Translation and
Experimental Medicine
2
UCL SCHOOL OF LIFE AND MEDICAL SCIENCES
Creating knowledge, achieving impact
PREFACE
UCL’s School of Life and Medical
Sciences encompasses arguably the
greatest concentration of biomedical
science and population health expertise
in Europe. Our performance in the UK’s
last Research Assessment Exercise
was outstanding, and for most key
measures the School comfortably
tops UK league tables.
In part because of UCL’s size and
organisational complexity, the scale
of the School’s achievements is not
always apparent. This publication, one
of four, seeks to address this. Our recent
reorganisation, with the creation of four
new Faculties, has been designed to
create a more coherent structure, of
which the Faculty of Medical Sciences,
headed by the Dean, Professor Patrick
Maxwell, is a clear example. But the
School’s restructuring has also placed
great emphasis on cross-Faculty
interactions and interdisciplinary research
– and indeed on interactions with UCL
departments outside the School. Such
interdisciplinary endeavour is promoted
through ‘Domains’, inclusive strategically
led fluid networks. This approach allows
us to connect all our activities related to
translation and experimental medicine,
promoting collaboration and the sharing
of expertise, platforms and resources.
Professor Maxwell is also interim chair
of the Experimental Medicine Domain.
UCL is acutely aware that scientific
advance of real relevance to society is
not only aided by an interdisciplinary
approach but also through collaborative
strategic alliances with other researchintensive institutions with complementary
strengths. Our founding partner status
in the new Francis Crick Institute
engages us in what will be the
European powerhouse of biomedical
research expertise. Our links with our
London Academic Health Science
Centre partners also include our joint
engagement together with the Medical
Research Council in a new imaging
company, Imanova, and our commitment
to the London Life Sciences Concordat.
Wider linkage to the London and South
East super-cluster is secured by our
involvement in the Global Medical
Excellence Cluster (GMEC) for which
we lead in the field of rare diseases.
Our growing collaboration with our
Bloomsbury neighbours, the London
School of Hygiene and Tropical
Medicine, is fuelling exciting
developments in genetic epidemiology
and pathogen research.
The breadth and quality of our research
creates almost unique opportunities.
Our recent merger with the London
School of Pharmacy adds to our capacity
to lead medical advance through
embracing additional talent associated
with drug development, formulation and
adoption. Our highly productive links to
the health service, through UCL Partners,
provides access to unmatched clinical
expertise and large patient groups.
We are fortunate to be partners in three
National Institute for Health Research
(NIHR) Biomedical Research Centres
and a new NIHR Biomedical Research
Unit in dementia, the principal focus
of which is experimental medicine.
The School’s academic environment is
one in which intellectual curiosity can
prosper, while a high priority is also given
to the practical application of knowledge
to improve health and quality of life.
This can take many forms, including
commercialisation of new products as
well as developing and informing health
and social policy, and engaging with
important stakeholders, including the
public. UCL’s wholly owned subsidiary,
UCL Business, ensures that discovery
really does lead to new treatments and
diagnostics and that our translational
endeavour supports the UK’s Life
Sciences Strategy.
This publication, one of four (see right),
showcases some of the outstanding
research in translation and experimental
medicine being carried out within the
School and with collaborators across
UCL and our NHS partners, in London,
nationally and internationally. It is
impossible to be comprehensive, but
the stories give a flavour of the breadth,
quality and impact of the School’s
research in this area. Looking forward,
our aims are to enhance and expand our
research to ensure we remain a global
leader, and to see more people benefit
from the groundbreaking research being
carried out across the School.
Sir John Tooke
Vice-Provost (Health) and Head of the UCL
School of Life and Medical Sciences
1
Basic Life Sciences:
‘Discovery’ research, from
molecules to ecosystems.
2
Translation and
Experimental Medicine:
Driving translation to
benefit patients’ health
and well-being.
3
Neuroscience and
Mental Health:
The science of the brain
and nervous system,
from synapse to social
interactions.
4
Population Health:
Protecting and improving
the health of populations,
UK and globally.
CONTENTS
Overview: Cycles of innovation
2
Driving translation and experimental medicine.
Section 1: Detection, diagnosis and discrimination
4
Using new technologies to identify disease and stratify
patient groups.
Feature: The space to do research
10
Section 2: Small and perfectly formed
12
Small-molecule chemical agents still have an important role to play
in medicine.
Section 3: The cellular route to health
18
Manipulation of cells is an increasingly popular way to achieve
medical benefits.
Feature: Imaging the future
26
Section 4: Repair and regeneration
28
Gene therapy, stem cell treatments and novel biomaterials are
providing innovative new ways to repair damaged tissues.
Feature: Business benefits: Commercialisation
with a conscience
36
Section 5: Translation: The hard and the soft
38
From engineering to implementation, diverse areas of research
can drive the development and uptake of new medical applications.
UCL institutes, support services, partners, funding and sponsors.
46
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
1
CYCLES OF INNOVATION
Driving translation and experimental medicine
Ensuring that new knowledge really does
benefit people is the driving force of
translation. Translation is a multistep process.
For experimental science, the jump to
studies in people – experimental medicine
– is the most challenging step along the
translation pathway.
The explosive growth of
knowledge in biomedical
science has not been
matched by concomitant
improvements in people’s
health and well-being.
‘Translational gaps’ have
been identified, particularly
at the transition from
laboratory research to
studies in people, and the
implementation of validated
treatments into routine
clinical practice. As a result,
translation – and particularly
tackling translational gaps –
has become a major priority.
According to the traditional
view of translation,
new knowledge from
laboratory studies diffused
automatically through
to application. It is now
clear that, although the
concentration of potential
medical advances is very
high, passive diffusion
is frustratingly slow. The
question many are now
wrestling with is, how can
this process be accelerated?
Unfortunately, genuine
translation is very difficult
indeed. It is almost without
exception a long, slow and
expensive process with a
very high rate of failure.
2
In large part this is because
the constraints on the
end-product – what a
new intervention must be
and do – are exceedingly
tight. We expect medical
products to be effective
and safe. The evidence
has to be generated to
this effect before they are
licensed. Before a potential
remedy is tested on people,
we need to be confident
that it is unlikely to harm
them and likely to have a
beneficial effect. Complex
regulatory approvals are
widely recognised to be a
significant impediment to
research.
As always, money is
essential. Pharmaceutical
and healthcare companies
have traditionally funded
later stages of R&D. Biotech
companies have often
been the bridge between
academic research and ‘big
pharma’, with venture capital
or similar support.
The situation is now more
fluid. Funding agencies
have begun to provide
more translational and
development funding (in
the UK, primarily provided
through the Medical
Research Council and the
Wellcome Trust). Charities
Successful translation is almost certainly going
to depend on cross-disciplinary collaboration.
such as Cancer Research
UK and the British Heart
Foundation also fund heavily
in this area. As well as the
MRC, UK Government
translational funding is
also routed through the
National Institute for Health
Research (NIHR), when
work has progressed to
human studies.
chemistry, pharmacokinetics
and pharmacodynamics.
This expertise is more
commonly found in the
commercial sector. Work
in humans also requires
a plethora of regulatory
approvals. Protection of
intellectual property also
needs to be considered.
Money is essential, but so
too is expertise. Translational
research is not the same
as the curiosity-driven
research from which it
derives. Researchers may
be unwilling or unable to
adapt to a more milestonedriven, pragmatic type of
research with a far more
circumscribed endpoint than
research projects typically
enjoy.
Driving on
Of great importance is the
transition to work in humans.
This calls for a background
in medicine, or at the very
least a strong grasp of
human biology and close
collaboration with clinically
qualified researchers or
clinicians. Drug development
calls for specific skills in
areas such as medicinal
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
So much for the challenges:
what can be done to
accelerate translation?
There is no one model that
can secure successful
translation, but there are
some general principles that
can make it more likely.
Successful translation is
almost certainly going to
depend on cross-disciplinary
collaboration – facilitation of
which is a key aim of the UCL
Research Strategy. Clinical
scientists will know about
diseases and treatments
and how they affect patients,
and will have a clearer
sense of the practicalities
of healthcare delivery. Work
on animal models will almost
certainly be necessary;
developing the best models
and understanding what
the results mean to human
disease is essential.
Depending on the condition,
researchers from a wide
range of disciplines may be
required, alongside specialist
support in areas such as
imaging or genetic analysis.
UCL is fortunate in having
many exceptional clinical
academics, the rare group
of individuals whose
expertise and eminence
spans medicine and
research. Also invaluable
are its close relationships
with outstanding clinicians
at UCLH, Great Ormond
Street Hospital, Moorfields
Eye Hospital, the Royal
Free Hospital and others
through UCL Partners.
The strength of these
relationships is reflected in
the £165m five-year funding
awarded in 2011 by the
NIHR, providing continuing
support for the three
existing NIHR Biomedical
Research Centres and a new
Biomedical Research Unit
specialising in dementia.
Indeed, what often
distinguishes translation
is not so much a oneway transition from lab to
application but a two-way
dialogue between clinic
and lab. Clinical problems
and insight set the agenda
for laboratory studies, while
experimental advances
open up opportunities for
application. These synergies
are difficult to establish
unless there is close
integration of laboratory
and clinic, clinician and
researcher.
Furthermore, the balance
of research arguably
needs to shift more towards
experimental studies in
people – both to improve
understanding of disease
processes and to test
new interventions more
efficiently. Proof of concept
can feed back into laboratory
studies or pave the way
for clinical trials.
Such experimental
medicine studies require
specialist facilities. UCL
has outstanding facilities
for such work, through its
partnerships with UCLH,
Great Ormond Street
Hospital and Moorfields
Eye Hospital.
Research in these facilities
– and clinical research
across UCL more generally
– is backed up by extensive
expertise in clinical
research management,
from regulatory approvals
through to research
governance and patient
care. UCL’s clinical trials
units support everything
from small ‘first-in-human’
studies to international
multicentre trials.
UCL has the scope
and breadth – and the
institutional commitment –
to support extensive crossdisciplinary collaborations.
But development often
requires partnerships
with external bodies,
to draw upon expertise
found predominately in the
commercial sector. UCL has
established several highly
successful collaborations
with industry. For example,
GlaxoSmithKline has been a
strong supporter of Professor
Sir Mark Pepys’s work, while
partnerships have been
set up with AstraZeneca,
Pfizer and Roche in eye
research. UCL also works
with numerous biotech
companies, in the UK
and internationally.
A key enabling role is played
by UCL Business plc.
Part of UCL Enterprise, a
UCL-wide drive to promote
innovation, UCLB offers
advice to researchers,
supports intellectual
property protection, provides
translational funding and
establishes licensing
agreements, spinouts and
partnerships.
PEOPLE AT THE HEART
OF TRANSLATION
Translation is often portrayed as a linear process starting with
laboratory discoveries. However, this underplays the important
role played by clinical practice and studies in people to shape
laboratory research and drive translation. Furthermore, results
from pre-clinical development and clinical trials will feed back to
inform future studies. In terms of patient benefits, the importance
of implementation should also not be neglected.
Human
studies
Laboratory
studies
Pre-clinical
Clinical
practice
Trials
Product
Opportunity knocks
The opportunities for
translational research
have never been greater.
Stem cells are offering
an exciting new wave of
treatments, particularly when
combined with advanced
materials. Gene therapy is
at last beginning to fulfil its
enormous promise. UCL has
played a world-leading role
in both these fields.
Other new areas are
emerging. Manipulation of
immune cells is opening new
opportunities in treatment
of cancer and autoimmune
conditions. Exciting
advances in imaging are
enhancing treatments and
accelerating translation.
What is often most exciting
is when these approaches
come together. Gene therapy
is used to alter the behaviour
of stem cells or immune cells.
Materials science improves
the cellular behaviour of
implants. Chemists develop
new tracers for imaging.
Implementation
But translation is not just
about new therapeutics. It is
about using new knowledge
to improve health, and
that knowledge may also
be about brain function
and behaviour, driving
new psychological and
behavioural interventions.
Engineering and
technological advances
also hold potential. Medicine
will continue to depend
on new devices, new
surgical techniques and
new forms of rehabilitation.
Diagnostics and tools to
support stratification of
patient groups will grow
in importance, supporting
the more effective use of
therapeutics.
And the importance of the
second translational gap
should not be overlooked.
New therapeutics are of little
value if they are not used.
Overcoming this gap could
have just as much impact
as a new wonderdrug.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
3
SECTION 1
DETECTION,
DIAGNOSIS AND
DISCRIMINATION
A trend towards more individualised
treatments calls for enhanced ways
to diagnose disease and discriminate
between patients, so treatments
better reflect underlying mechanisms
of disease and the uniqueness of
patients’ physiology.
Chordoma cells containing multiple copies of the brachyury gene (red dots).
POPULATION HEALTH School of Life and Medical Sciences
4
Imaging technologies are a key way to detect and characterise disease non-invasively.
Diagnosis has always been
at the heart of medicine,
guiding the choice of
treatments a patient
receives. Before the advent
of modern medicine, doctors
had to rely on external signs,
inspection of body fluids
and patient descriptions to
arrive at a diagnosis. Modern
medicine, by contrast, can
draw upon a battery of
biochemical, genetic and
imaging technologies.
This trend has led to
increasingly refined
disease categorisations,
ideally that have value in
choice of treatments, and
a shift from symptoms to
underlying causes. A further
important trend has been
towards earlier diagnosis.
For cancer, early diagnosis
can improve survival, as
the cancer can be tackled
before it has chance to
become established in the
body. Pushed to its logical
conclusion, early diagnosis
elides into the territory
of prediction, screening
or identification of at-risk
individuals or groups.
Perhaps the most significant
recent development has
been the growing use
One conclusion from several years’ intense
endeavour, however, is that very few genetic
factors have a large impact on common
conditions.
of genetic and genomic
approaches in analysis
of disease mechanisms.
Furthermore, with the
development of genomewide association studies,
genetic analyses have
moved from being principally
relevant to single-gene
conditions to shed light
on complex, multifactorial
conditions.
One conclusion from several
years’ intense endeavour,
however, is that very few
genetic factors have a
large impact on common
conditions. Genome-wide
association studies have
been highly successful
at revealing pathways
potentially involved in
disease, but have yet to
provide much information
of immediate medical benefit
to individuals.
To date, outside cancer,
genetics has yet to provide
much additional value to
risk prediction for common
conditions. And even when
benefits are possible, it is not
necessarily straightforward
to see them implemented in
practice. Professor Steve
Humphries and colleagues
have demonstrated the value
of testing relatives of people
found to have an inherited
predisposition to high blood
cholesterol levels (familial
hypercholesterolaemia),
but implementation within
the NHS has been patchy
(see page 7).
Another strand of Professor
Humphries’ work illustrates
how improved genetic
understanding, combined
with existing approaches,
could enhance risk-related
clinical decision making.
Coronary heart disease
is a classic multifactorial
condition with many
environmental and genetic
influences. Current practice
is to assign a ‘risk score’
on the basis of an analysis
of these risk factors, with
those at the highest risk put
on preventive treatment.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
5
However, the ‘medium’ risk
category includes large
numbers of patients who
will go on to suffer a heart
attack (more, in fact, than in
the high-risk group, as there
are many more people within
the medium-risk group).
Genetic testing may provide
a way to enhance this ‘risk
stratification’, helping to
identify the people who
appear to be at medium risk
but are, because of their
genetic inheritance, actually
at higher risk1.
A similar approach may be
possible with abdominal
aortic aneurysm, a complex
multifactorial condition in
which the large blood artery
supplying blood to the lower
body swells dangerously,
potentially causing it to
burst. The current approach
is to monitor the size of the
aneurysm by ultrasound
and to repair the vessel
surgically when it reaches
a dangerous size. With
a better understanding
of genetic risk factors,
genetic tests could add
additional risk information to
guide treatment. Professor
Humphries is part of an
international consortium
that has identified the first
genetic risk factors for the
condition through a genomewide association study.
Cancer
As an essentially genetic
disease, cancer has been
at the forefront of efforts
to understand disease
mechanisms in terms
of underlying genetic
defects, and then to use
this information to develop
targeted treatments. In
some cases, single genes
can be highly diagnostic of
particular cancer types –
as with the brachyury gene,
which is an excellent marker
for chordoma, a type of bone
cancer (see page 7).
Professor Gareth Williams
and Dr Kai Stoeber have
6
Image processing algorithms can be used to manipulate and superimpose images of the gut.
tackled the problem from a
different direction, targeting
the core machinery involved
in copying DNA during cell
division. In particular, they
have identified key proteins
associated with different
stages of the cell cycle,
including those linked to the
coordinated start of DNA
synthesis. One application
has been in diagnosis (see
page 8), but the work may
also lead to better use of
existing therapies.
For example, Professor
Williams and Dr Stoeber
have identified combinations
of proteins that indicate
which part of the cell cycle
cells are in (S phase, when
they are synthesising DNA;
M phase, when they are
actively dividing; or G1 or
G2, ‘gap’ phases between
the two). The relative levels
of these markers in tissue
samples provide important
information about the nature
of the underlying cancer.
In breast cancer biopsies,
for example, cancers could
be grouped into three
categories, one of which
had markedly lower survival
rates2. This division was
not apparent in histology,
suggesting that cell cycle
marker analysis could have
significant prognostic value.
Furthermore, many new
cancer agents target specific
stages of the cell cycle,
so this characterisation of
cancers might also be able
to guide treatment. Indeed,
examining treatments given
to each biopsied patient,
Professor Williams and
Dr Stoeber found that a
quarter of patients had been
given additional therapy they
would probably have not
responded to, while half had
not been given medications
from which they might have
benefited.
Genetic profiling is an
increasingly popular
approach in cancer. But
there remains considerable
scope for other methods
to be used to distinguish
cancer types – particularly
imaging-based approaches.
Professor Mark Emberton’s
team, for example, has
used advances in magnetic
resonance imaging (MRI)
to identify potential prostate
cancers for more accurate
analysis by biopsy and to
guide targeted treatment
(see page 8).
Radiology continues to be
a core medical imaging
technology, and new
applications continue to
emerge. Professor Steve
Halligan has led a large
multicentre trial of ‘virtual
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
colonoscopy’ – computed
tomography (CT) scanning
of the colon – to identify
large polyps and established
cancers in patients with
symptoms suggestive of
colon cancer (see pages
26–27). The trial’s findings
are already feeding into
clinical guidelines.
Alongside CT, MRI is
emerging as an increasingly
popular approach, not
least because it does not
use potentially harmful
X-rays. Professor Stuart
Taylor is exploring MRI
use in Crohn’s disease and
other conditions. Other
applications of medical
imaging are discussed
on pages 26–27.
Ultrasound is one of the
screening tools being
assessed in the UK
Collaborative Trial of Ovarian
Cancer Screening, being led
by Professor Usha Menon
(see companion volume
on Population Health).
1 Holmes MV, Harrison S, Talmud PJ,
Hingorani AD, Humphries SE. Utility
of genetic determinants of lipids and
cardiovascular events in assessing risk.
Nat Rev Cardiol. 2011;8(4):207–21.
2 Loddo M et al. Cell-cycle-phase
progression analysis identifies unique
phenotypes of major prognostic and
predictive significance in breast cancer.
Br J Cancer. 2009;100(6):959–70.
Chordoma cells showing multiple copies of the brachyury gene.
Blood vessels in the heart.
A MARKER FOR THE FUTURE
A MISSED OPPORTUNITY
Testing for familial hypercholesterolaemia is now
officially recommended – but that does not mean it is
being implemented.
Around one in 500 people are at significantly increased risk of heart
attack because they carry a gene predisposing them to high levels
of cholesterol in the bloodstream. Without treatment, half of men with
‘familial hypercholesterolaemia (FH)’ will suffer a heart attack before
the age of 55 as will one-third of women by age 60. Furthermore, firstdegree relatives have a 50:50 chance of having inherited an FH gene.
Professor Steve Humphries has done much to identify the genetic
basis of FH, but a possibly greater challenge has been to ensure that
practical use is made of this knowledge.
FH has been one of the most intensively studied genetic conditions
and a great deal is known of its causes. Genetic testing can identify
a significant proportion of FH-causing mutations. Treatments with
cholesterol-lowering statins are highly effective, and someone
identified early in life and treated with statins can expect a full life
expectancy.
Because it is relatively common and treatable, there is much to
be gained from early diagnosis. It is estimated that around 100,000
people in the UK have undiagnosed FH – around six or seven in
a typically sized general practice. Population screening is not
practicable but tracing of close relatives of those diagnosed –
‘cascade’ testing – could pick up a sizeable number of those at risk.
Indeed, Professor Humphries has led pilot studies demonstrating
the feasibility of cascade testing. These studies have also shown that,
although incurring costs during implementation, a testing programme
would generate savings within three years because of the reduced
numbers of heart attacks. The evidence was compelling enough for
the National Institute for Health and Clinical Excellence to recommend
cascade testing in 2008.
Unfortunately, the immediate costs associated with implementation
appear to be acting as a disincentive. In audits carried out for the
Royal College of Physicians, Professor Humphries and colleagues
found very low take-up of cascade testing in the UK – particularly
in England where just 5 per cent of families were being tested.
The result, suggests Professor Humphries, is that one undiagnosed
FH patient suffers a heart attack every day.
Humphries SE et al. Genetic causes of familial hypercholesterolaemia in
patients in the UK: relation to plasma lipid levels and coronary heart disease
risk. J Med Genet. 2006; 43(12):943–9.
Nherera L, Marks D, Minhas R, Thorogood M, Humphries SE.
Probabilistic cost-effectiveness analysis of cascade screening for familial
hypercholesterolaemia using alternative diagnostic and identification
strategies. Heart. 2011;97(14):1175–81.
Taylor A et al. Mutation detection rate and spectrum in familial
hypercholesterolaemia patients in the UK pilot cascade project. Clin Genet.
2010;77(6):572–80.
Hadfield SG et al. Family tracing to identify patients with familial
hypercholesterolaemia: the second audit of the Department of Health
Familial Hypercholesterolaemia Cascade Testing Project. Ann Clin Biochem.
2009;46(Pt 1):24–32.
A gene affecting mouse tail growth is central to a class
of tumours affecting the spine.
Distinguishing different types of cancer is increasingly important
as treatments are tailored to the specific defects in individual
cancers. A notable example is Professor Adrienne Flanagan
and colleagues’ work on chordoma, a rare malignant cancer of
the spine: identification of a specific marker for the tumour has
transformed diagnosis and may yet lead to new therapies.
Cancers have typically been characterised according to
their cellular appearance, but genetic approaches permit
categorisation based on more fundamental properties – the
mutations that have caused cells to become cancerous.
To unpick the genetic basis of a family of bone-related
tumours, Professor Flanagan and colleagues characterised gene
expression in nearly 100 different types of tumour. Interestingly, all
chordomas in the sample showed abnormally high expression of
a gene known as brachyury. In more detailed follow up, high-level
expression was seen in all 53 chordomas tested but in none of
300 control cancers. The brachyury gene is thus a highly specific
marker for chordomas.
The gene, discovered in mice in the 1920s, has an important
role in defining the notochord – a cartilaginous rod-like structure
that serves as a kind of embryonic backbone. Although its role is
complete by the end of embryogenesis, some cells resembling
notochord precursors can persist into adulthood. Potentially,
continued brachyury expression in these cells could cause them
to grow abnormally into a cancer.
Indeed, Professor Flanagan found high brachyury copy
number in around half of sporadic cases examined. Moreover,
reducing brachyury expression in a chordoma cell line inhibited
cell division, suggesting that the gene is important in driving cell
proliferation.
Tests of brachyury expression have rapidly become the key
diagnostic tool for chordomas worldwide. A longer-term possibility
is the development of therapies targeted at brachyury or genes
affected by it.
Professor Flanagan is now collaborating with the Wellcome
Trust Sanger Institute, which is carrying out genome-wide
sequencing on a set of chordomas. The project is being funded
by the US Chordoma Foundation, established by Simone
Sommer, whose son was affected by chordoma, and by Skeletal
Cancer Action Trust, a small charity based at the Royal National
Orthopaedic Hospital. This work has already revealed that a
proportion of cancers are characterised by sudden, catastrophic
rearrangement of chromosomes.
Vujovic S et al. Brachyury, a crucial regulator of notochordal development,
is a novel biomarker for chordomas. J Pathol. 2006;209(2):157–65.
Presneau N et al. Role of the transcription factor T (brachyury) in the
pathogenesis of sporadic chordoma: a genetic and functional-based
study. J Pathol. 2011;223(3):327–35.
Stephens PJ et al. Massive genomic rearrangement acquired in a single
catastrophic event during cancer development. Cell. 2011;144(1):27–40.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
7
Professor Mark Emberton.
VISUALISING THE FUTURE
A VIRTUOUS CYCLE
High-power imaging may be the route to more targeted
treatment of prostate cancer.
Targeting the core mechanisms of cell division may be
the route to better diagnosis and treatment of a wide range
of cancers.
Prostate cancer is common and potentially deadly. So, in theory,
early detection and treatment should be a priority. However,
it typically affects men later in life and they may die of other
causes before it becomes a problem. Moreover, conventional
treatments have serious side-effects. Deciding what to do and
when, therefore, is a considerable headache. Now, Professor
Mark Emberton and colleagues suggest high-resolution
magnetic resonance imaging (MRI) could transform both
diagnosis and treatment.
Clues to the appearance of prostate cancer typically come
from elevated levels of a biochemical marker, prostate-specific
antigen (PSA). But PSA levels give only a crude indicator of
a possible problem. Further information comes from physical
examination and biopsy. The clinical decision then comes down
to ‘active surveillance’ – regular check-ups to see if the cancer
is developing – or radical treatment.
Although treatment might seem like a good option, sideeffects are common and have a major impact on quality of
life. Significant numbers of patients go on to suffer erectile
dysfunction and urinary or bowel problems.
In an ideal world, it would be possible to characterise lesions
more easily and to treat them more effectively. Professor
Emberton suggests both these goals are now within reach.
On the visualisation side, high-resolution MRI provides a way
to categorise lesions. In particular, it provides an alternative to a
biopsy for patients identified by PSA screening – most of whom
won’t actually have a cancer – or undergoing active surveillance,
which includes regular biopsies. When MRI reveals a potentially
serious cancer, a patient can be referred for a biopsy. The result
will be fewer unnecessary biopsies, better biopsies, and better
risk stratification.
Furthermore, knowing the precise location of a lesion raises
the prospect of localised or ‘focal’ therapy of just the cancerous
area. Again, new technologies are offering this precision,
including photodynamic therapy, high-frequency ultrasound
or image-guided radiotherapy.
MRI has performed well in ‘proof of principle’ studies.
It now needs testing in randomised trials, to explore its costeffectiveness and the practicalities of integrating it into an
enhanced clinical care pathway. These are among the aims of
a new multicentre clinical trial, PROMIS, being led by Professor
Emberton.
The recent trend in cancer treatment has been to target the specific
biochemical mechanisms disrupted in cancer cells. Despite a few
notable successes, this approach has turned out to be more challenging
than initially hoped, largely due to the enormous complexity of cellsignalling networks. Around a decade ago, Dr Kai Stoeber and
Professor Gareth Williams suggested a radical alternative: why
not target the machinery of DNA replication, which is common to all
proliferating cells? This seemingly heretical approach has turned out
to be highly fruitful.
When a cell divides, its DNA must be duplicated. This highly
coordinated process is broken down into specific stages – S (synthesis)
phase when new DNA is made and M (mitosis) phase when the cell
divides, with G (gap) phases between the two.
At the start of S phase, replication of DNA begins at several thousand
sites across the genome. DNA synthesis depends on a large complex
of proteins bound to the origins of replication, poised to initiate
replication when a ‘go’ signal is received. Dr Stoeber and Professor
Williams have used a greater understanding of the components of this
‘licensing’ complex to improve cancer treatment (see page 16).
The most developed applications, however, are in cancer detection.
The levels of some components of the licensing complex, such as
the Mcm5 protein, are very good markers of proliferating cells. With
the US company BD Diagnostics, Dr Stoeber and Professor Williams
have developed a detection system for identifying proliferating cells
in cervical smears. This system is significantly better at identifying
abnormal cells than conventional visual screening and may therefore
reduce the incidence of missed smears. A recent trial of several
thousand women using the BD test resulted in 55 per cent fewer
referrals to hospital for more invasive tests.
A second application exploits the layering of cells in epithelia, the
sheets of cells lining the lumen of organs such as gut, bladder and
prostate. In epithelia, proliferating cells are present in lower layers,
generating cells to replace those continuously lost at the surface.
If a cancer is present, however, some cells in the outer layers are
also dividing and, in an organ like the bladder, are shed into the urine.
With Cambridge-based company UroSens Ltd, Dr Stoeber and
Professor Williams have developed a highly sensitive Mcm5 test to
identify proliferating cells in urine samples. The product, currently
undergoing clinical trials, won a 2008 UK Medical Futures Innovation
Award For Cancer. Similar Mcm5 tests are in development for other
tumour types, including oesophageal, pancreatic and prostate cancers.
Rouse P et al. Multi-Parametric Magnetic Resonance Imaging to Rule-In
and Rule-Out Clinically Important Prostate Cancer in Men at Risk:
A Cohort Study. Urol Int. 2011;87(1):49–53.
Williams GH et al. Improved cervical smear assessment using antibodies
against proteins that regulate DNA replication. Proc Natl Acad Sci USA.
1998;95(25):14932–7.
Ahmed HU et al. Characterizing clinically significant prostate cancer
using template prostate mapping biopsy. J Urol. 2011;186(2):458–64.
Stoeber K et al. Diagnosis of genito-urinary tract cancer by detection of
minichromosome maintenance 5 protein in urine sediments. J Natl Cancer Inst.
2002;94(14):1071–9.
Ahmed HU et al. Focal therapy for localized prostate cancer: a phase I/II
trial. J Urol. 2011;185(4):1246–54.
Ahmed HU et al. High-intensity-focused ultrasound in the treatment
of primary prostate cancer: the first UK series. Br J Cancer.
2009;101(1):19–26.
8
Human breast cancer cells dividing.
Dudderidge TJ et al. Diagnosis of prostate cancer by detection of
minichromosome maintenance 5 protein in urine sediments. Br J Cancer.
2010;103(5):701–7.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
A major effort has been underway for many years
to use brain imaging to identify early stages of
neurodegeneration.
Inside the brain
One of the most
challenging areas has
been the early diagnosis
of neurodegenerative
conditions such as
Alzheimer’s disease and
Parkinson’s disease.
By the time symptoms
become apparent,
the brain has already
sustained considerable
damage. Genetic studies
have identified a range of
genetic factors increasing
the risk of such conditions
but they are of diagnostic
value only in the relatively
small proportion of cases
inwhich mutation of a single
gene is responsible for the
condition (see companion
volume on Neuroscience
and Mental Health). An
example is LRRK2, identified
by Professor Nick Wood
and colleagues, where
commercially available
diagnostic tests have been
developed3.
A major effort has been
underway for many years
to use brain imaging to
identify early stages of
neurodegeneration. Brain
imaging has also played
an important role in guiding
surgical interventions for
epilepsy (see companion
volume on Neuroscience
and Mental Health).
Professor John Collinge and
colleagues have developed
a blood test for variant
Creutzfeld–Jakob disease
(vCJD), the human form of
BSE. The condition is usually
picked up late, in its terminal
phases, and confirmed
by brain biopsy. The new
test identified around
three-quarters of cases in
blood samples tested, but
3 Gilks WP et al. A common LRRK2
mutation in idiopathic Parkinson’s
disease. Lancet. 2005;365(9457):415–6.
generated no false positives.
Potentially, the test could
be used to screen donated
blood and prevent onward
infection from people who
are unaware they are carriers
of the condition.
Curiously, the eye might
also provide a glimpse of
deterioration in the brain.
Neurodegeneration also
affects neurons in the retina,
where cell death is easier
to visualise. Early detection
of dying cells might be a
sign not just of eye disease
such as glaucoma but also
neurodegeneration in the
brain (see right).
Biomarkers
Work on brain imaging
and on genetic factors
contributing to common
disease may ultimately have
direct relevance to patients,
but may also accelerate
translation by providing
convenient ‘biomarkers’.
Although therapies aim to
achieve clinical changes,
measuring these changes
can be difficult – they may be
hard to measure, particularly
in a large trial, and they may
take a long time to appear.
Biomarkers are extremely
valuable surrogate markers
that are more convenient
to measure, respond more
quickly, but do still provide
a reliable guide to clinical
improvements.
An important initiative
in this area is the new
£20m Leonard Wolfson
Experimental Neurology
Centre at UCL, which will
focus on experimental
medicine studies across a
range of neurodegenerative
diseases (see companion
volume on Neuroscience
and Mental Health).
Confocal microscope image of cells in the retina.
USING DARC TO SEE THE LIGHT
The eye may provide a window into neurodegeneration
in the brain.
Vision is the principal way we gain information about the world
around us. Yet, as Professor Francesca Cordeiro and colleagues
have discovered, the eye may provide a way of extracting
important information about the brain.
At the heart of the eye’s light-detection system is the retina.
As well as light-detecting photoreceptor cells, rods and cones,
the retina also includes a network of neurons, retinal ganglion
cells (RGCs), that integrate signals before sending them on to
the brain. Loss of these cells, typically due to increased fluid
pressure in the eye, leads to glaucoma – the second most
common form of blindness.
Diagnosis of glaucoma has traditionally been based on
impairment of vision, but this is only apparent once between 20
and 40 per cent of RGCs have already been lost. It also means
that clinical trials are protracted affairs, as it takes years for it to
be clear whether drugs are having any beneficial effect.
To get a better handle on the early stages of glaucoma,
Professor Cordeiro has focused on the RGCs themselves.
Dying cells undergo well-characterised changes and, because
eye fluids are transparent, these processes can be visualised
directly in the eye.
Early in apoptosis (programmed cell death), specific lipids
appear on the surface of cells and can be detected by binding
of a fluorescently labelled protein known as annexin. Other dyes
have been developed to detect cells undergoing necrosis, less
orderly cell death. The reagents used in this approach – known
as ‘DARC’ (detection of apoptosing retinal cells) – are non-toxic
and can be visualised using standard ophthalmological tools.
As well as revealing early stages of glaucoma, DARC may have
wider application. It is becoming clear that neurodegenerative
conditions such as Alzheimer’s disease and Parkinson’s disease
are also accompanied by loss of RGCs. Thus detection of
degenerating cells in the retina may provide a window into
changes in the brain in these conditions. As no good methods
yet exist for early diagnosis, and no convenient biomarkers are
available to assess treatment responses, DARC has enormous
potential in both diagnosis and therapeutic trials.
Plans are in place to apply DARC in phase I glaucoma treatment
trials. A step towards application in neurodegenerative conditions
has come from collaborations with other UCL groups, which have
shown a good correlation between RGC apoptosis and the degree
of neurodegeneration and behavioural abnormalities, in transgenic
models of both Alzheimer’s disease and Parkinson’s disease.
Cordeiro MF et al. Imaging multiple phases of neurodegeneration: a novel
approach to assessing cell death in vivo. Cell Death Dis. 2010;1:e3.
Guo L et al. Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad
Sci USA. 2007;104(33):13444–9.
Cordeiro MF et al. Real-time imaging of single nerve cell apoptosis in
retinal neurodegeneration. Proc Natl Acad Sci USA. 2004;101(36):
13352–6.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
9
Experimental medicine requires high-quality specialist
facilities where research on people can be carried out safely.
UCL has an extensive range of facilities and infrastructure
support for such studies.
THE SPACE TO DO RESEARCH
At some point, translation
of biomedical interventions
requires studies to be carried
out on humans. Experimental
medicine studies are
challenging to conceive,
plan and carry out. The
UK’s regulatory framework
is daunting; studies require
expert medical assistance;
and planning, project
management and analysis all
require specialist expertise.
As well as the intellectual
expertise, UCL also has
excellent facilities and
infrastructure to support
such studies.
The establishment of UCL
Partners, a collaboration
between UCL and NHS
hospitals, demonstrated
UCL’s commitment to
translation. An umbrella
for experimental medicine
studies is provided by UCL’s
three National Institute for
Health Research (NIHR)
Biomedical Research
Centres (BRCs) – at UCLH,
at the Institute of Child
Health/Great Ormond Street
Hospital and at the Institute
of Ophthalmology/Moorfields
Eye Hospital – and the
Biomedical Research Unit
in dementia.
Each site includes dedicated
facilities for patient-based
research, including specially
trained support staff.
The UCLH/UCL Clinical
Research Facility is based
in the Elizabeth Garrett
Anderson wing of UCLH.
Supported by funding from
the NIHR, Wellcome Trust
and Wolfson Foundation,
10
The Somers Clinical Research Facility at Great Ormond Street Hospital.
it includes a 20-bed unit with
associated clinical laboratory
space, dispensary and a trial
pharmacy. The facility has a
particular focus on clinical
studies in cancer.
As well as providing
a bespoke space for
experimental medicine
studies, the UCLH/UCL
Clinical Research Facility
also acts as a centre
of excellence, ensuring
studies rigorously follow
good practice in research
governance and clinical
care. It hosts studies from
a wide range of disciplines,
funded by research
councils, charities and via
collaborations with industry.
At the Institute of Child
Health/Great Ormond Street
Hospital BRC, studies are
carried out in the newly
opened Somers Clinical
Research Facility, which
provides specialist day care
accommodation for children
and young people taking
part in clinical research
studies. Construction was
generously funded by Mrs
Somers and the JN Somers
Charitable Wills Trust
and the Friends of Great
Ormond Street Hospital. The
attractively designed Somers
Clinical Research Facility
includes a play area and a
range of individual clinical
rooms (all named after British
trees). Rooms are equipped
to a high-dependency
standard (and include top
of the range entertainment
equipment).
Clinical research is
supported by the Children’s
Research Nursing team,
working alongside the
regional Medicines for
Children Research Network
team. Research focuses on
three key themes: molecular
basis of childhood diseases
(led by Professor Phil Beales,
see companion publication
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
on Basic Life Sciences),
gene, stem and cellular
therapy (led by Professor
Adrian Thrasher; see page
33), and novel therapies
for childhood diseases (led
by Professor Francesco
Muntoni; see page 30).
Development of the
Institute of Ophthalmology/
Moorfields Eye Hospital
Clinical Research Facility
was supported through
the original £13.5 million
NIHR grant awarded when
the BRC was established.
Work at the facility covers
a range of areas, including
age-related macular
degeneration, diabetes,
glaucoma, and paediatric
ophthalmology, including
inherited eye disease and
ocular surface disease.
The BRC has been the
location of groundbreaking
gene therapy trials (see
page 30) and stem cell
treatments (see page 32).
Part of the UCLH/UCL Clinical Research Facility.
It was the first UK laboratory
accredited by the Medicines
and Healthcare Products
Regulatory Agency (MHRA)
for stem cell transplantation
in the eye.
UCL is a specialist site for
experimental medicine
studies in cancer, being a
designated Experimental
Cancer Medicine Centre
(ECMC), part of a network
of such Centres in the UK.
It carries out a range of
first-in-human and early
phase studies in both solid
tumours and haematological
malignancies. It is currently
participating in 83 trials, of
which UCL is the lead on 49.
Each year, more than 1000
patients are involved
in ECMC studies at UCL.
Supporting research
Gaining approval for
experimental medicine
and other forms of
clinical research is not
straightforward. As well as
the need to secure funds
for such studies, they are
covered by an extensive
and complex regulatory
framework spanning the
healthcare system as well
as academia. UCL’s
Research Support Centre
aims to guide researchers
through these processes.
The Research Support
Centre provides an umbrella
service for research to be
carried out at UCLH and
the Royal Free Hampstead.
It provides professional
expertise in all relevant
areas, including research
management, biostatistics,
finance, contracts and
regulatory affairs. It also
provides research support
to the network of NHS Trusts
associated with UCL.
The Research Support
Centre incorporates the
Joint Research Office,
the management offices
of the UCLH/UCL BRC,
the UCLH/UCL Clinical
Research Facility and the
UCL Clinical Trials Unit. The
latter provides support for
the delivery of clinical trials
across UCL, from conception
to dissemination. Planning
and running a clinical trial is
now so demanding that it is
frequently beyond the scope
of individual investigators.
The CTU provides expert
input into trial design and
data analysis, as well as
practical support in areas
such as regulatory approvals
and project management.
The Research Support
Centre also includes a
Translational Research
Office, which supports
researchers working
at earlier stages in the
development pathway.
It provides specialist support
for researchers looking
Researchers in the Institute for Child Health.
to develop laboratory
research, helping them
design projects, apply for
translational funding and
manage projects. More
generally, it aims to promote
a culture of translation
across UCL.
These core services are
complemented by a cancerspecific facility, the Cancer
Research UK and UCL
Cancer Trials Centre, led
by Professor Jonathan
Ledermann. Founded in
1997 by the amalgamation of
clinical trials groups at UCL
and King’s College London,
the Centre is now one of the
largest cancer trials centres
in the UK and one of nine
accredited clinical trials
units of the National Cancer
Research Institute. The
Centre handles all aspects
of trial design, conduct and
analysis and has a dedicated
group managing legal and
regulatory procedures,
pharmacovigilance and
contracts.
The Centre originally
focused on later stage trials,
particularly multicentre
phase II and III trials but
has increasingly become
involved in earlier stages,
from phase I/II to feasibility
studies. These are carried
out in a range of locations,
including the Experimental
Cancer Medicine Centre
at UCL and the Clinical
Research Facility for earlyphase clinical trials.
Further extensive expertise
in clinical trials exists within
the MRC Clinical Trials
Unit, based within UCL.
Led by Professor Max
Parmar, the Unit coordinates
a wide range of clinical
trials, meta-analyses and
epidemiological studies,
with particular strengths in
infectious disease (especially
HIV/AIDS; see companion
volume on Population Health)
and cancer. Its 200 staff
are currently coordinating
around 60 trials and
other studies.
The Priment Clinical Trials
Unit, led jointly by Professor
Irwin Nazareth and Professor
Michael King, oversees a
range of clinical trials in
primary care and mental
health. A collaboration
between UCL and the MRC
General Practice Research
Framework, Priment has
particular strengths in
studies of mental health
and ageing (see companion
volume on Population
Health).
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
11
SECTION 2
SMALL AND
PERFECTLY
FORMED
Small molecules have been the mainstay of
pharmacological development for many years.
Thanks to UCL research, several promising
compounds are in the pipeline, while new uses
are being found for existing drugs.
Molecular models of C-reactive protein, one of the pentraxin family of proteins.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
12
Cultured nerve cells responding to trauma.
Drug development has
traditionally been based
on the development of
small-molecule agents that
interfere with the biological
actions of target molecules.
Small molecules have the
advantage of being easier to
synthesise on an industrial
scale, and they tend to be
more stable and easier to
analyse chemically.
The first step is to identify
target molecules playing
important roles in disease
processes. Huge libraries
of chemicals can then be
screened to identify agents
that bind to the target,
generating lead compounds
for further development.
More directed approaches
can also be used, with
agents specifically designed
to bind target proteins.
Professor David Selwood
used this approach to
design a chemical inhibitor
of neuropilin-1, starting
with the structure of a short
peptide known to bind
specifically to neuropilin-1.
An understanding of the key
points of interaction enabled
Professor Selwood’s team to
develop an inhibitor whose
Small molecules have the advantage of being
easier to synthesise on an industrial scale.
backbone mimicked the
structure of the natural ligand
(see page 17).
Bespoke design was also
the basis of development of
a drug-targeting chemical.
The ‘small-molecule carrier’
or ‘SMoC’ is based on
an alpha-helical peptide
domain4. The synthetic
version has been used to
deliver an inhibitor of the cell
cycle, geminin, into cancer
cells, and is being adapted
to deliver RNA-based
therapeutics.
Encouraging progress is also
being made in a range of
drugs for multiple sclerosis.
Sodium channel blockers
are being tested as a way
to protect neurons, while
a second agent, VSN16R,
has shown promise as a
way of treating muscular
spasms that affect people
with multiple sclerosis.
Development of VSN16R is
being taken forward by a
spinout company, Canbex
Therapeutics, which has
received translational
funding from the Wellcome
Trust and others. Clinical
trials are due to begin
shortly.
Professor Sir Mark Pepys
has had a long-standing
interest in a family of
molecules known as
pentraxins, which have a
characteristic pentameric
structure. Believed to have a
role in both defence against
infections and handling of
debris from the body’s own
tissues, they are potential
targets for treatment of a
range of human conditions.
For decades, Professor
Pepys has received MRC
funding for work on the
pentraxins C-reactive
protein and serum amyloid
P component (SAP).
The latter is implicated
in the potentially fatal
condition systemic
amyloidosis, in which
4 Okuyama M et al. Small-molecule
mimics of an alpha-helix for efficient
transport of proteins into cells. Nature
Methods. 2007;4(2):153–9.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
13
Cross-linking of serum amyloid P component by CPHPC (centre).
Gap junctions, stained blue and green.
OUT OF CIRCULATION
CONNEXINS FOR HEALTH
By fishing its target out of the bloodstream, a ‘palindromic’
chemical has opened the door to treatment of amyloidosis.
Studies of cell–cell communication in chick development
have opened the door to a highly promising wound-healing
treatment.
For more than 30 years, Professor Sir Mark Pepys has doggedly
pursued possible therapies for systemic amyloidosis, a potentially
fatal condition in which abnormal protein deposits (amyloid)
accumulate within body tissues. The agent he developed to tackle
these deposits had unexpected effects, but has nonetheless
opened up a way to target amyloid – and may even be of use
in Alzheimer’s disease.
Systemic amyloidosis is rare, responsible for around one in
every 1000 deaths in the UK. Although abnormal proteins are
normally disposed of rapidly, for some reason amyloid deposits
evade the body’s surveillance systems.
Professor Pepys’s interest centred on a protein, serum amyloid
P component (SAP), found associated with amyloid deposits, as
well as free in the bloodstream. In the mid-1980s, Professor Pepys
suggested that SAP might be contributing to amyloid disease,
coating the amyloid fibrils so they were rendered invisible to the
cells that normally clear debris from tissues.
Following this line of reasoning, Professor Pepys teamed up
with Roche to develop agents targeting SAP. Screening of a
large chemical library led to the development of a new chemical
entity, a palindromic drug, CPHPC. Although designed to block
the interaction between SAP and amyloid, CPHPC unexpectedly
led to the rapid clearance of SAP by the liver, almost completely
eliminating SAP from the bloodstream.
In early clinical studies, CPHPC prevented amyloid deposits
from growing. Unfortunately, CPHPC did not lead to clearance of
existing amyloid deposits, possibly because it did not strip away
all the SAP bound to amyloid in tissues.
However, with no circulating SAP, amyloid-bound SAP could
be targeted with anti-SAP antibodies. In exciting work on mice
engineered to make human SAP, treatment with CPHPC followed
by anti-SAP antibody led to rapid elimination of massive amyloid
deposits with no adverse effects.
Professor Pepys is now working with GlaxoSmithKline to
develop the new treatment for clinical trials. Furthermore, with
UCL’s Professor Martin Rossor, Professor Pepys has also shown
that CPHPC rapidly removes SAP not just from the bloodstream
but also from the cerebrospinal fluid in Alzheimer’s disease
patients. The proof-of-principle study suggests that targeting
SAP could be a fruitful strategy for Alzheimer’s disease.
Pepys MB et al. Targeted pharmacological depletion of serum
amyloid P component for treatment of human amyloidosis. Nature.
2002;417(6886):254–9.
Bodin K et al. Antibodies to human serum amyloid P component eliminate
visceral amyloid deposits. Nature. 2010;468(7320):93–7.
Kolstoe SE et al. Molecular dissection of Alzheimer’s disease
neuropathology by depletion of serum amyloid P component. Proc Natl
Acad Sci USA. 2009;106(18):7619–23.
14
A developmental biologist by background, Professor David Becker’s
interests lay in ‘gap junctions’, the hollow-tubed rivets that connect
cells together. These channels are formed by complexes of a family
of proteins known as connexins. One member of this family, connexin
43, has turned out to be important not just in development but also
in wound healing, and agents that target it look set to make a major
impact on treatment of hard-to-heal ulcers.
During wound healing, levels of connexin 43 fall in cells that need to
migrate to close the wound and rise in blood vessels as they become
inflamed. Excessive inflammation can actually inhibit wound healing,
so inhibition of connexin 43 might both enhance repair processes
and limit unwanted inflammatory responses, speeding up healing.
To test this idea, Professor Becker used a rapidly degraded
antisense DNA molecule to knockdown connexin 43 levels in
localised areas for short periods. He applied the DNA in a ‘Pluronic’
gel, which is liquid when cold but rapidly sets at body temperatures
and slowly releases the antisense DNA over time.
The results were striking: knocking down connexin 43 accelerated
cell migration and reduced inflammatory responses. Wounds healed
quicker and more cleanly.
With support from investors in North America and Australia,
Professor Becker has set up a company, CoDa Therapeutics, to
develop a commercial product, Nexagon. As well as anti-scarring
treatment, the area of biggest unmet need is hard-to-heal ulcers,
such as venous ulcers, pressure sores and diabetic foot ulcers.
It turned out that connexin 43 levels are abnormally high in these
conditions, causing cell migration to stall at the edge of wounds.
Clinical trials on venous ulcers have generated impressive results –
after just three applications over four weeks, Nexagon reduced the
size of venous leg ulcers by 69 per cent, and the complete healing
rate of 31 per cent was five times that seen in controls.
Furthermore, the product has already been making a medical
difference. It has been given ‘compassionate use approval’ for
situations where no other treatments are available, and saved the
sight of a construction worker in New Zealand whose cornea had
been destroyed by a chemical burn. It has also been granted FDA
orphan drug status for persistent epithelial defects in the eye.
Wang CM, Lincoln J, Cook JE, Becker DL. Abnormal connexin expression
underlies delayed wound healing in diabetic skin. Diabetes. 2007;56(11):
2809–17.
Mori R, Power KT, Wang CM, Martin P, Becker DL. Acute downregulation
of connexin43 at wound sites leads to a reduced inflammatory response,
enhanced keratinocyte proliferation and wound fibroblast migration.
J Cell Sci. 2006;119(Pt 24):5193–203.
Qiu C et al. Targeting connexin43 expression accelerates the rate of wound
repair. Curr Biol. 2003;13(19):1697–703.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
discoveries to feed into drug
development pipelines.
Macrophages engulfing amyloid deposits in mouse spleen after anti-SAP treatment.
aggregated fibrils of
misfolded proteins
accumulate in and damage
organs and tissues of the
body. Amyloid deposits
are also seen in other
conditions, most notably
Alzheimer’s disease and
type II diabetes, though their
exact contribution to these
diseases is unclear.
Professor Pepys is a world
authority on systemic
amyloidosis. With longterm support from the UK
Department of Health, he
has established the national
referral centre for the
condition, the NHS National
Amyloidosis Centre, located
within the UCL Centre for
Amyloidosis and Acute
Phase Proteins, which sees
over 2000 patients per year,
including around 500 new
cases.
The Centre has had a major
impact. Improved clinical
management has extended
lifespan from around 18
months from diagnosis to
several years. Professor
Pepys also developed the
first non-invasive diagnostic
imaging procedure
for amyloidosis, SAP
scintigraphy. It has been
routinely used in the Centre
for over 20 years for the
diagnosis and monitoring
of disease progression.
He has also undertaken the
more challenging task of
developing agents to treat
amyloid conditions. After
the initial development, in
collaboration with Roche,
of a specific drug to
target SAP (see page 14),
Professor Pepys continued
to work on the compound
and eventually all the
intellectual property was
divested in 2008 to a UCL
spin-out company, Pentraxin
Therapeutics Ltd, set up
by UCL Business to hold
all his IP and proprietary
knowledge.
Recently, pharmaceutical
companies have become
more willing to invest in rare
diseases and to collaborate
with academia on drug
discovery. Professor Pepys
has gone on to establish a
highly successful relationship
with GlaxoSmithKline,
who licensed the invention
of CPHPC and anti-SAP
antibody for treatment of
systemic amyloidosis. In
a powerful new approach
to drug development, the
new treatment is being
progressed towards
clinical trials in a very close
collaboration between the
company and the group
at UCL.
Highly promising results
have also been obtained in
transthyretin amyloidosis,
a rare form of the disease
in which amyloid deposits
are formed by misfolding
and aggregation of
transthyretin, a normal blood
protein. Unexpectedly,
palindromic agents designed
to crosslink and deplete
transthyretin from the
blood, as CPHPC does
with SAP (see page 14),
instead were bound avidly
by the protein, preventing
amyloid formation5. The
‘superstabilisers’ are highly
promising lead compounds
for drug development and
have been licensed for
collaborative development
with UCL by GSK, who have
tagged Professor Pepys their
first ‘academic superstar’.
While most amyloidrelated diseases are rare,
Alzheimer’s disease is
not. Preliminary work has
shown that targeting SAP
has promise (see page 14),
and current experimental
studies in collaboration
with neurophysiologists
at UCL are providing very
encouraging results which
strongly support early
clinical trials.
Working with the
pharmaceutical industry
is necessary in order to
develop safe and effective
drugs and bring them to
market. This specialist
expertise is still found almost
exclusively in industry.
As business models
change, and pharma looks
increasingly to academia
for new ideas, there is
plenty of scope for more
Although proteins are
the usual targets of small
chemical agents, it is
also possible to direct
therapeutics at earlier
points in the pathway from
gene to protein. Professor
David Becker, for example,
has drawn on his use of
small RNAs to ‘knockdown’
expression of specific genes
in embryonic development
to create agents that lower
levels of connexin 43 at
the site of tissue injury, to
promote wound healing.
RNA is delivered in a
paste that is fluid at low
temperatures but sets when
warmed; it can be stored in
a fridge then smeared onto
a wound, where it sets. Initial
clinical trials on hard-toheal ulcers have generated
extremely promising results
(see page 14).
Liver failure is the focus of
a promising agent initially
studied by Professor
Rajiv Jalan and now being
developed under licence
by a US company, Ocera
Therapeutics, Inc. The
bloodstream of patients
with liver failure or cirrhosis
often accumulates to
high levels, which can
affect the brain, causing
coma and disorientation
(hepatic encephalopathy).
The agent developed by
Professor Jalan, ornithine
phenylacetate (OCR-002),
directly reduces circulating
ammonia levels. Following
successful pre-clinical
development and phase I
trials, OCR-002 has been
awarded orphan drug status
and fast-track designation
in the USA to accelerate its
development, in view of the
lack of effective treatments
for hepatic encephalopathy.
5 Kolstoe SE et al. Trapping of
palindromic ligands within native
transthyretin prevents amyloid
formation. Proc Natl Acad Sci USA.
2010;107(47):20483–8.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
15
Cancer
Despite the growth of
biological and other
novel treatments,
chemotherapeutic agents
are likely to remain central
to the oncologist’s armoury.
A number of UCL groups
are working on early-stage
agents with promise in
cancer. Professor Gareth
Williams and Dr Kai Stoeber,
for example, are targeting
components of the cell cycle,
including Cdc7 as a possible
route to treatment of ovarian
cancer6. Blood vessel
formation (angiogenesis) is
a well-characterised target
process in cancer, as new
blood vessel growth is
required for tumours to grow.
As well as biological agents
interfering with angiogenesis,
Professor John Greenwood
is also screening for smallmolecule inhibitors of LRG1,
which seems to be involved
in growth of new vessels in
adults (see page 17).
Clinical trials are essential
to drug development. The
Cancer Research UK and
UCL Cancer Trials Centre
is one of the UK’s largest
cancer clinical trials centres
in the UK, and one of nine
accredited by the UK’s
National Cancer Research
Institute. Its 50 or so current
clinical trials cover surgical
and radiotherapeutic
approaches as well as
chemotherapy, and early
safety trials as well as
multicentre phase III studies.
Trials are carried out at UCL
facilities (see page 10) and
other sites.
Notable trials have included
groundbreaking studies of
non-small cell lung cancer,
Study 11, which showed
improved survival with
use of gemcitabine and
carboplatin, as well as fewer
side-effects, which led to
changes in recommended
treatment7. The ABC series of
trials demonstrated the value
of the same combination
16
in advanced biliary tract
cancer 8. Follow-on trials,
ABC-03 and ABC-04, are
now examining whether
additional agents can
enhance survival still further.
Although other treatments
are available, tamoxifen is
still widely used globally
in breast cancer. A large,
long-term study showed that
treatment with tamoxifen for
five years rather than two
reduced the chances of
dying or developing cancer
in the opposite breast 9.
As an unexpected bonus,
tamoxifen also reduced
the chances of dying from
heart disease. Effects were
greatest in younger women
(those aged 50–59 at time
of diagnosis). The results
should encourage women to
complete five-year courses,
while the heart disease
benefits may also influence
choice of treatment.
Chemotherapy can often
be of benefit in combination
with other approaches, such
as radiotherapy. The first
UKCCCR Anal Cancer Trial
(ACT I), for example, found
that radiotherapy combined
with use of 5-fluorouracil
and mitomycin C was better
than radiotherapy alone for
epidermoid anal cancer –
benefits recently confirmed
in a long-term follow up
12 years after treatment,
with risk of death from anal
cancer reduced by almost
a third10. After 12 years, for
every 100 patients receiving
chemotherapy on top of
radiotherapy, there were 25
fewer with local recurrence
and 12 more who were alive
and relapse-free. These
and other results led to the
adoption of chemoradiation
as the therapy of choice
worldwide.
same time as radiotherapy
but, contrary to expectations,
not when used after
radiotherapy11. Head and
neck cancers are becoming
more common, mainly
because of tobacco use
and alcohol consumption.
After ten years, for every 100
patients receiving combined
therapy, there were around
10 fewer patients who
suffered a recurrence, a new
tumour, or died. The trial was
important in demonstrating
the value of affordable, welltolerated agents, suitable
for patients who are often
in poor general health and
cannot be given platinumbased drugs.
Important trials of cancer
treatments are also
coordinated by the Medical
Research Council Clinical
Trials Unit, which is based
at UCL. One significant
resent study found that
there was no survival
disadvantage associated
with delayed chemotherapy
in ovarian cancer12. Relapse
is common in women with
advanced ovarian cancer,
and is usually detected
by increased levels of a
bloodstream marker. The
MRC-funded multicentre
international OVO5 trial found
that delaying treatment until
symptoms appeared did not
affect survival. Potentially,
this could allow women
a longer period of grace
before they begin debilitating
chemotherapy.
Similarly, 10-year follow-up
of the UK Head and Neck
(UKHAN1) trial, of nearly
100 patients, found that
chemotherapy improved
outcomes when used at the
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
6 Kulkarni AA et al. Cdc7 kinase is
a predictor of survival and a novel
therapeutic target in epithelial
ovarian carcinoma. Clin Cancer Res.
2009;15(7):2417–25.
7 Rudd RM et al. Gemcitabine plus
carboplatin versus mitomycin,
ifosfamide, and cisplatin in patients
with stage IIIB or IV non-small-cell lung
cancer: a phase III randomized study
of the London Lung Cancer Group.
J Clin Oncol. 2005;23(1):142–53.
8 Valle J et al. Cisplatin plus
gemcitabine versus gemcitabine for
biliary tract cancer. N Engl J Med.
2010;362(14):1273-81.
9 Hackshaw A et al. Long-term benefits
of 5 years of tamoxifen: 10-year follow-up
of a large randomized trial in women at
least 50 years of age with early breast
cancer. J Clin Oncol. 2011;29(13):
1657–63.
10 Northover J et al. Chemoradiation for
the treatment of epidermoid anal cancer:
13-year follow-up of the first randomised
UKCCCR Anal Cancer Trial (ACT I).
Br J Cancer. 2010;102(7):1123–8.
11 Tobias JS et al. Chemoradiotherapy
for locally advanced head and neck
cancer: 10-year follow-up of the UK
Head and Neck (UKHAN1) trial.
Lancet Oncol. 2010;11(1):66–74.
12 Rustin GJ et al. Early versus
delayed treatment of relapsed
ovarian cancer (MRC OV05/EORTC
55955): a randomised trial. Lancet.
2010;376(9747):1155–63.
Mouse retina with oxygen-induced retinopathy.
A developmental drug binding to neuropilin-1.
A GROWING PROBLEM
THREE STRIKES AND OUT
Work on a rare inherited eye disease has led to a
potential new treatment for common forms of blindness,
and possibly cancer as well.
A promising new drug may have a triple whammy effect
on tumours.
In 2005, Professor John Greenwood was approached to see if
he would be willing to contribute to an international consortium
investigating a rare inherited eye condition, macular telangiectasia,
supported by substantial philanthropic funding from a family
affected by the disease. Unusually, the ‘no strings’ funding
enabled Professor Greenwood, with his collaborator Professor
Steve Moss and postdoc Xiaomeng Wang, to undertake the kind
of exploratory study few conventional funding mechanisms will
support. It turned out to be a highly productive exercise.
Rather than the ‘approved’ hypothesis-driven approach, the
group looked for vascular genes whose activity was altered in four
eye conditions characterised by abnormal blood vessel growth.
The screen turned up 62 genes, with the biggest change seen
in an obscure gene, LRG1, coding for a secreted protein of
unknown function.
Delving deeper, the group discovered that LRG1 was a
powerful stimulator of new blood vessel formation across a range
of assays. It was a surprise, therefore, when LRG1 knockout mice
showed few abnormalities in blood vessel formation.
Biochemical studies provided an answer to this paradox.
LRG1 modifies transforming growth factor (TGF ) signalling in
endothelial cells by altering the composition of TGF receptors
recruited to the receptor complex on the cell surface. This
results in a switch in TGF intracellular signalling away from a
predominantly homeostatic pathway towards one that is proangiogenic.
While blood vessel development in embryogenesis is very
finely controlled, in pathogenic settings in adults it is more
chaotic, creating ‘disorganised networks of vessels that contribute
to pathology. LRG1 appears to promote this pathogenic
vessel formation but has much less influence on physiological
angiogenesis.
With translational funding from the MRC, Professor Greenwood
and Professor Moss are generating an LRG1-blocking monoclonal
antibody, as a possible therapy for conditions such as the wet
form of age-related macular degeneration, the most common form
of blindness in older people, and proliferative diabetic retinopathy.
But anti-angiogenic agents are also used to treat cancer, and
Professors Greenwood and Moss are also exploring the potential
of anti-LRG1 agents in various cancer models. Since smallmolecule inhibitors would be more suitable for cancer treatment,
they are collaborating with UCL chemists on the design of suitable
inhibitors. Interestingly, an approved drug for AMD, avastin,
began life as a cancer drug. By contrast, LRG1 agents may go
in the opposite direction, from eye to cancer.
VEGF (vascular endothelial growth factor) is a well-recognised
target for anti-cancer drugs – blocking its action is supposed to
prevent the formation of blood vessels required for tumour growth.
New small molecules being developed by UCL researchers with Ark
Therapeutics offer a novel twist on VEGF inhibition, and their multiple
effects on cancer cells could make them powerful anti-cancer agents.
The drug discovery programme started with a receptor known as
neuropilin-1. VEGF binds to this receptor on the surface of cells lining
blood vessels, activating cell signalling cascades that ultimately
lead to new blood vessel formation.
Neuropilin 1 has been implicated in numerous cancers, and
antibodies blocking its association with VEGF enhance the effects
of anti-VEGF therapies. However, therapeutically, small-molecule
inhibitors would be preferable to antibodies.
Hence Professor David Selwood, Professor Ian Zachary,
Dr Snezana Djordjevic and colleagues set about rationally designing
small-chemical inhibitors of neuropilin-1, based on its crystal
structure. They began with a 28 amino acid fragment of VEGF
known to bind neuropilin-1, and used mutagenesis and structural
approaches to identify residues critical to binding. They then
searched for chemical scaffolds mimicking these key residues,
generating a suite of chemicals that interfered with VEGF binding
and intracellular signalling through the neuropilin-1 receptor.
When tested on a range of cancer cells, one of these agents
had a number of exciting properties. As well as interfering with VEGFmediated tumour growth, it also inhibited the migration of cancer
cells, probably by blocking interactions between neuropilin-1 and
the extracellular matrix. Hence neuropilin-1 antagonists may also
have inhibitory effects on metastasis.
Furthermore, it also rendered cancer cells more susceptible
to commonly used anti-cancer agents, including paclitaxel and
cisplatin, pointing to possible use in combination therapies. Animal
studies have also been positive, with the peptide significantly slowing
the growth of tumours in rodents with no signs of toxicity.
As well as cancer, this class of drug could also be applied to other
conditions characterised by unwanted blood vessel growth, such
as age-related macular degeneration. Furthermore, neuropilin-1 is
involved in binding by several growth factors, and its inhibition could
have other therapeutic benefits. Promising results have already been
obtained in limiting the formation of fatty liver tissue in cirrhosis and
promoting brain repair after stroke. The VEGF inhibitors may therefore
be the first of an entirely new class of drugs.
Jia H et al. Characterization of a bicyclic peptide neuropilin-1 (NP-1) antagonist
(EG3287) reveals importance of vascular endothelial growth factor exon 8
for NP-1 binding and role of NP-1 in KDR signaling. J Biol Chem 2006;281:
13493–502.
Jarvis A et al. Small molecule inhibitors of the neuropilin-1 vascular endothelial
growth factor A (VEGF-A) interaction. J Med Chem. 2010;53(5):2215–26.
Jia H et al. Neuropilin-1 antagonism in human carcinoma cells inhibits
migration and enhances chemosensitivity. Br J Cancer. 2010;102(3):541–52.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
17
SECTION 3
THE CELLULAR
ROUTE TO HEALTH
Alongside small-molecule agents and ‘biologicals’,
there is growing interest in cell-based therapies.
While stem cells are of particular interest in
regenerative medicine (see section 4, page 28),
there are many other ways in which cells can be
used therapeutically.
A tumour-homing cell labelled with red dye.
18
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
Cultured human T cells.
One intriguing idea is to
exploit the body’s own
cellular responses, an
approach that holds
promise for treatment of
heart disease. Professor
Derek Yellon, Professor
Derek Hausenloy, Professor
Raymond Macallister and
others have found that
it is possible to protect
blood vessels by ‘remote
ischaemic preconditioning’ –
temporarily restricting blood
flow to a limb. This procedure
induces changes to blood
vessels that protect them
from later oxygen starvation,
even at sites far distant from
the treated limb.
As well as exploring the
physiological mechanisms
underlying this phenomenon,
the UCL group has applied
it clinically, with encouraging
results (see page 20).
A similar approach might
also be able to protect other
organs, including the brain.
And there may also be
value in ‘post-conditioning’
– stimulating protective
responses after a period
of oxygen starvation.
Professor Yellon’s work
epitomises how translation
Conditioning phenomena are both dissected
experimentally and applied clinically, with a
very clear goal of identifying ways to improve
treatment.
can be driven by the
integrated two-way flow
of information between
clinic and lab. Conditioning
phenomena are both
dissected experimentally and
applied clinically, with a very
clear goal of identifying ways
to improve treatment.
Harnessing the
immune system
One of the most intensive
areas of research centres
on the immune system.
The destructive powers of
the immune system have
long been exploited by
vaccination. More recently,
there has been growing
interest in provoking immune
responses to cancer.
Conversely, there is a need to
eliminate unwanted immune
responses in transplantation
and autoimmunity.
Dr Karl Peggs and Dr Sergio
Quezada aim to integrate
laboratory science and
clinical application as fully
as possible, so laboratory
research is grounded in
the practicalities of clinical
delivery and therapies
are alive to the emerging
possibilities generated by
research. Their partnership
dates back several years,
when both worked in James
Allison’s lab at Memorial
Sloan-Kettering Cancer
Center, New York. Their work
has centred on control of
T-cell responses – enhancing
them to treat cancer or
inhibiting them to prevent
autoimmune disease.
Because of the power of
the immune system, many
checks and balances are in
place to ensure it is powered
up only when needed. Some
T-cell populations promote
immune responses, others
hold it in check. Stimulating
immune responses against
cancer might therefore
mean putting a foot on the
accelerator to boost cancerkilling cells, or taking the foot
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
19
Eliminating B cells may be a way to treat rheumatoid arthritis.
Multiphoton imaging of muscle blood vessels.
A RENAISSANCE IN B-CELL THERAPY
REMOTELY INTERESTING
The idea of removing antibody-producing B cells to treat
rheumatoid arthritis went from speculation to reality in
little more than a decade.
An ordinary cuff used to measure blood pressure is
surprisingly good at protecting the heart from damage.
In the mid-1990s, research into the immunological basis of
autoimmune conditions such as rheumatoid arthritis was
dominated by T cells. A lone voice, Professor Jo Edwards
proposed that the B cell had been prematurely dismissed. Fifteen
years later, this heresy is the new orthodoxy and B-cell-targeted
therapies are used throughout the world for rheumatoid arthritis
and other autoimmune conditions.
Rheumatoid arthritis is characterised by the presence
of antibodies that bind to ‘self’ molecules to form ‘immune
complexes’. For several decades these were seen as central to
disease processes, but the tide turned in the 1980s and 1990s
as the T cell, the cellular arm of the immune system, came to be
seen as the dominant force in immunology.
However, Professor Edwards suspected B cells had been
dismissed too quickly. A growing understanding of immune
system mechanisms suggested that antibodies, from B cells,
might drive disease in rheumatoid arthritis after all, with T cells
playing a ‘permissive’ role.
He proposed a radical solution – eliminating B cells. Turning
to oncologists for help, he discovered that an agent capable of
wiping out B cells – the monoclonal antibody rituximab – had just
been proven to be an effective treatment for B-cell lymphoma.
After a small trial confirmed he was on the right track, a larger
randomised controlled trial provided convincing evidence that
B-cell depletion by rituximab was beneficial in rheumatoid
arthritis. Fears that patients would be left with a diminished ability
to respond to infectious agents proved ungrounded, possibly
because not all B cells are eliminated.
Eventually self-reactive antibodies do return and patients
require further rounds of treatment. The first wave of patients have
been treated repeatedly at UCL; a published audit at seven years
found little evidence for loss of effectiveness and few adverse
effects. A key finding was that the disease takes two forms, one
needing treatment frequently and one only every one to four
years. Current research focuses on the immunological basis for
the difference, a better understanding of which could provide a
strategy for achieving longer remissions in both groups.
Rituximab is now licensed for rheumatoid arthritis worldwide.
It has also been used in other autoimmune conditions such as
vasculitis and systemic lupus while another anti-B cell agent,
belimumab, has now been shown to be effective in lupus.
Edwards JC et al. Efficacy of B-cell-targeted therapy with rituximab in
patients with rheumatoid arthritis. N Engl J Med. 2004;350(25):2572–81.
Edwards JC, Cambridge G, Leandro MJ. Repeated B-cell depletion in
clinical practice. Rheumatology. 2007;46(9):1509.
Lu TY et al. A retrospective seven-year analysis of the use of B cell
depletion therapy in systemic lupus erythematosus at University College
London Hospital: the first fifty patients. Arthritis Rheum. 2009;61(4):482–7.
20
Coronary heart disease is one of the UK’s biggest killers, responsible
for some 120,000 deaths a year. Although good treatments are
available, improvements are always welcome. One intriguing
possibility, being explored by Professor Derek Yellon and
colleagues, is that restricting blood flow before heart bypass surgery,
using inflatable blood pressure cuffs, may protect the heart and
improve outcomes.
In the 1990s, work on experimental models revealed that
temporarily restricting blood flow to the heart made it better able to
survive a later, more severe reduction in blood supply. Although the
detailed mechanisms of this ‘preconditioning’ effect are not clear,
the initial reduction in blood flow seems to trigger a protective
response in heart muscle that renders it more resistant to the
subsequent interruption.
Professor Yellon and colleagues have been both characterising
the underlying mechanisms of preconditioning and identifying
ways in which the phenomenon could be used therapeutically.
His group was the first to show, in coronary artery bypass surgery,
that preconditioning also occurred in human heart. It subsequently
emerged that the heart could be protected non-invasively (through
tourniquets) and by restricting blood flow in other parts of the body,
such as limbs – a phenomenon known as ‘remote preconditioning’.
In people, this could be achieved using standard inflatable blood
pressure cuffs.
Using this approach, Professor Yellon and colleagues tested the
effects of remote preconditioning during coronary artery bypass
surgery. In two independent randomised controlled trials, on 57
and 45 patients, three five-minute cycles of cuff inflation reduced
the levels of markers of heart damage by more than 40 per cent in
both cases.
Although confirming proof of concept, the study did not show
that the approach actually improved outcomes. The UCL team is
now addressing this key question in the multicentre ‘ERICCA’ trial
of remote preconditioning before heart bypass surgery, which will
assess outcomes at one year. The trial is being funded by the NIHR,
MRC and British Heart Foundation.
With surgery increasingly being carried out on older patients
and those with diabetes, who are at greater risk of adverse events,
preconditioning could have a major clinical impact. Moreover,
as it uses standard medical equipment, the approach could be
implemented almost immediately and at negligible cost.
Hausenloy DJ et al. Effect of remote ischaemic preconditioning on myocardial
injury in patients undergoing coronary artery bypass graft surgery:
a randomised controlled trial. Lancet. 2007;370(9587):575–9.
Venugopal V et al. Remote ischaemic preconditioning reduces myocardial
injury in patients undergoing cardiac surgery with cold blood cardioplegia:
A randomised controlled trial. Heart 2009;95:1567–71.
Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning: underlying
mechanisms and clinical application. Cardiovasc Res. 2008;79(3):377–86.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
In the future, cellular therapy is likely to be
enhanced further by genetic manipulation.
One goal is to engineer T cells so that they
specifically recognise tumour cells.
off the brake – removing the
inhibition on such cells.
For example, blocking a
critical inhibitor of immune
responses – a protein known
as CTLA4 – enhances the
effects of cancer-killing
cells13. Moreover, it also
inhibits regulatory cells
that might apply the brakes
to cancer-killing cells.
Antibodies against CTLA4
have recently been licensed
for use in cancer in the USA.
Dr Quezada also made
the intriguing discovery
that a class of T cells best
known as orchestrators of
immune responses – CD4 T
cells – could under certain
circumstances take on the
guise of killers14. These
CD4 killer cells led to the
regression of tumours in a
mouse model of melanoma.
Dr Quezada is currently
attempting to understand
the molecular mechanisms
triggering this switch from
‘orchestrator’ to ‘killer’.
Depletion
Nowhere is control of
immune responses more
critical than in bone marrow
transplantation, where a
patient’s immune-generating
cells are eliminated and
replaced by those from a
donor. There is a fine balance
to be struck. Donor cells
should offer protection from
infection, and also attack any
residual cancer cells, but
they should not damage a
patient’s own tissues (graftversus-host disease).
As well as developing less
severe methods to eliminate
bone marrow, Professor
Steve Mackinnon and
colleagues have pioneered
the use of multiple infusions
of lymphocytes to improve
treatment of several blood
cancers. In addition, to
minimise graft-versushost disease, T cells are
specifically eliminated before
infusion (T-cell depletion;
see page 24).
However, T-cell depletion
raises the risk that
common viruses, such as
cytomegalovirus or Epstein–
Barr virus, are not controlled
by the immune system.
To counter this threat,
Dr Peggs and colleagues
have shown that it is possible
to grow large numbers of
cytomegalovirus-specific
T cells which protect
patients after bone marrow
transplantation (page 23).
Similarly, Professor Persis
Amrolia and colleagues have
shown that T-cell depletion
improves survival after bone
marrow transplantation in
young children and adults
with leukaemia. He is also
aiming to refine depletion, so
that only self-reactive T cells
are eliminated15. This should
prevent graft-versus-host
disease but leave patients
still able to mount effective
antiviral responses. His
group has also developed
much milder methods for
eliminating bone marrow, for
extremely sick children with
inherited immunodeficiencies
(see page 23).
It is not just depletion of
T cells that can be used
therapeutically. Professor
Jo Edwards has pioneered
the use of B-cell depletion to
treat autoimmune conditions
such as rheumatoid arthritis
(see page 20).
Genetic manipulation
In the future, cellular
therapy is likely to be
enhanced further by genetic
manipulation. One goal is to
engineer T cells so that they
specifically recognise tumour
cells. During bone marrow
transplantation, for example,
cells could be engineered so
that they target any residual
cancer cells.
13 Peggs KS, Quezada SA, Chambers
CA, Korman AJ, Allison JP. Blockade
of CTLA-4 on both effector and
regulatory T cell compartments
contributes to the antitumor activity of
anti-CTLA-4 antibodies. J Exp Med.
2009;206(8):1717–25.
14 Quezada SA et al. Tumor-reactive
CD4(+) T cells develop cytotoxic
activity and eradicate large established
melanoma after transfer into lymphopenic
hosts. J Exp Med. 2010;207(3):637–50.
15 Samarasinghe S et al. Virus-specific
T cells engineered to coexpress
tumor-specific receptors: persistence
and antitumor activity in individuals
with neuroblastoma. Nature Med.
2008;14(11):1264–70.
Cultured bone marrow cells.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
21
More generally, imaging is an important
component of the experimental studies that are
an essential forerunner of, and complement to,
clinical cancer studies.
Dr Martin Pule is turning
T cells into targeted killing
machines. He has developed
‘chimeric antigen receptors’,
which combine the antigenrecognition fragment of an
antibody with the intracellular
signalling domain of a T-cell
receptor. The result is a
highly specific molecular
‘switch’. When the antibody
fragment docks with its target
– such as an antigen found
only on cancer cells – the
intracellular signalling domain
is activated, driving the T cell
into action.
The approach combines the
targeting ability of antibodies
with the advantages of cellbased immune responses:
the T cell is an efficient killing
machine, it can proliferate,
and it can release mediators
that attract other cells to
support its work.
While at Baylor College
in the USA, Dr Pule
engineered T cells to target
neuroblastoma, a common
cancer in children16. The T
cells targeted a molecule that
is found only on the surface
of neuroblastoma cells but
does not normally stimulate
a T-cell response. At UCL,
he has refined the technique,
improving the design of the
chimeric receptors, and
incorporating structures that
promote stronger binding
to target cells. He has also
added ‘suicide’ genes,
which provide a safety valve
if engineered cells begin
to proliferate excessively.
Exposed to a simple drug
or antibody, the T cells
are induced to undergo
programmed cell death.
One advantage of the
approach is its flexibility.
It can be targeted at more
or less any tumour type
that expresses an antigen
22
not found elsewhere in the
body. A particularly notable
application is an international
multicentre clinical trial being
led by Professor Amrolia,
which is testing a chimeric
antibody specific for CD19,
an antigen found on acute
lymphocytic leukaemia, the
most common leukaemia of
children. The new therapy
will be given to patients
who relapse after stem cell
transplantation (typically
around one in five of those
treated).
Another project is examining
the potential of engineered
T cells to mop up residual
glioma cells after surgery.
Relapse is nearly always
associated with expansion
of these residual cancer cells
at the edge of treated tissue.
Genetic manipulation may
have other applications in
solid-organ transplantation.
Dr Pule and Professor
Amrolia have developed a
novel approach to tackle
viral multiplication after
solid organ transplants,
where long-term use of
immunosuppressants to
prevent rejection means
that T-cell-based antiviral
strategies are not possible.
To overcome this problem,
T cells have been generated
in which the molecular
target of commonly used
immunosuppressants,
calcineurin, is engineered
to be resistant to
immunosuppressant use.
In culture, viral-specific
engineered T cells retained
their usual properties and
ability to kill infected cells,
even in the presence of
immunosuppressants17.
Professor Kerry Chester
is also using the targeting
potential of antibody
fragments. However, her
Emission tomography imaging in rodents.
engineered structures are
designed to deliver deadly
packages to cancer cells –
either a toxic peptide or an
enzyme that metabolises a
pro-drug into its toxic form.
This approach has been
tested in a phase I study
targeting a tumour protein
found on carcinomas but
few adult tissues.
Clinical work relies on special
facilities to manufacture the
hybrid agent, using a yeastbased protein production
system. The laboratory
includes a licensed
production facility to make
antibody-based therapeutics
in compliance with Good
Manufacturing Practice.
Targeting can be used in
imaging as well as therapy.
One novel approach has
been to target magnetic
iron oxide nanoparticles to
tumours, to enhance MRI.
These nanoparticles could
also be used therapeutically,
as alternating magnetic
fields heat the particles and
destroy cells.
More generally, imaging is an
important component of the
experimental studies that are
an essential forerunner of,
and complement to, clinical
cancer studies. Cancer
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
groups therefore have close
links with UCL’s Centre
for Advanced Biomedical
Imaging (CABI), led by
Dr Mark Lythgoe.
CABI includes a wide range
of technologies for imaging
in animal models. As well
as MRI, these include
nuclear imaging via emission
tomography, encompassing
PET (positron emission
tomography) and SPECT
(single photon emission
computed tomography).
These technologies rely on
radiolabelled molecules
or ‘tracers’. While several
standard tracers exist
for imaging metabolic
processes, new agents
are also being developed
by Dr Erik Arstad in
UCL’s Department of
Chemistry, where a new
research facility has been
established specifically
to develop tracers for use
16 Pule MA et al. Virus-specific
T cells engineered to coexpress
tumor-specific receptors: persistence
and antitumor activity in individuals
with neuroblastoma. Nature Med.
2008;14(11):1264–70.
17 Brewin J et al. Generation of EBVspecific cytotoxic T cells that are
resistant to calcineurin inhibitors for
the treatment of posttransplantation
lymphoproliferative disease. Blood.
2009;114(23):4792–803.
Dr Karl Peggs.
Professor Persis Amrolia.
A HELPING HAND
THE GENTLE TOUCH
Providing recipients of bone marrow transplants with
specially grown T cells may help them resist a potentially
harmful common virus.
Development of milder treatments has enabled even
extremely sick children to undergo bone marrow
transplantation.
Bone marrow transplantation is a well-established treatment for
many blood cancers. A patient’s bone marrow is eliminated and
repopulated by cells from a suitable donor. A patient’s immune
responses are inevitably weakened during this process, and
infectious agents that are not normally a problem, such as the
almost ubiquitous cytomegalovirus (CMV), can pose a serious
threat to health. A possible solution, developed by Dr Karl Peggs
and colleagues, is to supply patients with specially cultured
T cells specific for CMV.
CMV, like other herpes viruses such as the cold sore virus,
persists in a lifelong ‘latent’ state following initial infection.
Although rarely a problem in healthy people (except in
pregnancy), CMV is a handful for the immune system – around
10 per cent of immune system activity is devoted to keeping it
under control. After bone marrow transplantation, there is a risk
that CMV will escape these shackles and cause more serious
problems. Excessive proliferation and dissemination of CMV can
affect a range of organs, including the liver, lungs and bowel.
Although antiviral drugs are available, they have potentially
severe side-effects.
Dr Peggs and colleagues have developed an alternative
approach, generating a reliable supply of CMV-specific T cells
that can be given after bone marrow transplantation to keep CMV
in check. White blood cells are collected from the bone marrow
donor and CMV-specific T cells specifically expanded in culture
before being given to patients shortly after the transplant. More
recently, cells have even been obtained directly from donor blood,
avoiding the need for culture to expand the cells in the laboratory.
A recent phase I/II trial showed not only that the biological
principle was successful – CMV-specific T cells prevented
reinfection in most patients – but also safe. There were no signs
that the donor T cells were attacking the patients’ own cells
(graft-versus-host disease, a potential concern with T-cell-based
strategies).
Dr Peggs is currently leading a randomised phase III study
(CMV~IMPACT) in 16 transplant centres across the UK to confirm
the effectiveness of the approach, and to establish the feasibility
for a central facility to generate medical-grade cells for use at
regional centres.
Bone marrow transplantation is often a life-saving procedure. Before
it can be carried out, a patient’s existing bone marrow has to be
eliminated to make space for donor cells – a procedure known as
conditioning. By developing less severe methods of conditioning,
Professor Persis Amrolia, Professor Paul Veys and colleagues
have been able to extend treatment even to very sick children.
Bone marrow transplantation is typically used for patients with
leukaemias or other blood cancers, caused by excessive proliferation
of cells derived from bone marrow. It is also used for patients who
are not generating functioning immune cells, often because of
an inherited condition. In these latter cases, there is less need to
eliminate all a patient’s bone marrow – there just needs to be space
for donor cells to become established.
Conditioning has traditionally been based on powerful
chemotherapeutic drugs, which have many side-effects. Over
the past decade, Professor Amrolia and Professor Veys, who
run Europe’s largest paediatric bone marrow transplant centre,
have developed and tested milder procedures, reduced-intensity
conditioning, for children with inherited immunodeficiencies. As well
as improving survival, these approaches have reduced the incidence
of longer-term complications and significantly improved patients’
quality of life. They have now been adopted across most of Europe
and the USA.
However, there are still patients for whom even reduced-intensity
conditioning is too much, such as those under one year of age or with
serious organ damage. To help these children, the UCL team has
swapped chemotherapy for antibody-based approaches, targeting
two molecules (CD45 and CD52) found only on bone marrow and
blood cells.
This novel approach, minimal-intensity conditioning, was first tried
on a group of 16 severely ill children, of average age less than one,
most of whom had previously been on life support. The results were
spectacularly positive – at an average of 40 months later, 13 out of 16
(81 per cent) were still alive and had functioning immune systems.
As a next step, Professor Amrolia is aiming to refine targeting
still further. With Professor Kerry Chester, he is developing agents
targeted at c-KIT, a marker of blood stem cells, in order to eliminate
only those bone marrow cells that generate new blood cells.
Peggs KS et al. Directly selected cytomegalovirus-reactive donor T cells
confer rapid and safe systemic reconstitution of virus-specific immunity
following stem cell transplantation. Clin Infect Dis. 2011;52(1):49–57.
Peggs KS et al. Cytomegalovirus-specific T cell immunotherapy promotes
restoration of durable functional antiviral immunity following allogeneic
stem cell transplantation. Clin Infect Dis. 2009;49(12):1851–60.
Amrolia P et al. Nonmyeloablative stem cell transplantation for congenital
immunodeficiencies. Blood. 2000;96(4):1239–46.
Rao K et al. Improved survival after unrelated donor bone marrow
transplantation in children with primary immunodeficiency using a reducedintensity conditioning regimen. Blood. 2005;105(2):879–85.
Straathof KC et al. Haemopoietic stem-cell transplantation with antibodybased minimal-intensity conditioning: a phase 1/2 study. Lancet.
2009;374(9693):912–20.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
23
Transplant surgery may benefit from a cytomegalovirus vaccine.
Professor Steve Mackinnon.
VACCINE VICISSITUDES
BEATING BLOOD CANCER
Against the odds, a prototype vaccine may protect
transplant patients from a common and potentially
deadly virus.
Innovative refinements have made stem cell treatments
for blood cancers more successful and suitable for a
wider range of patients.
Although it affects around half the UK population, cytomegalovirus
(CMV) is generally not considered a major health threat. The two
main exceptions are women of child-bearing age, as the virus may
be transmitted to a fetus and cause a range of problems, and people
receiving transplants, whose diminished immune responses may
enable the virus to replicate to dangerously high levels. Although
antiviral drugs can control infections, Professor Paul Griffiths has
championed the use of a CMV vaccine, and a recent phase II trial
has provided encouraging evidence of its value.
Transplant recipients are at risk from CMV either because an
existing quiescent infection reignites or, more seriously, because they
acquire an infection from a donated organ. To counter this problem,
transplant centres typically give antiviral drugs to all patients as
a prophylactic treatment. Although effective over the short-term,
problems can arise when patients stop taking the drugs, as they
have not had the opportunity to develop immunity to the virus.
Professor Griffiths and his team have pioneered an alternative
approach, in which CMV levels are monitored and antiviral drugs
given when a certain threshold is reached. Using this approach,
the transplant team has essentially eliminated severe CMV disease.
Even so, a vaccine would potentially offer further benefits,
reducing use of potent antiviral drugs. Despite considerable
scepticism that the currently available CMV vaccine would be
effective or provide any clinical benefits, Professor Griffiths
eventually secured funds from the US National Institutes of Health
for a randomised controlled trial in kidney and liver transplantation.
Patients were monitored and treated as usual but half received the
prototype vaccine before transplantation.
The results vindicated Professor Griffiths’s reasoning. All vaccinetreated patients generated antibodies, and those with the highest
antibody levels typically had the shortest periods of high CMV
proliferation (viraemia). Furthermore, in CMV-free patients receiving
CMV-infected organs, vaccine use significantly reduced the duration
of viraemia and antiviral use.
The results suggest that the prototype CMV vaccine, which should
be amenable to further development and improvement, could indeed
protect patients from CMV after transplant. As well as paving the way
for a larger phase III trial, the study has also raised interest in its use
for other groups, including women of child-bearing age.
To treat cancers derived from blood cell precursors, such as
leukaemias and lymphomas, patients are often given bone marrow
transplants. Stem cells in these transplants populate the patient’s
bone marrow and generate a supply of new blood cells. Over the
past two decades, Professor Steve Mackinnon and colleagues
have pioneered refinements to these procedures that, despite initial
scepticism, have been adopted worldwide.
During bone marrow transplantation, patients are irradiated to
eliminate their bone marrow. However, the severity of this procedure
used to mean it was only suitable for young, relatively fit patients.
Over time, less intensive ‘conditioning’ regimens have been
introduced, so a wider range of patients can be treated.
However, one drawback of reduced-intensity conditioning is that
some of a patient’s bone marrow may persist, increasing the risk of
relapse. To overcome this issue, Professor Mackinnon’s team has
promoted the use of additional donor cell transfusions, and has
shown convincingly that full conversion to donor bone marrow is
associated with better survival.
Donor cells have a further role – attacking residual cancer cells.
However, donor cells may also attack a patient’s normal cells.
As procedures have improved, this ‘graft-versus-host disease’
(GVHD) has become of growing importance.
To reduce GVHD, Professor Mackinnon’s team pursued the idea
of eliminating T cells from donor infusions. The idea was met with
some scepticism: as well as reducing GVHD, it was feared that
donor cells would be less able to eliminate residual cancer cells.
Across several conditions, Professor Mackinnon and colleagues
have shown these fears are unfounded. As a result, reducedintensity conditioning and T-cell depletion can be used with older,
more frail patients, and those who have not responded to other
treatments. In follicular lymphoma, a four-year survival rate of 76 per
cent was achieved with patients who had already been treated an
average of four times. And for non-Hodgkin’s lymphoma patients
averaging five previous treatments, four-year survival was nearly
50 per cent.
Work continues to improve success rates and to expand the
range of patients who can be treated. Despite initial doubts, the
world-leading survival rates achieved have convinced clinicians
across the world to adopt the treatment innovations.
Griffiths PD et al. Cytomegalovirus glycoprotein-B vaccine with MF59
adjuvant in transplant recipients: a phase 2 randomised placebo-controlled
trial. Lancet. 2011;377(9773):1256–63.
Thomson KJ et al. T-cell-depleted reduced-intensity transplantation followed
by donor leukocyte infusions to promote graft-versus-lymphoma activity
results in excellent long-term survival in patients with multiply relapsed
follicular lymphoma. J Clin Oncol. 2010;28(23):3695–700.
Thomson KJ et al. Favorable long-term survival after reduced-intensity
allogeneic transplantation for multiple-relapse aggressive non-Hodgkin’s
lymphoma. J Clin Oncol. 2009;27(3):426–32.
Peggs KS et al. Reduced-intensity conditioning for allogeneic
haematopoietic stem cell transplantation in relapsed and refractory Hodgkin
lymphoma: impact of alemtuzumab and donor lymphocyte infusions on
long-term outcomes. Br J Haematol. 2007;139(1):70–80.
24
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
However, points out
Professor Griffiths, the
cultured virus may not
behave like infectious strains
(it has in fact lost multiple
genes in its adaption to life
in culture) and what happens
in mice may not necessarily
reflect human infections.
Moreover, cytomegalovirus
may be a problem only
when the amount of virus
in the body (‘viral load’)
reaches high levels. Simply
lowering virus levels, rather
than eliminating it, might be
sufficient to prevent disease.
Transmission electron micrograph image of cytomegalovirus.
in pre-clinical and clinical
studies. Dr Arstad has also
developed a novel tracer that
incorporates a radiolabel into
a fluorescent tag, enabling
simultaneous nuclear
and optical imaging18.
Autoimmunity
As well as work on cancer
vaccines, Professor Hans
Stauss and colleagues are
also engineering T cells to
inhibit immune responses,
as a possible treatment for
autoimmune conditions.
One experimental approach
has been to isolate selfreactive T cells from sites
of tissue damage and to
transfer their T cell receptor
genes into regulatory T cells
(Tregs). These engineered
cells therefore recognise
disease-triggering antigen,
but respond by inhibiting
immune responses.
Significantly, this approach
does not require any
knowledge of which specific
antigen is triggering the
damaging immune response.
Vaccines
Vaccines have long been
among the most effective
biological and cellular
agents. Vaccine development
and testing continues in a
number of other important
areas, not least HIV/AIDS.
Professor Robin Weiss, who
in the 1980s identified CD4
as the cellular receptor for
HIV, has worked for many
years on immune responses
to HIV and strategies to
prevent infection, including
vaccination. He is leading
a US$25 million European
Vaccine Discovery
Consortium, funded by
the Bill and Melinda Gates
Foundation, which is hunting
for neutralising antibodies
in order to identify antigens
that would elicit protective
immunity after vaccination.
One strand of research
is focused on unusually
compact antibodies
produced by llamas and
other members of the camel
family. Fragments of these
antibodies are being used to
explore key epitopes on HIV
surface proteins, but may
themselves have potential
use in microbicides to block
HIV entry19.
Although animal models
play an important role in
translation, studies in people
will always provide the most
useful results. Professor
Paul Griffiths’s work on
cytomegalovirus illustrates
the power of experimental
medicine to test therapies
and to generate important
information about the
mechanisms of disease
and therapeutic action.
Cytomegalovirus is very
common and usually
poses little threat to health.
However, it can be a
problem during pregnancy
– if transferred to the fetus,
it can cause a range of
abnormalities including
hearing problems and
learning difficulties – and in
transplant patients: before
antiviral drugs became
available, around one in ten
would die from uncontrolled
viral replication.
Development of a vaccine
has been slow, however,
for a range of reasons.
It is technically challenging,
as the virus has evolved
numerous tricks to evade the
immune system. Research
has also been held back by
the belief that cell-mediated
(T cell) rather than antibodybased (B cell) immunity
would be crucial to viral
control, largely on the basis
of work on cultured cells
and mice.
This strategy has been made
possible by the development
of methods to assess viral
load rapidly (by quantitative
PCR). In transplant patients,
antiviral treatment can now
be targeted just at those
that need it.
Despite stiff opposition,
Professor Griffiths has also
persevered with the idea
of vaccination, persuading
a vaccine-manufacturing
company to let him test a
prototype vaccine (see page
24). The encouraging results
have led to discussions
about the design of a larger
phase III trial. The study
has also sparked interest in
CMV vaccine development,
and their use in other
vulnerable groups, such
as pregnant women.
18 Yan R et al. One-pot synthesis of
an 125I-labeled trifunctional reagent
for multiscale imaging with optical and
nuclear techniques. Angew Chem Int Ed
Engl. 2011;50(30):6793–5.
19 Forsman A et al. Llama antibody
fragments with cross-subtype human
immunodeficiency virus type 1
(HIV-1)-neutralizing properties and
high affinity for HIV-1 gp120. J Virol.
2008;82(24):12069–81.
Hinz A et al. Crystal structure of the
neutralizing Llama V(HH) D7 and its
mode of HIV-1 gp120 interaction.
PLoS One. 2010;5(5):e10482.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
25
Advances in imaging are both improving existing treatments
and accelerating the translation of new applications.
IMAGING THE FUTURE
Being able to look inside
the body has been one of
medicine’s most valuable
technologies. Within
months of Roentgen’s first
X-ray images, physicians
were already using them
in their clinics. Since
then, technologies such
as ultrasound, computed
tomography (CT), magnetic
resonance imaging (MRI)
and positron emission
tomography (PET) have all
been widely applied across
medicine.
New opportunities to
improve medical imaging
are emerging from
developments in both
hardware and software.
Hardware advances include
higher-power and dual-use
scanners (CT–MRI and
PET–MRI), while computing
and software development
is offering ever-greater
scope for image analysis
and modelling. Newer
technologies also often
add functional information
– about tissue metabolism,
for example – as well as
structural detail.
A feature of medical
imaging research is
its close connection to
clinical practice. Research
therefore reflects extensive
dialogue between clinicians
and researchers, and
generally responds to the
‘pull’ from clinical needs.
Much research is highly
‘pragmatic’, reflecting the
actual way healthcare is
delivered (and paid for)
within the NHS.
One of the most active
areas is cancer, where
imaging is used to identify
and characterise tumours
and to guide surgery or
radiotherapy. Professor
Mark Emberton, for
example, has worked with
Professor David Hawkes
on high-resolution imaging
for prostate cancer, a step
towards improved diagnosis
and targeted treatments
(see page 8). Professor
Hawkes is currently director
of the £10 million UCL/KCL
Comprehensive Cancer
Imaging Centre, funded by
Cancer Research UK and
the EPSRC, which aims to
improve the detection and
management of breast and
colon cancer, as well as
image-guided focal therapy
of lung, liver and prostate
cancer.
A long-standing problem
in medical imaging arises
from the natural dynamics of
tissues and organs. Image
analysis has traditionally
aimed to capture as much
data as possible and then
filter out the ‘noise’. In a £6
million collaboration with
other academic groups and
high-tech companies, funded
by the EPSRC, Professor
Hawkes is pursuing
an alternative strategy,
generating computational
models of organ motion so
imaging data are analysed
as they are generated. The
project is initially focusing
on cancer, blood flow to the
heart, and fetal and neonatal
brains.
Radiology continues to be
a core medical imaging
technology, and new
applications continue
to emerge. For patients
showing symptoms of colon
cancer, Professor Steve
Halligan has explored the
use of CT-based imaging
(‘virtual colonoscopy) as an
alternative to barium enema
and invasive colonoscopy, in
the multicentre SIGGAR trial1.
On critical measures such
as the number of cancers
missed, CT performed
better than barium enema
and was at least as good
as colonoscopy. Clinical
guidelines now recommend
discontinuing barium
enemas (though as around
300,000 are carried out each
year in the UK this is likely
to take time).
The symptoms of colon
cancer are both common
and non-specific, so
diagnosis is a significant
practical challenge. Since
colonoscopy is a technically
difficult procedure with
a small but significant
risk of injury, CT imaging
could become the first-line
approach, with colonoscopy
reserved for cases requiring
biopsy or excision.
The magnetic field of a magnetic nanoparticle used in imaging.
26
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
Ironically, perhaps, medical
imaging does not always
generate a clear picture of
disease; uncertainty often
persists regarding whether
or not patients have a
particular condition, and this
may vary from radiologist
to radiologist. While
biochemical measures often
provide easily comparable
numerical values, imaging
generates complex and
subjective visual data that
may be harder to interpret
and compare. Professor
Halligan and Professor
Hawkes are working on
approaches to generate
quantitative information from
scans, including software
tools that can analyse
such data – the field of
computer-aided detection
(CAD). These have been
applied to CT colonography
for diagnosis of colorectal
cancer and polyps, and
have been used to register
abnormalities between
scans taken in patients at
different times.
One disadvantage of CT
is its use of radiation,
particularly if patients are
assessed repeatedly over
periods of time. Professor
Stuart Taylor is exploring
the use of MRI to diagnose
and track conditions
such as lymphoma, lung
and colon cancer, and
1 Halligan S et al. Design of a multicentre
randomized trial to evaluate CT
colonography versus colonoscopy or
barium enema for diagnosis of colonic
cancer in older symptomatic patients:
the SIGGAR study. Trials. 2007;8:32.
2 Hafeez R et al. Diagnostic and
therapeutic impact of MR enterography
in Crohn’s disease. Clin Radiol. 2011
Sep 22.
IMAGING AND TRANSLATION
Crohn’s disease2. As well
as structural information,
MRI also provides some
functional information, for
example on blood flow,
which can also aid clinical
management. UCLH has
already switched to MRI
for monitoring of Crohn’s
disease and Professor Taylor
is planning a multicentre
clinical trial to assess
its potential for wider
application.
MRI is also emerging as
a valuable tool in cardiac
medicine. It is one of
the tools being used by
Professor Andrew Taylor,
who leads a specialist group
focusing on cardiovascular
imaging, mainly in children
with congenital heart
abnormalities.
In adults, Professor Taylor
has been working with Dr
James Moon at the Heart
Hospital on a new technique,
equilibrium contrast cardiac
MR, to pick up signs of
fibrosis in the heart 3. Fibrosis
is an important indicator of
poor heart health, but can
normally only be assessed
by biopsy. A non-invasive
method of assessment could
therefore be of great value.
In children, MRI has been
used to identify patients with
damaged heart valves who
could be fitted with a stent
containing an artificial valve.
Thanks to a new surgical
procedure, the stent can
Imaging technologies are pivotal to the translational studies
underpinning the development of new therapies. UCL’s Centre for
Advanced Imaging (CABI) provides a range of imaging platforms
for UCL researchers, and hosts multiple collaborations with
clinically oriented groups.
Imaging plays a particularly important role in cancer research,
providing a way to visualise tumours – often human cancer
cells in rodent models – and assess their response to novel
therapeutic agents.
Central to such studies are PET and SPECT imaging (see page
22), but ‘bioluminescent’ approaches can also be used, where
cells are engineered to emit light at specific frequencies.
A further exciting new technology is photoacoustic imaging,
which combines ultrasound with laser light and can be used to
image blood vessels – and their response to anticancer drugs –
in three dimensions in living tissue in real time.
As well as cancer studies, CABI works closely with Professor
Derek Yellon and colleagues in cardiovascular medicine (see
page 20) as well with Professor John Martin on the action of
stem cells in heart repair (see page 32). CABI has also recently
acquired an experimental radiotherapy set up for studies of
CT-guided in vivo irradiation.
be implanted via a catheter
inserted into the groin rather
than by open-heart surgery,
but the standard stent fits
only about 15 per cent
of patients.
As well as identifying
suitable patients, structural
information from patients has
been used to generate threedimensional reconstructions
of affected vessels, to allow
modelling of alternative
stent designs 4. Ultimately,
if a range of stents were
developed, imaging could
help clinicians choose
the appropriate device
for each patient 5.
Professor Taylor’s longerterm aim is to integrate
imaging and other data –
on, for example, electrical
activity in the heart – to
create dynamic models of
heart structure and function.
Surgical procedures could
then be modelled virtually,
using real patient data,
before being carried out.
Alternative procedures
could also be compared
in a virtual environment.
Although such simulations
are now becoming
technically feasible, they
need to be validated before
they can be applied with
confidence in patients.
Imaging technologies are
also critical for clinical
neuroscience, particularly
neurodegenerative disorders
such as Alzheimer’s
disease (see companion
volume on Neuroscience
and Mental Health). UCL
has also entered into a
partnership with the MRC,
KCL and Imperial College to
establish Imanova Ltd, which
manages the renowned
Clinical Imaging Centre
at Hammersmith Hospital.
3 Flett AS et al. Equilibrium contrast
cardiovascular magnetic resonance for
the measurement of diffuse myocardial
fibrosis: preliminary validation in
humans. Circulation. 2010;122(2):
138–44.
4 Capelli C, Taylor AM, Migliavacca F,
Bonhoeffer P, Schievano S. Patientspecific reconstructed anatomies and
computer simulations are fundamental
for selecting medical device treatment:
application to a new percutaneous
pulmonary valve. Philos Transact A Math
Phys Eng Sci. 2010;368(1921):3027–38.
5 Schievano S et al. First-in-man
implantation of a novel percutaneous
valve: a new approach to medical
device development. EuroIntervention.
2010;5(6):745–50.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
27
SECTION 4
REPAIR AND
REGENERATION
Many medical problems are caused by ‘faulty parts’ –
the results of genetic mutations that affect the function of
key biological molecules. In later life, even in the absence
of specific mutations, the toll of daily life causes tissues
and organs to deteriorate. New technologies are now
offering exciting opportunities to repair and replace faulty
and damaged cells and organs.
Cellular manipulation is underpinning a host of new therapies.
28
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
Gene therapy is showing promise in several conditions.
Despite several false dawns,
there are encouraging
signs that gene therapy
is beginning to realise its
enormous promise. One of its
pioneers has been Professor
Adrian Thrasher, who led
the UK’s first gene therapy
trial, with colleagues at Great
Ormond Street Hospital.
This groundbreaking work,
begun in 2002, was based
on viral delivery of a gene to
treat an inherited condition
preventing development
of the immune system.
A decade on, the first
wave of patients are doing
remarkably well (see page
33).
Professor Thrasher also
helped to identify the
reasons why early gene
therapy vectors occasionally
triggered cancer – the
problem being integration
of the vector close to genes
controlling cell proliferation.
New generation vectors have
been redesigned to eliminate
this problem. Trials are
planned or in progress for a
range of immunodeficiencies
and other severe conditions
affecting children.
Gene therapy is a flexible technology. As well as
repair of genetic defects, it has potential use in
other areas of medicine.
Major progress has also
been achieved in treatment
of inherited forms of
blindness. The eye has
advantages as a target
for gene therapy, as it is
relatively accessible, small,
and treatment can be highly
localised. An early trial of
replacement therapy for the
inherited condition Leber’s
congenital amaurosis,
carried out by Professor
Robin Ali, Professor James
Bainbridge and colleagues,
was designed primarily to
test safety in a small number
of patients, but also found
encouraging evidence of
an impact on vision (see
page 30).
The work on the eye again
provides proof of principle
that gene therapy could
be a practical medical tool
(though much development
work still needs to be
done). In the longer term,
there is also potential to
use gene therapy to deliver
therapeutically useful
proteins, to maintain or repair
eye cells.
Several other UCL groups
are pursuing gene therapy.
Professor Ted Tuddenham’s
group, for example, is
investigating its use in
haemophilia20. Dr Amit
Nathwani and colleagues
have reported encouraging
results in non-human
primates21, and a phase I
clinical trial began in 2010.
Dr Nathwani and Dr Simon
Waddington have also been
exploring prenatal gene
therapy in animal models, for
example to correct factor IX
deficiency.
20 Ward NJ et al. Codon optimization
of human factor VIII cDNAs leads
to high-level expression. Blood.
2011;117(3):798–807.
21 Nathwani AC et al. Long-term
safety and efficacy following
systemic administration of a selfcomplementary AAV vector encoding
human FIX pseudotyped with serotype
5 and 8 capsid proteins. Mol Ther.
2011;19(5):876–85.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
29
Professor Francesco Muntoni.
Professor James Bainbridge examining a patient.
SKIP TO THE GOOD BIT
A VISION FOR GENE THERAPY
‘Exon skipping’ therapy may be able to provide the
muscle protein missing in boys with Duchenne muscular
dystrophy.
The eye may be particularly amenable to gene therapy,
and early trials have confirmed its potential.
Duchenne muscular dystrophy (DMD) affects about one in 3500
boys. It is caused by mutation in the gene for a muscle protein,
dystrophin, which forms part of large protein complexes that
maintain the structural integrity of muscle fibres. Without functional
dystrophin, muscles gradually degenerate, confining boys to
wheelchairs in their teens; they rarely survive beyond their mid-20s.
A promising new technique developed by Professor Francesco
Muntoni and colleagues may enable some boys with a faulty
dystrophin gene to produce enough functional protein to rescue
degenerating muscle fibres.
Like most human genes, the dystrophin gene comprises
alternating coding (exon) and non-coding (intron) regions. It is
actually the longest gene in the human genome, with 79 exons that
are spliced together after transcription to create messenger RNA.
Several thousand different mutations affect the dystrophin gene,
but many cluster in a ‘hotspot’ around exon 50.
Notably, though, up to half of patients have some ‘revertant’
fibres that seem to contain functional dystrophin. This seems to
reflect chance mistakes in the processing of dystrophin messenger
RNA, which misses out (‘skips’) the faulty exon. The resulting
dystrophin protein is missing a small section, but maintains some
residual function.
This observation raised the possibility of reversing DMD
by artificially inducing exon skipping. A growing number of
experimental therapeutics, RNA molecules or RNA analogues
(known as ‘morpholinos’), have been designed to interfere with
RNA. Although most are designed to eliminate RNAs and hence
silence genes, they can also be used to target a specific splice site
to induce exon skipping.
Following promising work on experimental animal models,
Professor Muntoni and colleagues ran a small clinical trial on seven
DMD patients, injecting an exon 51 skipping morpholino into a
muscle in the foot. As patients suffered no ill-effects and some
began producing dystrophin, the team organised a larger trial on
19 patients testing higher doses. Seven patients responded, and
one patient had detectable dystrophin in more than half of muscle
fibres examined.
Although the impact on muscle strength has not been assessed,
the promising results have confirmed proof of principle and safety.
It will not be suitable for all patients, but may offer hope to boys
who currently have no other options.
A wide range of inherited conditions affect the eye, leading to
impaired vision and blindness. In the world’s first clinical trial of
gene therapy for eye disease, Professor Robin Ali, Professor
James Bainbridge and colleagues have treated several patients
with Leber congenital amaurosis (LCA) caused by mutation in the
RPE65 gene. The lack of adverse events and encouragingly positive
responses in patients suggest it is a strategy with great potential
– possibly for common conditions as well as rare inherited diseases.
RPE65 codes for a component of the biochemical pathway that
regenerates light-sensitive molecules in rod cells after exposure
to light. Mutations in RPE65 cause rod cells to degenerate during
childhood. Although cone cells are not directly affected, they also
gradually degenerate, leading to total blindness by the time patients
are in their 30s.
LCA is a good target for gene therapy. Degeneration is gradual,
and gene therapy may be able to halt the further progression and
perhaps even restore vision. It is also possible to deliver the vector
to a restricted area of the body, the retina.
In addition, good animal models of LCA exist. Proof-of-principle
studies have been carried out on mouse models and the technique
has also been successfully applied in a naturally occurring breed of
dogs, Briards, that have a mutation in the canine version of RPE65.
The patient trial involved injection of an adeno-associated virus
vector containing an intact RPE65 gene into the retina of young
people with LCA. At this stage, the trial was predominantly to
assess safety issues and, reassuringly, no serious ill-effects have
been seen to date.
Patients have also undergone a series of tests to assess their
vision, including an innovative ‘obstacle course’ developed in
collaboration with UCL’s Engineering Department, which assesses
patients’ ability to navigate through a complex environment under low
light conditions. Remarkably, many patients have shown a markedly
enhanced ability to navigate the environment and also reported
subjective improvements in vision.
The UCL team is planning a further trial and developing
techniques for other eye-related conditions. A long-term aim is to
use gene therapy not just for ‘replacement therapy’ but also as a
mechanism to deliver therapeutic proteins – thereby expanding the
approach to common conditions, such as macular degeneration
or diabetic retinopathy.
Bainbridge JW et al. Effect of gene therapy on visual function in Leber’s
congenital amaurosis. N Engl J Med. 2008;358(21):2231–9.
Kinali M et al. Local restoration of dystrophin expression with the morpholino
oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind,
placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol.
2009;8(10):918–28.
Cirak S et al. Exon skipping and dystrophin restoration in patients with
Duchenne muscular dystrophy after systemic phosphorodiamidate
morpholino oligomer treatment: an open-label, phase 2, dose-escalation
study. Lancet. 2011;378(9791):595–605.
30
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
Future surgery is likely to depend ever more on artificial materials.
Gene therapy is a flexible
technology. As well as repair
of genetic defects, it has
potential use in other areas
of medicine. Professor
Mary Collins, for example,
is using gene therapy as a
vaccination strategy, using
vectors that target dendritic
cells, which play a key
role in stimulating immune
responses. The technology,
currently being adapted for
clinical use, could be used to
stimulate immune responses
against viruses or tumours.
In the translation of gene
therapy, supply of clinical
grade vectors is often a
roadblock. To help overcome
this obstacle, a vector
development facility has
been established, the UCL
Gene Therapy Consortium,
funded the Wellcome Trust
and managed by Dr Olivier
Danos, to promote the
translational development
of vectors for groups
across UCL.
Genetic information flows
from DNA through RNA
to proteins, and RNA
intermediates provide
an alternative target for
molecular interventions.
A good example is Professor
Francesco Muntoni’s use of
RNA analogues to modulate
splicing of dystrophin mRNA,
a possible way to rescue
muscle function in boys
with Duchenne muscular
dystrophy (see page 30).
At a less advanced stage
of application, Dr Stephen
Hart and colleagues have
developed liposome-based
nanoparticles that deliver
small RNAs which trigger
the elimination of specific
messenger RNAs22. The
nanoparticles incorporate
peptides to target them to
specific cell types. Other
nanoparticles have been
designed specifically to
target cancer cells, carrying
in DNA coding for cytokines
to boost anti-cancer immune
responses23. In collaboration
with researchers at King’s
College London and Bristol,
Dr Hart is leading a £1.4m
project funded by the
Engineering and Physical
Sciences Research Council
to develop nanotechnologies
for the targeted delivery
of novel therapies for
Alzheimer’s disease.
22 Tagalakis AD, He L, Saraiva L,
Gustafsson KT, Hart SL. Receptortargeted liposome-peptide
nanocomplexes for siRNA delivery.
Biomaterials. 2011;32(26):6302–15.
23 Tagalakis AD et al. Integrintargeted nanocomplexes for tumour
specific delivery and therapy by
systemic administration. Biomaterials.
2011;32(5):1370–6.
Regeneration
Stem cells are opening up
exciting new opportunities
in regenerative medicine.
Stem cells can be broadly
categorised as embryonic
(derived from very early
embryos) or adult. Embryonic
stem cells are more flexible
– they can generate any
type of cell in the body – but
their use does raise ethical
questions. Adult stem cells
are more restricted in their
developmental potential,
but are easier to obtain, and
if a patient’s own cells are
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
31
Stem cell-based treatments are in development for a wide range of conditions.
used there is no danger of
rejection. UCL researchers
are exploring the use of
both types of cell.
Professor Pete Coffey is
leading a large collaboration
using embryonic stem cells
to treat the most common
form of blindness in old
age, age-related macular
degeneration (see page 37).
The programme, known as
the London Project to Cure
Blindness, was founded on
a major philanthropic
donation and has attracted
significant additional charity
and industrial funding.
Professor Coffey is also
exploring the potential of
‘induced pluripotent stem
cells’ – adult cells, taken
from the skin, that have been
genetically reprogrammed so
they behave like embryonic
stem cells. His group has
converted skin cells to retinal
cells via induced pluripotent
stem cells in the laboratory,
in collaboration with Dr
Amit Nathwani. Although
a very exciting prospect,
32
clinical application will
require a different approach
to reprogramming, as the
laboratory processes are
based on viral vectors
that integrate into DNA.
Professor John Martin has
been a long-term advocate
of adult stem cells to repair
the heart. He was involved
in the UK’s first trial of adult
stem cells, with Professor
Anthony Mathur of Barts
and The London School of
Medicine, and is now running
five trials to explore their use
in different clinical situations.
To date, results with adult
stem cells have been
mixed, in part because
trials have been too small
to demonstrate a beneficial
effect convincingly. The
current trials should provide
a clearer picture. They are
being run in collaboration
with Ark Therapeutics Group
plc, a UCL spinout company
with facilities in the UK and
Finland. This arrangement
provides a site for specialist
clinical development, such
as obtaining clinical grade
material and all relevant
regulatory licences, which
would be difficult to develop
within a university setting.
The close relationship
between the company and
academic labs ensures
that translation is rapid.
One trial is looking at stem
cell therapy after heart
attack. Since treatment after
heart attack needs to be
given as rapidly as possible,
the trial will test the effect of
injecting stem cells derived
from a patient’s own bone
marrow into the heart within
six hours. The trial plans
to recruit 100 patients.
A second trial will look at
similar treatment for patients
with chronic heart failure,
while a third is focusing
on stem cell therapy for
dilated cardiomyopathy –
a potentially fatal weakening
and swelling of the heart.
In a fourth project, Ark
Therapeutics is leading
a 5.3 million EU-funded
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
international collaboration
aiming to improve the design
of stents – small tubes used
to repair damaged blood
vessels. In a novel twist,
a biodegradable stent will be
seeded with stem cells from
bone marrow, so by the time
the stent finally disappears
a new vessel has developed
in its place. This innovative
multidisciplinary project
involves teams at Barts
and The London School of
Medicine, Yale and biotech
companies across Europe.
The fifth trial is also an
international EU-funded
collaboration, and again
involves stem cell therapy
after heart attacks. Across
27 European centres, some
3000 patients will be treated,
providing a definitive picture
of the value of stem cell
therapy after heart attacks.
One of the major advantages
of adult stem cell therapy
is its practicality. Using a
patient’s own cells eliminates
many safety issues and the
risk of rejection. Costs are
Professor Adrian Thrasher.
Artificial airways are saving patients’ lives.
THE IMMUNE SYSTEM BACK IN ACTION
NEW TUBE
Long-term follow up of the first wave of infants treated with
gene therapy suggests it is a viable approach for inherited
immunodeficiencies.
A unique team effort has enabled UCL researchers
to carry out the world’s first stem cell-derived organ
transplants.
Among the most urgent targets for gene therapy are inherited,
potentially lethal conditions such as immunodeficiencies. With patients
alive and well a decade after treatment, Professor Adrian Thrasher and
colleagues can argue with some confidence that gene therapy is now a
viable treatment option.
Babies born with severe combined immunodeficiency (SCID) have
little or no immune system to defend them from infections. It can be
treated by bone marrow transplant, but the success of this procedure
declines markedly if a well-matched donor such as a sibling is not
available.
The UK’s first gene therapy trial, led by Professor Thrasher, attempted
to correct the defect causing X-linked SCID, using an engineered
virus to insert a functioning copy of the defective gene into a patient’s
blood cells. The approach was also applied to a second form of SCID,
ADA-SCID, caused by a mutation that affects a metabolic enzyme but
ultimately prevents the immune system from developing normally. It can
be treated by enzyme replacement therapy, but this requires constant
lifelong treatment.
Initial results from the trials were encouraging, but long-term follow up
is important both to check that benefits are maintained and to examine
for possible adverse effects. Indeed, in several early trials, viral vectors
inserted close to cancer-causing genes, leading some patients to
develop leukaemia.
Of Professor Thrasher’s first group of X-linked SCID patients, all
ten were still alive at an average of seven years, and all were showing
normal or near-normal T-cell development. B-cell immune responses
were not restored quite as fully. One child had developed leukaemia
but was in remission after chemotherapy. All patients attended normal
nursery or school and showed no signs of any abnormal development.
Given that 10-year survival for patients receiving mismatched
transplants is 72 per cent, these results are highly encouraging.
Similarly, all six ADA-SCID patients were still alive after an average of
three and a half years. Four patients recovered immune system function
and three were able to come off enzyme-replacement therapy. None
developed leukaemia. The slightly lower success rate may relate to
additional complications linked to the ADA mutation, in particular its
effects on development of the thymus.
The results of the follow up provide just cause to pursue gene therapy
for these conditions. Although development of leukaemia has been an
issue, the mechanisms involved have been identified and new vectors
developed that lack the DNA elements thought to have activated
cancer-causing genes. The safety of these new vectors is being tested
in clinical trials.
The past five years have seen the prospect of organs built
from a patient’s own cells move from science fiction to reality.
Perhaps the most stunning accomplishments have been the
trachea transplants carried out by Professor Martin Birchall
and a cross-disciplinary team of UCL researchers.
Tremendous advances have been made in stem cell
biology, and many possible applications can be envisaged.
Replacement organs are one exciting goal, but it is clear that
stem cells alone will not be the complete answer. Equally
important are the substrates or scaffolds to which stem cells
adhere, providing the foundation on which new tissues and
organs can develop.
One approach is to use natural biological structures as
scaffolds. In 2008, a 30-year-old mother of two received the first
artificial, stem cell-derived organ, based on a donor trachea
that was stripped of donor cells to leave a bare cartilage
scaffold. The patient’s own stem cells were then grown on
the scaffold before it was transplanted. The procedure was a
success and the patient is still leading a normal life years later,
with no need for immunosuppressive drugs.
A second procedure, in 2010, on a 10-year-old boy, was also
based on a donor cartilage scaffold populated with the patient’s
own stem cells. The operation again went without a hitch and
the child – who would undoubtedly have died without the
intervention – remains well.
A third operation has been carried out on a young woman
who had received a stem cell transplant outside the UK, but
whose replacement organ had begun to fail. This procedure
made use of the wholly artificial trachea developed by Professor
Alex Seifalian (see page 34).
These landmark transplants have depended on an extensive
UCL-wide collaboration encompassing stem cell biologists,
cell therapy laboratories, epithelial cell biologists, paediatric
surgeons, as well as people like Professor Seifalian developing
new materials and others involved in commercialisation of the
technology. Indeed, UCL may be unique in possessing this
range of expertise, and combination of research and clinical
excellence.
With MRC funding, Professor Birchall is leading a project to
compare the fully synthetic and donor-based scaffolds in animal
models. It remains to be seen which is the better bet in the
long term, or whether hybrid devices are possible. While these
important experimental studies are performed, surgery will be
limited to the occasional ‘compassionate use’ for patients who
have no other options left.
Gaspar HB et al. Long term persistence of a polyclonal T cell repertoire after
gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med.
2011;3(97):97ra79.
Gaspar HB et al. Hematopoietic stem cell gene therapy for adenosine
deaminase-deficient severe combined immunodeficiency leads to longterm immunological recovery and metabolic correction. Sci Transl Med.
2011;3(97):97ra80.
Macchiarini P et al. Clinical transplantation of a tissue-engineered
airway. Lancet. 2008;372(9655):2023–30.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
33
Synthetic trachea have been successfully used in human patients.
Age-related macular degeneration.
ARTIFICIAL ORGANS COME OF AGE
REPAIR OF THE EYE
The world’s first transplant of an artificial windpipe could
herald a new era of ‘spare part surgery’.
Stem cell therapy may be a way to tackle the most common
form of age-related blindness.
Artificial organs have long been a goal of regenerative medicine.
Progress has been disappointingly slow, however, mostly because
the body does not take kindly to the presence of artificial material.
Now, advances in biomaterials science and stem cell technology
are opening up the prospect of hybrid devices combining
biocompatible artificial structures with a patient’s own cells –
as illustrated by the recent development of an artificial windpipe
by Professor Alexander Seifalian and colleagues.
Thanks to millions of years of evolution, the body’s structural
components are finely tuned to their roles. The challenge for
researchers is to develop materials that mimic their mechanical
properties but are also biocompatible and are not rejected by the
body. Ideally, they are not just tolerated but actually integrated into
the body, acting as a scaffold onto which host cells can attach
and develop into organised tissues.
Nanotechnologies are providing a route by which these
demanding specifications can be achieved. The latest materials
are light, strong and biologically inert. They have a surface that
promotes cell attachment and is porous. Extensive work in cell
culture and experimental animal models have confirmed their
potential, and set the stage for trials in people.
For the first transplant, Professor Seifalian’s team constructed a
replacement trachea, which was sent to Sweden where Professor
Seifalian’s collaborators added stem cells extracted from the patient
and transplanted the replacement organ. After the procedure, the
patient was discharged and returned to university to continue his
postgraduate degree.
Age-related macular degeneration (AMD) is the most common
cause of sight loss in older people, affecting around one in four
people over 60. Through the London Project to Cure Blindness,
established by a large philanthropic donation, Professor Pete
Coffey is working with Moorfields Eye Hospital surgeon Dr Lyndon
da Cruz and Karen Cheetham, Director at UCL Business, on
pioneering clinical trials of embryonic stem cell treatments for AMD.
AMD affects the most sensitive central region of the retina,
the macula. Although characterised by progressive loss of
light-sensitive photoreceptor cells (rods and cones), AMD is
actually caused by abnormalities in a layer of cells underlying the
retina. These cells, retinal pigment epithelial cells, support and
nourish retinal cells, supplying them with essential metabolites
and removing waste products and cell debris. When retinal
pigment epithelial cells die off, this support function is lost and
photoreceptor cells also degenerate.
Human embryonic stem cells may provide a source of cells to
replace these degenerating support cells. Embryonic stem cells
are pluripotent, able to differentiate into any of the cell types of
the human body. Professor Coffey has shown that they can be
converted into retinal pigment epithelial cells, and improve vision
can when transplanted into animal models.
Cultured embryonic stem cells are grown into retinal pigment
epithelial cells and coated onto a tiny scaffold, which is then
transplanted into the macula.
Jungebluth P et al. Tracheobronchial transplantation with a stem-cellseeded bioartificial nanocomposite: a proof-of-concept study. Lancet.
2011;378(9808):1997–2004.
Vugler A et al. Elucidating the phenomenon of HESC-derived RPE:
anatomy of cell genesis, expansion and retinal transplantation. Exp Neurol.
2008;214(2):347–61.
Chen FK et al. Long-term outcomes following full macular translocation
surgery in neovascular age-related macular degeneration. Br J Ophthalmol.
2010;94(10):1337–43.
Carr AJ et al. Protective effects of human iPS-derived retinal pigment
epithelium cell transplantation in the retinal dystrophic rat. PLoS One.
2009;4(12):e8152.
34
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
Nanotechnology have
provided a way to overcome
these difficulties. New
materials have been
developed with structural
properties designed to
promote cellular attachment
but without triggering an
immune response. These
materials typically have
nanoscale surface features
which help cells to adhere
and tiny pores that can be
loaded with useful materials
and are readily colonised
by cells.
Brenda, a patient who underwent a landmark larynx transplant.
low and the techniques used
relatively straightforward.
If the trials obtain positive
results, the therapy could be
adopted by health services
almost immediately.
Adult stem cells have also
been used by Professor
Martin Birchall, in
collaboration with Professor
Paolo Macchiarini, from
Florence, in groundbreaking
procedures to repair severe
airway damage. Entire new
sections of trachea have
been transplanted into a
30-year-old woman and a
10-year-old boy affected by
extreme narrowing of the
airways, who was operated
on at Great Ormond Street
Hospital (see page 33).
In both cases, a donor
trachea was stripped of its
cells, leaving a collagen
scaffold. This was then
seeded with the patients’
own stem cells before being
transplanted. Both patients
are thriving, with no need for
powerful immunosuppressive
drugs.
In other notable work,
Professor Birchall has been
involved in a landmark
transplantation of larynx,
trachea and thyroid gland in
a US patient, who became
able to speak for the first
time in 11 years, and can
now also smell and taste.
This procedure, and other
complex interventions such
as face transplants, are
being made possible by
experimental advances,
particularly the ability to
reconnect nerves and restore
fine muscle control.
Nanotechnology and stem
cell biology have been
two of the most exciting
areas of science over the
past decade. Professor
Alexander Seifalian’s team
is combining the two in ways
that are turning regenerative
medicine from pipe dream
to practice.
Artificial organs have been
a long-standing goal of
medical science, but apart
from a few successes –
such as artificial hips and
heart valves – little progress
has been made. A major
challenge has been to make
materials biocompatible,
so they are not rejected by
the body’s immune system.
Highly inert substances,
though, do not integrate
well into the body.
The second key development
has been the ability to isolate
adult stem cells with wide
differentiation potential from
bone marrow. These cells
can be grown in culture then
used to colonise the artificial
scaffolds. Work in cell culture
and in animal models has
shown that cells differentiate
and form coherent tissues,
and the artificial components
are resilient and do not
trigger rejection responses.
The potential applications
are almost endless. The
first clinical use was for a
patient with an inoperable
cancer of the windpipe (see
page 34). But Professor
Seifalian’s principal interest is
in artificial vessels for heart
bypass surgery. Currently,
almost a third of patients who
need surgery do not have
suitable arteries that could
be used for the bypass. With
development funding from
the Wellcome Trust, Professor
Seifalian’s team is developing
artificial arteries which
act as scaffolds on which
circulating stem cells attach
and develop into endothelial
lining, to protect against
thrombosis. Again, animal
studies have been highly
promising – after a year, 85
per cent of grafted arteries
remained open, while vessels
made from simple PTFE were
all blocked within two weeks.
A graft has been implanted
in a patient’s lower limb, who
is doing well six months after
surgery, and the first human
trials are due to begin shortly.
Patients without suitable
arteries are an immediate
priority. If the approach is
successful it could be an
alternative to conventional
grafting, opening up a huge
market worldwide.
Other possible applications
include artificial bile ducts,
larynxes, heart valves and
tear ducts. A tear duct
made from nanocomposite
materials and silver
nanoparticles has already
been implanted in a patient
by Dr Karla Chaloupka at
Zurich University Hospital.
Professor Seifalian has
even helped to generate a
new nose for a 50-year-old
patient who had lost most
of his own to cancer. The
nose has been constructed
using a glass mould made
from the patient’s CT scan,
which was then used to
make a nanomaterial-based
3D scaffold. Patient stem
cells were grown on the
nanocomposite scaffold,
which was then implanted
under the skin of the patient’s
arm before transplantation to
replace the cancerous nose.
As well as these immediate
applications, Professor
Seifalian is developing
a whole range of
nanocomposite materials
to suit different tissues
and organs with Arnold
Darbyshire, the team’s
polymer chemist.
Professor Seifalian is
also looking to give his
nanocomposite materials
useful biological properties,
for example by incorporating
bioactive molecules such
as nitric oxide-eluting
molecules. Dr Achala de
Mel has tested a range
of implants including
cardiovascular stents and
heart valves in animal models
as a prelude to clinical trials.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
35
What do socks worn by English Premier League footballers,
an early warning system for tropical storms and magnetic
nanoparticles for cancer detection have in common?
All owe their existence to the work of UCL Business.
BUSINESS BENEFITS:
COMMERCIALISATION
WITH A CONSCIENCE
For new discoveries to
benefit patients, some form
of commercial investment is
usually needed to support
product development,
secure regulatory approvals,
and deliver and market a
final product. Established
in 2006, UCL Business plc
(UCLB) aims to accelerate
this process, offering expert
advice and practical support
to researchers keen to see
their research developed
commercially and identifying
the most appropriate route
for commercial development.
UCLB also has a budget
to support small ‘proof
of principle’ projects, to
generate data to support
further commercial
development. It is also
responsible for an extensive
consultancy programme,
helping to establish and
negotiate consultancy
arrangements for UCL’s
many world-leading experts.
UCLB manages all
forms of commercial
development, negotiating
licensing agreements,
establishing spinout
companies or facilitating
collaborative research
between academic and
commercial partners. UCLB
has established excellent
working relationships with
several large pharmaceutical
companies, helping to
36
broker agreements with
GlaxoSmithKline, Pfizer,
AstraZeneca and others.
It has also forged
agreements with a number
of dynamic biotech and
medical device companies,
based in the UK and
overseas.
Staff expertise covers
all areas from patent
protection, through project
management and negotiation
of partnerships and
licensing arrangements with
commercial partners. Staff
also provide support for
clinical trials at UCL’s clinical
research facilities, and make
an important contribution
to activities at UCL’s NIHR
Biomedical Research
Centres. As well as general
advice on commercial
development of ideas,
UCLB also offers a complete
project management
service for labs undertaking
translational projects.
Medical applications
Reflecting UCL’s status as
a global powerhouse of life
science research, medical
applications make up a
significant proportion of
UCLB’s portfolio. Indeed,
UCLB has been involved in
many of UCL’s most exciting
translational research
projects.
For example, it has worked
with Professor Michael
Wilson on photoactivated
antimicrobial compounds,
from which the Canadian
company Periowave Dental
Technologies has developed
a ‘photodisinfection’ system
for treatment of gum disease.
Periowave was developed
in partnership with Ondine
Biomedical Inc., which is
also involved in a project
to produce light-activated
antimicrobial urinary
catheters (see page 42).
With Professor Dave
Selwood, UCLB helped
to establish Canbex
Therapeutics Ltd to take
forward development
of promising drugs for
controlling involuntary
movements (spasticity)
affecting people with multiple
sclerosis. Canbex has
received £1.75m Technology
Transfer funding from the
Wellcome Trust, as well
as commercial backing.
UCLB has also helped
to broker a relationship
between Autifony
Therapeutics, a subsidiary
of GlaxoSmithKline, and the
UCL Ear Institute. Autifony
represents an innovative
approach bringing together
academic partners, research
and the charitable sector
in the search for new agents
for tinnitus and other
hearing problems.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
The charitable sector is
also involved in a three-way
agreement involving UCLB,
the National Centre for
Young People with Epilepsy
and Special Products
Ltd. The agreement will
enable commercialisation
of Epistasus, a product
developed from research
at the Institute of Child
Health that can prevent
an epileptic seizure
developing potentially fatal
complications. Epistasus
has been used ‘off-label’ for
more than a decade, and
now Special Products are
seeking approval from the
Medicines and Healthcare
Products Regulatory Agency
for ‘official’ use in such
situations.
Bringing benefits
Commercial development is
an important route by which
the potential of academic
research can deliver
practical benefits. As well as
generating a profit, UCLB
aims to fulfil a broader aim
of UCL, to improve the lot
of humankind, while also
generating an income stream
to reinvest in UCL and
support its work.
This perspective has
enabled UCLB to adopt
projects that are unlikely
to be huge money-spinners,
or may take many years
to come to fruition, but are
socially desirable.
The spinout company
EuroTempest, for example,
generates income from its
weather-modelling activities.
But a non-profit side
project, Tropical Storm Risk,
provides free information to
17,000 subscribers, helping
developing countries plan for
impending severe weather
and possible flooding.
Similarly, activities linked to
the UK Collaborative Trial of
Ovarian Cancer Screening,
led by Professor Usha
Menon (see companion
volume on Public Health),
may have a significant
health benefit but these
are some way down the
line. Thousands of samples
are being stored (with
accompanying health data),
providing a potentially
valuable ‘biobank’ resource.
UCLB and venture capital
company Albion Ventures
recently invested £1m in
Abcodia, which aims to
use the serum resource to
develop novel biomarkers
of disease. Crucially, the
investments will ensure that
this store of knowledge will
not be lost once funding
for the original trial comes
to an end.
Key UCLB Facts
UCLB SPINOUTS
A selection of UCL spinout companies:
Pentraxin Therapeutics Ltd: Pentraxins holds all the
intellectual property rights associated with Sir Mark Pepys’s
research at UCL (see page 14).
Ark Therapeutics: Ark Therapeutics was set up in 1997 by
Professor John Martin, Stephen Barker and Professor Seppo
Yla-Herttuala, based in Finland. It has a range of interests,
including stem cell applications in cardiac medicine and gene
therapy (see page 32). It floated on the London Stock Exchange
in 2004 but maintains close links with UCL.
Endomagnetics Ltd: Based on research at the London
Centre for Nanotechnology and the University of Houston,
USA, Endomagnetics has developed a technology for detecting
magnetic nanoparticles, initially for use in cancer detection.
In August 2011, it secured £1.8m venture capital funding
for further development of its technologies.
FROM SMALL ACORNS...
Several UCL spinouts have gone on to achieve considerable
commercial success:
Arrow Therapeutics Ltd: Arrow Therapeutics focuses on
antiviral development, including treatments for respiratory
syncitial virus. In 2007, it was acquired by AstraZeneca
for US$150m.
BioVex: A cancer vaccine business set up by former UCL
researcher Robert Coffin, BioVex was bought by US biotech
company Amgen for US$1bn in 2011.
Stanmore Implants Worldwide Ltd: An orthopaedic company,
Stanmore Implants designs and manufactures specialist
prosthetic limbs and similar devices, including those implanted
directly into bone (see page 39). In 2008 it was acquired by a
syndicate led by MDY Healthcare and Abingworth Management.
LICENSED TECHNOLOGIES
Pfizer: UCLB has worked with Professor Pete Coffey to establish
an arrangement with Pfizer to license outputs from the London
Project for Blindness, which is developing a novel stem cell
therapy for age-related macular degeneration at the Institute
for Ophthalmology (see page 32).
Ocera Therapeutics Inc: UCL and Ocera are working
collaboratively to develop a drug treatment for patients with
high levels of ammonia in the bloodstream due to liver failure,
which can cause a form of encephalopathy. Developed by UCL’s
Professor Rajiv Jalan, the therapy is undergoing clinical trials
under exclusive license to Ocera.
IN THE PIPELINE
• £9.4M TURNOVER 2010/11
• 45 EQUITY HOLDINGS AS AT 31 JULY 2011
• 287 TOTAL LICENCES AS AT 31 JULY 2011
• 37 NEW PATENTS APPLIED FOR IN 2010/11
• 34 PROOF OF CONCEPT PROJECTS FUNDED
IN 2010/11 WITH A VALUE £796,000
UCLB funding has been used to develop several promising lines
of research towards commercial development. These include:
Synthetic peptide drugs: Professor Nikos Donos, Professor
Irwin Olsen and Mr Harsh Amin have developed synthetic
versions of peptides that promote bone, blood vessel and nerve
development. Their work received a commendation at the 2011
Medical Futures event.
• 295 PATENT FAMILIES AS AT 31 JULY 2011
• 38 DRUG DISCOVERY PROJECTS AS AT
31 JULY 2010
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
37
SECTION 5
TRANSLATION:
THE ‘HARD’ AND THE ‘SOFT’
Translation is typically viewed in terms of
new therapeutics or diagnostics. Yet there
are numerous other ways in which new
knowledge can be put to medical advantage,
from exploitation of new technologies
to influencing of individual and
population behaviour.
Psychotherapies have been developed for a wide range of psychiatric conditions.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
38
Modern prosthetic limbs are more comfortable and flexible.
Engineering and
technology hold much
promise, particularly in the
development of new body
parts and prosthetics.
In their development of
novel prosthetic implants,
Professor Gordon Blunn
and colleagues have drawn
inspiration from nature –
specifically, the antlers of
deer. Attaching prosthetic
limbs to limb stumps can
cause discomfort, and
excessive wear may lead to
tissue damage and infection.
Anchoring prosthetic limbs
directly to bone would
overcome this problem,
but involves penetrating
the skin, the body’s ‘seal’
against threats from the
outside world. It is very rare
for structures to breach this
barrier – teeth are the only
human structures that do so.
With colleagues from the
Royal Veterinary College,
Professor Blunn therefore
turned to a natural model
of ‘transcutaneous’ bone
attachment – antlers.
Ultrastructural and
biomechanical analysis
identified features of antler
attachment that prevent the
Ultrastructural and biomechanical analysis
identified features of antler attachment that
prevent the main problems associated with
transcutaneous implants.
main problems associated
with transcutaneous implants
– downgrowth of cells as
they try to burrow below
an ‘invasive’ implant and
re-establish an intact barrier,
and infection as microbes
enter the body where the
seal is not perfect. The
key features included very
tight adherence at the skin
surface and specialised
regions of bone that anchor
the antler and are firmly
attached to surrounding
tissue through collagen
fibres.
This understanding shaped
the development of novel
implants that directly attach
to the bone of amputees.
Recipients have included
a victim of London’s 7/7
terrorist bombings. The
technology has also been
used by vets for animals that
otherwise would have been
put down. In the longer term,
Professor Blunn hopes to
enhance the technology and
attach nerves to allow finer
control of prostheses.
Professor Alex Seifalian’s
team is combining
innovations in materials
science and stem cells to
develop artificial tissues
and organs (see page 34).
Working with Professor
Seifalian, Dr Gaetano
Burriesci and colleagues in
the Faculty of Engineering
Sciences are developing
a range of devices for
cardiovascular medicine,
including novel polymerbased heart valves. The
valves, currently undergoing
pre-clinical assessment, are
designed to be as flexible
as biological replacements
but longer-lasting.
Dr Richard Day is
exploring the potential
of novel materials to aid
intestinal healing and
repair. One promising
line of enquiry centres on
synthetic microspheres for
repair of perianal fistulae,
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
39
Artificial tissue is being developed for heart repair.
abnormalities common in
Crohn’s disease that often
result in fecal incontinence
(see page 40). The spheres
pack tightly, acting as a kind
of alimentary ‘polyfilla’.
New materials are also
central to the collaboration
between Professor Michael
Wilson and Professor Ivan
Parkin in the Department of
Chemistry. Light-activated
antimicrobial dyes are
being incorporated into
urinary catheters to prevent
colonisation by harmful
bacteria (see page 42).
Radiotherapy is a medical
technology that has been
used for more than a century,
but it remains possible to
make important innovations.
Dr Jayant Vaidya and
colleagues, for example,
have pioneered a new
approach to radiotherapy for
breast cancer, with a single
dose of radiation being
delivered directly into the
breast at the same time as
surgery (see page 41).
40
Nano-engineering
Engineering research may
also lead to advances in
both medical imaging and
drug delivery. Dr Eleanor
Stride and Professor
Mohan Edirisinghe have
been exploring the medical
use of ‘microbubbles’,
polymer or lipid-based
spheres in the nanometre
and micrometre size range.
One use is to improve
the quality of ultrasound
imaging in particular for
diagnosing heart disease
and small tumours. Unlike air
bubbles, encapsulated gas
bubbles are safe for use in
people. As well as imaging,
microbubbles could also be
used to deliver anti-cancer
drugs, as they burst when
exposed to high-power
ultrasound. Although it has
proven difficult to target
microbubbles to tumours
using biochemical methods,
it may be possible using
magnetic particles, which
can be precisely positioned
by external magnetic fields
– an area being explored
‘Microbubbles’ may have value in imaging and drug delivery.
by Dr Stride and Professor
Quentin Pankhurst.
Indeed, microbubbles
have great potential in drug
delivery – an often neglected
but hugely important aspect
of the drug development
process. Encapsulation
in microbubbles could be
a way to improve delivery
of poorly soluble drugs
and to control the rate at
which drugs are released
in the body. Dr Stride and
Professor Edirisinghe
have developed a novel
encapsulation process
in which a coaxial tube
attached to an ultrafine
nozzle generates a
spray of drug-containing
nanoparticles. Notably, the
size and structure of the
particles produced are highly
uniform and can be easily
adjusted24. One application
is in encapsulation of poorly
soluble drugs25. Dr Stride
recently took up a new post
at the University of Oxford,
but retains a visiting position
at UCL.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
Nanotechnology may also
have a role to play in a new
generation of diagnostic
devices. A world-leading
figure in ‘nanocantilever’
devices for measuring
extremely small forces,
Dr Rachel McKendry is also
developing devices with
healthcare applications.
One approach is for devices
that can detect binding of
antibiotics to their microbial
targets, with sufficient
sensitivity to distinguish
between binding to wildtype and antibiotic-resistant
targets, thereby revealing
the presence of drugresistant bacteria26.
24 Enayati M, Ahmad Z, Stride
E, Edirisinghe M. One-step
electrohydrodynamic production of
drug-loaded micro- and nanoparticles.
J R Soc Interface. 2010;7(45):667–75.
25 Bohr A, Kristensen J, Stride E,
Dyas M, Edirisinghe M. Preparation of
microspheres containing low solubility
drug compound by electrohydrodynamic
spraying. Int J Pharm. 2011;412
(1-2):59–67.
26 Ndieyira JW et al. Nanomechanical
detection of antibiotic-mucopeptide
binding in a model for superbug drug
resistance. Nature Nanotechnol.
2008;3(11):691–6.
Microspheres are a promising technology for tissue ‘filler’.
Targeted radiotherapy has benefits for breast cancer patients.
MIND THE GAP
ONCE IS ENOUGH
Biodegradable microspheres may be an ideal ‘polyfilla’
for repairing damaged tissues.
A single dose of radiotherapy during surgery can prevent
the most common form of breast cancer from recurring.
There is great interest in using natural or artificial scaffolds to
repair damaged tissue and organs. Dr Richard Day, for example,
has been developing a range of biodegradable and bioactive
microspheres that pack tightly into damaged areas and promote
colonisation with new cells. Microspheres hold great promise for
difficult gastrointestinal conditions but could also have applications
in other areas – such as wound healing, where a biodegradable
‘polyfilla’ could provide a physical scaffold for migrating cells.
Dr Day is particularly interested in biomaterials based on
biodegradable polymers, similar to those used in surgical sutures.
He has developed a technique to manufacture porous spheres,
with a unique structure making them suitable for minimally invasive
delivery.
The method has several advantages. Firstly, agents such as
antibiotics or growth factors can be loaded into the microspheres
with high efficiency. In addition, the microspheres have a structure
ideal for promoting cell integration, with a central hollow core and
a lattice-like structure with channels large enough for cells to enter
and migrate through. By the time the microspheres disappear, cells
have created stable new tissues.
Dr Day envisages their use in conditions such as perianal fistulae,
commonly seen in Crohn’s disease, where channels ramify from the
gut, sometimes to outer skin, leading to seepage of bowel contents.
As well as their physical bulk, microspheres have been engineered
to include antimicrobial agents (such as silver nanoparticles) and
antibodies to TNF , which are known to be beneficial in repair
of perianal fistulae but are difficult to deliver directly to the right
location.
Dr Day’s team has also been experimenting with microspheres
as a delivery mechanism for cells, such as smooth muscle cells to
treat atrophied or damaged sphincter muscle (a common cause of
fecal incontinence). They could also be of value as bulking agents
in deep wounds where substantial amounts of tissue have been
lost. To date, Dr Day has demonstrated success in a range of in vivo
models, and has received Technology Transfer funding from the
Wellcome Trust to move the technology towards human application,
with clinical trials scheduled for 2013.
Invasive ductal carcinoma, the most common form of breast cancer,
accounts for around 80 per cent of cases. Early-stage tumours are
typically removed surgically, conserving as much breast tissue
as possible. Women then undergo daily radiotherapy of the entire
breast for several weeks to prevent recurrence. However, an
international clinical trial led by Professor Michael Baum, with
Dr Jayant Vaidya and Professor Jeffrey Tobias, suggests that
a single session of localised radiotherapy at the time of surgery
is just as good at preventing recurrence.
Although conventional treatment is effective, the radiotherapy
sessions are gruelling and inconvenient for women, who have to
visit hospital every day for several weeks. Radiotherapy is used
to ensure that any clusters of abnormal cells do not develop into
secondary cancers. However, when they do recur, secondary
tumours generally arise from the same area of breast as the initial
cancer. This suggested that radiotherapy restricted to the original
tumour site might be equally effective.
To test this idea, the TARGIT-A (targeted intraoperative therapy)
trial compared the approach – surgery and a course of wholebreast radiotherapy – with a single procedure combining surgery
and localised radiotherapy.
The trial involved more than 2000 women aged 45 and older
from nine countries, all with early-stage invasive ductal carcinoma.
Women were examined every six months for 5 years, and then
annually up to 10 years. The number of recurrences was very low,
and almost identical in the two groups.
Although long-term follow-up is continuing, recurrence
is generally apparent by two to three years – and localised
radiotherapy is a match for conventional treatment at four years.
The TARGIT-A group experienced more fluid build-up in the wound
area, but this was more than offset by fewer side-effects, such as
pain, as well as the reduced treatment burden.
Localised radiotherapy is associated with very low rates of
recurrence, possibly because it is highly targeted and also
delivered in a timely fashion – immediately after surgery. A second
trial, TARGIT-B, has therefore been organised to compare its
use as a tumour bed boost against conventional external beam
radiotherapy, in women with early stage breast cancer where
there is a high risk of tumour recurrence.
Foong KS, Patel R, Forbes A, Day RM. Anti-tumor necrosis factor-alphaloaded microspheres as a prospective novel treatment for Crohn’s disease
fistulae. Tissue Eng Part C Methods. 2010;16(5):855–64.
Blaker JJ et al. Assessment of antimicrobial microspheres as a prospective
novel treatment targeted towards the repair of perianal fistulae. Aliment
Pharmacol Ther. 2008;28(5):614–22.
Blaker JJ, Knowles JC, Day RM. Novel fabrication techniques to produce
microspheres by thermally induced phase separation for tissue engineering
and drug delivery. Acta Biomater. 2008;4(2):264–72.
Vaidya JS et al. Targeted intraoperative radiotherapy versus whole breast
radiotherapy for breast cancer (TARGIT-A trial): an international, prospective,
randomised, non-inferiority phase 3 trial. Lancet. 2010;376(9735):91–102.
Vaidya JS et al. Targeted intraoperative radiotherapy (TARGIT) yields very
low recurrence rates when given as a boost. Int J Radiat Oncol Biol Phys.
2006;66(5):1335–8.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
41
A web-based tool is helping stroke patients recover reading skills.
A bacterial biofilm, which can form in catheters.
UP TO SPEED
A FLASH OF GENIUS
Animated text can improve reading speeds in patients
whose vision has been damaged by stroke.
Catheters impregnated with light-activated antimicrobial
chemicals may provide a way to tackle healthcareassociated infections.
The effects of strokes depend on which areas of the brain are
affected. In some cases, damage to regions of the visual cortex
robs patients of vision in discrete regions of their field of view. If this
impinges on the most sensitive central region, the fovea, activities
such as reading can be severely affected. Dr Alexander Leff and
colleagues at UCL Multimedia have explored the basis of disrupted
reading in one group of such patients, and developed a web-based
therapy that significantly improves reading ability.
Patients who lose visual input on one side of their visual field,
usually the right, may develop ‘hemianopic alexia’ and struggle to
read text. In effect, the brain is deprived of visual information about
upcoming words, and cannot plan an efficient set of reading eye
movements for each line of text.
Using eye-tracking equipment, Dr Leff discovered that this
impairment has a subtle but important impact on how people read.
Normally, the eye scans across a line of text, periodically stopping
for around 200 milliseconds before jumping to a new position
along the line, typically a new word. It probably takes only around
50 milliseconds to absorb visual information; the rest of the time
is spent on preparing the next eye movement.
Although patients might be expected to compensate by moving
their point of fixation to the right, in fact they typically fixated to the
left of the ‘ideal’ spot in a word. Not only does this give them less
information about the full word, but it also means that the next point
of fixation is generally still within the same word, rather than in the
following word. This slows down reading considerably.
In normal subjects, reading speeds can be increased by training
on a scrolling text bar (like a news ticker). To see if this could help
patients, Dr Leff carried out a controlled trial, supplying patients with
Sherlock Holmes novels scrolling at different speeds. As a control,
patients completed spot-the-difference tests, which stimulate eye
movements but not reading skills.
In a group of 19 patients with stable hemianopic alexia, the
training had a significant impact on reading speeds, on average
by 18 per cent. The effect was associated with an increase in
the size of rightwards (but not leftwards) eye movements. A free
web-based version has been developed, with funding from the
Stroke Association, and is available at www.readright.ucl.ac.uk.
Analysis of data from 29 participants has shown a beneficial effect,
similar to that seen in the clinical trial.
Leff AP et al. Impaired reading in patients with right hemianopia. Ann Neurol.
2000;47(2):171–8.
McDonald SA et al. Patients with hemianopic alexia adopt an inefficient eye
movement strategy when reading text. Brain. 2006;129(Pt 1):158–67.
Innovation often emerges from fruitful interactions between
researchers in different disciplines. A good example is the
collaboration between Professor Michael Wilson at UCL’s Eastman
Dental Institute and Professor Ivan Parkin in UCL’s Department
of Chemistry, who are developing a urinary catheter impregnated
with a light-activated antimicrobial that may prevent bacterial
colonisation and infection of patients.
Hospital-acquired infections – particularly by antibiotic-resistant
strains of microbes such as MRSA – are a major health problem,
causing some 5000 deaths a year in the UK. Urinary tract infections
account for around a third of all such infections, and three-quarters
of these are linked to catheter use.
To address this problem, Professor Wilson has promoted the
use of photoactive dyes that release highly reactive moieties (such
as free radicals) when pulsed with light of particular wavelengths.
These inflict widespread damage on bacterial structures and cellular
processes, making it highly unlikely that bacteria will develop
resistance. Furthermore, photoactive dyes have already been safely
used in people, simplifying the route to medical application.
In partnership with the Canadian company Ondine Biomedical,
Inc. this approach was used to develop a treatment for periodontal
disease, Periowave, which is now licensed for use in Canada and
Europe, and is going through US approval processes. In the new
collaboration, supported by development funding from the MRC,
Professor Wilson and Ondine have teamed up with Professor Parkin
as well as clinical urologists and medical physicists. Photoactive
dyes are being incorporated into catheter tubing to create lightactivated antimicrobial catheters, initially for use in the urinary tract.
Preclinical studies have shown that the catheter materials,
containing photoactive dyes and gold nanoparticles, are highly
effective at killing both Gram-negative and Gram-positive bacteria.
They also prevent the adhesion of bacteria to the catheter surface.
The detailed composition of the material is now being refined,
alongside the practicalities of light delivery so the product is easy
to use in hospital or even domestic settings. A portable laser light
source would be used every few hours to ‘photodisinfect’ the
catheter. At the end of the development phase, a prototype device
should be ready for testing in clinical trials. If successful, there is
also considerable scope to develop other forms of catheter,
for example for intravascular use.
Andersen R, Loebel N, Hammond D, Wilson M. Treatment of periodontal
disease by photodisinfection compared to scaling and root planing.
J Clin Dent. 2007;18(2):34–8.
Perni S et al. The antimicrobial properties of light-activated polymers
containing methylene blue and gold nanoparticles. Biomaterials.
2009;30(1):89–93.
Perni S, Prokopovich P, Parkin IP, Wilson M, Pratten J. (2010). Prevention
of biofilm accumulation on a light-activated antimicrobial catheter material.
J Mater Chem. 20(39):8668–73.
42
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
The behaviour change wheel.
H1N1 flu vaccine take up was surprisingly low.
These technologies are not
only highly sensitive, but
rapid – giving results within
minutes – and require no
complex amplification or
labelling of samples. Another
potential application is in
‘smart chips’ to diagnose
and monitor HIV, work
being taken forward in a
public–private collaboration
awarded £1.6 million funding
by the Engineering and
Physical Sciences Research
Council (EPSRC).
suffering from hemispatial
neglect.
Rehabilitation
On the other hand, lifestyle
factors generally reflect
behavioural choices, and
the experience of history is
that human behaviours are
difficult to shift.
The impact of some diseases
persists long after an initial
episode. This is particularly
true of stroke. The abilities
lost following stroke vary
according to which parts
of the brain are affected.
Dr Suzanne Beeke is
exploring methods to
help those who have lost
language skills, while Dr Alex
Leff has developed a webbased tool for patients with
impaired reading abilities
(see page 42). Professor
Masud Husain is testing
whether a pharmacological
approach (with guanfacine,
a noradrenergic agonist)
benefits stroke patients
Behaviour change
How we live our lives has a
profound effect on our health.
Indeed, with infectious
disease much less of a risk
than a century ago, ‘lifestyle’
factors are among the most
important influences on
health at a population level.
It stands to reason, therefore,
that they offer enormous
scope for health-promoting
interventions.
It was once thought that
unhealthy lifestyle choices
reflected lack of knowledge.
Once people were aware of
risks, they would naturally
be inclined to make healthy
choices. It is now clear that
this simplistic notion rarely
holds true. Shock tactics,
forcefully pointing out the
downside of practices,
have also been advocated.
Although this approach can
have an effect in the right
circumstances, it has its
limitations.
During the H1N1 swine flu pandemic, for example,
vaccine rollout was debated at great length yet
how people would respond was barely discussed.
In the event, take up was very low, even among
healthcare professionals.
The problem with these
simple solutions is that
they do not reflect the
complexities of human
decision-making and
behaviour. They view
people as rational beings
weighing up options and
choosing optimal actions.
Yet psychology has provided
ample examples of biases
and influences on behaviour,
many of them subconscious.
People’s ‘health behaviours’
typically receive little
attention, but can have a
profound impact. During the
H1N1 swine flu pandemic, for
example, vaccine rollout was
debated at great length yet
how people would respond
was barely discussed. In
the event, take up was very
low, even among healthcare
professionals.
Behavioural interventions
are usually complex, so it
can be difficult to identify
reasons for success
or failure, to combine
information from different
studies, or to develop new
interventions by building
on past evidence. To tackle
this issue, Professors
Susan Michie and Robert
West have developed an
integrated framework of
interventions and policies to
support behaviour change,
the ‘behaviour change
wheel’ (see above), which
takes a comprehensive
and theoretically based
approach27 and builds on
a systems-based model
of behaviour, COM-B.
The intervention functions
also link to a common
‘taxonomy’ of behaviour
change techniques28. These
will enable implementation of
evidence-based interventions
and the accumulation of
knowledge across research
27 Michie S, van Stralen MM, West R.
The behaviour change wheel: A new
method for characterising and designing
behaviour change interventions.
Implement Sci. 2011;6:42.
28 www.ucl.ac.uk/health-psychology/
BCTtaxonomy/.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
43
Implementation research addresses take up of proven interventions.
projects, much in the way
that standardised gene
nomenclature or receptor
categorisation benefits
biomedical science.
Behaviour change is highly
context dependent, which
complicates extrapolation.
Behaviour change
interventions therefore
need to consider a range of
influences, and are likely to
require a suite of measures
to be effective. In turn, this
introduces complexity into
evaluation. Professor Michie
has been part of a team
(with UCL’s Professor Irwin
Nazareth) that developed the
MRC’s influential guidelines
on the development and
evaluation of complex
interventions29.
Hence, although behaviour
change can be achieved,
it requires careful analysis,
planning and coordinated
action. Though superficially
attractive, subtle ‘nudges’
on their own are unlikely to
be effective – a message
conveyed by Professors
Michie and West, and others,
to the UK House of Lord’s
Select Committee whose
report, Behaviour Change,
was published in 2011.
44
As well as the behaviour
of patients, the actions of
healthcare professionals
are also important. As
the people who actually
deliver healthcare, their
decision-making will impact
on whether ‘evidencebased medicine’ is actually
provided. Implementation
is therefore a fundamental
yet often overlooked stage
in the translational pathway.
There is thus a growing
interest in ‘implementation
research’, examining how
individual and organisational
behaviours affect the
uptake of evidence-based
healthcare.
Ideally, then, there is a need
to learn from implementation
projects – which should both
be based on good practice
and provide evidence to
refine good practice. This
is best achieved if rigorous
evaluations are embedded
into such projects from
the beginning. However,
there is often a desire by
planners, policy-makers
and service managers to
bring about change as
rapidly as possible. Taking
the time not just to plan an
implementation strategy
The CHI + MED project is studying interactions with medical devices.
There is a growing interest in ‘implementation
research’, examining how individual and
organisational behaviours affect the uptake of
evidence-based healthcare.
but also to integrate research
to evaluate implementation
requires considerable effort.
Ultimately, though, ‘learning
while doing’ should provide
substantial payback.
With Professor Steve Pilling,
Professor Michie is also
Co-Director of the Centre
for Outcomes Research
and Effectiveness (CORE).
CORE has a strong focus
on using psychological
theory to improve health
interventions, particularly
in mental health. As well as
multiple clinical guidelines
for NICE, it has also
developed the Department
of Health’s Health Trainer
Handbook, as well as the
competency framework for
the Improving Access to
Psychological Therapies
programme. CORE also
develops mental health
guidelines for NICE, through
the National Collaborating
Centre for Mental Health,
of which Professor Pilling
is Co-Director.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
Technology and human
behaviour come together
in the field of human–
computer interactions, an
area of significant medical
importance. The UCL
Interaction Centre is leading
a £5.7 million multicentre
EPSRC-funded project
– ‘CHI+MED’ – studying
interactions with medical
devices, with the ultimate aim
of improving device design
to reduce human error.
29 Craig P et al. Developing and
evaluating complex interventions:
the new Medical Research Council
guidance. BMJ. 2008;337:a1655.
Psychotherapies have been validated in clinical trials.
Evidence-based approaches exist for people who want to quit.
A FAILURE OF ATTACHMENT
A HARD HABIT TO BREAK
A psychotherapy based on developing patients’
‘mentalising’ skills is highly effective in borderline
personality disorder.
A better understanding of what works – and why – has laid
the foundations for an NHS-wide training programme for
healthcare workers helping people to give up smoking.
Borderline personality disorder (BPD) is a common, complex
condition with a very great impact on patients. Suicide attempts
and self-harm are extremely common. Based on a model of the
psychological abnormalities characteristic of BPD, Professor Peter
Fonagy has developed a ‘mentalising based therapy’ that has
proven highly effective in clinical trials.
BPD patients typically have problems controlling their emotions
and attention, and a distorted view of themselves and how they
appear to others. They are often impulsive and prone to selfdamaging behaviours, fearful of abandonment, and likely to have
difficulties managing close relationships.
The therapy developed by Professor Fonagy is based on the
idea that BPD results from poorly developed attachment early
in life. Often this is due to some kind of psychological trauma
during childhood, or at least the absence of caring and nurturing
parenting. This leads to impaired development of ‘mentalising’
abilities – understanding one’s own mental state and sense of
self and those of others.
The therapy incorporates aspects of other psychological
therapies but specifically addresses the core features of BPD.
It was also designed to be practical – it can be delivered with a
minimal amount of training by mental health teams.
At its heart are a series of steps in which a therapist develops a
rapport with a patient, and then begins to explore, in a shared way
with the patient, experiences and interpretations and alternative
viewpoints. A central aim is to improve management of emotions.
It is a careful balancing act: overstimulation of patients can be
counterproductive and there is a risk that patients develop an
unhealthy level of attachment to a therapist.
In a hospital-based clinical trial, the therapy led to significant
drops in depressive symptoms, suicidal acts and self-harm,
and improved interpersonal interactions at six months, and
improvements were maintained at 12 months. A follow up at eight
years found some vestigial impairments, but only 14 per cent still
met diagnostic criteria for BPD, compared with 87 per cent of
controls. As the therapy is relatively straightforward to implement,
it offered excellent value for money.
A second clinical trial in an outpatient setting provided further
positive results, while an independent study by a Dutch group has
provided further evidence of the therapy’s effectiveness. It is now
being adapted for substance use disorder and eating disorders.
Although many attempts have been made to change people’s
smoking behaviour, with some success, assimilating evidence
and identifying best practice has been a formidable challenge.
By developing a systematic taxonomy of behaviour change
techniques, Professors Susan Michie and Robert West and their
colleagues have been able to identify successful strategies and
develop a training programme to promote their application.
Although smoking has declined in the UK, 21 per cent of the
population are still active smokers. Many have a strong desire to
quit – some 800,000 seek help from the NHS every year. They are
supported by the NHS’s Stop Smoking Services programme.
Although this programme is delivering evidence-based support,
as with many behavioural interventions, the evidence base has
been difficult to integrate. In part this has reflected the lack of a
common framework for comparing interventions.
To overcome this problem, Professor Michie and colleagues
developed a taxonomy of behaviour change techniques, by
deconstructing current repositories of ‘best practice’. This work has
identified more than 90 techniques across a range of domains.
This taxonomy was then applied to treatment manuals collected
from Stop Smoking Services nationwide. Although there was
considerable variation in the techniques included (and not all
services even had manuals), manuals on average included 22
techniques. Fourteen were associated with self-reported or
objectively measured quit rates, or both.
As well as clarifying behaviour change techniques reliably
associated with quitting, the analysis also identified skills or
‘competencies’ practitioners need to deliver them. Focusing on
those supported by evidence from randomised controlled trials,
the UCL group was able to draw up a list of evidence-based
individual and group competencies.
This list has been used to develop a training programme for
practitioners within the NHS, being delivered through an innovative
NHS–academic partnership – the NHS Centre for Smoking
Cessation and Training (ncsct.co.uk), directed by Dr McEwen
together with Professors Michie and West. In its first year, more than
3000 practitioners registered for two-stage training (via the web
and face-to-face) and over 100 are now fully certified practitioners.
Initial evaluations of practitioners’ competence and confidence are
positive, and objective measures of the programme’s impact on
smoking cessation are currently being developed.
Bateman A, Fonagy P. The effectiveness of partial hospitalization in the
treatment of borderline personality disorder – a randomised controlled trial.
Am J Psychiatry 1999;156:1563–9.
Michie S, Hyder N, Walia A, West R. Development of a taxonomy of
behaviour change techniques used in individual behavioural support for
smoking cessation. Addict Behav. 2011;36(4):315–9.
Bateman A, Fonagy P. 8-year follow-up of patients treated for borderline
personality disorder: mentalization-based treatment versus treatment as
usual. Am J Psychiatry 2008;165:631–8.
Michie S, Churchill S, West R. Identifying evidence-based competences
required to deliver behavioural support for smoking cessation. Ann Behav
Med. 2011;41(1):59–70.
Bateman A, Fonagy P. Randomized controlled trial of outpatient
mentalization-based treatment versus structured clinical management
for borderline personality disorder. Am J Psychiatry 2009;166:1355–64.
West R, Walia A, Hyder N, Shahab L, Michie S. Behavior change techniques
used by the English Stop Smoking Services and their associations with
short-term quit outcomes. Nicotine Tob Res. 2010;12(7):742–7.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
45
TRANSLATION AND EXPERIMENTAL MEDICINE AT UCL
Component institutes
Experimental Medicine domain
Translation is a priority across all of UCL’s School of Life
and Medical Sciences. It is a naturally strong focus of the
UCL Faculty of Medical Sciences, which comprises:
• UCL Division of Infection and Immunity
The Experimental Medicine Domain at UCL aims to
promote interactions between researchers and clinicians
to drive forward the development of new diagnostics and
therapeutics, with a particular focus on early-stage studies
in humans. It encompasses researchers across the whole of
the UCL School of Life and Medical Sciences and their work
with colleagues outside the School.
• UCL Division of Surgery and Interventional Science
Domain Chair: Professor Patrick Maxwell
• UCL Medical School
• UCL Division of Medicine
• UCL Cancer Institute
www.ucl.ac.uk/slms/domains/experimental-medicine
• UCL Eastman Dental Institute
• Wolfson Institute of Biomedical Research
• UCL Institute of Hepatology
www.ucl.ac.uk/medical-sciences
Other Faculties
The Faculty of Medical Sciences is one of four Faculties
within the School, the others being Brain Sciences,
Life Sciences and Population Health Sciences.
UCL in London
Partners
Researchers in the UCL School of Life and Medical
Sciences occupy a range of buildings on UCL’s central
Bloomsbury Campus, at the nearby Royal Free Hospital
and Whittington Hospital/Archway Campus sites,
and other central London locations.
UCL School of Life and Medical Sciences works
closely with a range of local, national and international
partners. Of particular significance are its close links to
local NHS bodies, collectively forming UCL Partners,
one of just five UK Academic Health Science Centres.
These links underpin UCL’s NIHR Biomedical Research
Centres at UCLH, the UCL Institute of Child Health (with
Great Ormond Street Hospital) and the UCL Institute of
Ophthalmology (with Moorfields Eye Hospital) and its
Biomedical Research Unit in dementia.
1 UCL Main Campus
2 UCL Hospital
3 Great Ormond Street Hospital and
UCL Institute of Child Health
4 Moorfields Eye Hospital and
UCL Institute of Ophthalmology
5 Royal Free Hospital and UCL School of Medicine
6 Whittington Hospital and Archway Campus
The School has also developed ties with nearby academic
centres, including the London School of Hygiene and
Tropical Medicine and Birkbeck College. As well as many
joint research initiatives, the institutions also liaise at a
strategic level.
With the MRC, Wellcome Trust and Cancer Research
UK, UCL is also a founding partner of the Francis Crick
Institute, led by Professor Sir Paul Nurse, which is due
to open in 2015.
6
5
2 1 4
3
London UCL also establishes wider partnerships in the UK,
for example with Imperial College to set up the London
Centre for Nanotechnology, and with Imperial, King’s
College London, the MRC and GlaxoSmithKline on the
‘Imanova’ clinical imaging initiative. The agreement
was forged under the umbrella of the Global Medical
Excellence Cluster (GMEC), a public–private partnership
bringing together world-leading academic, health and
industrial partners in South-East England.
As well as numerous international research collaborations,
UCL has developed a strategic alliance with Yale
University, the Yale–UCL Collaborative, to promote
cross-fertilisation and joint ventures across education,
research and application.
46
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
Support: Resource centres and platforms
Research income
The scale of UCL’s research enables it to provide a range
of technical infrastructure platforms to support research.
These include outstanding facilities and technical expertise
in molecular and cellular imaging, as well as pre-clinical
and clinical imaging, and several sites specialising in
high-throughput sequencing and genome analysis.
‘Live’ grants as at 1 September 2011
Other core platform technologies cover small-chemical
libraries, proteomics, biological services and transgenics,
and informatics. UCL researchers are also involved in
numerous biobanking initiatives and cohort studies,
providing access to extensive collections of materials
and data.
UCL also provides capital infrastructure funding to
enable labs to develop their equipment base.
For clinical research, a Research Support Centre
provides access to essential support for work on people
and patients, including liaison with the UCLH/UCL NIHR
Biomedical Research Centre, UCL Clinical Trials Unit
and UCLH/UCL Clinical Research Facility.
The Translational Research Office works to promote the
translation of research into therapies, techniques and
products with therapeutic value.
www.ucl.ac.uk/platforms/
www.ucl.ac.uk/slms/research_support_centre
UCL Research Strategy
The UCL Research Strategy calls for a transformation
of the understanding of the role of our comprehensive
research-intensive university in the 21st century.
NIHR and other UK Government
£177.1m
MRC
£194.6m
Other UK Research Councils
UK charities
£83.3m
£500.4m
Commercial (UK and international)
EU
£53.6m
Other international, inc. NIH
Other
£62.6m
£78.4m
£14.7m
Total£1164.7m
Figures refer to research within the UCL School of Life and Medical Sciences.
NIHR: National Institute for Health Research; MRC: Medical Research Council;
NIH: National Institutes of Health.
In addition to highlighting the need to nurture and
celebrate individual curiosity-driven research, the strategy
sets out for UCL an innovative cross-disciplinary research
agenda – designed to deliver immediate, medium- and
long-term benefits to humanity.
UCL will marshal the breadth of its expert perspectives,
in order to address issues in their full complexity and
contribute to the resolution of the world’s major problems.
Its key aims are to:
• continue to foster leadership grounded in excellence in
discipline-based research
• expand the distinctive cross-disciplinarity of our
research, collaboration and partnerships
• increase the impact of our global university’s research,
locally, regionally, nationally and internationally.
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
47
Sponsors of research
We are grateful to all the individuals and organisations who support
research in the UCL School of Life and Medical Sciences.
Abbott France, Abbott Laboratories, Ablynx NV, Academy of Medical Sciences,
Action Medical Research, Action on Hearing Loss, Adam Dealy Foundation,
Against Breast Cancer, Age UK (Formerly Research Into Ageing), Agennix AG,
Aims 2 Cure, Alcohol Education and Research Council, Alder Hey Children’s NHS
Foundation Trust, Alexion Pharmaceuticals, Allergan Inc., Alpha-1 Foundation,
Alzheimer’s Society, Alzheimer’s Research UK, Amyotrophic Lateral Sclerosis
Association, Anatomical Society of Great Britain & Ireland, Anna Freud Centre,
Anthony Nolan Bone Marrow Trust, Apatech Ltd, Apitope Technology (Bristol) Ltd,
Aqix Ltd, Argonne National Laboratory, Ark Therapeutics Ltd, Arthritis Research
UK, Arts and Humanities Research Council, Assisted Conception Unit, Association
for International Cancer Research, Association Francaise Contre les Myopathies,
Association Monegasque Contre Les Myopathies, Association of Coloproctology
of Great Britain and Ireland, Asthma UK, Astra Zeneca (UK) Ltd, Ataxia UK,
Autonomic Disorders Association – Sara Matheson Trust, AVI BioPharma Inc.,
AXA Research Fund, Bachmann-Strauss Dystonia and Parkinson Foundation,
Baily Thomas Charitable Trust, Baily Thomas Charitable Trust, Barts and The
London Charity, Batten Disease Family Association, Baxter Healthcare Corp.,
Bayer – AG, Bayer SAS, Big Lottery Fund, Bill & Melinda Gates Foundation,
Biochemical Society, Biocompatibles Ltd, Biogen, Biogen Idec Inc., Biomarin
Pharmaceutical Inc., Biorex R&D, Biotechnology and Biological Sciences
Research Council, Birkbeck College, Biss Davies Charitable Trust, Boehringer
Ingleheim, Bone Cancer Research Trust, Brain Research Trust, Breast Cancer
Campaign, Bristol Myers Squibb, British Academy, British Council for Prevention
of Blindness, British Heart Foundation, British HIV Association, British Lung
Foundation, British Medical Association, British Neurological Research Trust,
British Orthodontic Society, British Pharmacological Society, British Psychological
Society, British Retinitis Pigmentosa Society, British Skin Foundation, British
Society for Haematology, British Tinnitus Association, British Urological
Foundation, BUPA Foundation Medical Research Charity, Burdett Trust for
Nursing, Burroughs Wellcome Fund, Cambridge University Hospital NHS
Foundation Trust, Camden and Islington Health Authority, Canadian Institutes of
Health Research, Cancer Fund, Cancer Research Institute USA, Cancer Research
UK, Carbon Trust Ltd, Carl Zeiss Surgical GMBH, Celera Corp., Cell Medica Ltd,
Centocor Inc., Central and East London CLRN, Central Research Fund, Cephalon
Inc., Charles Wolfson Charitable Trust, Chemel AB, Child Growth Foundation, Child
Health Research Appeal Trust, Children Living with Inherited Metabolic Diseases
(CLIMB), Children With Cancer UK, Children’s Brain Diseases, Children’s Cancer
and Leukaemia Group, Children’s Liver Disease Foundation, Children’s Research
Fund, Children’s Trust, Chordoma Foundation, Chronic Fatigue Syndrome
Research Foundation, Chronic Granulomatous Disease Trust, Chugai Pharma
Europe Ltd, Cincinnati Children’s Hospital Medical Center, Circulation Foundation,
CLEFT – Bridging The Gap, Clement Wheeler Bennett Trust, CMT UK, Cobra
Bio-Manufacturing PLC, Cochlear Research and Development Ltd, Coda
Therapeutics Inc., Cogent (Holdings) Ltd, Colgate-Palmolive Europe, College of
Optometrists, Colt Foundation, Creating Resources for Empowerment and Action
Inc., Cure Parkinson’s Trust, Cure PSP – Society for Progressive Supranuclear
Palsy, Cyberonics Inc., Cystic Fibrosis Research Trust, Cystinosis Foundation
Ireland, Cystinosis Research Network Inc., David and Elaine Potter Charitable
Foundation, Davis Schottlander & Davis Ltd, Deafness Research (Formerly
Defeating Deafness), Defense Advanced Research Projects Agency, Department
for Children, Schools and Families, Department for Education and Skills,
Department for International Development, Department of Health, Department of
Health and Human Services, Department of Trade and Industry, Dermatitis and
Allied Diseases Research Trust, Deutsche Forschungsgemeinschaft, Diabetes
Research and Wellness Foundation, Diabetes UK, Diagenode SA, Doctors
Laboratory, Dowager Countess Eleanor Peel Trust, Duchenne Parent Project,
Dystonia Medical Research Foundation, Dystrophic Epidermolysis Bullosa
Research Association, East Midlands Specialised Commissioning Group,
Economic and Social Research Council, Edinburgh University, Edmond J Safra
Philanthropic Foundation, Effort – Eastman Foundation, Efic, Eisai (London)
Research Laboratories Ltd, El.En. S.p.A, Elan Pharmaceuticals Ltd, Eli Lilly and
Co. Ltd, Emergency Nutrition Network, Engineering and Physical Sciences
Research Council, Epic Database Research Company Ltd, Epilepsy Action,
48
Epilepsy Research UK, Eular – European League Against Rheumatism,
Eurocoating S.P.A, European and Developing Countries Clinical Trials, European
Association for the Study of Liver, European Commission, European Huntington’s
Disease Network, European Organisation For Research and Treatment of Cancer,
European Orthodontic Society, European Parliament, European Respiratory
Society, European Society for Immunodeficiencies, Eve Appeal, Experimental
Psychology Society, F Hoffmann La Roche Ltd, Fidelity Foundation, Fight For Sight,
Fondation de France, Food Standards Agency, Foundation for Fighting Blindness,
Foundation for Liver Research, Foundation for the Study of Infant Deaths,
Foundation Leducq, Frances and Augustus Newman Foundation, Frost Charitable
Trust, Fundacao Bial, Gatsby Charitable Foundation, Gen-Probe Life Sciences Ltd,
Genentech Inc., General Charitable Trust of ICH, General Medical Council,
Genethon, Genex Biosystems Ltd, Genzyme Corp., Gilead Sciences Inc.,
GlaxoSmithKline, Glaxosmithkline (China) R&D Co. Ltd, Global Alliance for TB
Drug Development, Government Communications Planning Directorate, Great
Britain Sasakawa Foundation, Great Ormond Street Hospital Charity, Great
Ormond Street Hospital Special Trustees, Grifols UK Ltd, Grovelands Priory
Hospital, Grunenthal GMBH, Guarantors of Brain, Guide Dogs for the Blind
Association, Gynaecological Cancer Research Fund, H J Heinz Co. Ltd, Harbour
Foundation, Health and Safety Executive, Health Foundation, Health Protection
Agency, Healthcare Commission, Healthcare Quality Improvement Partnership,
Heart Research UK, Helpage International – Africa Regional Development, Henry
Smith Charity, Hestia Foundation, High Q Foundation, Histiocytosis Research
Trust, Hospital For Sick Children, Human Early Learning Partnership, Human
Frontier Science Program, Human Genome Sciences Inc., Huntington’s Disease
Association, Ichthyosis Support Group, Illumina Cambridge Ltd, Imperial College
Consultants Ltd, Imperial College of Science, Technology and Medicine, Inhibox
Ltd, Institut de Recherche Servier, Institut Straumann AG, Instrumentarium Science
Foundation, Intensive Care Society, International Association for the Study of Pain,
International Balzan Foundation, International Child Development Programme,
International Glaucoma Association, International Primary Care Respiratory Group,
International Serious Adverse Events Consortium, International Spinal Research
Trust, Ipsen Fund, Ipsen Ltd, Iqur Ltd, ISTA Pharmaceuticals, ITI Foundation,
Jabbs Foundation, James S McDonnell Foundation, James Tudor Foundation,
Janssen Pharmaceutica NV, Janssen-Cilag Ltd, Japan Society for the Promotion
of Science, Jean Corsan Foundation, Jerini Ophthalmic Inc., John Templeton
Foundation, John Wyeth & Brother Ltd, Johns Hopkins University, Johnson &
Johnson Consumer Services EAME Ltd, Juvenile Diabetes Foundation, Katherine
Dormandy Trust, Kay Kendall Leukaemia Fund, Kidney Research UK, Kids
Company, Kids Kidney Research, King’s Fund, King’s College London, Legal and
General Assurance Society Ltd, Leonard Cheshire Disability, Leukaemia and
Lymphoma Research, Leverhulme Trust, Lincy Foundation, Linkoping University,
Linnean Society of London, Lister Institute of Preventive Medicine, Liver Group,
London Borough of Camden, London Deanery, London School of Hygiene and
Tropical Medicine, Lowe Syndrome Trust, Lowy Medical Research Institute,
Ludwig Institute for Cancer Research, Lund University, Lupus UK, Lymphoma
Research Trust, Macmillan Cancer Relief (UK Office), Macular Disease Society,
Marc Fisher Trust, Marie Curie Cancer Care, Mars Symbioscience, Mary Kinross
Charitable Trust, Mason Medical Research Foundation, Matt’s Trust Fund for
Cancer, Maurice Hatter Foundation, Max Planck Institute for Molecular Genetics,
Max Planck Institute of Biology and Ageing, Medac GmBH, Medical Research
Council, Medical Research Council of Canada, Medical Research Foundation,
Melford Charitable Trust, Mend Central Ltd, Meningitis Research Foundation,
Meningitis Trust, Merck Ltd, Merck Serono, Mermaid, Michael and Morven Heller
Charitable Foundation, Michael J Fox Foundation for Parkinson’s Research,
Middlesex Hospital Special Trustees, MIND, Mologic Ltd, Monument Trust,
Moorehead Trust, Moorfields Eye Hospital (LORS), Moorfields Eye Hospital
Development Fund, Moorfields Eye Hospital Special Trustees, Moorfields Hospital
NHS Foundation Trust, Motor Neurone Disease Association, Moulton Charitable
Trust, Mr and Mrs Fitzpatrick, MRCP(UK), MSS Research Foundation, Multiple
Sclerosis International Federation, Multiple Sclerosis Society of Great Britain and
Ireland, Mundipharma Research Ltd, Muscular Dystrophy Association, Muscular
Dystrophy Campaign, Myasthenia Gravis Association, Myeloma UK, National
Association for Colitis and Crohn’s Disease, National Brain Appeal, National
Cancer Institute, National Centre for Social Research, National Centre for the
TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
Replacement, Refinement and Reduction of Animals in Research, National Contest
for Life, National Eye Institute, National Geographic, National Health and Medical
Research Council, National Institute for Health and Clinical Excellence, National
Institute for Health Research, National Institute of Academic Anaesthesia, National
Institute of Mental Health, National Institutes of Health, National Kidney Research
Fund, National Multiple Sclerosis Society, National Osteoporosis Society, National
Screening Committee, Natural Environment Research Council, NCL Stiftung,
Netherlands Organisation for Scientific Research, Neuroblastoma Society,
New England Research Institutes Inc., Newlife Foundation For Disabled Children,
NHS Blood and Transplant, NHS Executive, NHS Patient Safety Research
Programme, Nicholls Foundation, Nicox SA, NIHR School of Primary Care
Research, Nippon Telegraph and Telephone Corporation, No Surrender Charitable
Trust, Nobel Biocare AB, North Essex Mental Health Partnership NHS Trust,
Northern California Institute for Research and Education, Novartis Pharma AG,
Novartis Pharmaceuticals Corp., Novartis Pharmaceuticals UK Ltd, Novo Nordisk
Pharmaceuticals Ltd, Nuffield Foundation, Ocean Park Conservation Foundation,
Ocera Therapeutics Inc., Octapharma, Office for National Statistics, Options
Consultancy Services Ltd, Organisation for the Understanding of Cluster
Headache, Organon Laboratories Ltd, Orphan Europe (UK) Ltd, Ovarian
Cancer Action, Overweight and Heart Diseases Research Trust, Oxalosis
and Hyperoxaluria Foundation, Oxford Optronix Ltd, Oxigene Inc., Ozics OY,
Paediatric Rheumatology Discretionary Fund, Palaeontological Association,
Pancreatic Cancer UK, Parkinson’s Disease Society, Path Vaccine Solutions,
Pathogen Solutions UK Ltd, Pathological Society of Great Britain and Ireland,
Paul Hamlyn Foundation, PCI Biotech, Pelican Cancer Foundation, Peptide Protein
Research Ltd, Pervasis Therapeutics Inc., Peter Samuel Fund, Petplan Charitable
Trust, Pfizer Ltd, Philips Medical Systems NL BV, Philips Oral Healthcare Inc.,
Physiological Society, Planer Plc, Polycystic Kidney Disease Charity, Primary
Immunodeficiency Association, Procter and Gamble Technical Centre Ltd,
Progressive Supranuclear Palsy (PSP Europe) Association, Prostate Action,
Prostate Cancer Research Centre, PTC Therapeutics Inc., Qatar National
Research Fund, Race Equality Foundation, Rank Bequest, Raymond and Beverly
Sackler Foundation, Raynaud’s and Scleroderma Association, Repregen Ltd,
Research in Motion Ltd (Canada), Research into Childhood Cancer, Rheumatology
Discretionary Fund, Rho Inc., RMS Innovations UK Ltd, Roche Bioscience, Roche
Products Ltd, Rockefeller Foundation, Roddick Foundation, Ronald McDonald
House Charities UK, Rosetrees Trust, Roslin Cells Ltd, Royal Academy of
Engineering, Royal Centre for Defence Medicine, Royal College of Anaesthetists,
Royal College of General Practitioners, Royal College of Ophthalmologists, Royal
College of Paediatrics, Royal College of Physicians, Royal College of Radiologists,
Royal College of Surgeons of England, Royal Free Cancer Research Trust, Royal
Free Hampstead NHS Trust, Royal Free Hospital Special Trustees, Royal National
Institute for the Blind, Royal Society, Samantha Dickson, Sanofi Pasteur,
Sanofi-Aventis, Santhera Pharmaceuticals Ltd, Sarah Cannon Research UK Ltd,
Sarcoma Alliance for Research Through Collaboration, Save The Children, Science
and Technology Facilities Council, Scope International AG, Selcia Ltd, Sheffield
Teaching Hospitals NHS Foundation Trust, Shire Human Genetic Therapies AB,
Siemens plc, Sir Halley Stewart Trust, Sir Jules Thorn Charitable Trust,
Skeletal Cancer Action Trust Plc, SMA Trust, Smith & Nephew Plc, Society for
Endocrinology, Society for Pediatric Radiology, Sport Aiding Medical Research
For Kids (SPARKS), St George’s Hospital Medical School, St Peter’s Research
Trust, Stanford University, Stanley Medical Research Institute, Stanley Thomas
Johnson Foundation, Stanmore Implants Worldwide Ltd, Stroke Association,
Sue Harris Bone Marrow Trust, Summit plc, Supreme Biotechnologies Ltd, Susan G
Komen Breast Cancer Foundation, Swiss National Science Foundation, Syngenta,
Sysmex Ltd, Takeda Cambridge Ltd, Takeda Europe Research and Development
Centre Ltd, Takeda Pharmaceutical Co. Ltd, Tana Trust, Target Ovarian Cancer,
Tavistock and Portman NHS Trust, Tavistock Trust for Aphasia, Technology and
Medicine, Technology Strategy Board, Teenage Cancer Trust, Thomas Pocklington
Trust, Thrombosis Research Institute, Tissue Regenix Group Plc, Tourette
Syndrome Association Inc., Toyota Motor Europe, Tuberous Sclerosis Association
of Great Britain, UBS AG, UCB Pharma SV, UCB S.A, UCLH/UCL Comprehensive
Biomedical Research Centre, UK Clinical Research Collaboration, UK Human
Tissue Bank, UK Stem Cell Foundation, Unilever UK Central Resources Ltd, United
Kingdom Continence Society, United Therapeutics Corporation, University College
London Hospitals, University College London Hospitals Charities, University
Medical Center Hamburg–Eppendorf, University of Alabama at Birmingham,
University of California, University of Coimbra, University of Iowa, University of
Kansas Medical Center, University of Kwazulu-Natal, University of London,
University of Oulu, University of Oxford, University of Rochester, University of
Southampton, University of Sussex, University of Washington, University of
Western Australia, Varian Ltd, Ventana Medical Systems Inc., Veterinary
Laboratories Agency, Vitaflo International Ltd, Vital Therapies Inc., Vitol Charity
Fund, Wayne State University, Weight Concern, Weizmann UK, Wellbeing of
Women, Wellchild, Wellcome Trust, Welton Foundation, Wockhardt UK Ltd, Wolfson
Foundation, World Cancer Research Fund, World Health Organization, World
Vision International, Wyeth Laboratories and Wyeth Pharmaceuticals Inc.
SUPPORT LIFE-SAVING
RESEARCH AT UCL
You can make a difference by making a donation to
support research at UCL.
For complete details of how to make a donation, go to
www.ucl.ac.uk/makeyourmark
Alternatively, email makeyourmark@ucl.ac.uk or call
+44 (0)20 3108 3834 to discuss how you can best
support our work.
CREDITS
Commissioned photography: David Bishop (page 33)
Other images from UCL/UCLH collections except: pages 4, 7 (right): Professor
Adrienne Flanagan; page 6: Professor Steve Halligan; page 7 (left): SPL; page
8 (left) Ian Jones; pages 8 (right), 9: Dr David Becker/Wellcome Images; page
12: Dr Tim Evans/SPL; page 13: Riccardo Cassiani-Ingoni/SPL; page 14 (left):
Professor Sir Mark Pepys; page 14 (right): Regina Nickel/Wellcome Images;
page 15: Professor Sir Mark Pepys; page 17 (left): Professor John Greenwood;
page 17 (right): Professor David Selwood; page 18: K L Ordidge, A Badar,
R Yan, E Arstad, S M Janes, M F Lythgoe, UCL Centre for Advanced Biomedical
Imaging; page 19: A Walker, L Sharp, J Pryde/Wellcome Images; page 20 (left):
SPL; page 20 (right): Professor Derek Yellon; page 21: Ivor Mason/Wellcome
Images; page 22: Dr Adam Badar, UCL Centre for Advanced Biomedical
Imaging; page 23 (left): Ian Jones; page 25: Institut Pasteur/SPL; page 26:
J Riegler, J Wells, P Kyrtatos, A Price, QA Pankhurst, MF Lythgoe, UCL Centre
for Advanced Biomedical Imaging; page 28: James King-Holmes/SPL; page
29: Rob Eagle; page 33 (right): Pasieka/SPL; page 34 (left): UCLB; page 36:
Scientifica/Visuals Unlimited/Corbis; page 38: Angelo Cavalli/Corbis; page
39: iStockphoto/Blend_Images; page 40 (left): iStockphoto/miralex; page
40 (right): Dr Eleanor Stride; page 41 (left): Dr Richard Day; page 42 (right):
Professor Michael Wilson; page 43 (right): iStockphoto/RyersonClark; page
44 (right): Justine Desmond, Wellcome Images; page 45 (left): iStockphoto/
nullplus; page 45 (right): iStockphoto/ruzanna.
Text: Ian Jones, Jinja Publishing Ltd
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TRANSLATION AND EXPERIMENTAL MEDICINE UCL School of Life and Medical Sciences
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About UCL
UCL is one of the world’s top universities. Based in
the heart of London it is a modern, outward-looking
institution. At its establishment in 1826 UCL was radical
and responsive to the needs of society, and this ethos –
that excellence should go hand-in-hand with enriching
society – continues today.
UCL’s excellence extends across all academic
disciplines; from one of Europe’s largest and most
productive hubs for biomedical science interacting with
several leading London hospitals, to world-renowned
centres for architecture (UCL Bartlett) and fine art
(UCL Slade School).
UCL is in practice a university in its own right, although
constitutionally a college within the federal University of
London. With an annual turnover exceeding £800 million,
it is financially and managerially independent of the
University of London.
UCL’s staff and former students have included 21 Nobel
prizewinners. It is a truly international community: more
than one-third of our student body – around 25,000
strong – come from nearly 140 countries and nearly
one-third of staff are from outside the UK.
www.ucl.ac.uk
UCL
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London WC1E 6BT
Tel: +44 (0)20 7679 2000