network
News from the
Medical Research Council
Summer 2014
Leading science for better health
Imaging
the
unimaginable
How collaboration and complementary expertise have
given birth to a structural biology breakthrough
Front line operations:
MRC fieldworkers in The Gambia
Opinion:
Why basic research is needed to
understand human disease
Network can also be downloaded as a PDF at:
www.mrc.ac.uk/network
CONTENTS
COMMENT FROM
News
Groundbreaking new research collaboration
3
Welcoming openness on animal research
4
Beat box: open access for all 5
John
Savill
CHIEF EXECUTIVE
People
Prizes, awards and honours NEWS
10
Latest discoveries
New atlas for genome navigation
14
A dietary fibre mystery unravelled 15
Funding
Combatting antimicrobial resistance
20
Next generation regenerative medicine
21
Features
Imaging the unimaginable8
Front line operations12
My work space: Dr Lori Passmore 16
Working life: Dr Richard Coward 18
Opinion: Why basic research is needed to
understand human disease22
On the 25 April, we welcomed the
Chancellor of the Exchequer, the Rt
Hon George Osborne MP, at the MRC
Laboratory of Molecular Biology. In
his speech the Chancellor confirmed
the Government’s commitment to
invest £7bn in capital funding for
research over the next five years,
and launched a consultation on the
future shape of that investment.
This commitment to long-term,
stable funding is good news for medical research, and UK
science overall.
The consultation provides an excellent chance for us to
highlight opportunities for the UK to lead in medical research.
At the recent MRC Directors’ meeting, a large majority
indicated that availability of small and medium range capital
had been a limiting factor since 2010. I therefore encourage
our researchers to respond to the capital consultation.
Our collaboration with AstraZeneca to create a joint research
facility in Cambridge is another exciting development,
representing our strong commitment to supporting
open innovation.
Developments such as these demonstrate our commitment
to long-term investment in UK infrastructure and will help to
keep the UK internationally competitive. They also offer great
opportunities for the science community to decide its own
priorities and speed up the development of new treatments
for diseases, for better health.
Sir John Savill
MRC Chief Executive
The capital consultation, which closes on 4 July,
is available at mrc.io/science-capital-consultation
Groundbreaking new research collaboration
A collaboration between the MRC and AstraZeneca, announced in March,
is aiming to better understand the mechanisms of human disease.
The AstraZeneca MRC UK Centre for Lead Discovery joint research
facility will be created within the new AstraZeneca site at the Cambridge
Biomedical Campus and is due for completion in 2016.
For an initial period of five years, MRC-supported researchers will work
alongside AstraZeneca scientists to identify new methods to better
understand a range of diseases and potential treatment options. The
MRC will fund up to 15 screening projects per year at the new centre.
Sir John Savill, Chief Executive of the MRC, said: “This is a unique
collaboration that will give MRC researchers unparalleled access to
AstraZeneca’s state-of-the-art screening capabilities, world-leading
infrastructure and an extensive, high quality compound library. It is
an exciting move that will fast-track research that might not otherwise
have been carried out, and will ultimately mean better treatments
for patients.”
Universities and Science Minister, the Rt Hon David Willetts MP, said:
“AstraZeneca, one of the world’s largest pharmaceutical companies, has
signaled a huge vote of confidence in our UK science base by selecting
the MRC as their partner of choice for this exciting new collaboration.
Forging these strong business and academic partnerships supports our
Life Sciences Industrial Strategy and is vital in reinforcing the UK's
reputation as a global leader in medical research."
Watch a video about the collaboration here
mrc.io/astrazeneca-collaboration
Long-term science capital investment
On 25 April, Chancellor of the Exchequer, the Rt Hon George Osborne MP, visited the MRC Laboratory
of Molecular Biology (LMB) in Cambridge to announce details of the Government’s £7bn science capital
budget for long-term science capital investment.
Mr Osborne highlighted the LMB’s achievements and ‘fantastic pedigree’
including the discovery of the structure of DNA, nine Nobel Prizes and
various spin-out companies: “You are testament to the world leading
science and innovation that we have in Britain. What you have achieved,
together with the rest of the British scientific community, is one of
Britain’s greatest and most exciting success stories.”
Read about some recent LMB research on page 8 and explore
an LMB researcher’s work space on page 16.
LMB Director, Sir Hugh Pelham, said: “It is very encouraging to hear of a
long-term commitment to science funding, with a real increase in capital
expenditure. This will help to keep the UK internationally competitive,
and offers a great opportunity for the science community to decide its
own priorities.”
Declan Mulkeen, the MRC’s Chief Science Officer, said: “The MRC
particularly welcomes the scope for broad expert input on the science
areas where major facilities are needed, and also on the balance between
very large national level facilities and smaller but more
flexible developments.”
The Chancellor takes questions following his presentation with
Universities and Science Minister, the Rt Hon David Willets MP.
MRCNetwork | 3
NEWS
Welcoming openness on animal research
A Concordat on Openness on Animal Research in the UK published on 14 May has
been signed by the MRC, along with more than 70 organisations from the scientific sector.
To help the public learn more about animal research, the concordat
states that communication about animal research should provide
accurate descriptions of the benefits, harms and limitations of research,
be realistic about the potential research outputs and be open about its
impact on animal welfare and the ethical considerations involved.
In order to demonstrate the impact of European funding on medical
research, MRC Harwell opened its doors to Labour MEP candidates on 30
April. A significant part of MRC Harwell’s large programme of
collaborative research is funded by the European Commission.
Anneliese said: “On top of innovations in healthcare, the facility provides
a huge number of jobs at a range of skill-levels. It shows how British
scientists have been able to take advantage of European funding, to
benefit today's and tomorrow's patients and the regional economy”.
MRC Harwell director Steve Brown said: “It’s crucial that Europe maintains
funding to support the evolution of these initiatives and ensure
continued Europe-wide and international scientific collaboration.”
To find out more, the concordat is available at
www.mrc.ac.uk/animal-research-concordat
Anneliese Dodds, Labour’s elected candidate in the South East for the
European elections on 25 May, joined by fellow candidate John Howarth,
met MRC Harwell and Mary Lyon Centre Directors Steve Brown and Sara
Wells, and Martin Fray, head of the Biological Resources Group at
MRC Harwell.
Beat box: open access for all
MRC research was the topic of the winning entry to the
Europe PubMed Central ‘Access to Understanding’
science writing competition, announced in March.
“Making research open access greatly enhances the
dissemination of discoveries and new ideas, creating a
more responsive and inclusive research environment.”
Early career researchers are asked to write about one of a
selection of research papers published in the Europe
PubMed Central open access archive.
Elizabeth explained: “Even the best scientific experiments
will not have the impact they deserve if their audience
cannot understand the nature or relevance of the
findings. In focusing on our own research, we can
sometimes forget that its purpose may not be clear to
those outside our immediate field of study. It is
important that we are able to communicate this purpose
in a manner tailored to the audience.”
Elizabeth Kirkham, a University of Sheffield PhD student,
won first prize for her article based on a publication by Dr
James Rowe from the MRC Cognition and Brain Sciences
Unit, Cambridge. The research found that part of the
brain involved in Parkinson’s disease is responsible for
how the brain predicts rhythm.
“I was delighted when I learned that Elizabeth had
written about this research, and even more so when it
won,” said Dr Rowe.
Elizabeth Kirkham with Sir Mark Walport,
Government Chief Scientific Advisor,
at the awards ceremony.
The research paper is available here
europepmc.org/articles/PMC3593578 and Elizabeth’s
winning entry, published in eLife, available at
elifesciences.org/content/3/e02658
From left to right: MRC Mary Lyon Centre Director Sara Wells, MEP candidates Anneliese
Dodds and John Howarth and MRC Harwell Director Steve Brown.
Why one size does not fit all
On 2 May, UK Biobank launched its imaging study, inviting participation
from 100,000 adults in the UK. The study will collect images of
participant’s brains, hearts and bones to help predict which factors may
increase the risk of developing dementia.
During any study involving human participants, it is possible that
researchers may make findings with potential health implications for
individual participants. For example, during a brain imaging study,
researchers might identify a brain tumour.
Given the lack of evidence on whether and how findings arising during a
study should be fed back to the participant, we have worked with the
Wellcome Trust and the Health Research Authority, supported by other
scientific and health organisations, to develop a framework to help
researchers and research ethics committees identify and consider the
relevant issues.
Sir John Savill said: “There can be no ‘one size fits all’ policy on whether
to feed back information to study participants. Research contexts vary
widely and so the balance of public and individual harms and benefit
must be assessed on a study-by-study basis. We need further empirical
evidence before we know the best approach to take but in the meantime
it is important that researchers consider these issues carefully.”
Takea
Find out more about the UK Biobank imaging study at
imaging.ukbiobank.ac.uk and watch a video of the first volunteer being
scanned here www.bbc.co.uk/news/health-27253626
Dr Andrew Bastawrous, Research Fellow in international eye health at the
London School of Hygiene and Tropical Medicine, was recently made a
Technology, Entertainment and Design (TED) Fellow.
A commentary on health-related findings in The Lancet, co-authored by
Sir John Savill, is available at mrc.io/uk-funders-framework
He gave an inspirational talk about his portable
eye examination kit, also known as Peek, at the
TED conference in Vancouver. Peek has been
named the winner of the Digital category of
the Designs of the Year awards.
Andrew was inspired with the idea for Peek –
which consists of a mobile app and clip-on
4 | MRCNetwork
hardware that transforms a smartphone into
a portable eye examination tool – while leading
a field trial in Kenya as part of his PhD at
the school.
Find out more and watch the
TED talk here mrc.io/peek-ted-talk
Dr Andrew Bastawrous during Fellows Talks Session 2, TED2014 - The Next
MRCNetwork | 5Canada.
Chapter, Mach 17-21, 2014, Vancouver Convention
Centre, Vancouver,
NEWS
Science festival spotlight
A scientific legacy
Mini Scientists explore
A commemorative meeting to celebrate the future of the
science that Professor David Barker inspired will be held at
Southampton General Hospital on Thursday 18 September.
Registration for the meeting is open until the end of August.
Are there any alien cells on earth? Why do I have dreams? Just some of
the questions asked during the MRC’s Mini Scientists workshop, at the
2014 Edinburgh International Science Festival. More than 1,200 children
were introduced to cells, viruses, public health research, chromosomes
and the intricacies of human hearing. Feedback from children and their
parents was excellent with many being thrilled to meet real
research scientists.
David and his team discovered that common chronic diseases
result from poor nutrition in the womb and his ideas
stimulated worldwide research.
Entrants to the Young Investigator Poster Competition could win
the opportunity to give an oral presentation. The deadline for
entry submission is 8 July.
Register and find instructions on how to enter the poster
competition at www.mrc.soton.ac.uk
Making brains
At the 2014 Oxfordshire Science Festival, visitors of all ages tried their
hands at making a nerve cell or a brain and heard about how the MRC is
funding research into dementias and neurodegenerative diseases. One
young visitor, who made his own brain T-shirt, said: “This is really cool.
Now I know what my brain looks like and I get to show it off to everyone
else.” Another visitor said: “My Dad has Alzheimer’s. It’s been fascinating
and really encouraging to hear about the research you’re doing
into dementia.”
Radiation oncology research
The Cancer Research UK (CRUK)/MRC Gray Institute for Radiation
Oncology and Biology has been renamed the CRUK and MRC Oxford
Institute for Radiation Oncology.
EMPOWERING
women science
in
The MRC National Institute for Medical Research (NIMR) has become
one of the first research institutes to win an Athena SWAN Award.
The Equality Challenge Unit’s Athena SWAN charter celebrates
good practice in recruiting, retaining and promoting women in
science, technology, engineering, maths and medicine (STEMM) in
higher education.
The bronze award recognises the institute’s commitment to supporting
women’s careers in science and their efforts to create a supportive
environment that ultimately benefits everyone.
event: “It has brought together passion, ideas and support from all levels.
Although women-focused, this can only benefit everyone involved
through long-term improvements we’re able to make.”
At the Athena SWAN Research Institutes launch and awards event at the
Royal Society on 1 May, Dr Anne O’Garra, Chair of the MRC NIMR
Self-Assessment Team accepted the award: “The Athena SWAN charter
has been fruitful in giving us tools and a framework to help empower
women to higher level positions and to inform how future institutes can
help support women to take leadership positions across the country.”
All MRC units, institutes and other research institutes are eligible to join
the scheme. The MRC Laboratory for Molecular Cell Biology at UCL has
held a Silver Athena SWAN award since 2010, renewed in 2013 led by
Dr Sara Mole.
Louise Gillic, Head of Human Resources at MRC NIMR, attended the
Read about Anne’s research at the MRC NIMR on page 22
For more information go to www.athenaswan.org.uk
This follows the naming convention for all CRUK institutes, recognising
the joint funding from the MRC.
Institute Director, Professor Gillies McKenna, said: “The CRUK/MRC
Oxford Institute for Radiation Oncology will remain at the forefront
of multidisciplinary research in radiobiology, biophysics and
medical imaging.
Insight into science
Over 100 MRC-funded scientists and staff took part in the 20th
Cambridge Science Festival. Offering a great insight into science,
activities from across the MRC research portfolio demonstrated how
medical research changes lives. Exhibits ranged from ‘Virus Wars’,
‘Marvellous metabolism’ and ‘Don’t just be a statistic’, to looking behind
the scenes of cancer research.
6 | MRCNetwork
“It will maintain its fundamental research focus in DNA repair, the tumour
microenvironment and predictive modelling, as well as training future
researchers. In the clinic, it will continue advanced cancer research
applications and influencing national research protocols and guidelines.”
For more information visit www.rob.ox.ac.uk
OXFORD INSTITUTE FOR RADIATION ONCOLOGY
From left to right: Dr Iris Seckler, Louise Gillic, Dr Anne O’Garra, Chair of NIMR Athena SWAN
Self-Assessment Team, David Ruebain, Chief Executive, Equality Challenge Unit and Amy McGregor.
MRCNetwork | 7
FEATURE
Learn about Venki Ramakrishnan’s Nobel Prize-winning research in our short film, one of a series produced in
2013, to celebrate the MRC’s 100 years of life-changing discoveries www.youtube.co.uk/mrccomms
Imaging
the
Collaboration and complementary expertise have given birth to a
structural biology breakthrough at the MRC Laboratory of Molecular
Biology (LMB), Cambridge. Isabel Baker finds out more.
Advances in biological understanding would be impossible without
structural biology techniques. In turn, biological problems often spur
methodological improvements. “People like Max Perutz were among
the first to realise that you can’t have methods development in a
vacuum, you need important projects to drive the process. It’s only
when you have this combination that things work well,” explains Venki
Ramakrishnan, Deputy Director of the LMB and joint head of the
Structural Studies Division.
Single nucleotides and ions can be distinguished in the density map due to
the high level of structural detail obtained using cryo-electron microscopy.
Venki, who shared the 2009 Nobel Prize for Chemistry for his work on
ribosome structure and function, co-initiated and led the project*.
“In the division we have people interested in microscopy, people
developing computing algorithms to make the best analysis of the
data, along with those looking at important biological problems.
I like to think that our projects are often test beds for improvements
in the microscopy and analysis of the resultant data.”
Many important cellular processes are carried out by large complexes,
difficult to crystallise for structural determination using traditional
methods, such as X-ray crystallography. But by combining their
expertise, the team used electron microscopy (EM) to determine the
structure of the yeast mitochondrial ribosome to an unprecedented
level of detail. This is the first time that EM has yielded the atomic
structure of a large asymmetric complex at such high resolution.
“The project started because of a chance dinner conversation
between John Walker and me,” explains Venki. “John, at the time
the Director of the MRC’s Mitochondrial Biology Unit, shared
the 1997 Nobel Prize for Chemistry for his work on the structure
of the ATP synthase enzyme from mitochondria that makes ATP,
the energy currency of the cell. He said, ‘What about looking at
mitochondrial ribosomes?’”
Ribosomes are large assemblies translating information in our genes
into thousands of proteins critical for cell functioning. Mitochondria
are tiny structures inside our cells, responsible for the production
of energy. Mitochondria have their own small genome which codes
for only a few proteins, made by mitochondrial ribosomes
8 | MRCNetwork
(mitoribosomes). Mitoribosomes are indispensable for life, synthesising
essential proteins within the mitochondria. Many genetic diseases
are caused by defects in mitochondrial components, including
their ribosomes.
The reason why there has, until now, been
no structure of a mitoribosome is because
they are difficult to purify in large amounts.
So John and Venki recruited Alexey Amunts
to work on mitoribosomes.
The structure of the yeast
mitoribosomal large subunit.
At the time, using EM to determine their
structure was unthinkable. EM uses a beam
of electrons to illuminate samples and
produce magnified images. Averaging
thousands of images enables the structural
determination of large macromolecules.
For decades, Wasi Faruqi and Richard
Henderson led the development of better
detectors for EM. “In 1975, when we were
developing early EM methods it became
clear there were more things we could do if
we planned ahead,” says Richard, “So we spent 40 years
developing methods.”
Their work led to the development of the Falcon II detector, in
collaboration with the Max Planck Institutes in Frankfurt and
Martinsried and the Rutherford Appleton laboratory, resulting in its
commercialisation. Richard says: “It’s a mini-revolution in structural
biology. Because we planned these new detectors 10 years ago,
we had ordered all of the equipment three years ago. It works even
better now than we thought it would.”
In parallel, Sjors Scheres was determining how to analyse EM images of
single particles. “The data are better because of a better detector and
you can get more from the data with better statistical algorithms,”
explains Sjors, whose program RELION, is used worldwide.
When Israel Sanchez, in Venki’s group, and Sjors started working
on characterising ribosomes by EM they found they could get to
unprecedented resolutions. So Alexey and Xiaochen Bai, in Sjors’
group, decided to collect data on mitoribosomes.
“Once all the pieces were in place we worked at the microscope for four
days,” says Sjors. “It took one month of image processing using our big
computer cluster, we have 3000 computing cores altogether, which
gives the 3D density distribution map inside the
protein complex – like a big 3D puzzle.”
Solving that 3D puzzle to obtain an atomic
structure took months of work by Alan Brown
and Jose Llácer in Venki’s group, with help from
Tanweer Hussain. Paul Emsley modified his
widely-used model-building program, Coot,
to build new proteins into the EM maps and
optimise their fit.
To ensure chemically correct structures, Garib
Murshudov and Fei Long, modified Garib’s
refinement program, REFMAC. “We saw that we
could help speed up the process, so we adapted
our software for use with EM maps. Conclusions
depend on the validity of data; if the data are
accurate, the model is accurate and you can draw
accurate conclusions,” says Garib.
“This is the first example of using cryo-EM to obtain a resolution high
enough to build an atomic structure of such a large asymmetric
complex without prior knowledge,” says Alexey. “We will now be able to
study different processes of protein synthesis and look at the ribosome
in the context of the membrane.”
“These advances are going to transform structural biology,”
says Venki. “For the first time in 100 years there is an alternative
to X-ray crystallography for obtaining the structures of the large
molecular assemblies that are at the heart of many
biological processes.”
Published online at www.sciencemag.org
*This research was supported by MRC grants MC_
U105184332, MC_UP_A025_1013 and MC_UP_A025_1012;
A Wellcome Trust Senior Investigator award, the Agouron
Institute, and the Jeantet Foundation; and fellowships
from Human Frontiers Science Program, EU FP7 Marie
Curie, FEBS and EMBO.
MRCNetwork | 9
PEOPLE
New appointments
Sir John Savill reappointed as MRC Chief Executive
and Deputy Chair
On 24 March the Universities and Science Minister, the Rt Hon David
Willetts MP, announced the reappointment of Sir John Savill as Chief
Executive and Deputy Chair of the MRC, until 31 March 2016.
Mr Willetts said: “I am delighted that Sir John Savill has been
reappointed as Chief Executive and Deputy Chair of the MRC for a
further term. His extensive experience in academia and the public
sector make him very well placed to continue taking forward the
council’s aim to support world-leading medical science.”
Of his reappointment, Sir John said: “I am delighted to be serving
the MRC as it moves into a second century of discovery for health
and wealth.”
Dr Sara Wells appointed as Director of the
Mary Lyon Centre at MRC Harwell
The Mary Lyon Centre is a national facility supporting research
using genetically altered mice as models of human disease for the
international research community. The Centre works in close
collaboration with the MRC Mammalian Genetics Unit and
MRC Harwell.
Sara joined MRC Harwell in 2002 as Deputy Head of Transgenics and
Mutagenesis. As the first Scientific Manager of the Mary Lyon Centre
when it opened in 2004, she became Head of Operations in 2009,
then Interim Director in 2013.
Sara said: “The future of the Mary Lyon Centre lies in producing the
very best quality mouse models for studying human disease. By
combining the latest in technical developments with excellent animal
care we are helping scientists move closer to understanding some of
the most debilitating genetic illnesses.”
Sir John Savill
10 | MRCNetwork
Dr Sara Wells
Prizes, awards and honours
2014 MRC Fellows of the Royal Society
Professor Amanda Fisher, Director of the
MRC Clinical Sciences Centre, Imperial College
London, has been elected a Fellow for her
pioneering work on HIV pathogenesis,
T lymphocyte development, embryonic stem
cells and epigenetic gene regulation.
May Professor of Medicine, Nuffield Department of Clinical Medicine at the
University of Oxford Professor Rajesh Thakker has been recognised for his
sustained series of major contributions to endocrinology, particularly parathyroid
and renal disorders affecting calcium homeostasis. Raj chairs the MRC/NIHR
Efficacy and Mechanism Evaluation programme panel, working closely with the
MRC’s translational funding programmes to translate research into
clinical efficacy trials.
As Chief Medical Officer for England and Chief
Scientific Adviser for the Department of Health,
MRC Council member Dame Sally Davies has
been elected for the outstanding contribution to
science she has made through her exceptional
leadership in health research.
Astbury Professor of Biophysics, School of Molecular and Cellular
Biology at the University of Leeds, and a member of the MRC’s
Molecular and Cellular Medicine Board Professor Sheena
Radford has been made a Fellow for her seminal contributions to
understanding how the dynamical properties of proteins enable
them to fold and function biologically, or to misfold and cause
degenerative diseases.
Professor Trevor Robbins, Director of the
MRC/Wellcome Trust Behavioural and Clinical
Neuroscience Institute at the University of
Cambridge, has been co-awarded the €1m Brain
Prize by the Grete Lundbeck European Brain
Research Foundation, for his pioneering research
on higher brain functions.
Professor Cyrus Cooper, Professor of
Rheumatology and Director of the MRC
Lifecourse Epidemiology Unit at the University
of Southampton, has been awarded the Pierre
Delmas award, by the International Osteoporosis
Foundation and the European Society for Clinical
and Economic Aspects of Osteoporosis
and Osteoarthritis, to honour his significant
contribution to the field of osteoporosis and
musculoskeletal science.
Dr Karalyn
Patterson
has been elected as
one of the prime
initiators of the field
of cognitive
neuropsychology.
During her 30 years
as a programme leader at the MRC
Cognition and Brain Sciences Unit,
Cambridge, she contributed much of her
ground-breaking work in the areas of
acquired dyslexia and semantic dementia.
2015 Biochemical Society Award Winners
The Biochemical Society awards recognise the excellence of the work of scientists and the
profound implications of their work for the research community and wider society.
• Dr Helen Walden, a principal investigator at the MRC Protein
Phosphorylation and Ubiquitylation Unit at the University of Dundee
has been awarded the Colworth Medal, the most distinguished award
that a biochemical researcher in the early stages of their
independent research can receive in the UK. Helen’s research focuses
on the understanding of a critical biological process called ‘protein
ubiquitylation’, which plays a fundamental role in controlling virtually
all aspects of biology.
• The MRC Clinical Science Centre's Professor David Carling, in the
Cellular Stress Group, has been chosen to give this year's Sir Philip
Randle Lecture. David was awarded the prize for his group's work on
the regulation of energy metabolism by the AMP-activated protein
kinase cascade.
The awards also include two leading MRC-funded scientists at
University College London, Professor of Neuroscience John
Hardy, awarded the Thudichum Medal for his work on neurological
disease, and Dr Nick Lane, awarded the Biochemical Society Award
for his sustained and diverse contribution to the molecular
life sciences.
Three MRC researchers were honoured in the Biochemical Society
Early Career Research Awards, recognising the impact of research
carried out by early career scientists.
• Dr Rozbeh Baradaran, a former PhD student and postdoc
at the MRC Mitochondrial Biology Unit, Cambridge, won the
award for Energy and Metabolism.
• Dr Patricia Muller of the MRC Toxicology Unit, Leicester, a
Programme Leader Track scientist, is leading a group investigating the
role of mutant p53 in invasion and chemo-resistance of cancer cells
and won the award for Genes.
• Dr Paul Elliot of the Protein and Nucleic Acid Chemistry
(PNAC) Division at the MRC LMB Cambridge won the award
for Cell Signalling, for his molecular insights into signal
transduction processes.
Find out more at www.biochemistry.org/Awards/2015AwardWinners
MRCNetwork | 11
Working with communities.
Labelling sample tubes.
FEATURE
OPERATIONS:
MRC
fieldworkers
in The Gambia
The MRC’s unit in The Gambia has an international reputation for groundbreaking research into some of the leading causes of death and disease in
the developing world. Forming the front line of research operations,
fieldworkers carry out a vital role. Ashwin Mehta, from the MRC resilience
team, supports training in the field and explains how the work carried out
by fieldworkers is fundamental to saving lives and improving health.
MRC research operations in The Gambia consist of fieldwork in
communities and clinical work in hospitals and clinics, which generates
samples and data to be used in laboratory research.
As well as interacting with communities to promote the MRC mission and
getting consent from communities to conduct medical research,
fieldworkers are responsible for a wide range of activities from
disseminating health information to collecting data and samples from
people in local communities.
The MRC Unit in The Gambia currently employs more than 300
fieldworkers across three main sites in Fajara, Keneba and Basse.
Fieldworkers are recruited from the local population with the equivalent
of secondary-school education, and trained up on the job.
Mafuji Dibba, Fieldworker Training Manager, has been working in the field
for 30 years and has worked at all three sites: “Fieldworkers’ experience
as they progress gives them a good idea of disease prevention and
treatment. This allows them to serve as advisors in their communities.
Their work helps disease research and public health across many
developing countries, from implementing Haemophilus influenzae type B
(Hib) and pneumococcal vaccine programmes, to preventing bacterial
eye infections such as trachoma through provision of latrines. None of
this can be achieved without fieldworkers, who are the interface
with communities.”
Samba Baldeh, is a Fieldworker Supervisor on the Severe Pneumonia
Studies Platform in Fajara: “I come from a community concerned about
12 | MRCNetwork
Working in the clinic.
get the medicine,” explains Pa Camara, a Fajara fieldworker with 20 years
of experience in TB fieldwork. “People take medicine for two months,
feel better, and stop taking it. They get worse and need to start again.”
Data and sample collection
health. I thought by joining the MRC I could help by disseminating health
information. The community are aware that the MRC contributes
towards national development. This allows me to be well known and
well respected.”
Another important responsibility of the fieldworker is to collect data and
samples from local communities. This includes taking physical body
measurements, demographic data and biological samples for
laboratory analysis.
Consent
Lamin Sanneh is a Field Coordinator working on the Global Fundsponsored TB project in Fajara: “Every Monday I meet community
leaders and tell them about intended programmes in their community
that week. On Wednesday volunteers register, the process is explained,
addresses are taken in case confidential meetings are needed, and
volunteers are given cups for sputum samples. Thursday we collect
samples, which are taken to the lab and tested. Mostly, on Monday or
Tuesday results will come through. Fieldworkers are responsible for
contacting the patients, asking for a confidential meeting, giving them
the news, and a referral letter to the nearest clinic.”
A crucial element of a fieldworker’s role is gaining consent to work in
communities. “Communication is key to every aspect of the MRC’s work,
especially at the field and community level in our setting,” explains
Abdoulie Cham, Community Relations Officer at the unit.
“Good community relations help to prepare the ground before the
fieldworker goes into the community. We advise and help in sensitising
the community before the projects begin and help guide the field teams
in explaining the MRC’s mission. We bridge the gap between the unit and
our stakeholders, working to maintain good relationships with everyone.”
Fama Manneh-Dibba is a fieldworker on the tuberculosis (TB) Reach for
Kids project. Her role includes community sensitisation and gaining
families’ consent for their children to be enrolled. “I do finger prick tests
for malaria in children and Mantoux tests for screening TB,” she says.
Fieldworkers are trusted members of communities and become a focal
point for first-line health advice. “Before people come to a clinic, you
must convince them that TB is an illness, that they must take medicine to
get better, and that they must visit the clinic every day for six months to
Training
High-quality training is essential for this demanding and diverse role. A
year ago, the front-line training model was to train newly recruited
fieldworkers through a 12-week classroom-based tutor-led course. Over
the last year our team have developed a new style of ‘blended learning’
training course incorporating e-learning, problem-based and practical
learning, and peer-discussion workshops. By changing the style of
training, we have improved learning and fieldwork performance and cut
the overall cost of training by a third.
d by M
ikes use
Motorb rs.
e
rk
fieldwo
RC
Taking
measurements.
Pa feels that the IT skills training element of the course is particularly
important. “The time will come when data will be collected on
computers, not on paper, so if you are not using a computer frequently, it
will be difficult.” In parallel with changes in data collection, we hope this
will help to transform the nature of fieldwork in Africa.
We hope this project will enable further development of front line
workers across the MRC, to initiate a paradigm shift towards student-led,
on-demand learning to support high quality medical research.
To find out more about research at MRC Unit, The Gambia visit
www.mrc.gm or read the spring 2014 issue of the unit’s newsletter, TAMA,
available at www.mrc.gm/tama
For information on implementing e-learning or blended learning to
realise efficiency in front-line operations,
contact [email protected]
To learn more about TB research turn to page 22
MRCNetwork | 13
LATEST DISCOVERIES
Organ regenerated by
gene manipulation
New atlas for genome navigation
A dietary fibre
mystery unravelled
Artificial skin grown in the lab
Researchers from the MRC Centre for Regenerative
Medicine, at the University of Edinburgh, have
regenerated the ‘elderly’ organ of a mouse by
manipulating a single protein.
An international team of over 200 researchers,
including scientists from the MRC Institute of
Genetics and Molecular Medicine (IGMM) at the
University of Edinburgh, has produced a DNA map
of how our genetic material is regulated in order to
make the human body work.
MRC Clinical Sciences Centre (CSC) and Imperial
College London researchers have helped unravel a
long-standing mystery about how dietary fibre
supresses appetite.
A team part-funded by the MRC, led by King’s
College London and the San Francisco Veteran
Affairs Medical Center (SFVAMC), has developed
the first lab-grown skin with properties similar to
real skin.
The thymus, located in front of the heart, deteriorates and shrinks
with age, causing the immune system to become less effective at
fighting infection.
By targeting the protein, FOXN1, which helps control how
important genes in the thymus are switched on, the team used
genetically modified mice to increase levels of FOXN1 using
chemical signals. In response, immature cells in the thymus –
similar to stem cells – rebuilt a functioning organ in the older mice,
of similar structure and gene expression to that of the young mice.
This discovery could pave the way for future human therapies and
have broad implications for other areas of regenerative biology.
The three year project, FANTOM5, steered by the RIKEN Center for
Life Science Technologies in Japan, has studied the largest ever set
of cell types and tissues from human and mouse in order to
identify how a network of switches, built into our DNA, controls
where and when certain genes are turned on and off.
All of our cells contain the same instructions, but genes are turned
on and off at different times in different cells. This process is
controlled by switches – called promoters and enhancers – found
within the genome. It is the flicking of these switches that makes a
muscle cell different to a liver or skin cell.
Acetate is released when we digest fibre in the gut and is
transported to the brain where it produces a signal to tell us to
stop eating. By feeding mice on a high-fat diet, with or without
added fibre, the team found that adding fibre caused mice to eat
less and gain less weight; a correspondingly high level of acetate
was found in their guts.
Using positron emission tomography scans, the researchers tracked
acetate through the body and showed that it ended up at the
hypothalamus in the brain, which controls hunger.
Lead author Professor Gary Frost, from Imperial College London,
said: “Our research has shown that release of acetate is central to
how fibre suppresses our appetite and this could help scientists to
tackle overeating.”
Until now, tissue engineers have been unable to grow epidermis in
the lab – the outermost layer of human skin – with the functional
barrier needed for drug testing. Also a limited number of cells can
be grown from a single skin biopsy sample.
The epidermis was grown from human induced pluripotent
stem cells (iPSCs) which produced an unlimited supply of pure
keratinocytes – the predominant cell type in the epidermis.
The resulting 3D epidermis, built using keratinocytes to form a
functional permeability barrier, showed no significant difference
from human epidermis.
Dr Theodora Mauro, who led the SFVAMC team, said: “The ability
to obtain an unlimited number of genetically identical units can be
used to study a range of conditions where the skin’s barrier is
defective due to mutations in genes involved in skin barrier
formation, such as ichthyosis (dry, flaky skin) or atopic dermatitis.”
Professor Clare Blackburn, who led the research, said: “By targeting
a single protein, we have been able to almost completely reverse
age-related shrinking of the thymus. Our results suggest that
targeting the same pathway in humans may improve thymus
function and therefore boost immunity in elderly patients, or those
with a suppressed immune system. However, before we test this in
humans we need to carry out more work to make sure the process
can be tightly controlled.”
Dr Martin Taylor, from the MRC IGMM, said: “The research gives us
an insight as to why humans are different from other animals, even
though we share many genes in common. Comparing the mouse
and human atlases reveals extensive rewiring of gene switches that
has occurred over time, helping us to understand more about how
we have evolved.”
Different types of cells (red and green) in the thymus. Over-expression of Foxn1 is
able to regenerate the aged thymus so that it resembles a young organ.
Structure of human DNA.
The biodistribution of acetate in the brain, liver and heart
determined by PET scanning.
Histology section of epidermis generated from iPS cells.
Published online at dev.biologists.org, April 2014
Published online at www.nature.com, March 2014
Published online at www.nature.com/ncomms, April 2014
Published online at www.cell.com/stem-cell-reports, April 2014
14 | MRCNetwork
MRC CSC co-author, Professor Jimmy Bell, said: “It’s exciting that
we have started to really understand what lies behind fibre’s natural
ability to suppress our appetite and identified acetate as essential
to the process. In the context of the growing rates of obesity in
western countries, the findings of the research could inform
potential methods to prevent weight gain.”
Dr Dusko Ilic, leader of King's College London team, said: “Our new
method can be used to grow much greater quantities of lab-grown
human epidermal equivalents, and thus could be scaled up for
commercial testing of drugs and cosmetics.”
MRCNetwork | 15
MY WORK SPACE
Dr Lori Passmore is head of the
Mechanisms of Macromolecular
Machines group in the Structural
Studies Division at the MRC
Laboratory of Molecular Biology
(LMB). She showed Isabel Baker
around her shiny new office where
she approaches biological questions
using structural biology methods.
Picture of DNA
I have two daughters, aged six and two. This is a picture drawn by my
six-year-old; she drew what she thought DNA might look like. She loves
science, talking about it and asking what I’m working on. I just did a
demonstration using paper
chromatography with her class
at school which was a lot
of fun.
Copper foil
Coasters
These coasters were made
by a friend of mine who
does glass fusing. She’s put
some actual electron
microscopy (EM) grids,
which we use to image
proteins, inside the glass.
Each grid is 3mm in
diameter, made of a disc of metal such as copper or gold, often with a
layer of carbon on top. To use these grids in the lab, we pipette a few
microlitres of protein in solution on top and remove the excess solution,
leaving a thin layer containing the protein. For cryo-EM – where we
freeze the samples at liquid nitrogen temperature to preserve them in
the vacuum of the microscope – the carbon has holes in it. When you
freeze the grid, the protein molecules are trapped in ice suspended
across the holes. We then image the protein, in the suspension of ice
across the grid.
Nobel chocolate coin
These are chocolate coins from a Nobel Prize dinner. In 2009, just after I
was a postdoc with Venki Ramakrishnan, he won the Nobel Prize for his
work on the ribosome. Almost everyone who had worked with him on
ribosomes went to Stockholm. We attended the Nobel Prize lecture,
celebrated with Venki and got to spend a few days together. It was an
exciting time. Venki’s lab has always worked really closely together as a
team. The reunion in Stockholm was a great time to catch up.
16 | MRCNetwork
To find out more visit
www2.mrc-lmb.cam.ac.uk/groups/passmore
Light box
We purify large protein complexes and image them in the microscope. I think
it’s amazing to see individual protein molecules, only 20 nanometres across!
Until two years ago we always took EM images on film. I use this light box and
magnifying glass to look at film images. Each of the spots is an individual
protein complex. Now, new electron detectors mean we don’t have to use
film any more, but occasionally I still look at them. It’s a fascinating time for
EM; in the space of two years it’s been revolutionised.
This is a piece of copper foil with a one carbon atom-thick layer of
graphene on top. We’ve recently started using graphene to help image
proteins in EM. When imaging thin layers of solution, proteins are
attracted to the air-water interface, which damages them. To prevent
damage, we put a layer of carbon on the grid for proteins to stick to.
However carbon can produce lots of background signal. The proteins
also move in the electron
beam resulting in blurry
EM images. Graphene is a
good alternative: it’s
invisible at EM resolutions
and helps reduce
movement. My postdoc,
Chris Russo, has
developed a way to
produce graphene and
make it hydrophilic, so
that proteins can stick to
it, improving the quality of
EM images.†
Folders
Fanconi anaemia (FA) is a rare disorder causing bone marrow failure and
cancer predisposition, due to mutations in genes which code for DNA
repair proteins. A key player in the disease pathway is the large multiprotein FA core complex. Understanding how this complex works
provides insights into processes involved in DNA repair and cancer. A
postdoc in my lab, Eeson Rajendra, has been able to purify the complex
and reconstitute its activity. We’re collaborating with a colleague KJ
Patel, a geneticist and cell biologist, to learn more about its function. It’s
exciting to be able to mix our two quite diverse areas of expertise.*
Helmet
I cycle into the lab every day as I live not too far away. I take my time, I
don’t cycle fast and I have a bit of time to think about my day (and
science) before I get into the lab.
Lab books
I have lots of books including all of my lab notebooks. They’re from
different topics and time periods, even some of my PhD notes are up
there. I still do experiments myself and I really love being in the lab with
my group, not just sitting at my desk. My lab focuses on the large protein
complexes that act on messenger RNAs (mRNA), either to add or remove
their polyA tails. This is important for their translation into protein and for
mRNA stability.
†Published online at mrc.io/nature-methods. Supported by an MRC Centenary
award, MRC grant MC_U105192715 and an ERC starting grant.
*Published online at mrc.io/molecular-cell Supported by an MRC Centenary
award, MRC grants MC_U105192715 and MC_U105178811.
MRCNetwork | 17
WORKING LIFE
Dr Richard Coward, MRC Senior Clinical Fellow and head of research
for the School of Clinical Sciences, University of Bristol
My MRC Senior Clinical Scientist Fellowship enables me to combine clinical and basic scientific work,
allowing me to continue my laboratory and research interests as well as my clinical commitment
to paediatric nephrology.
I was attracted to research at the end of my clinical training. The drive to
do this was because I looked after a patient who had an inherited
condition called congenital nephrotic syndrome, a disorder passed down
through families in which a baby develops massive amounts of protein in
the urine. Soon afterwards it became clear that the podocyte cell, a
beautiful cell in the glomerulus – the filtering unit of the kidney – that
looks like a big octopus, was involved; the gene responsible for the
disorder was discovered to code for a protein located exclusively in
the podocyte.
This motivated me to undertake a PhD studying the molecular biology of
the podocyte. The kidney is the world’s most sophisticated filter,
processing around 180 litres of water and small molecules per day. In
early stage kidney disease the filter can break down, which can cause
essential plasma proteins to leak into the urine and lead to End Stage
Renal Failure (ESRF). Diabetic kidney disease is the leading cause of ESRF
in the developed world and podocyte loss is an excellent predictor of
progression into ESRF.
During my PhD I initially studied a condition called acquired nephrotic
syndrome, however on discovering that podocyte cells were insulinsensitive, I changed my research focus towards the insulin-signalling
pathway in the podocyte and its relevance to kidney disease.
In 2006 I secured an MRC Clinician Scientist Fellowship, which enabled
my family and me to relocate to Canada, to work in the world-leading
glomerular laboratory in Toronto, with Professor Susan Quaggin. There I
generated a model of podocyte insulin resistance in a functional
glomerulus. By making changes to specific genes coding for the major
receptor for insulin in transgenic mice, I produced insulin receptordeficient podocytes. This change caused the mice to develop kidney
disease, revealing that the podocyte needs to be insulin sensitive to work
normally and prevent protein from leaking into the urine.
In 2013 I was awarded an MRC Senior Clinical Fellowship which has
allowed me to reduce my clinical commitment, consolidate my research
and develop my research team. Four weeks per year I still look after the
acute admissions of children from the South West of England with renal
problems, including acute kidney injury requiring dialysis, as well as
children undergoing kidney transplantation. Furthermore I run a clinic in
which I see children with long-term kidney problems who I have been
looking after for many years now.
I really like being able to maintain contact with patients, but it gives me
the flexibility to not be overburdened with a lot of clinical work that
would be detrimental to the research. I find the clinical work really
helpful as is it informs me of the
important, clinically relevant,
The glomerulus, the filtering unit of the kidney,
scientific questions that need to
is encased in podocyte cells.
be answered.
Career in brief
• Trained in medicine.
• Specialised in paediatrics.
• MRC Clinical Scientist Fellowship in paediatric nephrology.
18 | MRCNetwork
A good clinical example is a
disorder called haemolyticuremic syndrome. This usually
occurs when an infection in the
digestive system produces toxic
substances that attack small
blood vessels causing kidney
injury, and in some cases
involves the brain and other
organs of the body. It is the
leading cause of acute kidney
failure in children and has an associated mortality rate of approximately
5 per cent; we think the podocyte may be involved in this process. In an
attempt to prove this – with the help of an MRC-funded Clinical
PhD Fellowship – we have developed a transgenic mouse to mimic
this system.
After returning from Canada I wanted to look at the insulin pathway in
more detail and make my research more translational by looking at
therapeutic targets. Because my work has gone well, I have been invited
to give talks in different parts of the world including Melbourne,
Australia. At the end of my presentation there, someone from
pharmaceutical company Novo Nordisk came up to me and said they had
enjoyed the talk. We started talking, I went over to visit them in
Copenhagen and it has since developed into a postdoctoral
academic fellowship.
Novo Nordisk are excellent collaborators because they’re the biggest
producers of insulin in the world. They have a great deal of experience
and expertise in the insulin and insulin like growth factor signalling
pathways which is very relevant to my research. We want to develop
models to work out how important insulin signalling is in diabetic kidney
disease in humans. I've got full freedom to publish whatever we find and
I’ve got a very experienced postdoc, funded by Novo Nordisk.
Our good relationship with industry is driven by funders like the MRC
looking favourably on people trying to work together with industry, to
translate the benefit of basic scientific discoveries into new therapies to
benefit patients and society.
As told to Isabel Baker
“I find the clinical work really
helpful as is it informs me of
the important, clinically
relevant, scientific questions
that need to be answered”
For more information visit www.bristol.ac.uk
Coming soon: Look out for a short film featuring Richard and his research
on our YouTube channel this summer www.youtube.co.uk/mrccomms
MRCNetwork | 19
For the latest information on MRC funding opportunities,
deadlines and guidance, visit our new website at
www.mrc.ac.uk/funding
FUNDING
Combatting antimicrobial resistance
The MRC, on behalf of the research councils, is
pleased to announce a call for proposals tackling
the rise in antimicrobial resistance.
Proposals will be managed by the MRC and should address the following
four themes: Understanding resistant bacteria in context of the host;
accelerating therapeutic and diagnostics development; understanding
the real world interactions; behaviour within and beyond the health care
setting. A variety of modes of support are available under different themes.
The deadline for proposals is 2 September 2014. For more information
visit www.mrc.ac.uk/amr or email [email protected]
EU support for
stem cell research
On 28 May the European Commission issued a
statement rejecting the ‘One of Us’ Citizens’ Initiative
campaign to end funding of activities that presuppose
the destruction of human embryos, including stem
cell research.
Stem cell research has the potential to lead to the development of
treatments and therapies for patients suffering from many diseases and
illnesses including incurable neurodegenerative conditions as well as
chronic conditions. It is important that all avenues of stem cell research
are kept open and proportionately regulated until scientists are able to
find the optimal techniques and materials to develop therapies. A number
of clinical trials are currently underway in Europe and the US.
Dr Rob Buckle, Director of Science Programmes and Head of Regenerative
Medicine at the MRC said: “The MRC welcomes the response from the
European Commission and its continuing support for funding for stem
cell research, which will help scientists to translate the burgeoning
knowledge in regenerative medicine into new treatment strategies.
During its last Framework Programme the Commission established a
number of collaborative stem cell programmes which have global
recognition, and it was essential that the Commission endorsed its
existing support in this area as any new restrictions could potentially have
been highly damaging to European science and competitiveness.”
Next generation
regenerative medicine
April saw the announcement of a new Immunomodulation Research Hub and disease/systems-focused awards
that together complete the £25m UK Regenerative Medicine Platform (UKRMP) investment programme.
A £2.3m investment by the Biotechnology and Biological Sciences
Research Council, the Engineering and Physical Sciences Research
Council and the MRC will set up a new multidisciplinary research ‘hub’
to address important immune challenges in translational
regenerative medicine as part of the UKRMP.
The Immunomodulation Research Hub will focus on harnessing
immunomodulatory approaches and will complement the
other four hubs established last year. These five strategic
investments will provide the foundation for a world-leading
and integrated programme of activity able to tackle some
of the critical challenges in developing new regenerative
treatments from discoveries made in the laboratory.
In addition, a new £6m investment from the UKRMP in partnership with
Arthritis Research UK and with additional funding from the Dutch Arthritis
Foundation Reumafonds will support five cutting-edge research consortia
at UK research institutions.
Dr Rob Buckle, Director of the UKRMP, Director of Science Programmes
and Head of Regenerative Medicine at the MRC, said: “This investment
through the UKRMP will help us to go much further in developing next
generation regenerative medicine products and treatments to provide
long term benefits and cures for patients. Additionally, these awards will
contribute to the goal of establishing a coordinated and connected
research community as we seek to ensure that the UK retains its position
as a world leader in the field of regenerative medicine.”
Full details are available at www.ukrmp.org.uk
20 | MRCNetwork
MRCNetwork | 21
OPINION
Why basic research is needed to
understand human disease
100 years after the MRC was set up to tackle tuberculosis, Dr Anne
O’Garra, Head of the Division of Immunoregulation at the MRC National
Institute for Medical Research (NIMR) and Professor in infection
immunology at Imperial College, explains why the disease is still a major
human threat but how a better understanding of the immune response
will help improve its management
My research involves using basic research to try and understand the
immune response in tuberculosis (TB), a disease caused by the pathogen
Mycobacterium tuberculosis (M. tuberculosis).
TB is predominantly an infection of the lung, however forms of TB exist
outside of the lungs, including meningitis and lymph node infection.
Active TB causes about 1.4 million deaths worldwide per year. With
approximately 9.4m new cases reported each year, there is still an
untreated mortality rate of 50 per cent.
Of the 2 billion people estimated to have been infected or exposed to M.
tuberculosis and remain asymptomatic, 10 to 20 per cent will reactivate
within their lifetime and go on to develop active disease. However, it is
still not clear why some remain protected and others develop disease.
Furthermore, it is possible that people with what looks like latent TB,
actually have sub-clinical disease and at some point will go on rapidly to
develop active TB.
Despite a century of progress in the field we do not yet clearly
understand what constitutes a protective immune response against
M. tuberculosis infection.
The host-pathogen interaction is extremely complicated. Changes within
the pathogen’s genome can cause outbreaks of disease, while people’s
susceptibility is influenced by genetic, and other, factors such as nutrition
and diabetes.
A major problem is that diagnosis of TB is difficult. There is not yet a
proper test to distinguish between people with latent or active TB. To
diagnose TB, and identify drug resistance, M. tuberculosis needs to be
cultured from the sputum of the individuals, which is not always
available. For diagnosis of extra-pulmonary forms of TB, invasive
procedures are needed, which can be difficult. Other diseases can also
22 | MRCNetwork
present with similar symptoms, such as the autoimmune disease
sarcoidosis, and certain pneumonias or lung cancer.
In terms of protective vaccines, the efficacy of the BCG vaccine is
variable. Effective in protecting children from TB meningitis, it offers
variable and limited protection against adult TB. Many are looking for
new ways of vaccinating against M. tuberculosis but this is a long, hard
road; it takes years to determine whether the vaccine has worked.
Multi-drug resistance is another big challenge. This can result from
people not taking their medication; there are often many pills that must
be taken for six months and a strong regimen of pills can have side
effects and toxicity.
Developing new drugs against TB is important but there are no proper
biomarkers to determine response to treatment. My research is looking
at the immune response by measuring the transcriptional signature – a
set of genes which are changed – in the blood of patients with TB, and
comparing those who are latent with asymptomatic TB (and other
diseases which may be confused with TB on diagnosis), to
healthy individuals.
This TB signature, present in active TB patients in London, is missing from
healthy controls and the majority of latent individuals. In collaboration
with London hospitals and clinician scientist researcher Robert Wilkinson,
based remotely in Cape Town, South Africa but a member of the MRC
NIMR mycobacterial division (led by Douglas Young), we have validated
the signature in patients with TB in South Africa.
A large number of genes are up-regulated or down-regulated in the TB
signature; in order to produce a viable diagnostic test, which can be put
on a simple platform and developed for the clinic, we need to reduce this
number. We're hoping this will allow the development of diagnostic tools
to support current clinical tests, monitor TB treatment and contribute
towards therapeutic strategies for treatment.
The signature is also present in 10 to 20 per cent of the latent individuals
therefore our next goal is to investigate if these people have sub-clinical
disease. By predicting which individuals will progress to active TB it may
be possible to target treatment.
Understanding the type of immune response determining why
individuals infected with M. tuberculosis develop TB, or not, can tell us a
lot. We have identified an interferon-inducible signature in the blood of
active TB patients. Interferons are soluble molecules of the immune
response which can both protect against M. tuberculosis (interferon
gamma) or, as we have recently shown, block the protective response
against infection and exacerbate TB (Type 1 interferon).
Although we've defined some molecules, this is the beginning. Knowing
which inflammatory factors exacerbate disease will help us find
compounds to block these pathways. Further knowledge of immunology
and inflammation in relation to infection generally, can also inform us
about non-communicable diseases, for example diabetes, cancer
and obesity.
The future of TB management will improve by bringing together the
highest level of basic research, in experimental models and human
disease, to better understand the pathogen itself and host immune
factors contributing to protection or disease; at MRC NIMR our expertise
strongly supports these goals.
Philosophical Transactions of the Royal Society: Biological Sciences
recently published a themed issue entitled ‘After 2015: infectious
diseases in a new era of health and development’, compiled and edited
by Christopher Dye and Anne O'Garra.
Read the articles and watch a video podcast at
rstb.royalsocietypublishing.org/content/369/1645.toc
MRCNetwork | 23
YOUR
FEEDBACK
Network is for anyone who has an interest in the work of the
MRC, including scientists, doctors and health professionals
involved in medical research, government departments and
parliamentarians, and university staff and students. The aim is
to provide a quick, easy-to-read summary of activities across
the MRC, from research news through to funding, grant
schemes and policy issues, with pointers to more in-depth
information on websites and in other publications.
We are keen to receive feedback on Network and suggestions
for new features from our readers. So if you have any
comments, please email: [email protected]
Deadline for news items in autumn issue: 13 August.
Deadline for winter issue: 3 November.
Network is produced by the MRC Corporate Affairs Group.
Editor: Isabel Baker
Designer: Vin Kumar
A limited number of copies are available in print.
Network can also be downloaded as a pdf at:
www.mrc.ac.uk/network
IMAGES
Front and back cover: © David Scharf/Science Photo Library
Page 3: © MRC Images
Page 4: © MRC Images
Page 5: Europe PubMed Central
© British Library imaging services, Peek © Ryan Lash
Page 6: © The Barker Family
Page 7: © Eoghan Brennan
Page 8: © Alan Brown and Alexey Amunts
Page 9: © Lesley McKeane and Alexey Amunts
Page 8/9: © Laguna Design/Science Photo Library
Page 10: © MRC Images, Dame Sally Davies © Department of Health
Page 11: Professor Rajesh Thakker © University of Oxford, Professor Sheena
Radford © University of Leeds
Page 12-13: © MRC Images
Page 14: © Nicholas Bredenkamp, © Science Picture Co/Science Photo Library
Page 15: © Gary Frost, © Anastasia Petrova and Dusko Ilic
Page 16-17: © MRC Images
Page 18-19: © MRC Images, © Thomas Deerinck, Ncmir/Science Photo Library
Page 20: © Steve Gschmeissner/Science Photo Library
Page 21: © Dr David Hay and Ms Dagmara Szkolnicka
Page 23: © MRC Images
Medical Research Council (Swindon office)
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Coloured Scanning Electron
Micro-graph of clusters of
microspheres, used to calibrate
optical and electron microscopes.