Professional Documents
Culture Documents
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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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Wellcome NEWS
Telling the stories of the Wellcome Trusts work 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 wellcome.news@wellcome.ac.uk www.wellcome.ac.uk/wellcomenews To subscribe: T +44 (0)20 7611 8651 E publishing@wellcome.ac.uk 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).
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Wellcome NEWS
Issue 68, autumn 2011
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 peoples 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 trusts 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. Saras 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.
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Cover: Artwork using X-rays of everyday objects. See page 20. Hugh Turvey
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Left to right: Professor Herbert Jckle, 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
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 Librarys Arabic manuscripts and rich descriptions of the texts, illustrations and bindings. It was built in partnership with the Bibliotheca Alexandrina, Egypt, and Kings College London Digital Humanities department.
order the magazine and browse other articles, videos, image galleries, lesson ideas and more at www.wellcome.ac.uk/ bigpicture/food.
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.
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FUNDING NEWS
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
Wellcome Trust Engagement Fellows Richard Barnett (left) and Kevin Fong (right). Wellcome Images
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.
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.
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.
FuNDING oPPoRtuNItIES
www.wellcome.ac.uk/funding
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Wellcome Images
RESEARcH NEWS
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.
Mnnikk R et al. Diabetes 2011;60(6):181322.
Model of AZT, the first antiretroviral to be approved for use against HIV. Theasis/iStockphoto
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 cells signalling processes, is involved in the disorder and could be a target for drugs. It is also one of the first genegene interactions confirmed in humans.
Australo-Anglo-American Spondyloarthritis Consortium et al. Nat Genet 2011;43(8):7617.
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
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):80610.
Researchers at Kings 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 CXCL5s role in mediating pain.
Dawes JM et al. Sci Transl Med 2011;3(90):60.
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]
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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):67590. Ishizu T, Zeki S. Toward a brain-based theory of beauty. PLoS One 2011;6(7):e21852.
African and non-African populations continued to interbreed long after the evolutionary exodus out of Africa 60000 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 10000 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 100000 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 60000 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 20000 to 40000 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):4936.
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cAREERS
DAVID NooNAN
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www.wellcome.ac.uk/sdd/wn
oPINIoN
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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 didnt 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 Imperials purpose-built Reach out Lab. Shes also passionate about developing early-stage researchers, supervising several PhD students and postdocs in her lab and
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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 trusts 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 were 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. Saras 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 whats 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 marrows 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.
Sourcing cells
Its 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 patients 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 Londons 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, its 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. Its going to be expensive, and will be an invasive procedure, says Sara. As a pharmacologist by training, she has a different idea. What were 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 didnt begin her career working on
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stem cells. When she moved to Imperial College in 1995, supported by a Wellcome trust Career Development Award, she joined Professor tim Williamss 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. thats the basic model. At the same time, interest in stem cells was growing among researchers. Collaborating with a biotechnology company, Saras 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, youd 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 were interested in, says Sara. they will also be investigating the impact of age on mesenchymal stem cells. As I get older, I realise that its taking longer for my body to repair
Sara on
mentoring I currently mentor four postdocs in other peoples labs. It can be time-consuming, but it is rewarding. Generally its 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
early careers in science I think its 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 its about identifying peoples key skills and directing them to areas in which you think theyll excel. Past students now have successful careers in academia but also in the pharmaceutical industry, as science communicators and as scientific software developers.
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 whats 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 theyre 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
as clinical waste and incinerated, but theyre actually rich sources of stem cells, says Sara. Saras priority is her research, but she sees outreach and art projects as another way to focus on her science. Its an important part of my professional identity to do these other activities, but I couldnt 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 whats 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):20511. 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;19:58393. Pitchford SC et al. Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell 2009;4:6272. Rankin SM. The bone marrow: a site of neutrophil clearance. J Leukoc Biol 2010;88:24151.
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cLOSE-UP
ARtS AWARDS
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 (inner eye) 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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ONLINE HIGHLIGHTS
alert. If youd like to contribute, email the editor, Mun-Keat Looi, at m.looi@ wellcome.ac.uk.
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
Wellcome Trust and Wellcome Collection films the Dirt Season and the trusts 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
In Wellcomes Dirtbusters, we go undercover with Wellcome Collections 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 Wellcomes vision in this short film, which distils 75 years of the trusts history into a fascinating five minutes. using a combination of recently shot and digitised archive material from the trusts own holdings, the film draws the viewer into the scope and legacy of Sir Henrys remarkable achievements. www.youtube.com/ watch?v=YpndFoa8D40
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
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
the house dust mite is one of the principal causes of asthma. Although its been known for some time that waste products from the mites contain an allergycausing protein, its only now that researchers have discovered a way to block its action. By doing so, they
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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 studys Scientific Director, Professor George Davey Smith.
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MoDEL oRGANISMS
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 Kings 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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Zygote period
(Up to 45 minutes) This is the newly fertilised egg. Researchers can have the zygote manipulated to have only the mothers 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
(2448 hours) 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
Gastrula period
(510 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
F A
Illustrations by Carolina Rivera. With thanks to Prof. Corinne Houart, Kings College London.
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With continuous Wellcome trust funding since 1984, Professor Chris Fairburn is one of the worlds 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, BBCs 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 peoples 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 wasnt 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. Shed been very open in general, but she hadnt 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
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CAREER HIGHLIGHtS
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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 1980 1984 1982 1983 1981
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As a junior doctor, Chris Fairburn sees his first cases of bulimia nervosa in Edinburgh 1979 1976 1978 1977 1975
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Wellcome Trust Senior Lectureship 1990 1986 1989 1988 1987 1985
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StanfordColumbia Oxford replication of the Oxford studies of CBT 1994 1992 1993 1991
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Develops a cognitive behaviour therapy (CBT) for bulimia nervosa
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First randomised controlled trial of CBT for bulimia nervosa published. Shows that CBT is effective but that another talking therapy shows promise
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Three-way controlled treatment trial demonstrates the importance of the cognitive aspects of treatment. CBT found to be the most effective of the treatments
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First publication on the new treatment
Chris Fairburns original call for volunteers in April 1980s Cosmopolitan. Wellcome Images
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 Id kept the letter I got back, he says. It said something like, fascinating,
28 | Wellcome NEWS
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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
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Conducts three interconnected randomised controlled trials of the new transdiagnostic treatment. Emerging findings indicate that it works across the eating disorders
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Wellcome Trust Strategic Award to investigate the use of the web to train therapists to deliver evidence-based psychological treatments 2006 2009 2008 2007 2005 2010 2011
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2000
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Wellcome Trust Principal Research Fellowship Develops self-help version of CBT in book form
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Develops a transdiagnostic version of CBT designed to be suitable for all forms of eating disorder
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NICE strongly recommends CBT for bulimia nervosa
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I wanted to dismantle CBT to see if focusing just on the patients behaviour had the same effects.
really nice design but weve 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 womens 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 patients 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.
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
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, Chriss 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 Chriss 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 whod 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 womens magazine to include information on an unknown illness, but Chriss 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;9:42948. 2. Fairburn CG, Cooper PJ. Self-induced vomiting and bulimia nervosa: an undetected problem. BMJ 1982; 284:11535. 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: 41928. 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;166:3119.
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. 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.
Chris Fairburn explains the cycle of dysfunctional thoughts and behaviours behind eating disorders. Wellcome Images
30 | Wellcome NEWS
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 trusts 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 youve already decided that youre 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 youre interested in an early-career fellowship from the Wellcome trust, youll need to persuade the committee that youre sharp, have a great project, and have a suitable supervisor with whom to work. You wouldnt 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 dont believe all they say. of course they
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 supervisors 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, its likely you wont either. As you audition prospective mentors, bear in mind Nobel laureate Paul Nurses 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, youll almost certainly be asked if you wrote the proposal yourself. What were really asking is whether youve engaged in a dialogue with the most appropriate possible supervisor and co-evolved the best possible proposal. We wouldnt 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 cant 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 19222011. Nat Cell Biol 2011;13(5):520.
www.wellcome.ac.uk/ta
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CHALK DRAWING
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?
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 (17471818). Although there had always been educated and skilful surgeons in France, the period around the Revolution (17891799) 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.
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 Angoulme, from whom Imbert-Delonnes removed a huge facial tumour and whose nose he then reconstructed.
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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, Im 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. Im 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 Annas work, including the Communicating Bacteria project, funded by a Wellcome trust Arts Award, see www.normalflora.co.uk.
34 | Wellcome NEWS
At the cutting edge of biomedical training, discussion and debate. 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. 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 (rt@hinxton.wellcome.ac.uk). For details of all upcoming Advanced Courses and Scientific Conferences, please visit: www.wellcome.ac.uk/hinxton
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