

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