Wellcome NEWS Issue 68, autumn 2011
TAKING RADIOGRAPHY FOR A RIDE Explore a project on how X-rays work and what they can do.
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A free display showcasing the work of some of the influential people who have contributed to the living history of the Wellcome Trust. Until December 2011, The Lightbox, Wellcome Collection. This display is part of a series of events celebrating our 75th anniversary. Find out more at www.wellcome.ac.uk/75
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Bone marrow. Steve Gschmeissner/SPL
14 Sara Rankin: In your bones contents
inside this issue In brief Message from the Director Funding news Research news
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In depth How I Got Intoâ€Ś medical robotics: David Noonan In your bones: Prof. Sara Rankin Blog and film update Q&A: Prof. George Davey Smith Bringing order to chaos: Prof. Chris Fairburn A guide to success
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Opinion Is your mind closed to open innovation? Appliance of Science: we all need to engage with bacteria
Picture features X-ray visions Nuts and Bolts: zebrafish From the Archive: Imbert-Delonnes by Pierre Chasselat
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Wellcome NEWS Telling the stories of the Wellcome Trust’s work
Message from the Director SIR MARK WALPORT
Editor Chrissie Giles Assistant Editors Tom Freeman, Kirsty Strawbridge Writers Chrissie Giles, Emma James Design Malcolm Chivers Photography David Sayer Publisher Hugh Blackbourn Contributors: Zebrafish illustration Carolina Rivera David Noonan illustration Bret Syfert Ideas, comments, suggestions? Get in touch: Wellcome News Wellcome Trust Gibbs Building 215 Euston Road London NW1 2BE E firstname.lastname@example.org www.wellcome.ac.uk/wellcomenews To subscribe: T +44 (0)20 7611 8651 E email@example.com www.wellcome.ac.uk/subscribe All images, unless otherwise stated, are from the Wellcome Library. You can get copies through Wellcome Images (images.wellcome.ac.uk). Wellcome Trust We are a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests. www.wellcome.ac.uk This is an open access publication and, with the exception of images and illustrations, the content may, unless otherwise stated, be reproduced free of charge in any format or medium, subject to the following constraints: content must be reproduced accurately; content must not be used in a misleading context; the Wellcome Trust must be attributed as the original author and the title of the document specified in the attribution. The views and opinions expressed by writers within Wellcome News do not necessarily reflect those of the Wellcome Trust or Editor. No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. ISSN 1356-9112. First published by the Wellcome Trust, 2011. Wellcome News is © the Wellcome Trust and is licensed under Creative Commons Attribution 2.0 UK. The Wellcome Trust is a charity registered in England and Wales, no. 210183. Its sole trustee is The Wellcome Trust Limited, a company registered in England and Wales, no. 2711000 (whose registered office is at 215 Euston Road, London NW1 2BE, UK). PU-5185/14.5K/08-2011/MC
This document was printed on material made from 25 per cent post-consumer waste & 25 per cent pre-consumer waste.
Wellcome NEWS Issue 68, autumn 2011
TAKING RADIOGRAPHY FOR A RIDE Art project showing how X-rays work and what they can do.
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Cover: Artwork using X-rays of everyday objects. See page 20. Hugh Turvey
It is almost two years since we proposed changing the way the Wellcome Trust funds scientists in universities and other research institutions. Our aim was to give our grantholders more time and more freedom to tackle challenging, interesting and important research questions. Thanks to many people’s hard work in implementing the new scheme, we awarded the first Wellcome Trust Investigator Awards this summer. Between them, the first 20 Senior Investigators and seven New Investigators cover all of the Wellcome Trust’s research challenge areas, from genetics to the environment and from the brain to infections and chronic diseases. In each case, the grantholder receives individually tailored support, providing flexibility and the opportunity to be creative, take risks and explore more speculative lines of enquiry. What it means for someone like Senior Investigator Professor Sara Rankin, featured in this issue of Wellcome News, is that she can focus wholly on pursuing her scientific goals and developing the right team to achieve them. Sara’s research is looking at possible ways of activating stem cells from bone marrow to stimulate the regeneration of tissues such as the brain and the heart. New therapies based on this research could improve the health of many thousands of people. That vision and the capacity to deliver it are exactly what our Investigator Awards have been designed to support. We will be announcing the next group of Investigators soon, and we have extended the Investigators model to researchers in the medical humanities and ethics. The same principle applies: providing substantial long-term funding to talented researchers and their teams. The Wellcome Trust is always looking for ways to optimise support for scientists and foster a culture in which the brightest minds can flourish. Investigator Awards have now taken their place alongside our fellowships and Strategic Awards among the major ways we fund research. I am looking forward to many exciting discoveries in the years ahead.
Wellcome Trust announces new open access journal In collaboration with the Howard Hughes Medical Institute and the Max Planck Society, we are supporting a new open access online journal for biomedical and life sciences research. The journal aims to publish the very best research, that which makes a highly significant contribution to our understanding and extends the boundaries of scientific knowledge. “We will attract the most outstanding science for publication by establishing a journal in which researchers have confidence in robust editorial decisions taken by their scientific peers. This will be a journal
Left to right: Professor Herbert Jäckle, Max Planck Society Vice President, Sir Mark Walport, Wellcome Trust Director, and Dr Robert Tjian, Howard Hughes Medical Institute President. Wellcome Images
for scientists edited by scientists,” says Sir Mark Walport, Director of the Wellcome Trust. Professor Randy Schekman, a distinguished cell biologist and current Editor-in-Chief of Proceedings of the National Academy of Sciences USA, has been appointed as the first editor of the journal. “My priority will be to launch the new journal promptly and with
Olympics kits for schools In early 2012, we will be sending a free educational kit to every UK school to help young people explore the physiology and psychology underlying exercise, movement, performance and rest, and to bring the science of the Olympics to life. ‘In the Zone’ (www.wellcome.ac.uk/inthezone) is a national educational project providing free kits containing experimental equipment, teaching materials and resources. Each activity meets curriculum requirements for science and PE for pupils aged from four to 19 years. The latest issue of Big Picture magazine (the Wellcome Trust post-16 educational resource) focuses on food and diet: the topics covered include appetite, obesity, taste, food policy and behaviour. Read, download or
order the magazine and browse other articles, videos, image galleries, lesson ideas and more at www.wellcome.ac.uk/ bigpicture/food.
Miracles, charms and more at Wellcome Collection With the end of August came the end of the Dirt Season at Wellcome Collection, but Miracles and Charms will soon begin. This season includes an exhibition of Mexican votive paintings and Felicity Powell: Charmed life, a collection of artworks by Felicity Powell shown alongside 400 amulets from the Pitt Rivers Museum. It will run from 6 October 2011 until 26 February 2012. As usual, several events will run alongside the season, including Mexican Day of the Dead family activities on 5
November and a symposium on Science and Faith in December. Wellcome Collection will be bringing an interactive installation to Bloomsbury Festival in October, too. Further events in the ‘Exchanges at the Frontier’ series, in partnership with the BBC World Service, will be happening in October and November, and there are a number of food-themed events and a Chesil beach sound installation planned. See www.wellcomecollection.org for more.
great visibility,” he says. “Open access is the future and we will build on the pioneering efforts of the Public Library of Science so that scientists will have access to this literature and the data anywhere they are.” The first issue of the journal, which has yet to be named, is expected in summer 2012.
Arabic online Over the summer, the Wellcome Library celebrated the launch of the Wellcome Arabic Manuscripts Online project (wamcp.bibalex.org). This open access resource brings together detailed images of the Library’s Arabic manuscripts and rich descriptions of the texts, illustrations and bindings. It was built in partnership with the Bibliotheca Alexandrina, Egypt, and King’s College London Digital Humanities department.
Winning writing The winners of two Wellcome Trust prizes that recognise excellence in writing will be announced soon. The six books shortlisted for the Wellcome Trust Book Prize will be announced at The Times Cheltenham Literature Festival in October, and the winner of the Prize – celebrating the best of medicine in literature – will be announced at a ceremony at Wellcome Collection in early November. The two winners of the Wellcome Trust Science Writing Prize, in association with the Guardian and the Observer, will be announced on 12 October. Newly launched this year, the Prize aims to find the next generation of undiscovered science writing talent. Autumn 2011 | 5
Primate Cinema A project commissioned by The Arts Catalyst and part-funded by a Wellcome Trust People Award explores primate cognition and interspecies communication by making videos for chimpanzee audiences. Artist Rachel Mayeri and comparative psychologist Dr Sarah-Jane Vick worked with chimps at Edinburgh Zoo, studying their responses to TV programmes. The responses were used to help imagine the chimps’ inner worlds and create a film that engages them. Primate Cinema: Apes as family has as its exploring protagonist an animatronic chimp. After premiering at the AND Festival in Liverpool in late September, the film will be shown at The Arts Catalyst in London from 19 October to 13 November, and will tour next year. The chimps can also be seen watching it at Edinburgh Zoo. www.artscatalyst.org
Bioethics podcasts ‘Bio-Ethics Bites’ is a series of free podcasts interviewing leading thinkers in bioethics. Funded by a Wellcome Trust Strategic Award to the Oxford Centre for Neuroethics, David Edmonds and Nigel Warburton (of the ‘Philosophy Bites’ series) are producing ten podcasts. Those already available include ‘Life and Death’ and ‘Designer Babies’. Listen on iTunes U or at www.neuroethics.ox.ac.uk/ bio-ethics_bites.
Psychology award Trust-funded Professors Trevor Robbins and Barry Everitt (University of Cambridge) have received the 2011 American Psychological Association Distinguished Scientific Contribution Award for their work in behavioural and cognitive neuroscience. Few UK researchers have won this award, honouring theoretical or empirical contributions to basic research in psychology. Past winners include Jean Piaget and B F Skinner.
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First Engagement Fellows named
Wellcome Trust Engagement Fellows Richard Barnett (left) and Kevin Fong (right). Wellcome Images
The first recipients of our new Wellcome Trust Engagement Fellowships are Kevin Fong and Richard Barnett. These awards aim to raise the profile and prestige of public engagement by providing Fellows with the freedom, resources and environment to carry out projects that tackle the big scientific challenges faced by society. Kevin Fong, a consultant anaesthetist and honorary senior lecturer in physiology, holds degrees in astrophysics, medicine and engineering. He writes for Times Higher Education magazine and has
also presented a number of television documentaries. Richard Barnett is a medical historian who has taught at University College London and the University of Cambridge. In addition to writing for numerous popular magazines and academic journals, he received the 2006 Promis Prize for poetry. “This is a wonderful opportunity to get a host of new audiences involved with pioneering work in the medical humanities, and to give a generation of young scholars the chance to hone their skills in public engagement,” he says.
Eight projects receive Strategic Awards Strategic Awards are some of the largest awards we make, providing a highly flexible form of funding to research groups with outstanding track records in their fields. The Awards support innovative and ambitious projects that will address the Wellcome Trust’s five main challenges, by providing funds for equipment, support staff, consumables, networking and a range of research resources. The most recent awards gave a total of £35.1 million across eight different projects and initiatives. This includes £2.5m to a new centre at the University
of Edinburgh, which will promote interdisciplinary research into understanding the immunology of infections and evolution, and £5.3m to the Cambridge–UCL Mental Health and Neurosciences Network. In addition, an extension was awarded to the Karonga Prevention Study in Malawi, which aims to achieve disease control by understanding microbial transmission. These funds will help them to maintain their project while searching for a new director, with the expectation that they will reapply for funding next year.
FUNDING OPPORTUNITIES www.wellcome.ac.uk/funding
University College London (UCL) has four new Wellcome Trust Principal Research Fellows working in neuroscience and mental health. Professor Read Montague uses neural and behavioural data to create computer models for different mental health conditions, adding to the emerging field of computational psychiatry. He divides his time between the Wellcome Trust Centre for Neuroimaging at UCL and Virginia Tech Carilion Research Institute in the USA. Professor Angus Silver – a former Research Career Development Fellow and Senior Research Fellow – is working to understand how neurons in a network process information. He will study the brain’s cerebellar cortex to try to bridge the gap in understanding between the cellular and network levels. In the Institute of Cognitive Neuroscience, Professor Neil Burgess will develop a model of spatial memory showing how populations of neurons represent, store and retrieve information in health and disease. Finally, Professor Michael Häusser is also building on his Research Career Development Fellowship and Senior Research Fellowship work, to examine neural circuits to understand how their structure and pattern of activity represent and store information and help to determine behaviour.
Win new history of medicine book Just published, The Oxford Handbook of the History of Medicine (Oxford University Press, £95) celebrates the richness and variety of medical history around the world. Its three sections explore medical developments and trends in historical writing by period, place and theme. More than 650 pages long, it is the first large-scale review of medical history in over 20 years. The book was edited by Professor Mark Jackson, Director of the Wellcome Trustfunded Centre for Medical History at the University of Exeter. Many of the 37 international scholars that have contributed to the book have also received Trust funding.
Wellcome Trust Conference Centre at Hinxton Hall, Cambridge
Versatile conference centre, Hinxton
New Principal Research Fellows
With the countdown to the Olympics, conference venues in London for 2012 are becoming increasingly hard to find. The Wellcome Trust Conference Centre at Hinxton is a versatile venue located next to the M11 and with easy access to Cambridge, London and Stansted Airport. Bring together your brightest minds in a location to inspire. T 01223 495123 E firstname.lastname@example.org www.wtconference.org.uk
We have two copies to give away. For a chance to win one, tell us: in which year was William Harvey’s classic study of the circulation of the blood first published? Email your answer (one entry only per person) to wellcome.news@ wellcome.ac.uk using the subject line ‘History competition’. Wellcome News readers can also enjoy an exclusive 20 per cent discount on this book. To buy a copy for £76, go to ukcatalogue.oup.com/product/9780199546497.do, add the book to your shopping basket, and use the promotional code AAFLY5. Competition closes 17.00 GMT, 24 October 2011, after which two correct entries will be randomly selected. Winners will be notified by email by 31 November 2011 and announced in a future issue of Wellcome News.
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Switching channels A team including researchers from the Henry Wellcome Centre for Gene Function in Oxford have discovered how different mutations in the same amino acid (glutamate 1506) of a channel that controls glucosestimulated insulin secretion can cause either too much or too little insulin secretion. This results in the opposite clinical conditions of neonatal diabetes and congenital hyperinsulinaemia, respectively. The researchers propose that these mutations alter channel activity by influencing the amount of adenine nucleotides bound to the channel. Männikkö R et al. Diabetes 2011;60(6):1813–22.
Joint findings A study involving the Wellcome Trust Case Control Consortium has found a series of genetic variants associated with increased susceptibility to the autoimmune joint disorder ankylosing spondylitis. The study adds to evidence that the IL-23R pathway, part of the cell’s signalling processes, is involved in the disorder and could be a target for drugs. It is also one of the first gene–gene interactions confirmed in humans. Australo-Anglo-American Spondyloarthritis Consortium et al. Nat Genet 2011;43(8):761–7.
Feel the burn
Researchers at King’s College London have found a molecule in the body, CXCL5, that controls sensitivity to pain from UVB irradiation, identifying it as a new target for medicines to treat pain caused by other inflammatory conditions. It is part of a family of proteins called chemokines, which draw inflammatory immune cells to the injured tissue, triggering pain and tenderness. This is the first study to reveal CXCL5’s role in mediating pain. Dawes JM et al. Sci Transl Med 2011;3(90):60.
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HIV drugs can cause premature ageing
Model of AZT, the first antiretroviral to be approved for use against HIV. Theasis/iStockphoto
A class of antiretroviral drugs commonly used to treat HIV can cause premature ageing, according to a study from Newcastle University and the Royal Victoria Infirmary, which received Wellcome Trust support. Nucleoside analogue reversetranscriptase inhibitors (NRTIs) were the first class of drug developed to treat HIV, but came to be used less in highincome countries because of concerns over side-effects. No longer protected by a trademark and hence relatively cheap, the drugs have proved important for treatment in low-income countries. The researchers found that patients who had received NRTI drugs had damaged mitochondria – the ‘batteries’
People find health cash incentives unfair Financial incentives are increasingly being used to encourage patients to stick to health programmes, despite mixed or limited evidence that these financial ‘carrots’ really work. Now, a study funded by our Ethics and Society programme has revealed that members of the public disapprove of the use of cash incentives to change health behaviour. Researchers in London carried out a survey of 188 people in the UK and the USA, asking them to rate the acceptability of cash rewards and
in our cells. “The DNA in our mitochondria gets copied throughout our lifetimes and, as we age, naturally accumulates errors,” explains Professor Patrick Chinnery, a Wellcome Trust Senior Fellow in Clinical Science. “We believe that these HIV drugs accelerate the rate at which these errors build up.” The researchers argue that the drugs are still necessary in areas where more expensive medicines are not an option. They are now looking at ways to repair or stall the damage. Payne BA et al. Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nat Genet 2011;43(8):806–10.
penalties in different circumstances. They found that participants felt financial incentives to be less acceptable and fair than medical interventions. UK respondents more strongly supported funding treatment for groups who were not thought to be responsible for their condition than for those who were. The authors note that these results are from a small sample and that further exploration is necessary before these views are used to inform discussions on the introduction of incentive schemes. Promberger M et al. Acceptability of financial incentives to improve health outcomes in UK and US samples. J Med Ethics 2011 [epub ahead of print]
Using MRI to study the brain Depression is a serious condition that affects around 10 per cent of people at some point, yet it lacks clear biological markers to distinguish it from other disorders. New research from the Biomedical Research Centre for Mental Health at the Maudsley Hospital, London, might lead to a more objective means of diagnosis. With Wellcome Trust support, researchers carried out a meta-analysis of 143 magnetic resonance imaging (MRI) studies that had measured the brain structures of people with depression. They compared these findings with those from research into bipolar disorder. The researchers found that people with clinical depression showed reductions in the grey matter of the brain, including reduced volume of the frontal lobe, basal ganglia and hippocampus. Bipolar disorder, by contrast, was
associated with reductions in white matter. Discovering when and how these changes in the brain occur will help researchers to understand more about the causes of depression and, ultimately, how to treat it more effectively. In other work, researchers at University College London have discovered that the experience of beauty is associated with similar brain activity regardless of whether the source is visual or auditory. Functional MRI data revealed an increase in activity in the medial orbitofrontal cortex of the brain when participants were presented with paintings or music that they had previously rated as beautiful, in comparison to those they had rated as indifferent or ugly. Kempton MJ et al. Structural neuroimaging studies in major depressive disorder. Arch Gen Psychiatry 2011;68(7):675–90. Ishizu T, Zeki S. Toward a brain-based theory of beauty. PLoS One 2011;6(7):e21852.
Whole genomes reveal population history
Men and boys in Tanzania. Wellcome Library
African and non-African populations continued to interbreed long after the evolutionary exodus out of Africa 60 000 years ago, according to researchers at the Wellcome Trust Sanger Institute. They developed a computer algorithm to analyse whole individual genomes – one male genome each from China, Europe, Korea and West Africa – to infer population size and history. This approach makes fewer assumptions than previous methods, providing a fresh view of the history of humanity from one million to 10 000 years ago.
Dr Richard Durbin from the Sanger Institute explains: “First, we see an apparent increase in effective human population numbers around the time that modern humans arose in Africa over 100 000 years ago. Second, when we look at non-African individuals from Europe and East Asia, we see a shared history of a dramatic reduction in population, or bottleneck, starting about 60 000 years ago, as others have also observed. But unlike previous studies, we also see evidence for continuing genetic exchange with African populations for tens of thousands of
years after the initial out-of-Africa bottleneck until 20 000 to 40 000 years ago.” The researchers believe that this technique can be developed to enable even more finely tuned discoveries by sequencing multiple genomes from different populations, and could be used to investigate population-size histories of other species for which a single genome sequence exists. Li H, Durbin R. Inference of human population history from individual whole genome sequences. Nature 2011;475(7357):493–6.
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How I got into... MEDICAL ROBOTicS Working as a mechatronics engineer on Imperial College London’s Wellcome Trust-funded i-Snake® project means things are more complicated for David Noonan than when he was playing with Meccano sets as a child, but they are no less fascinating. He talks to Chrissie Giles.
t sounds a bit clichéd but I always wanted to be an engineer, and spent my childhood playing with Lego and Meccano. There weren’t any engineers in my family – they’re all accountants, businessmen and teachers – but from a very young age all I wanted to do was build stuff. While mechanical engineering is very well established and electronics has been around a while, the field that combines them – mechatronics – is relatively new. I like it because you get to make systems that move or make intelligent decisions, rather than purely functional, stand-alone items. The field straddles all disciplines: hardware, electronics, mechanical engineering and some programming. We also include some computer vision work: for example, using feedback from a camera to control a robot. It’s a bit of a ‘jack-ofall-trades’ field so you get to learn a lot about different areas, which is great. After a degree in mechatronics in Ireland, where I’m from, I took a job on a six-month project at St James’ Hospital, Dublin. The project was to build a device that can measure a low-amplitude oscillation of the eye called ocular microtremor, which can potentially be used to infer the brain activity of patients who have had a
stroke or those under anaesthetic. This project was really interesting, particularly as I got to interact directly with surgeons and clinicians. I became fascinated with the medical side of engineering and decided that’s what I wanted to work in. From work experience in engineering companies, I figured the most interesting place for me to work was in research and development. I moved to the UK and took up a research Master’s at King’s College looking at how robotic devices interact with soft tissue during surgery. After that, the opportunity came to join Professor Guang-Zhong Yang and Professor Lord Ara Darzi’s team at Imperial College London. I knew I wanted to do a PhD in medical robotics and was looking to either join this group or go to the USA. The right project for me was here. My first year involved helping put together the proposal for i-Snake®, an articulated ‘snake-like’ robotic device for use in keyhole surgery. I’ve been working on the project for three years now. Alongside my job working on i-Snake®, I’m writing up my PhD. While some PhDs are very theoretical, mine is very applied and that’s what I wanted – something with a grand challenge with lots of multidisciplinary problems to solve along the way. The bread and butter of any PhD student is to publish as many high-quality papers as possible,
but we couldn’t publish for the best part of two years because of patents we were filing. This has been restrictive for my thesis, but we recently published the first ‘system’ paper about the i-Snake® and it won the Best Medical Robotics Paper award at ICRA, the leading international robotics conference, which was really satisfying. As an engineer, the best thing you can do is to make things that help people. It’s very interesting to build a robot that will drive around a corridor but a practical application of the same technology inside a human has a greater potential benefit. When people ask what I do I say I work in medical robotics, developing medical devices for surgery. Sometimes I say I work on a snake robot for surgery. I’ve never had a negative reaction. ‘Snake robots for surgery?’ It sounds pretty cool, and not many people can think of a question to follow an answer like that! To find out more about mechatronics, visit www. imeche.org or www.ieee.org. Watch a short film and read more on i-Snake® at www.wellcome.ac.uk/isnake. STOP PRESS: As we were going to print, David got in touch to say that he has passed the viva for his PhD, entitled ‘A flexible access platform for robotic-assisted minimally invasive surgery’.
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Libby Welch/Wellcome Images
Seeding Drug Discovery
Earlystage smallmolecule drug discovery We help researchers with a potential new drug target or novel chemistry to embark on a programme of compound discovery and/or lead optimisation.
We welcome applications from universities and companies. Apply by 11 November 2011.
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“Is your mind closed to open innovation?” MARTINo PICARDO, CEO, STEVENAGE BIOSCIENCE CATALYST
tevenage Bioscience Catalyst (SBC) is the UK’s first open innovation bioscience campus, due to open at the beginning of next year. Backed by a £38 million investment by its founding stakeholders – GlaxoSmithKline, the Wellcome Trust, the Department for Business, Innovation and Skills, the Technology Strategy Board and the East of England Development Agency – it’s a multi-party initiative to help rejuvenate the UK pharmaceutical and biotechnology sector and facilitate development of new healthcare products. The focus on open innovation is, we believe, one of the most important and compelling characteristics of SBC. We’re nailing our colours to the mast on this. And when you nail your colours to the mast, out come the doubters. “There’s no evidence that open innovation has worked.” “You’ll never get it to work in practice.” “The pharmaceutical and biotechnology sector is too hung up on IP.” “Isn’t open innovation just collaboration by another name?” Using part of the definition coined by the area’s leading researcher, Professor Henry Chesbrough, open innovation is all about “the use of purposive inflows and outflows of knowledge to accelerate internal innovation, and expand the markets for external use of innovation”. In open innovation, all partners are created equal, and no one organisation is too big or too small to be involved
in any project. Since extensive collaboration across pharma, biotech, academia, the public sector and charities is believed to be one of the ways out of the industry productivity crisis, open innovation is the perfect mechanism for success in this multi-party new world. SBC is located on the Stevenage campus of one of our stakeholders, GlaxoSmithKline, as well as being in close proximity to Oxford, Cambridge and London (the home of the Wellcome Trust and the Francis Crick Institute). This places it right at the centre of a network of activity. E-interactions and initiatives will be important as well. Intellectual property plays an important role in the biopharmaceutical sector, and open innovation can be used to generate even more value through new business models. For example, there is excellent work going on in areas such as neglected diseases, with enhanced access to previously tightly held intellectual property in order to create even greater return. We have already started conversations with our stakeholders on how open innovation between us will work in real life. Given the long and risky timelines that are inherent in drug discovery and development, we don’t expect open innovation to be generating quick returns. However, the value it has added in consumer healthcare and other sectors makes us confident the same will happen in this area as well. www.stevenagecatalyst.com
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STEM CELL BIOLOGY
PROF. SARA RANKIN
IN YOUR BONES Pharmacologist turned stem cell researcher – and now a Wellcome Trust Senior Investigator – Sara Rankin is researching how the stem cells stored in the bone marrow inside each of us could be the key to tissue regeneration. Chrissie Giles went to meet her.
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The ultimate aim is to find drugs that can stimulate these cells to leave the bone marrow and travel to a site of injury in the body to help repair it.”
A white blood cell emerging from bone marrow. Sara Rankin, Peter Burdon and Ann Dewar, Imperial College London
couple of hours in a lab as a teenager was all it took to make Sara Rankin decide to be a scientist. “I didn’t come from a family of academics and I knew nothing about scientific research, but I loved science at school. I got the chance to visit a lab in the Bristol Radiotherapy Centre, which was supported by the charity where my mother volunteered. Dr Ann Light showed me HeLa cells in a dish and talked about trying to cure cancer by doing experiments on them. That was enough to make me want to do research.” Now Professor of Leukocyte and Stem Cell Biology at the National Heart and Lung Institute at Imperial College London, Sara is repeating the favour, hosting workshops for school students to experience real research in Imperial’s purpose-built Reach Out Lab. She’s also passionate about developing early-stage researchers, supervising several PhD students and postdocs in her lab and 16 | Wellcome NEWS
mentoring those in others. Running through all of this is her work researching bone marrow and the stem cells within. She currently has a particular interest in mesenchymal stem cells, which have the potential to turn into different body components, including cartilage, fat and bone. As part of her work, she is investigating how to use drugs to trigger the release of these cells from the bone marrow into the blood so they can help repair and regenerate the body. Earlier this year, she was named as one of the Wellcome Trust’s first Senior Investigators. Hearing the news, she says, was incredibly exciting. “Applying was a very rigorous process, and I enjoyed writing the application because it was very different to what we’re normally asked to write. Usually, applications are about the minutiae of experiments, but for this grant the focus was on the individual and their vision. It came at just the right time – I know exactly where I want my work to go.”
Stimulating stem cells The timing is apposite in terms of history, too, coming in the 50th anniversary year of the first experimental demonstration of stem cells. In 1961, Canadian biophysicist Dr James Till and former physician Dr Ernest McCulloch were examining the effects of radiation on mice when they showed that bone marrow cells could give rise to colonies of other cells, in effect proving that stem cells exist. The cells they had identified – haemopoetic stem cells – divide and differentiate into the red and white cells and platelets that make up our blood. “These are the stem cells that everybody knows about,” Sara says. They can be released into the blood by treating with G-CSF, or granulocyte colony-stimulating factor, a protein made in the body that stimulates bone marrow to release stem cells. This treatment has been used for the past 30 years as the basis of bone marrow transplants. Another kind of stem cell is found in
Sara Rankin is keen to encourage early-career researchers, and has a number of PhD students and postdocs in her lab. Wellcome Images
the marrow, although this kind is much rarer. It is these mesenchymal stem cells that Sara and her team are targeting, to understand better what they are, where they are, and how they work. The ultimate aim is to find drugs that can stimulate these cells (or a subset within them) to leave the bone marrow and travel to a site of injury or wear in the body to help repair it. Sara’s group was the first to show that it is possible to selectively release mesenchymal stem cells into the blood, a finding that led to a patented therapy. “When mesenchymal stem cells were originally discovered, it was thought that their main function was to provide what’s called the stem-cell niche for haemopoetic stem cells, the environment in which they live,” Sara says. “People started showing that if they grew these cells in culture they could get them to differentiate into different cell types, so it was thought this could be another function.” Mesenchymal stem cells can develop into some of the cells that make up
bone, fat, muscle and cartilage. As well as playing supporting actors to the bone marrow’s haemopoetic stem cells, mesenchymal stem cells have recently been shown to have a wider influence. They secrete a variety of chemicals, such as growth factors, signalling proteins called cytokines and antiinflammatory factors. These chemicals act on nearby tissues to have two main effects: to promote regeneration and to dampen the immune system. There is a lot of interest in the potential of mesenchymal stem cells to treat disease. Clinicaltrials.gov, a database of clinical trials in humans, lists 174 trials involving these cells, to explore their regenerative and antiinflammatory potential. The diseases under study include cardiovascular disease, brittle bone disease and several respiratory conditions, such as chronic obstructive pulmonary disease. Also of interest are therapies to treat acute graft-versus-host disease, a major reason for the failure of some bone marrow transplants.
It’s not just bone marrow that contains mesenchymal stem cells – fat is an abundant source. Researchers use fat removed during liposuction procedures to isolate these stem cells. Sara Rankin and her team are comparing the function of mesenchymal stem cells taken from fat with that of cells taken from bone marrow. Mesenchymal stem cells seem to provoke a much smaller immune response than haemopoetic stem cells, which make up bone marrow transplants. This means that rejection of mesenchymal stem cells that are not the patient’s own should be less of a concern than with bone marrow transplants, although further work is needed to explore this.
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For this grant the focus was on the individual and their vision. It came at just the right time – I know exactly where I want my work to go.” Sara Rankin works in Imperial College London’s award-winning Sir Alexander Fleming Building. Wellcome Images
“In all these clinical trials, researchers isolate stem cells from a tissue in the patient or donor, grow them by cell culture and inject them back into the patient,” Sara says. “For example, it’s been shown in large animal models that this can promote regrowth and suppress the remodelling of the heart that happens after a heart attack. These cells are thought to be regenerative in the context of heart disease.” Building up the whole heart again would be unlikely, she says, but an aim might be limiting damage and promoting repair to keep the heart working. There are, however, many practical and technical hurdles to overcome to develop that kind of therapy in humans. “It’s going to be expensive, and will be an invasive procedure,” says Sara. As a pharmacologist by training, she has a different idea. “What we’re trying to do is to bypass that process by being able to give somebody a medicine or a therapy that would release these cells from the bone marrow into the blood, allowing them to be recruited to the damaged tissue or organ.” On the move Sara didn’t begin her career working on 18 | Wellcome NEWS
stem cells. When she moved to Imperial College in 1995, supported by a Wellcome Trust Career Development Award, she joined Professor Tim Williams’s lab, investigating how white blood cells move from the bone marrow into the blood and subsequently to the lungs in a model of asthma. The team identified the molecules involved in mobilising eosinophils, a type of white blood cell, from the bone marrow into the blood and eventually to the lung. “I then started looking at a number of different models of inflammation to see if that paradigm existed in other models of inflammation, and indeed it did,” says Sara. “There were different factors that were generated, dependent on the type of inflammation, and they basically signalled to the bone marrow to release specific subsets of white cells (neutrophils, eosinophils, monocytes) so that they could be recruited into body tissues. That’s the basic model.” At the same time, interest in stem cells was growing among researchers. Collaborating with a biotechnology company, Sara’s team was involved in studies showing that plerixafor (a drug that blocks a protein receptor called CXCR4 and was originally developed to treat HIV) could be used to stimulate the release of haematopoietic stem cells
from the bone marrow. Industrial collaborations are also important to Sara, who wants to find ways to translate her findings into novel regenerative medicines in the future. “It was a very logical progression to start looking at stem cells,” says Sara. “I basically hypothesised that, in the same way that you can selectively release different subsets of white cells from the bone marrow, you’d be able to do the same thing looking at different subsets of stem cells. And that was essentially what we were able to demonstrate experimentally.” The focus of her Investigator Award will be the study, at the level of the bone marrow, what the molecular mechanisms of mobilising these stem cells are, developing therapies that could most effectively mobilise them. She and her team will also try to understand the mixture of cells that make up mesenchymal stem cells. “We think that some of the cells may be better at forming one particular type of tissue, such as cartilage, so we might use a specific drug regimen to activate the cells that we’re interested in,” says Sara. They will also be investigating the impact of age on mesenchymal stem cells. “As I get older, I realise that it’s taking longer for my body to repair
Sara on… …mentoring I currently mentor four postdocs in other people’s labs. It can be time-consuming, but it is rewarding. Generally it’s about being a sounding board, providing objective career advice and suggesting paths for personal development but it can also be, for example, about the practicalities of balancing a scientific career with motherhood. Section through the head of a femur, showing red and yellow bone marrow. Steven Fruitsmaak/Wikipedia
itself. If my children fall over, the next day you can hardly see a scar,” she says. “We want to understand at the molecular level what’s going on and if age makes a difference to the mesenchymal stem cells, in terms of how many there are, how they function and their ability to mobilise.” Getting wasted In between the labwork, Sara is part of a collaboration called ‘Wasted’ with artist Gina Czarneck. “We met in 2008 and we started a project that is still evolving and really interesting. These artworks provide a way of engaging with a completely different audience. Fundamentally they’re about getting people to think, to make links and to ask questions.” They produced Pixiedust, a film that looks at limb regeneration. It was shown at the 2010 Winter Paralympics and on the BBC Big Screens, which broadcast in 20 cities across the UK. They are now working on a series of sculptures, including two supported by a Wellcome Trust Small Arts Award. “These are sculptures made of body parts that are generally wasted: liposuction fat and femoral hip joints removed during hip replacements. These body parts are usually regarded
…early careers in science I think it’s definitely getting harder for young people to stay in science. To move from a postdoc into that first position can be really tough. I was lucky as I obtained a Wellcome Career Development Award, which was critical for allowing me to develop as an independent researcher.
...being a supervisor You always want the people that come into your lab to develop and go on to do great things. In the past, career success as a scientist meant becoming a respected academic, but careers today are much more flexible, less linear, and cross-disciplinary. More and more it’s about identifying people’s key skills and directing them to areas in which you think they’ll excel. Past students now have successful careers in academia but also in the pharmaceutical industry, as science communicators and as scientific software developers.
as clinical waste and incinerated, but they’re actually rich sources of stem cells,” says Sara. Sara’s priority is her research, but she sees outreach and art projects as another way to focus on her science. “It’s an important part of my professional identity to do these other activities, but I couldn’t do them unless the research was excellent,” she says. Sara always wanted to do outreach, and she and her lab regularly welcome primary and secondary school groups. “Stem cell science is one of the areas where you can do something a bit inspirational to get people interested, while also delivering what’s required in the curriculum,” Sara says. “After all, for one person the trip could be a lifechanging event.” References Jones CP, Rankin SM. Bone marrow-derived stem cells and respiratory disease. Chest 2011;140(1):205–11. Martin C et al. Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 2003;19:583–93. Pitchford SC et al. Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell 2009;4:62–72. Rankin SM. The bone marrow: a site of neutrophil clearance. J Leukoc Biol 2010;88:241–51.
Autumn 2011 | 19
X-RAY VISIONS Attending hospital to undergo any procedure can be unsettling, but those that involve radiation can be particularly anxiety provoking. Now, radiographers and artists at Yeovil District Hospital, Somerset, have used X-rays to reveal the inner secrets of everyday objects, helping patients and their families understand more about medical imaging, as well as improving the environment of the radiology department. Senior radiographer and artist Sasha Moore, consulting radiologist Dr Richard Clarkson, arts coordinator Alex Coulter and colleagues invited X-ray artist Hugh Turvey to become artist-inresidence to undertake the inr-i (â€˜inner eyeâ€™) project. Principally funded by a
Wellcome Trust Small Arts Award, the project included a series of workshops and drop-in sessions during which members of the public and hospital staff and their families brought objects to be X-rayed. As the radiographer took the image, they explained the basics of X-raying to the participants. Toys, shoes, seashells and even a police helmet were among the items imaged. The 29 striking images produced are on permanent display at Yeovil District Hospital, and the team is exploring the possibility of touring the images around other UK hospitals. www.inr-i.com www.x-rayartist.com
X-ray images. Top and above: flowers. Right: Stingrays. Above left: bicycles. Below left: toys. Hugh Turvey
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Autumn 2011 | 21
Tasting words, busting dirt and more
BLOG & FILM
credit: strollerdos on Flickr
Wellcome Trust blog “Shall I compare thee to a summer’s day?” asked Shakespeare. Alas, summer is now behind us; did the bard feel equally melancholic about its passing? There’s much we can learn about sadness from his writings, as Penny Bailey discovered (wellc.me/kJ2A8P). What if Shakespeare could taste the words he wrote? That might seem like an odd question, but not to a lexical–gustatory synaesthete, as Chrissie Giles found out (wellc.me/ jDtM9f). Elsewhere, Ben Thompson introduces us to a lesser-known branch of the Tree of Life, the Archaea (wellc.me/oGJQdR, below) and Emma James, a ‘Child of the 90s’, tells us what it’s like to have been part of a scientific study since before she was born (wellc.me/ onxCU2). Budding writers won’t want to miss the tips from the professionals in our ‘How I write about science’ series (wellc.me/nVXNZ1).
Other highlights include a trip to the National Science Learning Centre in York, rapping on evolution (below) and whether drugs could – or should – be used to improve our morality (wellc.me/ nUVcri). Keep up to date at wellcometrust.wordpress. com, by RSS or by email
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alert. If you’d like to contribute, email the editor, Mun-Keat Looi, at m.looi@ wellcome.ac.uk.
Wellcome Trust and Wellcome Collection films The Dirt Season and the Trust’s 75th anniversary have inspired some great films on the Wellcome Trust and Collection YouTube channels. At Glastonbury, a virus was infecting the population of Shangri-La, and people were escaping to a new and better world – but not before being thoroughly physically and morally cleansed by a Decontamination Unit run by Guerilla Science and supported by the Trust. Sounds strange? This film shows how it all worked. www.youtube.com/ watch?v=SPO6LAYzwLU
Closer to home, all the talk of dirt got Wellcome Collection staff thinking about how clean the venue itself was. As part of the ‘Microbes and Me’ event, Professor Mike Wilson
and Dr Derren Ready enlisted some of the younger visitors to run an experiment swabbing door handles to measure the number of bacteria on each. This film follows one family as they have a go, and reveals the results of the experiment. www.youtube.com/ watch?v=IMRyOIdnH-I
hope to create an entirely new class of anti-asthma drug, targeting the root cause of the condition rather than its symptoms. In this film, Clive Robinson (University of London) and David Garrod (University of Manchester) explain how. www.youtube.com/ watch?v=hS3tPhElrrs
In ‘Wellcome’s Dirtbusters’, we go undercover with Wellcome Collection’s own cleaning team to find out how they keep everything spotless, despite the varied challenges they face (including a large building to clean, high numbers of visitors and, apparently, a ghost). www.youtube.com/ watch?v=Jmc6lOUzKtQ
Finally, enjoy a visual celebration of Sir Henry Wellcome’s vision in this short film, which distils 75 years of the Trust’s history into a fascinating five minutes. Using a combination of recently shot and digitised archive material from the Trust’s own holdings, the film draws the viewer into the scope and legacy of Sir Henry’s remarkable achievements. www.youtube.com/ watch?v=YpndFoa8D40
The house dust mite is one of the principal causes of asthma. Although it’s been known for some time that waste products from the mites contain an allergycausing protein, it’s only now that researchers have discovered a way to block its action. By doing so, they
IN THE HOT SEAT
tracking the children of the 90s
prof. George davey smith
The Avon Longitudinal Study of Parents and Children (ALSPAC), otherwise known as ‘Children of the 90s’, is a major longitudinal study that collects biological, psychological and environmental data from around 14 000 children and their families. Having been regularly questioned as a participant from birth, Emma James poses her own questions to the study’s Scientific Director, Professor George Davey Smith.
How did you come to be a part of ALSPAC? I’d been involved with the study, though not as the Director, for quite a long period of time. I’m very interested in early-life influences on development and health and disease – for example, how things that happen to us before we’re conceived or during pregnancy can influence our fetal development. Similarly, how things we’re exposed to in early life can relate to our health and disease later in life. Clearly, a birth cohort that recruits mothers when they’re pregnant is the ideal way to look at these things. Are there particular connections you’ve been looking for from the beginning? Among the extraordinary foresights of Jean Golding [who established ALSPAC] was the fact that she asked scientists from all different fields to suggest questions that could be asked, and collected data on everything she could. In many cases there was just no hypothesis at the time. The obvious examples are some of the genetic findings. For example, ALSPAC was key to identifying FTO, the first common genetic variant (carried by 10–20 per cent of the population) related to obesity. No one had any idea that this gene would be involved in obesity. It was known at the time as ‘fused toes’, because all that was known about it was that, in mice, mutations caused the toes to be fused. But then it turned out in humans to be important in relation to obesity. There have been lots of such unexpected findings. If participants choose not to take part in a particular aspect of the study, how much does that affect the science? Firstly, it produces a smaller sample size, which is bad news because in science we need as big a sample size as possible to have the greatest power and
statistical ability to demonstrate things. The second issue is that the study sample becomes less representative. You need a representative spread of people, behaviours and types of people to be able to get results that can be generalised to other populations. So any non-response makes the results less valuable. Some participants think that once they’ve stopped responding then we don’t want them back. But of course we do! If you’ve ever responded or have been included in Children of the 90s, we’d love to have you back at any time! What are your plans for the study? We’re going to include the fathers and partners more. The mothers were offered a clinical examination recently and this autumn we’re going to start a clinic for the fathers. They haven’t taken part to the same level as the mothers in the past, although they still have filled out many, many questionnaires about themselves and their children for us! The other exciting thing is that some of the participants are beginning to have children themselves, so we are getting ready to include the next generation. Finally, if you could discover anything from the data, what would it be? That’s a really good question! As an epidemiologist, I’d like to find some novel way of reducing the risk of disease. However, it’s not as though I have one very particular nut I’m trying to crack. For me, developing ways to get reliable information on how modifiable factors can influence health and development is what’s most exciting. For a longer version of this article, and Emma James’s reflections on being part of the study, see wellcometrust.wordpress.com. For more on ALSPAC, see www.bristol.ac.uk/alspac/.
Autumn 2011 | 23
nuts and bolts
ZEBRAFISH Danio rerio – more commonly known as zebrafish – are small tropical fish that originate from the Ganges river. Today, they are used to study the developmental biology of vertebrates. This quick guide looks into why these fish have become so important in genetics research. By Emma James. The zebrafish was first identified as a model organism for investigating developmental biology by Dr George Streisinger at the University of Oregon, who began to using them to study the genetics of the vertebrate nervous system. The zebrafish became the first vertebrate to undergo large-scale genetic screening successfully. Zebrafish are ideal research organisms as they are small and robust, and so are easy to look after in large numbers. The females regularly produce large numbers of eggs, which are fertilised externally. This means that researchers have easy access to
them. The grow quickly, too: following fertilisation, they develop from a single cell to an active fish within 72 hours. Perhaps most importantly, the embryos are transparent, so researchers can watch development as it happens. They can monitor the behaviour of single cells, trace them using dyes, and watch as they divide and form different parts of the body. The fish are made up of relatively few cells, which makes it easier to trace the development of individual cells. The fact that the embryos are transparent also means that researchers can use them to study integrative physiology and homeostasis,
which by nature need to be studied within an organism. Zebrafish are also used to study the causes of birth defects and effects of genes. Researchers can destroy cells or produce genetic mutations (by using chemicals, radiation or viral insertion) and then observe the characteristics that follow. Over the past ten years, the zebrafish genome has been undergoing sequencing at the Wellcome Trust Sanger Institute. This is now over three-quarters complete, and will help to speed up the process of genetic screening once finished.
Fish facility The Wellcome Trust has recently funded the development of a new zebrafish facility at King’s College London. An equipment grant will help them to expand their facility to host up to 40 000 fish, while a technology grant will allow for the development of a new technology called zinc finger nuclease (ZFN). ZFNs are a class of engineered proteins that bind to user-specified DNA targets and create doublestrand breaks. This results in specific gene deletions, integrations or modifications. By using this new technology, scientists can safely and cheaply build a collection of gene mutations identified as crucial for aspects of brain development and/or diseases. It might also be possible to introduce genetic information in a targeted fashion inside the genome.
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Adult (From 3–4 months) The zebrafish is now sexually mature and able to generate new offspring. Researchers can then see the effects of genes in further generations. Up to 6 cm in length.
Zygote period (Up to 45 minutes) This is the newly fertilised egg. Researchers can have the zygote manipulated to have only the mother’s genes, in order to study recessive mutations. They can also inject DNA or RNA to study gene function. It is around 0.7 mm wide.
Pharyngula period (24–48 hours)
The cells are organised so that organs and tissues will be formed in the correct locations. Researchers can inject dye into the cells to form fate maps, which will later show which regions of the zebrafish the cells differentiate to form. Cell transplantation can also be performed to study the effects of environment on cell behaviour and fate. The tail bud is now formed. Shield: organises the body axes and forms prechordal plate and notochord
The embryo continues to develop, and the head and tail begin to straighten out. The fins begin to form. Central nervous system: first neural circuits are forming Heart: now visible, begins to beat increasingly prominently Digestive tract: differentiating
Early larval period (From 72 hours)
The larva can actively move its jaws, fins and eyes, and demonstrates food-seeking and active avoidance behaviour. At 5 days, it has acquired a set of reproducible behaviours, which researchers can use to explore the genetic networks controlling behaviours. Swim bladder: inflates, allowing the larva to begin swimming around Mouth: continues to protrude
Illustrations by Carolina Rivera. With thanks to Prof. Corinne Houart, King’s College London.
Autumn 2011 | 25
neuroscience and mental health
Chris Fairburn in the garden of his department in Oxford.
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Prof. CHRIS FAIRBURN
With continuous Wellcome Trust funding since 1984, Professor Chris Fairburn is one of the world’s leading researchers on psychological treatments and eating disorders. He tells Chrissie Giles about the curious case that sparked it all off, the studies that redefined eating disorders and their treatment, and his plans to take treatment training online. andwiched between advice on recognising “the roaming male” and an interview with Barry Norman, a short article on the Health Reports page of the April 1980 issue of Cosmopolitan alerted readers to a “new and bizarre eating disorder affecting young women”. Readers with experience of self-induced, secretive vomiting were asked to write in to receive a questionnaire. Six months later, stimulated by the huge response to the Cosmopolitan piece, BBC’s Horizon featured a man and woman with the same disorder, and once again people with personal experience of it were asked to write in. “For three days I had my own personal post van in Oxford,” says Professor Chris Fairburn, the psychiatrist behind both requests, and now a Wellcome Trust Governor and Principal Research Fellow. “The hospital switchboard was blocked with phone calls.” The problem ruling these people’s lives – bulimia nervosa – was little known in the early 1970s, even among health professionals. Today, it is widely recognised – and it is estimated that around 2 per cent of young women
suffer from the disorder. For the last 25 years, Chris has led the field in developing ways to categorise, diagnose, assess and treat bulimia nervosa and the other eating disorders, and is about to start an ambitious new project to transform the way that therapists are trained. He saw his first case of bulimia nervosa in 1976 during psychiatry training at the University of Edinburgh. Asked to see a woman referred by her GP for an eating disorder, Chris entered the room and was surprised to see someone who looked completely normal – the patients referred had invariably been extremely thin. He took a history, which was consistent with anorexia nervosa, yet her weight was fine. Sheepishly, he went to see his professor, who told him he must have got her weight wrong. “When the professor discovered I was right, he told me to see her again and find out what was really going on – and to tell him the next week.” The patient was dieting, vomiting, exercising and taking laxatives, but her weight was normal – how could this be? In the pre-Google world of 1976, Chris went to the library to investigate, but in vain. “I tried to read the world literature
on this, but there wasn’t one,” he says. After several more appointments, he decided to ask the patient directly why her weight was normal. “With considerable embarrassment, she told me that she kept losing control over eating and was having repeated episodes of extreme overeating. She was very ashamed of this. She’d been very open in general, but she hadn’t told me about this part. Her weight now made sense.” This sent Chris on a different literature search, but he found just a handful of mentions of cases in books and an obscure feminist journal. His professor dismissed the case as an oddity. Just a matter of weeks later, though, another similar patient appeared. “The two women were in exactly the same situation,” Chris says. “Both were in their early to mid-20s, had had the condition for around five years, had kept it secret successfully and were physically unwell.” Over the following year, he saw more cases. He also asked colleagues to pass on similar patients, and he had soon amassed a relatively large group. Well treated Having gained experience of Autumn 2011 | 27
77 Develops a cognitive behaviour therapy (CBT) for bulimia nervosa
First randomised controlled trial of CBT for bulimia nervosa published. Shows that CBT is effective but that another talking therapy shows promise
First publication on the new treatment
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Stanford–Columbia– Oxford replication of the Oxford studies of CBT
Wellcome Trust Senior Lectureship
Chris Fairburn’s original call for volunteers in April 1980’s Cosmopolitan. Wellcome Images
As a junior doctor, Chris Fairburn sees his first cases of bulimia nervosa in Edinburgh
Submits an article to Cosmopolitan, calling for readers with self-induced vomiting to write in. The same is done following an episode of Horizon. The resulting studies demonstrate that bulimia nervosa is common but often successfully hidden
86–91 Three-way controlled treatment trial demonstrates the importance of the cognitive aspects of treatment. CBT found to be the most effective of the treatments
psychological treatment research as a medical student in Oxford, Chris knew something of cognitive behaviour therapy (CBT; see box, page 30). This talking therapy helps people to recognise and alter their dysfunctional ways of thinking and behaving. “The more I understood these patients, the more I was convinced that CBT would be a good way of helping them.” People with eating disorders think differently to those without these conditions. “They judge themselves exclusively in terms of their shape and weight – nothing else much matters in their lives,” Chris says. “They are dominated by their concerns about their shape and weight – eating disorders are par excellence ‘cognitive’ disorders.” To control their shape and weight, people with bulimia nervosa diet, but in an extreme and rigid way that can leave them prone to episodes of loss of control over eating, nowadays called binges. These binges can last for more than an hour and typically involve eating several
thousand calories. Those affected binge on so-called ‘forbidden foods’ that they are trying to avoid, such as ice cream, cakes, biscuits and bread. Afterwards, they try to compensate for the binges, either by dieting more or by vomiting and/or taking laxatives to purge. “The trouble is that the resulting dieting makes them yet more prone to binge, and so they get stuck in a vicious cycle that is difficult to escape from,” Chris says. With “quite a lot of trial and error”, he developed a cognitive behavioural theory concerning the processes that maintain the disorder and, on this basis, a new treatment. The first patient he treated got better in nine months. He applied what he had learned to his other patients and, within a couple of years, had pinned down how to treat most cases. Chris applied to the Medical Research Council (MRC) for funding to study the then-nameless condition. “I wish I’d kept the letter I got back,” he says. “It said something like, ‘fascinating,
96 Wellcome Trust Principal Research Fellowship
Develops a transdiagnostic version of CBT designed to be suitable for all forms of eating disorder
04 NICE strongly recommends CBT for bulimia nervosa
Develops self-help version of CBT in book form
really nice design but we’ve never heard of the disorder you are treating’.” He returned to Oxford in 1979. In August of that year, the condition finally got a name: bulimia nervosa, coined by the world-leading figure on eating disorders, Professor Gerald Russell. In his paper,1 Russell described bulimia nervosa as “an ominous variant of anorexia nervosa”. He presented 30 cases, warning that these patients were extremely difficult to treat. “That put me in a very interesting situation of having more cases than him and also being able to treat the disorder,” says Chris. The condition now had a name, but there was still the question of how common it was – something research funders needed to know. Chris suspected that it might be common, but hidden – after all, these patients looked normal and were highly secretive. This is when he had the idea to try to reach people with the condition using a women’s magazine. The Cosmopolitan piece was written and – combined with
the response to Horizon – resulted in over a thousand new cases being detected, most of whom thought they were the only one with the problem.2 In 1981, Chris received MRC funding for the first randomised controlled trial of a psychological treatment for bulimia nervosa. The study confirmed that the new form of CBT had a sustained, positive effect, but Chris was surprised to find that another therapeutic approach, with the same amount of personal contact with the therapist but without cognitive or behavioural aspects, was also quite beneficial. Chris was made a Wellcome Trust Senior Lecturer in 1984 and used this award to compare interpersonal therapy (IPT, which focuses only on patients’ relationships) to behavioural therapy and CBT. “I wanted to dismantle CBT to see if focusing just on the patient’s behaviour had the same effects,” Chris says. The patients were treated for 18 weeks and, as before, over half made a full and lasting response to CBT.
Wellcome Trust Strategic Award to investigate the use of the web to train therapists to deliver evidence-based psychological treatments 2005
Randomised controlled trial of self-help version of CBT. It emerges as highly effective for a mild form of bulimia nervosa, if given with some limited guidance
Conducts three interconnected randomised controlled trials of the new transdiagnostic treatment. Emerging findings indicate that it works across the eating disorders
I wanted to dismantle CBT to see if focusing just on the patient’s behaviour had the same effects.”
Interpersonal therapy was also quite effective, but it took far longer to work than CBT. By contrast, the dismantled version of CBT that was missing the cognitive elements had only a transitory effect.3 In 1994, with support from the US National Institute of Mental Health, Chris began a collaborative study of 220 patients recruited from Stanford and Columbia to see whether the Oxford findings could be replicated. They were, almost exactly. The study, published in 2000, concluded: “Cognitive-behavioral therapy was significantly more rapid in engendering improvement in patients with bulimia nervosa than IPT. This suggests that CBT should be considered the preferred psychotherapeutic treatment for bulimia nervosa.” Just four years later, the National Institute for Health and Clinical Excellence (NICE), the UK body that advises on what treatments the NHS should provide, published guidelines strongly recommending CBT for bulimia Autumn 2011 | 29
nervosa. This was the first psychological treatment recommended by NICE. A hidden problem If you were to ask people in the street about eating disorders, the majority of people would probably be aware of anorexia nervosa and some would be aware of bulimia nervosa. However, Chris’s work and that of others has recently shown most people diagnosed with an eating disorder have neither. Although some 10 per cent have anorexia nervosa and 30 per cent bulimia nervosa, the majority fall into a residual category termed ‘eating disorder not otherwise specified’, a type of eating disorder that is just as severe but has barely been studied. “Although not much remarked upon,” Chris says, “there are notable similarities between the eating disorders. They have very similar clinical characteristics, and patients commonly move between the diagnoses.” This led to Chris having an ‘aha’ moment in the late 1990s. “I thought, given these similarities and links, there are likely to be common processes maintaining the eating disorders. Therefore, if we are capable of addressing these processes in one condition, bulimia nervosa, we ought be able to do the same in the other eating disorders.” This so-called transdiagnostic way of thinking was highly contentious, and many in the field were sceptical about its ‘one-size-fits-all’ nature. Still, in 2000, Chris was awarded funding from the Wellcome Trust for a trial that would test whether CBT works for any eating disorder. Results from the first part of this trial
are promising. Looking at the patients who were not significantly underweight (i.e. the 80 per cent of patients with bulimia nervosa or ‘eating disorder not otherwise specified’), the team found that the new version of CBT, designed for any eating disorder, worked for two-thirds of the patients, regardless of their original diagnosis4 – a finding that has subsequently been replicated. Most recently, Chris has reported the results from the remaining patients, those with anorexia nervosa, and they too respond to the new treatment. Researchers are applying the transdiagnostic way of thinking to other mental health disorders, and clinicians now have a single treatment that can be used across the eating disorders. Not surprisingly, the demand for training in the new treatment is immense, and this topic – how to train therapists on a large scale – is the focus of Chris’s latest line of work. “The way people learn psychological therapies today is ad hoc, and not dissimilar to the time of Freud,” Chris says. Typically, trainee therapists attend an initial one- or two-day training event held by an expert, followed by some form of case supervision for six to nine months. “This method is all very well but it results in very few people being trained. Moreover, there is a major shortcoming – most therapists never see the therapy being implemented. If you needed cardiac surgery, would you like a surgeon who’d never seen the procedure being done? This is stunning to me, but is totally accepted by our field.” To investigate new ways of training that are suitable for use on a large scale,
Chris has been awarded a Wellcome Trust Strategic Award. He plans to create web-based forms of training that will provide trainees with the opportunity to view entire (simulated) treatments online, made up from amalgams of real past treatments but with any personal identifiers removed. Chris plans to test these new web-based approaches against more conventional training methods. To do this, however, he and his international group of collaborators need to develop new means of measuring therapist competence, something that he says will be both challenging and controversial. This may all seem a long way from negotiating with the editor of a women’s magazine to include information on an unknown illness, but Chris’s passion today is just as strong. “People with eating disorders and other mental health problems wait for years before seeking help, if they ever do,” he says, “but we have treatments that can work in just months. My job now is to develop cost-effective, large-scale ways of training therapists across the world how to implement them.” 1. Russell G. Bulimia nervosa: an ominous variant of anorexia nervosa. Psychol Med 1979;9:429–48. 2. Fairburn CG, Cooper PJ. Self-induced vomiting and bulimia nervosa: an undetected problem. BMJ 1982; 284:1153–5. 3. Fairburn CG et al. Psychotherapy and bulimia nervosa: the longer-term effects of interpersonal psychotherapy, behaviour therapy and cognitive behaviour therapy. Arch Gen Psychiatry 1993;50: 419–28. 4. Fairburn CG et al. Transdiagnostic cognitive behavioral therapy for patients with eating disorders: a two-site trial with 60-week follow-up. Am J Psychiatry 2009;166:311–9.
Simple as CBT…
Cognitive behaviour therapy is a psychological talking therapy. It helps people recognise and alter problematic ways of thinking and behaving. It is effective in treating a number of mental health disorders, particularly depression, eating disorders and anxiety disorders.
Chris Fairburn explains the cycle of dysfunctional thoughts and behaviours behind eating disorders. Wellcome Images
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It is effective when given face-to-face. Simplified forms of CBT are of help in some cases and can be delivered via computer, over the phone or through self-help books.
EARLY CAREERS PROF. DANNY ALTMANN
A guide to SUCCESS Want to advance early in your research career? An excellent supervisor will help you – and help your fellowship application – says Danny Altmann, the Trust’s Head of Pathogens, Immunology and Population Health. The early choices you make about a career in science may be some of the most important of your life. Biomedical researchers come in many shapes and sizes, and good ones may encompass a variable mix of theoretician, mathematician, technophile, inventor, observer, naturalist, philosopher, storyteller and visionary. Which are you? Where are you going to apply these talents? Even if you’ve already decided that you’re headed for, say, molecular genetics, public health or stem cell biology, each field contains a multitude of questions you may wish to address. This work is, hopefully, going to fuel the next few years of your professional activities – is it an area where there is unmet need? Can you amass the tools to make an impact and continue to do so for a number of years? If you’re interested in an early-career fellowship from the Wellcome Trust, you’ll need to persuade the committee that you’re sharp, have a great project, and have a suitable supervisor with whom to work. You wouldn’t walk out of your house and marry the first person you bump into, so why follow this logic in your academic career? What you should be looking for in a supervisor is an experienced figure in the field who can nurture your career, from shaping the research question and study design to advising you of the best experimental approaches. This suggests that they should have extensive, direct experience of the field, a department equipped with the infrastructure to work on it and, most of all, the time and inclination to talk science with you. Go to conferences and seminars and chat to prospective supervisors, but don’t believe all they say. Of course they
S Zaferis, Immersive 360/Wellcome Images
consider their own research area to be important, but what is the rest of the community saying about it? Is the approach central to the question or considered marginal? At this stage, you need to read a lot of papers and see where the field is really heading. Visit the supervisor’s department, speak to the other students and staff there and gauge the atmosphere. Science is generally a communal activity in which people benefit from discussion, critique and interaction – is this happening where you visit? Does it feel like a thriving, buzzing research environment? If nobody else is succeeding there, it’s likely you won’t either. As you audition prospective mentors, bear in mind Nobel laureate Paul Nurse’s description of his own, Murdoch Mitchison: “Every couple of days he would pull me into his office, and puffing endlessly on his pipe, discuss the latest experiments and what he was thinking about. These discussions, although they could go on for hours, circling topics, departing on tangents, and becoming blocked in
cul-de-sacs, were frequently stimulating, often provocative, and always driven by his passion of wanting to know answers just because he wanted to know, rather than in pursuit of publishing papers.”1 If you come for a fellowship interview at the Trust, you’ll almost certainly be asked if you wrote the proposal yourself. What we’re really asking is whether you’ve engaged in a dialogue with the most appropriate possible supervisor and co-evolved the best possible proposal. We wouldn’t imagine that you could or should draft it without strong input from those in the host department who hopefully have insights into the details and pitfalls of doing the work. After all, if your supervisor can’t offer substantial input to your initial proposal, how valuable will they be if you do get your fellowship? Professor Danny Altmann is Head of Pathogens, Immunology and Population Health at the Wellcome Trust. 1. Nurse P. Murdoch Mitchison 1922–2011. Nat Cell Biol 2011;13(5):520.
www.wellcome.ac.uk/ta Autumn 2011 | 31
FROM THE ARCHIVE
Imbert-Delonnes by Pierre Chasselat
32 | Wellcome NEWS
William Schupbach presents a detailed drawing of a man whose identity was solved by research in the Wellcome Library itself. What is it? A drawing of a gentleman in his study in 1799, surrounded by souvenirs of his life and work.
Why is it so special?
Details Above: Glass jar containing the giant testicular tumour Imbert-Delonnes removed from Charles Delacroix, French Foreign Minister. Below: Portrait of Perier de Gurat, Mayor of Angoulême, from whom Imbert-Delonnes removed a huge facial tumour and whose nose he then reconstructed.
Until recently, this was a portrait of an unknown man. Research – in the Wellcome Library – by Marc Fecker, a scholar and dealer of French art, uncovered his identity: he is a French surgeon prominent in the age of Napoleon, Ange-Bernard ImbertDelonnes (1747–1818). Although there had always been educated and skilful surgeons in France, the period around the Revolution (1789–1799) saw the whole profession of surgery rise in power and esteem. This portrait records an exemplary member of this newly elevated class, or at least one wing of it. Imbert-Delonnes represented the interventionist school, and he was not afraid of operating on large embedded tumours, such as the one shown in the jar on the right – yes, he had it displayed in his elegant study! The drawing is also notable from other points of view: for example, it is signed by the miniaturist Pierre Chasselat, but no other portrait by Chasselat with this richness of detail is known.
Can you see it? Yes. It can be seen in the Wellcome Library in London, on request, by anybody. At its full size (62.5 x 47.8 cm), it’s a memorable sight.
How can I learn more? Read Toby Gelfand’s book Professionalizing Modern Medicine: Paris surgeons and medical science and institutions in the 18th century (Westport, Commeticut and London: Greenwood Press; 1980). Find out more at catalogue.wellcome.ac.uk/ search~S8/o729420i
Autumn 2011 | 33
APPLIANCE OF SCIENCE “We all need to engage with bacteria” ANNA DUMITRIU, ARTIST
he importance of the public understanding of microbiology cannot be underplayed. Many businesses play on public fears in order to add value to their products, and newspapers and TV shows fill our minds with images of bacteria as armies of tiny monsters ready to attack unless we buy some new handwash or detergent. There is a huge amount of scaremongering around ‘superbugs’ in hospitals, with press coverage grossly out of proportion to the number of cases occurring. But what should we really be worrying about, and what, in terms of the relationship between humans and bacteria, is normal? As an artist, I’m fascinated by these questions. I collaborate closely with microbiologists and other scientists to make art that helps people engage more directly with the bacteria living within, on and around them. My current solo exhibition, Normal Flora, showcases some of the work I have created using live bacteria. This includes an antique Edwardian dress on which the existing white-on-white embroidery, known as whitework, has been pigmented with a bacterium called Chromobacterium violaceum (above). These bacteria change colour from white to purple when other bacteria of the same type are nearby.
In another piece I used Staphylococcus aureus bacteria taken from my own body alongside a multi-resistant strain, MRSA, to create designs on a quilt. I used different microbiological methods to create different patterns of growth of bacteria, which I then transferred onto the quilt. The piece has been autoclaved, so it contains no infectious material, but each square in the quilt shows a different aspect of the fight against MRSA. Like the quilt, a lot of my work is tactile, decorative and aesthetically pleasing, but it also has a dark side. I like the tension between the fact that bacteria are extremely beautiful, fascinating organisms and the disgust and horror they bring about in people. At college we once debated about whether all art is a political act, and, in a way, I think my work is political. I’m interested in conveying a bit more of the reality of the situation, helping equip the wider public with the tools needed to understand the issues. I try to use bugs from my own environment when I can. People think that something with bacteria on it is dirty, but the reality is that they are everywhere. Whether we need to be worried about them or not depends on the type, number and location.
For more on Anna’s work, including the Communicating Bacteria project, funded by a Wellcome Trust Arts Award, see www.normalflora.co.uk.
34 | Wellcome NEWS
DIARY Courses, conferences and workshops
Wellcome Trust Genome Campus
Wellcome Trust Genome Campus, Hinxton, unless otherwise specified. For more, see www.wellcome.ac.uk/ advancedcourses and www.wellcome.ac.uk/conferences Fundamentals of Clinical Genetics 2012 Conference, 17–20 January 2012 Complex Disease Genetics for Clinicians Conference, 26–27 January 2012 Genomics and Clinical Microbiology Course, 22–27 January 2012
Mathematical Models for Infectious Disease Dynamics Course, 13–24 February 2012 Working with Pathogen Genomes Mahidol–Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, 20–24 February 2012 Malaria Experimental Genetics Course, 4–10 March 2012 Therapeutic Applications of Computational Biology and Chemistry (TACBAC) 2012 Conference, 12–14 March 2012
Advanced Courses and Scientific Conferences
Perspectives in Clinical Proteomics 2012 Conference, 14–15 March 2012
At the cutting edge of biomedical training, discussion and debate.
Exome Sequencing Course, 15–24 April 2012
Wellcome Trust Advanced Courses and Scientific Conferences are hosted in dedicated facilities at the Wellcome Trust Genome Campus in Hinxton – a short distance from the historic city of Cambridge.
Genomic Epidemiology in Africa Course, Malawi–Liverpool–Wellcome Trust Clinical Research Programme, Blantyre, Malawi, 6–11 May 2012 Exploring Human Host–Microbiome Interactions in Health and Disease Conference, 8–11 May 2012
Wellcome Collection events and exhibitions Euston Road, London. www.wellcomecollection.org 75: Celebrating 75 extraordinary years Exhibition, until 23 December 2011 Miracles and Charms Exhibition, 6 October 2011–26 February 2012 Medicine Man and Medicine Now Permanent exhibitions
Oliver Burston/Wellcome Images
Mouse Models of Disease: Linking in vivo observations to pathology endpoints Conference, 1–3 February 2012
Funding is now available for new Advanced Courses and to seed the development of new Scientific Conferences. Please contact Dr Rebecca Twells, Programme Manager, for more information (email@example.com). For details of all upcoming Advanced Courses and Scientific Conferences, please visit: www.wellcome.ac.uk/hinxton
Event listings See website for details
in your next issue Exploring a career in medical engineering, plus updates on our funding and research activities.
Autumn 2011 | 35
REMONY CHOLINESTERASE MOSAIC EMBLEMATIC OIL ASYMPTOTE ASKLEPIOS LEARNING ELECTRON MICROSCOPE BASES UROSCIENCE SUBLIMINAL INVITING SUPER FASCINATING NEURON HIEROGLYPHICS ANEURYSM CHARIOT RETICENT PHOTOG ESERVATION LADYBIRD OPSONISATION PERSPICACITY SOLUTIONS MILLION MATERIA MEDICA NURSE FROND NINETEEN MOL RTURE REVOLUTIONARY INSPIRATION EMBRYO PHLEBOTOMY ANKLET LYMPH NODE OPERATION GLUCOSE GLORIFICATION NELLING CONTINUOUS PROCESS OF REINCARNATION DRAWER MICROSCOPE QUERIST ICONOGRAPHIC NEUROFIBROMATOS RIOUS NUDE GENETICS CENTURY ANTHROPOLOGY COSMOPOLITAN PAINTING FORAYS COIFFURE SCAMPER EUGENICS LON CEIPT UNUSUAL BULLET INFORMING DECORATED SORANUS JOINTS MONUMENTAL MUSCULOSKELETAL IMPROVING ROSES BSTITUTE KING ENLIGHTEN ENGAGEMENT POSSET RESTORATION PLETHORA NOMENCLATURE ORIENTAL HIPPOCRATES SYL CROBIOLOGIST IMPROVEMENT ARCHIVES TRANSCRIPTION KNOCKOUT INTERIOR SOURCE SNAPSHOT APOCALYPTIC VALUE E DANGEROUS ART OF SURGERY FLOATING OPTOMETRY PROTEINS STEROID FIDUCIARY SOMMONTE SWIM CANOPIC ACAD ALLENGE MYOCARDIUM ALLEGORICAL ILLUMINATIVE CONSERVATION BLING COUNTERPOINT PROPERTY FIFTEENTH BIRD D VER COMPARTMENT INTESTINE CADUCEUS ALLOPATHIC JEWEL TIMELESS SCROLLS CHILD MONOCHROME BIOHAZARD NEO RCAP IMPRESSED ANTRUM NOTEBOOK SCALABILITY CONFOCAL COMPASS CHASTITY BIOARCHAEOLOGY MASK FIGURE ST ONOSES FETUS PEOPLE ODDITY SANDAL BRUSH SCIENTIST AURAL AND VISUAL LANDSCAPE MENDELIAN ENIGMA BRAHMA AGMENT AMAZON COLOSSUS SCAR RENOVATION SHRUNKEN BIBLIOMANIA CANVAS ARTIFICIAL APPETITE ECORCHE FOREH ZOAR ERYTHROCYTE ALCOHOL CARVING PAROCHIAL DEPICTION MAGNILOQUENT ABSCESS ORNAMENT FLOURISH CONCEP EAR BORBORYGMI BOTTLES ABUNDANCE RECIPES DANCERS PUBLIC FILM ANAMORPHIC DIAGONAL DEVELOPMENTAL APOT ND AMALGAMATION MUTATION EFFIGY ESOTERICA DELICATE CHRYSALIS VIRUSES ELIXIR CLASS PHARMACOLOGY CODE TH AKES YOU HUMAN LIMB WITCH WOODEN STUCCOWORK OBSTETRIC ALBUMINOUS PARCHMENT BLOODLETTING SCOLD GES RACADABRA BRIDLE CONTINGENCY CONGENITAL RENAISSANCE SYMBOLISM MODERN MACHINE RITUALISED AMITOTIC DH ASTINATE PSEUDO PULSATING ANATOMY VEINS WAR DYNAMO BORDERS HUMUNGOUS PLASTINATION NUTRITION PHARMAC RVE SPHERES DEHYDRATE MOLOCHISM MINNESOTA RETROVIRAL EXQUISITE ABSTRACTION TATTOO INTIMATE BIOLOGICAL ALLENGING BODIES MALARIA EMBRYONIC MANUSCRIPT SNUFFBOX PHTHISIS ZYGOTE SHARING GARMENT SCENES EXPRE BY DRUGS WHIMSICAL PHILANTHROPY CRAFT SERENDIPITOUS SPECIMEN UNREQUITED SNORING ANOMALY ANTHROPOMO BALM WATERCOLOUR SCULPTURE STATUE SKELETON AMPUTATION TESTOSTERONE SILAS MAINVILLE BURROUGHS FLUOR ASSICAL GRAVE FIGMENT VITAMIN BIRTH HISTORICAL ICONOCLASTIC GROTESQUE CURIOSITY DREAM SMOKE MUSEUM CO AUTY SHRINE CADAVER HEAD ANTAGONIST DOCTOR ANATOMICAL KLEPTOMANIAC SKETCHING BRAIN HEAL ANTIDEPRESSA SEL ARMS WILL STASIS FLUX ANTIBODIES CERAMIC TOOTH MUMMY ALCHEMY DECAY GERATOLOGY TINNITUS TOILET ACUP AD SALVAGE MANIKIN STYLE MUSE HENRY SOLOMON WELLCOME NUCLEUS CALCIUM BRAND INLAY FLEETING MOLECULAR
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This issue includes a feature on Wellcome Trust Investigator Professor Sara Rankin and her work on stem cells, a quick guide to zebrafish, a...