Translation and Experimental Medicine by Morgan Williams

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

Basic Life Sciences: ‘Discovery’ research, from molecules to ecosystems.

Translation and Experimental Medicine: Driving translation to benefit patients’ health and well-being.

Neuroscience and Mental Health: The science of the brain and nervous system, from synapse to social interactions.

Population Health: Protecting and improving the health of populations, UK and globally.

CONTENTS

Overview: Cycles of innovation

Driving translation and experimental medicine. Section 1: Detection, diagnosis and discrimination

Using new technologies to identify disease and stratify patient groups. Feature: The space to do research

Section 2: Small and perfectly formed

Small-molecule chemical agents still have an important role to play in medicine. Section 3: The cellular route to health

Manipulation of cells is an increasingly popular way to achieve medical benefits. Feature: Imaging the future

Section 4: Repair and regeneration

Gene therapy, stem cell treatments and novel biomaterials are providing innovative new ways to repair damaged tissues. Feature: Business benefits: Commercialisation with a conscience

Section 5: Translation: The hard and the soft

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.

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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.

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.

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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 patientsâ&#x20AC;&#x2122; physiology.

Chordoma cells containing multiple copies of the brachyury gene (red dots). POPULATION HEALTH School of Life and Medical Sciences

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.

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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

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

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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.

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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.

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.

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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

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,

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

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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. UCLâ&#x20AC;&#x2122;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 Kingâ&#x20AC;&#x2122;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).

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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

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.

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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.

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.

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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.

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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

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

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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

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.

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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

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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.

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.

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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

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

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

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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.

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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.

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.

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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.

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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.

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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.

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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.

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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.

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

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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,

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

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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.

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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.

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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.

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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

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

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

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

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).

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

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.

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/.

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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.

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.

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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

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.

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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.

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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,

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 Design: Jag Matharu, Thin Air Productions Ltd © UCL. Text may not be reproduced without permission. The UCL ‘dome’ logo and the letters ‘UCL’ are the registered trademarks of UCL and may not be used without permission. TAP1540/28-05-12/V15

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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 Gower Street London WC1E 6BT Tel: +44 (0)20 7679 2000