Wellcome NEWS

Issue 69, winter 2011

NEGLECTED TROPICAL DISEASES

Researchers raising the profile of global health threats.

Winter 2011 | 1

Join a world-leading image collection

Can you contribute to our collection?
If you are a research scientist, a clinical photographer or an illustrator, we would love to see your work. You can access a wider audience through our biomedical image collection, used by clients across the world. Email images@wellcome.ac.uk Whats more, any images we receive before 16 January 2012 will be considered for the Wellcome Image Awards 2012. See the 2011 winners: www.wellcomeimageawards.org

images.wellcome.ac.uk

Darkfield light micrograph of the head of a honeybee. Spike Walker/Wellcome Images

2 | Wellcome NEWS

24 The neuron
CoNTENTS

INSIDE THIS ISSuE

In brief Message from the Director Funding news Research news In depth How I Got Into medical sociology: Prof. Clare Williams And other diseases Best of the blog: Patients of the past In the hot seat: Prof. Carol Robinson Winning ways: Science Writing Prize Welcome to the fold: structural biology Opinion The only way is Wikipedia Appliance of Science: no such thing as a non-science story Picture features Cells and the city Nuts and Bolts: The neuron From the Archive: Red or dead HIV/AIDS sandals 4 6 8 11 14 22 23 26 30 13 34 20 24 32
Winter 2011 | 3

Wellcome NEWS
Telling the stories of the Wellcome Trusts work Editor Chrissie Giles Assistant Editor Tom Freeman Writers Chrissie Giles, Lydia Harriss Design Marianne Dear Photography David Sayer Publisher Hugh Blackbourn Contributor: Neuron illustration and Prof. Clare Williams 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).
PU-5261/15.5K/11-2011/MD

MESSAGE fROM ThE DIRECTOR SIR MARK WALPoRT

50%

This document was printed on material made from 25 per cent post-consumer waste & 25 per cent pre-consumer waste.

Good communication underpins good science. From informal chats over coffee to presentations at conferences, from email exchanges to long-term collaborations, scientists are constantly sharing ideas and information. At the heart of scientific communication are the formal peerreviewed articles published in academic journals. There is no doubting their fundamental importance but there are questions over how the publication process works. With all the potential that new technology brings, we must be sure that researchers can communicate their findings in the most reliable and accessible ways that, above all, serve the needs of the scientific community. With this in mind, the Wellcome Trust, the Max Planck Society and the Howard Hughes Medical Institute will launch a new top-tier journal next year. online, open-access and peer-reviewed, it will have a senior editorial team made up exclusively of active scientists. We believe this will allow them to select truly outstanding, challenging and innovative research for rapid publication. It is an exciting proposition: scientific publishing by scientists, for scientists. Just as vital is good science communication beyond the research community. Two Wellcome Trust competitions celebrate and encourage science writing in particular, and we recently announced this years winners. The Wellcome Trust Book Prize recognises the eternal fascination that medical issues hold for great writers and their readers alike. My thanks to our esteemed judges for reading dozens of excellent books, whittling them down to a shortlist of six before deciding the winner Turn of Mind by Alice LaPlante. I did my own share of judging this year for the inaugural Wellcome Trust Science Writing Prize, run in association with the Guardian and Observer newspapers. We received an overwhelming 800 entries. To have received so many in the competitions first year is testimony to societys deep interest in science and to the desire of ever more scientists to communicate their work to the public. You can read the winning entries on page 26 and if you think you could do better, we look forward to reading your entry next year.

Cover: Artwork showing various neglected tropical diseases. See page 14.

4 | Wellcome NEWS

Alice LaPlante scoops Wellcome Trust Book Prize

The 2011 Wellcome Trust Book Prize has been won by Alice LaPlante for her novel Turn of Mind. The 25 000 Prize highlights outstanding works of fiction and non-fiction on the theme of health, illness or medicine. LaPlantes debut novel, the first work of fiction to win the Prize, is written from the perspective of Dr Jennifer White, an eminent former surgeon in the final stages of Alzheimers who comes under suspicion after the murder of her best friend. The narrators mind collapses as the story progresses. The judging panel for this years Prize was chaired by writer and broadcaster Vivienne Parry and included science writer and editor Roger Highfield, Birkbeck Professor

Journal update
Dr Mark Patterson, Director of Publishing at the Public Library of Science, has been named Managing Executive Editor of a new openaccess research journal being launched next year. The Deputy Editors are Professors Fiona Watt and Drtlef Weigel. The journal, eLife, is being supported by the Wellcome Trust, the Howard Hughes Medical Institute and the Max Planck Society.

Illustrating illness
Bobby Bakers graphic autobiography, Diary Drawings: Mental illness and me, has been named Book of the Year by the mental health charity Mind. Aiming to create a new painting every day, for over a decade she chronicled her journey through severe mental and physical illness to recovery. The artworks featured in the book were exhibited at Wellcome Collection in 2009. Diary Drawings was published by Profile Books in conjunction with the Wellcome Trust in 2010.

of History Joanna Bourke, author Tim Lott and Erica Wagner, Literary Editor of the Times.

Finding faith at Wellcome Collection

With the Miracles & Charms season now in full swing at Wellcome Collection, the critically acclaimed Infinitas Gracias and Charmed Life exhibitions continue to draw visitors intrigued by their exploration of faith, hope and chance. They run until 26 February and are accompanied by a host of events, such as how expectation and belief can influence our health (Cures of Conviction, 12 January) and how we relate to all things small (Miniatures, 19 January). If lucky charms and miracles have given you a taste for the supernatural, it can be indulged further at the Magic Supper Salon on 18 January, which introduces the healers and curse

breakers of 18th-century England and Wales, over dinner and wine. Alternatively, there is an opportunity to walk off the excesses of the holidays with medical historian Richard Barnett, on one of his Medical London walks. These continue on 8 January with Gallows, Ghosts and Golden Boys. Find out more at www.wellcomecollection.org

Researchers reach out for anniversary

As part of the Wellcome Trusts 75th anniversary year, many of our Strategic Award holders have been running activities to engage members of their local communities with their research. The Wellcome Trust Centre for Molecular Parasitology in Glasgow has developed an exhibition that explores the deadly mission of parasites as they invade the human body and shows what the Centres research in this area has achieved. The exhibition, which is accompanied by public lectures and a website, runs until the end of December at the Glasgow Science Centre. over the autumn, 11-to-14-year-old schoolchildren on Merseyside and in Blantyre, Malawi have been taught using lessons plans on malaria developed by researchers from the Wellcome Trust Tropical Centre in Liverpool and the MalawiLiverpool Wellcome Trust Clinical Research Programme in collaboration with

Liverpools World Museum. Students from both countries sent questions to scientists working in Malawi, who have answered them on film. The results are being presented at a celebration evening for students and parents in Liverpool in mid-December. Events involving other Wellcome Trust Centres are taking place in Dundee, London, Manchester, Cambridgeshire, Edinburgh and Bristol. Find out more at wellc.me/oR3VOy.

Winter 2011 | 5

fUNDING NEWS

African award
Dr Julie Makani has received the Royal Society Pfizer Award for making an innovative contribution to biological sciences in Africa. Dr Makani, who is a Wellcome Trust Intermediate Fellow in Public Health and Tropical Medicine working in Tanzania, has found evidence that morbidity and mortality in sickle-cell disease in the country is commonly caused by anaemia, and has developed a framework to conduct clinical trials of potential treatments. The award consists of a 60 000 grant for research and a 5000 personal prize.

New funding to support future leaders

The Wellcome Trust and the Royal Society have launched a joint scheme to identify and support future world leaders in biomedical research. The Sir Henry Dale Fellowships will provide the brightest biomedical scientists with the best possible start to their research careers in the uK. The partnership is named after Sir Henry Dale (18751968; right), one of the most eminent biomedical scientists of the 20th century. Dale (together with otto Loewi) was awarded the Nobel Prize in Physiology or Medicine in 1936 for the discovery of acetylcholine and its physiological actions. This revolutionised the understanding of the nervous system and the way in which drugs were designed and developed. Dale was Chairman of the Wellcome Trust from 1938 until 1960 and served as President of the Royal Society from 1940 to 1945. The new awards which bring

together the Royal Societys university Research Fellowships and the Trusts Research Career Development Fellowships into one new scheme will provide research support for up to eight years. The first awards will be made in June 2012. For more, see wellc.me/ta8z6Z.

Infectious wins
Professors Bob Snow and David Mabey have been awarded the George Macdonald Medal for research leading to health improvements in tropical countries. A Wellcome Trust Principal Research Fellow who works at the KEMRIWellcome Trust Research Programme in Kenya, Prof. Snow has developed an extensive programme to tackle the public health burden of malaria in Africa. Prof. Mabey works at the London School of Hygiene and Tropical Medicine; his achievements include demonstrating that HIV transmission can be reduced by improving the management of other sexually transmitted infections.

Latest Investigator Awards made

The second round of Wellcome Trust Investigator Awards has been made. The 14 awards range from three to seven years in duration and 500 000 to over 3 million in funding. Among the

Developmental prize
Professor Chittaranjan Yajnik has won the David Barker Medal for his contribution to understanding how early human development relates to chronic disease in later life. His research has highlighted numerous risk factors for developing type 2 diabetes and insulin resistance. Prof. Yajnik, supported by the Wellcome Trust for over 20 years, is Director of the King Edward Memorial Hospital Diabetes Unit and Research Centre in India.

15 Investigators is Professor Derek Jones (left) from Cardiff university, who will use his New Investigator Award to focus on the development and application of tractometry. This is a non-invasive imaging approach used to obtain detailed information about the microstructure of white matter, the connections that carry information between different parts of the brain. Prof. Jones believes that this approach will be instrumental in advancing our understanding of the brain in health, development and disease. At the university of Edinburgh, Prof. Rose Zamoyska has been made a Senior Investigator. She will explore the mechanisms that regulate T cells, an important component of the immune system, including understanding what goes wrong with this regulation in autoimmune conditions, in which T cells attack healthy cells. We consider applications for Investigator Awards in biomedical science four times a year. The next deadline is 16 December 2011. For more, see wellc.me/rqxQyd.

6 | Wellcome NEWS

Wellcome Library

Technology Transfer projects seek partners

Several Seeding Drug Discovery projects supported by Technology Transfer at the Wellcome Trust are looking for commercial partners. These include a programme that has led to the development of new, highly selective beta-blocker drug candidates that could be used to treat heart disease. While conventional beta-blockers worsen the symptoms of respiratory diseases, and prevent rescue medications such as inhalers from working, these new compounds are highly selective for the 1 receptors found in the heart, without showing an effect on the 2 receptors found in the lungs and blood vessels. This means that the new compounds can be used in all patients with heart problems even the high number with respiratory conditions. A second project has led to the identification of a candidate drug for treating allergy to house dust mites. This compound has already been shown to be effective when inhaled by animal models, and is ready for further preclinical and clinical development. Technology Transfer supports projects that address an unmet medical need, through the difficult early stages of research and development, taking them to the point where they become attractive to industry, venture capital firms and other investors. For more, see wellc.me/qSiYuS.

Science Policy in the News (Spin)

Science knows no country, because knowledge belongs to humanity, and is the torch which illuminates the world
Louis Pasteur Keep up to date with worldwide biomedical science policy through our free weekly newsletter Science Policy in the News (Spin). Sign up to receive Spin straight to your inbox and access our free, searchable archive dating back to 1992. www.wellcome.ac.uk/spin/wn

Diagrams of a bronchus (left) and the heart (right). Miles Kelly Art Library/Wellcome Images

Early clinical careers scheme launched

The Wellcome Trust has launched a new scheme for talented clinicians who have recently gained a higher degree (typically a PhD) and want to undertake postdoctoral research training in the best labs in the uK and abroad. Early Postdoctoral Training Fellowships for Clinician Scientists will help people work towards an independent research career and can be tailored, where appropriate, so that grantholders can continue their clinical training. We will take applications three times a year for these awards, which are open to individuals with a relevant connection to the European Economic Area for fellowships to be held in a uK or Republic of Ireland institution. Fellowships are for up to three years, normally providing up to 350 000. For more, see wellc.me/oxIrJf.

Winter 2011 | 7

Human embryo. Yorgos Nikas/Wellcome Images

RESEARCh NEWS

Mouse mutations
An international team led by researchers from the Wellcome Trust Sanger Institute and the University of Oxford have catalogued over 56 million genetic differences among 17 strains of mice. Having such information available should help reduce the number of mice bred for experiments and should also help research in the field progress faster.
Keane TM et al. Nature 2011;477:28994. Yalcin B et al. Nature 2011:477:3269.

Brain fold linked to recalling whats real

Scientists at the university of Cambridges Behavioural and Clinical Neuroscience Institute have found that normal variation in a fold at the front of the brain might explain why some people are better than others at distinguishing real events in memory from those they may have imagined or been told about, researchers have found. This brain variation, a fold called the paracingulate sulcus (PCS), is present in roughly half of the normal population. As one of the last structural folds to develop before birth, its size varies greatly among individuals. The researchers discovered that adults whose MRI scans indicated an absence of the PCS were significantly less accurate at memory tasks than people with a prominent PCS on at least one side of the brain. Interestingly, all
Wellcome Library

Diagnosing cancer
Researchers at the University of Liverpool and Newcastle University have identified the most accurate test yet for diagnosing human papillomavirus (HPV)-related head and neck cancers: a combination of testing for the p16 gene and quantitative PCR (used to determine levels of viral DNA). They hope that a combination test will become the diagnostic standard and have immediate clinical impact.
Schache AG et al. Clin Cancer Res 2011;17(19):626271.

participants believed that they had a good memory. PCS reductions have been reported in previous studies of schizophrenia; Dr Jon Simons, who led this latest research, argues that these findings are consistent with the idea that this structural variability might directly influence the functional capacity of surrounding brain areas and the cognitive abilities that they support.
Buda M et al. A specific brain structural basis for individual differences in reality monitoring. J Neurosci 2011;31(40):1430813.

Testing a new treatment for infant leukaemia

Scientists have found a chemical that could treat mixed-lineage leukaemia, the most common form of leukaemia in children under two, which is hard to treat with current therapies. The disease occurs when a gene called MLL gets fused to another gene. This produces a fusion protein that behaves inappropriately, switching on genes that drive the development of leukaemia. Researchers from the Wellcome TrustCancer Research uK Gurdon Institute and the Cambridge Institute for Medical Research collaborated with scientists from GlaxoSmithKline and Cellzome AG. They showed that MLL fusion proteins are targeted to leukaemia-causing genes by proteins from the BET family, which recognise certain chemical tags on chromatin, the scaffold on which DNA is organised. The researchers showed that a new chemical agent developed by GSK, I-BET151, mimics these chemical tags,

Kinky findings
The kink turn is a widespread structural motif in RNA that is involved in many RNA functions, including translation, RNA processing and genetic regulation. The kinked shape can be stabilised by metal ions or protein binding, and now researchers from the University of Dundee have found a third way of stabilisation: by interactions within a larger RNA structure. The results suggest that the combined influences of specific protein binding and these so-called tertiary interactions could be very important during the biogenesis of structures such as the ribosome.
Schroeder KT et al. Structure 2011;19(9):123340.

preventing BET and MLL from attaching to chromatin and activating the leukaemia genes. Treatment of leukaemia in mice and human cancer cells in the lab showed that the chemical could halt the disease, paving the way for its use in human trials. Senior author and inaugural WellcomeBeit Prize Fellow Dr Mark Dawson said: This is an exciting study with wider implications for cancer treatment, as it highlights the importance of understanding how proteins mutated in cancer alter the chromatin landscape to initiate and drive cancer.
Dawson MA et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 2011 2 Oct [epub].

8 | Wellcome NEWS

Wellcome Library

Researching rapid repair of tissue

When tissue is damaged, cells detect this via changes in their environment. Now, researchers at the university of Bristol and the university of Manchesters Wellcome Trust Centre for Cell-Matrix Research have examined the signalling process

that occurs in damaged tissues and identified the cellular mechanisms responsible for activating repair. Cell migration during tissue repair requires the turnover of cellular adhesions [repeated sticking and unsticking of cells], and the challenge

has been to determine how cells detect damage and modify their adhesive properties accordingly, says lead author Dr Mark Bass. By measuring the atomic force required to detach a cell, the researchers showed how a protein, syndecan-4, triggers the uptake and redeployment of adhesive molecules. This novel sequence of signals enables fibroblasts and other cells, which help a wound to contract and heal, respond to changes in tissue structure and migrate along the matrix fibres that make up the skin. By moving directly towards a long-range damage signal, cells arrive at a wound far quicker than if they searched for it randomly. The researchers hope this work will help find new ways to improve wound healing.
Bass MD et al. A syndecan-4 hair trigger initiates wound healing through caveolin- and RhoG-regulated integrin endocytosis. Dev Cell 2011 23 Oct [epub].

Left: Blood clot on a plaster. Anne Weston, LRI, CRUK/ Wellcome Images

Google Earth used to track typhoid

Scientists at the Wellcome Trust Major overseas Programme in Vietnam and the oxford university Clinical Research units in Nepal and Vietnam have found a way to map typhoid outbreaks in Kathmandu accurately. These findings may help in improving strategies to control the disease. Typhoid is caused by Salmonella typhi and S. paratyphi, spread through water or food contaminated with faeces. There are an estimated 27 million cases of typhoid across the world every year. Researchers tracing outbreaks of typhoid in Nepal have faced particular challenges, including that street names are not used, so capturing the addresses of people with typhoid infections is difficult. In this latest study, researchers combined DNA-sequencing technology and GPS to map the spread of typhoid and trace its sources onto Google Earth. They found that the clustering of typhoid in certain locations did not depend on population density, but on proximity to water spouts and living at a lower elevation. Dr Jimmy Whitworth, the Trusts Head of International Activities, said: Just as John Snows pioneering cholera maps of the 19th century showed that poor sanitation leading to contaminated water was spreading disease, this study further reinforces quality of water supplies and infrastructure for sanitation if we are to seriously tackle diseases such as typhoid.

the importance of improving the

Winter 2011 | 9

10 | Wellcome NEWS

CAREERS

PRoF. CLARE WILLIAMS

HoW I GoT INTo... MEDICAL SoCIoLoGY

After a childhood spent moving around the world, Clare Williams found herself in the uK at the age of 17 without any academic qualifications. Now a professor of medical sociology at Brunel university, she looks at the social forces that shape the use of medical technologies and how they might affect clinicians, scientists and patients. She talks to Emma James.
y father was in the Air Force, so as a child I was always moving from place to place. I went to about 12 different schools altogether, and ended up back in the uK at the age of 17 without any o levels. Having decided that I wanted to leave school, I was quite keen to go into nursing. I trained as a nurse in the 1970s at Hammersmith Hospital. It was a very important place for introducing new technologies including some of the first kidney transplants in the uK so I saw all sorts of exciting medical innovations there. I worked as a nurse and health visitor for 20 years, but during that time started to question the evidence behind various practices and procedures. Thats what got me thinking about research. After taking part in a six-week research course for nurses, I decided to do a part-time Masters degree in medical sociology, which I really loved. Looking back, I think I had been a bit of a frustrated academic so I just took to it and became one of those very boring students who does everything theyre supposed to! It was a complete revelation at the time, like a door opening, and its led me to this completely different way of life. During my Masters, I noticed that there was a lot of criticism of the medical profession quite rightly in many ways but I always felt that there was another side that could be explored. It was also noticeable that there was a lot of research being carried out on patient perspectives but far less on those of practitioners and clinicians. Coming from a nursing background, I always had at the back of my mind what I might do in particular situations. I think thats why a lot of my research has focused on the difficulties that practitioners and scientists can encounter in their work. It seems crazy now, but I dont think Id ever thought much about the social issues around medicine before then. The Masters really opened my eyes. After, I gained Department of Health funding to do a full-time PhD on managing chronic illness in teenagers. In 1999, I became the junior researcher on a two-year Wellcome Trust biomedical ethics project. We were exploring innovative early-stage antenatal screening techniques looking at what sorts of children might be born and who should make decisions around these techniques. The people I worked with helped me develop hugely and opened my mind to a lot of different areas. From then I really developed an interest in reproduction, and was awarded a three-year postdoctoral Wellcome Trust fellowship looking at fetal surgery. Next, I got funding for three related projects on human embryonic stem cell research, embryo donation for research and pre-implantation genetic diagnosis (PGD). PGD is for couples with a family history of a particular condition such as muscular dystrophy who want to have a child free from the condition. They go through IVF and only embryos without the condition are implanted. When PGD first came about it was only really used for life-threatening diseases that often caused terrible pain or death in childhood, yet now were seeing the uses expanding. Thats what Im really interested in how and why the initially strict boundaries for new technologies shift, and how the regulation and use of these often ethically contentious technologies manifests itself in the clinic or lab. Ive done a lot of work on reproductive technologies, but have recently moved on to study translational sometimes referred to as bench-tobedside research in neuroscience. There are some really fascinating areas there too. I consider myself very fortunate what other job do you get where you can travel, develop junior researchers, and teach and work on areas that youre really interested in with people passionate about what they do? Ive spent some 12 years working on brilliant projects, and thats what Id like to carry on doing.
Winter 2011 | 11

Wellcome Trust Translation Awards

We are a committed funder of translational R&D. We work with world-class investigators in academic institutions and companies alike, in pursuit of solutions for unmet medical needs.

We fund medical innovations in the following areas: therapeutics diagnostics enabling technology regenerative medicine vaccines medical devices. Forthcoming deadlines for Translation Award preliminary applications: 6 January 2012 20 July 2012.

www.wellcome.ac.uk/ta

The only way is Wikipedia

DR ALEx BATEMAN, WELLCoME TRuST SANGER INSTITuTE
n a world in which anti-science appears to be on the increase, it is imperative that scientists improve how they engage with the general public about their research. A traditional way to do this is to give talks at science fairs and engage directly with schools. A problem with this standard public engagement approach, however, is that the reach can be quite limited and is often a case of preaching to the converted. of course, if your research is hot enough you can push stories through the mass media, such as TV and newspapers, hoping that the results dont get too garbled in the telling. I believe that these limitations, combined with the fact that many of these activities are time-consuming, inhibit many scientists from communicating effectively with the public. If you really want to let the public know about your science then the only way is Wikipedia. For better or worse, Wikipedia has become the central repository of knowledge on the internet. If you dont believe me then try the following experiment. Pick a word and type it into Google. For most terms e.g. malaria, research or opinion Wikipedia is the top hit. If you want to get a quick overview of a topic, its likely youll go straight to Wikipedia. Now think about the hundreds of millions of internet users out there who will, at some point, want to find out something about science, technology or medicine. Im afraid that they will almost certainly not be heading to your latest research article to do so. Editing Wikipedia can seem daunting at first. Some researchers might be put off because their first impulse is to tackle editing an article there the same way as they would write a research paper perfect it and then let others review it before final publication. Wikipedia doesnt work that way. You dont need to rewrite the history of a science article, just add a sentence here, a reference there. You can make a useful contribution to Wikipedia without making a large investment of your time. So if you are interested in helping the public understand what your research is all about then I urge you to learn how to edit and improve Wikipedia. Find the relevant article and make whatever changes you think are needed to ensure that the content is scientifically accurate and up to date. It doesnt take a lot to make a big difference, and you get to fulfil some of your public engagement responsibilities in the process too.

oPINIoN

www.wikipedia.org

Winter 2011 | 13

NEGLECTED TROPICAL DISEASES

AND oTHER DISEASES

Neglected tropical diseases is a new name for old diseases that have long been ignored by most of the world. Michael Regnier spoke to some of the scientists-turned-advocates who are succeeding in changing our approach to these endemic global infections.

14 | Wellcome NEWS

Winter 2011 | 15

he big three infectious diseases in global health are the all too familiar: HIV/AIDS, malaria and tuberculosis. Less well known are a host of other infections endemic across the world. Caused by a motley variety of parasites, viruses and bacteria, these diseases are a serious problem in lowand middle-income countries, causing long-term disability and disadvantage. They are diseases of poverty, affecting the worlds poorest nations and trapping their people in a cycle of economic stagnation, but they do not receive anything like the attention or funding given to work on the big three. In the past five years or so, however, more focus has begun to fall on these other diseases. Years of neglect are being overturned by a campaign led predominantly by scientists and centred on a new name: neglected tropical diseases, or NTDs. The phrase was part of a drive to think about these diseases in a fresh light, says Professor Peter Hotez, President of the Sabin Vaccine Institute in Washington, DC and Editor-in-Chief
16 | Wellcome NEWS

of the journal PLoS NTDs. After the launch of the Millennium Development Goals in 2000, a lot of attention fell on HIV, tuberculosis and malaria. Goal 6 called for action on those three and other diseases. It led to a lot going on in HIV, tuberculosis and malaria, but those of us working on the other diseases felt we were on the outside looking in. We were driven to think afresh, to rebrand these conditions. His research is on vaccines for human hookworm infection and other parasitic worms. As with many NTDs, they are not lethal in themselves but infections can last for decades, impairing childrens growth, development and physical fitness and causing severe anaemia during pregnancy, which leads to low birth weight and increased infant and maternal mortality. The most common neglected tropical diseases have high morbidity and low mortality, explains Hotez. They are causes of poverty through their effects on children, pregnant women and workers. From descriptions in ancient texts, we know these diseases

have been around for ever. They are the opposite of emerging diseases. That is one reason why NTDs have been neglected. If they were unknown, emerging diseases, governments and international organisations would undoubtedly have demanded action and targeted funding for research. We are more scared of emerging diseases, Hotez suggests, but NTDs do more harm overall.

Definitions of neglect
Neglected tropical diseases is not a precisely defined term. Not all NTDs are exclusively tropical, for instance, and the nature of neglect varies. Sometimes neglect comes from the communities in which these diseases are found: lymphatic filariasis, for example, causes severe disfigurement and massively swollen limbs, which can lead to prejudice and stigma. In other cases, neglect is from the rest of the world, for which diseases such as schistosomiasis and dracunculiasis are entirely unfamiliar and infections such as cholera and leprosy are chapters from history rather than pressing medical problems.

Above: Professor Peter Hotez.

Research funders tended to focus on emerging infections. The pharma industry cut programmes because there wasnt a profitable market.
time, the prevalence of schistosomiasis there fell from 20 per cent to less than 5 per cent. He knew it was possible to reduce the burden of the disease until it was no longer a public health issue; his problem was in finding the support to apply this knowledge in other countries. Fenwick was awarded $30m to work with African countries to introduce national programmes to control schistosomiasis. The first treatment began in uganda in 2003 and after one year, the intensity of schistosome infection had fallen by 70 per cent. Disease control is an ongoing challenge, however: If we stop treating, he says, I fear that within five years it will come back again. The SCI has supported or is currently working in 12 African countries and is still expanding coverage. More than 100m people have been treated at least once. Moreover, it treated for three parasitic worm infections at the same time, in effect tackling four NTDs with one integrated programme. NTDs tend to cluster in rural areas, where any one person can be infected with several NTDs at the same time. Integrating programmes of mass drug administration increases their costeffectiveness and is more attractive to potential funders. Integration is made possible in part through initiatives such as the Global Network for NTDs, founded in 2005 by a group
Winter 2011 | 17

It doesnt help that the available information is not always reliable. NTDs are more common in regions of extreme poverty or conflict not situations that lend themselves to effective epidemiological monitoring Research into NTDs has been neglected too. In the late 20th century, research funders tended to focus on emerging infections and diseases such as cancer and cardiovascular disease. Meanwhile, the pharmaceutical industry cut programmes on parasitic infections because there wasnt a profitable market to invest in Frustratingly for those who did know about NTDs, effective drugs were available for a small number of infections but they were not being widely used. Even when drug companies began donating these drugs or supplying them at very low cost for use in low-income countries, programmes to implement mass drug administration struggled to find sustained funding Professor Alan Fenwick, Director of the Schistosomiasis Control Initiative (SCI) at Imperial College London, worked in Egypt for 15 years. In that

Proof of principle
Many organisations are interested in supporting research; some, like the Wellcome Trust, are mandated to only fund research, says Fenwick. But this left schistosomiasis and others in limbo: most of the research had been done. We had the tools which, if implemented properly, could help some 200 million people in sub-Saharan Africa. In 2002, he approached the newly established Bill & Melinda Gates Foundation and suggested they buy and distribute praziquantel, an effective schistosomiasis drug treatment, in countries where the disease was endemic. They agreed to allow me to test the proof of principle: Will these countries implement control if given access to drugs and funding?

How can you achieve primary education for all if the kids are full of worms? If they have no energy so that even if they go to school they fall asleep?

Right: Professor Alan Fenwick.

of researchers, including Hotez and Fenwick, with an interest in global policy efforts to combine such programmes as they grew in scale.

Drug development for NTDs

Programmes such as the SCI are successful not only because the drugs are donated or provided at low cost, but also because the drugs are safe and effective and can be given orally in a single dose every six or 12 months. The drugs available for many other NTDs are not so practical and there is a desperate need for new treatments. Professor Alan Fairlamb, CoDirector of the Wellcome Trust-funded Drug Discovery unit at the university of Dundee, agrees that only a handful of NTD drugs are truly fit for purpose: Many compounds were developed with a different indication in mind, maybe from cancer research or antifungal drug discovery programmes. The target product profile for these original indications does not take into account the association with poverty and the rural setting where most NTD drugs are needed. one thing frequently missing in
18 | Wellcome NEWS

the equation from the pharma perspective is low cost of goods, he adds. Expensive drugs are good for the odd safari but too costly for the local population. People often cant afford the treatment, so they dont complete the course and this drives resistance. The challenge is to develop cheaper and safer drugs. The Dundee unit works on the best potential targets wherever they come from, making concepts viable for further development in animal models. Fairlamb says they are always looking for scientists with a promising target but who dont have either the know-how or the infrastructure to do drug discovery. our vision is to take excellent basic science and turn it into useful medical products, he says. Their most successful project to date is based on an enzyme called N-myristoyltransferase (NMT), which was developed as a target at Imperial College London by Professor Deborah Smith, now at the university of York. The enzyme has been found in a number of parasites: the Dundee unit is working on developing a drug for human African trypanosomiasis

(sleeping sickness) while Smith is leading on developing drugs and vaccines for leishmaniasis. NMT may even be a target for new malaria drugs. Theres still a long way to go, she says, but even if the work on NMT does not lead to a viable drug for all these diseases, it will be valuable research. Were doing the groundwork for future potential opportunities, she concludes.

Approaching the problem from all angles

Some NTDs have no effective drugs or vaccines. Dengue virus, for example, causes fluid to leak from blood vessels into the abdomen and other cavities, leading to severe shock in some cases. The only available treatment is to replace the fluid in hospital, which puts a huge burden on health systems during outbreaks. Dengue is neglected in the sense that the true scale of the disease burden is poorly understood and certainly underestimated, says Professor Cameron Simmons, a Wellcome Trust Senior Research Fellow at the university of oxford, who studies dengue in Vietnam. As well as helping to develop

new drugs and vaccines for dengue, he is researching better diagnostic and prognostic tests to help doctors make decisions about dengue, and novel approaches to vector control. The important point, he says, is that all these approaches can be complementary. Were not going to eradicate the virus any time soon, so we need a swag of tools to control dengue. Its a point that applies to NTDs as a whole: each presents specific challenges and a range of strategies will be needed to control, eliminate or even eradicate each one. Hotez highlights some of the achievements made since 2005, when the first paper to use the term neglected tropical diseases was published: major initiatives from the uS Agency for International Development and the uK Department for International Development; a new Department of Control of Neglected Tropical Diseases at the WHo; and PLoS NTDs, the journal he edits, which launched in 2007. Grouping NTDs together doesnt necessarily help the research effort but it has definitely succeeded in drawing attention to the huge problem they

present collectively and the need for sustained, coordinated action. ultimately, says Fenwick, it will be impossible to achieve any of the Millennium Development Goals without tackling NTDs. How can you break the poverty cycle? he demands. How can you achieve primary education for all if the kids are full of worms? If they have no energy so that even if they go to school they fall asleep? Its a persuasive argument and one that he, Hotez and others will continue to make to anyone who will listen. I think as scientists we are taught not to be advocates, says Hotez. Thats something Im trying to correct.
You can read more about neglected tropical diseases in a series of four posts on the Wellcome Trust blog: wellcometrust.wordpress.com.

Cover images Outside: Aedes aegypti mosquitoes. Clockwise from top: Ascaris lumbricoides worm; Schistosoma haematobium parasite (Lanarkshire Infectious Unit/ Wellcome Images); schistosomiasis in the large intestine; larva of Ancylostoma duodenale hookworm; bilharziaspreading snails; women walking (N Durrell McKenna/ Wellcome Images); Leishmania donovani parasites (D Evans/Wellcome Images); dengue virus (CDC); Schistosoma haematobium worms. Pages 1415 images Woman carrying water (N Durrell McKenna/Wellcome Images); structure of praziquantel, a schistosomiasis drug; parachute (teacept/iStockphoto); mother and child on bench, and children in river (Joss Dimock); background (Richard Reithinger/Wellcome Images; W Peters/Wellcome Images). Pages 1617 images Prof. Peter Hotez (Agapito Sanchez, Baylor College of Medicine). Pages 1819 images Nerve networks; Prof. Alan Fenwick (Schistosomiasis Control Initiative); background (A Bryceson/Wellcome Images). Others from Wellcome Images.

More on NTDs
The Global Network for Neglected Tropical Diseases: www.globalnetwork.org WHO Neglected Tropical Diseases: www.who.int/neglected_diseases/en/ Schistosomiasis Control Initiative: www3.imperial.ac.uk/schisto Drug Discovery Unit, Dundee: www.drugdiscovery.dundee.ac.uk

Winter 2011 | 19

CLOSE-UP

uSING WELLCoME IMAGES

CELLS AND THE CITY

our bodies are permeable: the city enters our bodies through our skin, our lungs and our ears. I wanted to question this idea of fixed borders, of enclosing spaces which is central to map making by merging the boundaries of the body and the city, says Daksha Patel, an artist and PhD researcher at Northumbria university. Her works for the Diffusion project look at the ways in which people construct cities and are in turn affected by the cities they inhabit. Commissioned to produce a new series of drawings for the lightboxes at Manchester Piccadilly station, Patel turned to Wellcome Images for inspiration. I used this collection as a starting-point for the series of drawings, in which I map environmental data upon structures of the internal body. Following a period of research at the Human Geography department at Manchester Metropolitan university, she worked with Geographical Information Systems to map data about Manchesters growth, air quality and noise levels onto biological structures. The drawings were commissioned by the Hamilton Project and are being shown at Manchester Piccadillys Metrolink platform, until 30 December. The project was supported by the National Lottery through Arts Council England and is an associate event for this years Shisha-initiated Asia Triennial Manchester (ATM11). www.dakshapatel.co.uk www.asiatriennialmanchester.com www.thehamiltonproject.co.uk

Diffusion 1.4 Lung tissue (below, by Spike Walker) and Manchester orbital motorways (above).

To be considered for the Wellcome Image Awards 2012, you must contribute your biomedical images by 16 January 2012. For more details see page 2.

20 | Wellcome NEWS

Diffusion 1.1 Alveolar spaces in the lungs (above, by David Gregory and Debbie Marshall) as a contour map of Manchester (left, in red) with a choropleth map (green) showing 3+ car ownership per household in Greater Manchester.

Diffusion 1.2 A mast cell with histamine granules (above, from the University of Edinburgh) as a dot map showing sites of air pollution emissions in Greater Manchester (left).

Winter 2011 | 21

ONLINE hIGhLIGhTS

BEST oF THE BLoG

PATIENTS oF THE PAST

Jennifer Wallis, a history PhD student at Queen Mary, university of London and the recipient of a Wellcome Trust studentship, discusses general paralysis of the insane: a diagnostic category so illdefined it was called the darkest Africa ofpsychopathology.
Studying 19th-century psychiatry is always a bit of a challenge (that old joke about doctors handwriting? Just imagine that in cursive Victorian script), especially trying to make sense of diagnoses that, though bandied about with great confidence by contemporary writers, mean little to us today. Perhaps an exception to the rule is general paralysis of the insane, which it seems many 19th-century alienists (or psychiatrists, as we know them today) were just as flummoxed by as I have been. Despite the hundreds of words dedicated to the subject in journals of mental science, it appeared remarkably difficult for alienists to come to any definitive agreement about the character of general paralysis (also helpfully referred to by a host of other terms, such as dementia paralytica). General paralysis of the insane (GPI) was generally conceived of as a progressive deterioration of the whole mental and physical personality. Symptoms included an inability to pay attention, a clouding of consciousness, poor short-term memory, tremulous voice, reflex disturbances, pupil and retinal anomalies, and diminished skin sensation. Patients were often recognisable by their striking delusions of grandeur. I can think of several people fitting these criteria, so luckily there were further tests: many alienists pinpointed particular physical signs as the only conclusive proof (typically the exaggerated knee jerk and lack of reaction of the pupils to light). Most GPI patients were men, usually showing symptoms between age 35 and 45. They tended to be from urban areas, with many relating a history of intemperance and/or venereal disease. An 1896 paper on the supposed increase of GPI emphasised its prevalence in large towns where there were aboveaverage rates of drunkenness. In the view of the articles author, GPI was a preventable disease as its roots lay in the immoral behaviour of its victims. (Women, in case youre wondering, were less susceptible as they could readily remove themselves from the influence of alcohol and venereal excesses.) The argument appealed to contemporary fears of racial degeneration, explaining GPI as a reversion to a lower form of brain disease. other writers concluded that GPI was a disease of civilisation and the apotheosis of selfishness. From the mid-19th century, alienists had debated the link between GPI and syphilis the latter as direct or predisposing cause and modern historians of psychiatry are confident in explaining GPI as neurosyphilis (symptoms of which include seizures, sight disturbances and changes in personality). This link rests, however, on accepting the accuracy of 19thcentury doctors observations and their use of the term GPI. For me, discovering the truth of GPI is perhaps less interesting than its history as a diagnosis: it was a theory, said Alfred Fournier towards the end of the century, that [had] had ample scope to run riot. Bethlem Superintendent Theo Hyslop bemoaned the fact that we have nearly every possible abnormal mental manifestation included under General Paralysis, and perhaps this was precisely the point. The very adaptability of the diagnosis may have proved irresistible to alienists at a time when so little of mental illness could be assigned a definite cause. Within a context of rising concern for sexually transmitted diseases and the health of urban populations, alienists were able to contribute to public health debates that proved their expertise had application outside the walls of the asylum.

Blog
Wellcome Library This article first appeared on the Wellcome Trust blog. To read, comment on and share hundreds more posts on life from a Wellcome Trust perspective, see wellcometrust.wordpress.com.

22 | Wellcome NEWS

IN ThE hOT SEAT

SHEDDING LIGHT oN A MYSTERIouS MoToR PRoTEIN

PRoF. CARoL RoBINSoN

Why is ATPase interesting?
Its a fascinating rotary machine that is found in cells across all kingdoms of life. Its made from about 30 different protein subunits that form two main parts: a motor that sits in the cell membrane and a spinning head that protrudes into the cytoplasm [the liquid inside the cell]. The motor rotates a shaft that causes the head to spin. ATPase has two important roles. As the head spins, it synthesises ATP [adenosine triphosphate, which transports energy within the cell]. It can also work in the other direction by consuming ATP and using the energy released to pump protons across the membrane, maintaining the acidity of cells. We were particularly interested in this second mode of action because it has a number of physiological roles and is associated with diseases such as kidney failure, osteoporosis and cancer. When the head and the motor parts are together, they act in a coordinated way, but its known that these two parts separate in vivo, which has been proposed as a regulatory mechanism. When this happens, its likely that the head stops consuming ATP and the base stops pumping protons. one of many questions in the field has been: how do they stop when they become detached?

What did you do?

To our surprise, we were able to evaporate whole ATPase assemblies [with head and motor parts] without destroying them. We used a specially modified mass spectrometer to separate protein assemblies according to their cross-section [which depends on protein mass, charge and shape]. Smaller, more mobile proteins travel through quickly, while big, lumbering ones take much longer. It can tell you if a protein has changed shape, for example in response to binding a small molecule. The technique was originally invented for individual protein molecules, so it was exciting to use it with these much larger membraneembedded protein assemblies for the first time. We compared two different ATPases from different bacteria. We challenged them with various stimuli to see how they would respond, for example by changing the pH or ATP concentration.

The enzyme ATPase has been described as the most efficient, beautiful machine that nature has ever made. Professor Carol Robinson, a Royal Society Research Professor at the university of oxford Departmetn of Chemistry and a Wellcome Trust programme grant holder, has been using a new technique to find out more about this intriguing beast, as she calls it. She tells us about her latest study, the pinnacle of 15 years work.

What did you find out?

It had always been unclear whether lipid molecules [found in cell membranes] have a structural role in ATPase function. We were very surprised to find that lipids bind to the two ATPases in strikingly different ways, leading us to propose that they have different structural roles in regulating the motor proteins. We also proposed a new explanation for how ATPase stops pumping protons when the head and motor parts separate. We saw that one of the protein subunits moved away from the proton channel [the hole through which protons are pumped], which made us think that other lipids might move in and shut off the channel. This would stop protons from leaking through.
Zhou M et al. Mass spectrometry of intact V-type ATPases reveals bound lipids and the effects of nucleotide binding. Science 2011;334(6054):3805.

What were you hoping to find out?

Initially, we were just curious whether ATPase could survive intact during electrospray mass spectrometry, which involves evaporating water droplets containing the protein. It was hard to imagine how a molecular motor, normally embedded in a cell membrane with water on either side, could survive under these conditions. We reasoned that if we could get it into a gas environment whilst still intact, we would probably learn something new about how the head and motor talk to each other.

Winter 2011 | 23

NUTS AND BOLTS

NEuRoSCIENCE

THE NEuRoN
Neurons are highly specialised cells that conduct and process information in animals, enabling thought, perception and control of movement. Problems with neuronal function underpin a range of neurological and psychiatric disorders. Lydia Harriss presents a quick to these remarkable cells.
Individual neurons were first identified by Santiago Ramn y Cajal at the end of the 19th century. using a tissue-staining technique invented by Camillo Golgi, he produced microscopy images showing that the brain is not a continuous mesh of tissue but formed from individual cells, or neurons. A single neuron may be connected to as many as 200 000 others, via junctions called synapses. They form an extensive network throughout the body, and can transmit signals at speeds of 100 metres per second. This enables animals to process and respond to events rapidly, for example by carrying sensory information from the ears to the brain, then instructions for movement from the brain to the leg muscles. Within a neuron, signals are transmitted by a change of membrane voltage a variation in the difference in electrical charge between the inside and outside of the cell. This electrical signal moves along the neuron as an electrical pulse (the action potential). The nature of the connection between neurons was hotly debated until early-20th-century experiments by otto Loewi and Sir Henry Dale (a founding trustee and chairman of the Wellcome Trust) showed that signals are typically transmitted across synapses by chemicals called neurotransmitters. Researchers are investigating how changing levels of neuron activity alter the number of synapses and how well they transmit signals. This has given us insight into cognitive processes such as memory and learning, and has suggested treatments for diseases in which neural network activity becomes uncontrolled, such as epilepsy. There is also great interest in glial cells, found in the spaces between neurons. Some glial cells (astrocytes) maintain the composition of this watery space, helping neurons to function properly. others (oligodendrocytes) wrap neurons in an insulating myelin sheath, which can become damaged in neurodegenerative conditions such as stroke, spinal cord injury, multiple sclerosis and cerebral palsy. A better understanding of how neurons interact with glial cells may help in finding new treatments for these conditions.

Cell body (soma) Dendrites

Protrusions from the cell body that form branches connecting to other cells. These connections are input synapses, which receive signals from the axons of neighbouring neurons.
24 | Wellcome NEWS

Cell membrane
A film of fatty molecules that encloses the neuron.

Contains many components typically found in other types of cell. This includes DNA, located in the nucleus, which holds instructions for producing the proteins that determine the shape and function of the cell.

Node of Ranvier
See Myelin sheath.

Synapse
A connection between two neurons. When a nerve signal travelling along an axon reaches a synapse, it triggers the release of a chemical neurotransmitter (A) that diffuses across the synaptic gap (B) and binds to proteins (C) on the surface of the receiving neuron. This binding causes an influx of ions, changing the membrane voltage and initiating an electrical signal in the second neuron.

oligodendrocyte
A type of glial cell that makes the myelin sheath.

Myelin sheath
Many neurons are insulated by myelin: multiple layers of cell membrane that wrap around the axon. The sheath is interrupted at regular intervals ( nodes of Ranvier), where the channels that generate the electrical signal are located. Myelin reduces leakage of electrical charge from the axon, resulting in a signal that rapidly jumps from one node of Ranvier to the next, speeding up the conduction of information.

>

Nervous research
Current research in this field funded by the Wellcome Trust includes that of Professor David Attwell, University College London, who is investigating how proteins on the surface of certain glial cells may be responsible for the malfunction or death of neurons, as seen in conditions such as cerebral palsy, stroke and spinal cord injury. Neurons can readily change, which allows them to adapt to variations in environment but also makes the networks that they form inherently unstable. Professor Juan Burrone, Kings College London, is studying how neurons avoid drifting towards extreme levels of activity. Understanding this better will provide targets for treating diseases caused by uncontrolled neuron activity, such as epilepsy. Professor Peter Brophy, University of Edinburgh, has identified a gene that is mutated in people with a form of Charcot MarieTooth disease, which affects the peripheral nerves outside of the brain and spinal cord. He is using mouse models to understand why the absence of the protein encoded by the gene makes peripheral nerves degenerate.

Axon
The long projection that carries signals away from the cell body. The membrane voltage change from an incoming signal here triggers the opening of channels that allow ions (charged atoms) to flow into the cell from outside. This causes more channels farther along the axon to open, creating a voltage pulse that propagates along it (see arrow).

Winter 2011 | 25

Tess Shellard (left) and Penny Sarchet (right) after receiving their prizes, in Henrys club room at Wellcome Collection.

26 | Wellcome NEWS

NURTURING NEW TALENT

WELLCoME TRuST SCIENCE WRITING PRIZE 2011

WINNING WAYS
800 entries, two winners, one competition: 2011 saw the first ever Wellcome Trust Science Writing Prize, in association with the Guardian and the Observer. Here we present the two winning entries.

Tess Shellard
Occupation Health Project Coordinator for an international NGO. Whats your background? Ive been working in the charity sector for about ten years now, so it isnt a scientific background at all. That being said, Ive always had an innate curiosity about science and have always written for pleasure, which is why I went for the competition. Where did you get the idea for your article? I do a huge amount of reading and watch lectures online. The idea for this article came out of a TED talk, given by Professor Bonny Bassler at Princeton. Shes an amazing lady who has led the way in quorum-sensing research. I was blown away! It seemed so fascinating, but also the implications were huge. It could completely change the way that we design our medicines. What are your future plans? Im putting together plans for a website to use as an outlet for my writing. Ive done a blog before and got a lot of positive feedback, so Id like to start that again. Id love to get to the point where I could make some sort of living from writing. Well just have to see how it goes, but I will always carry on writing.

Penny Sarchet
Occupation Doctoral research student, Department of Plant Sciences, University of Oxford. Whats your background? During my PhD I realised that I really missed the reading and writing that I did as an undergraduate. I started writing for a couple of student magazines and the Oxford Science Blog, and have built it up from there. Where did you get the idea for your article? Whilst working on a piece for the Oxford University alumni magazine, I came across a press release from Irene Traceys lab, who had been looking at the nocebo effect in pain relief and pain perception. Id never heard about an opposite of the placebo effect, or the evil twin, as its often called. I found it really fascinating. What are your future plans? Im hoping to wrap up my experiments over the next six months and then write the thesis. It would be my dream to get a full-time job doing science journalism. Ive been writing for New Scientist about how awful the job market is for new graduates, so I guess Ill just have to see how I get on!

Winter 2011 | 27

BACTERIA AND THE PoWER oF TEAMWoRK

By Tess Shellard, winner of the non-professional category.
Imagine for a moment that we all have one firework and our sole purpose is simply to light it. With just one trick to last a lifetime, how would you use it? Setting it off randomly would achieve very little; few would even see it. But if you took a lesson from bacteria you would gather together to light them all at once, and illuminate the whole sky. Bacteria play a crucial role in life on this planet. They digest our food, synthesise our vitamins, help to make our wine and cheese. others are deadly, the cause of numerous diseases. But how have these single-celled organisms taken charge when they have no ears to hear, no sense of touch and no central intelligence to organise their assault? Their secret lies in teamwork. Each bacterium can secrete a chemical that can be read only by members of the same species; the concentration of this chemical can tell it how many of its siblings are nearby. This ability, called quorumsensing, helps the bacteria to time how and when they express their genes. They dont just act; they wait until there are enough of them for the action to be effective and coordinate their moves. Not only can a bacterium tell if kin are near, it can tell if it is among different types of bacteria, allowing it to build alliances that can help them all to thrive. Professor Bonnie Bassler of Princeton universitys department of molecular biology has led the research on quorum-sensing. She found that the Hawaiian bobtail squid hunts safely at night thanks to the quorum-sensing abilities of a bacterium called Vibrio fischeri. By day, the squids bury themselves in the sand, coming out at night to hunt in the shallows. But they cast a shadow in the moonlit waters, which can leave them vulnerable to predators. Enter V. fischeri. These live in a sac in the squids mantles and, when there are enough of them, they switch on their light. Their bioluminescence disguises the squids silhouette on the sea bed. To get it just right, sensors on the squids back gauge the strength of moonlight, with filters adjusting the light emitted from the sacs. In return for all this handy illumination, the bacteria are kept well fed. In the morning, the squid purges itself of its visitors and, as the bacterias numbers drop below the quorum threshold, they turn off their light. The remaining population then do what they do best and multiply throughout the day, reaching sufficient numbers by nightfall to start glowing all over again. Not all bacteria are quite that endearing: chancing upon the wrong kind can be deadly. Modern medicine has allowed us to blitz anything lethal to us with antibiotics, but this has led to problems, too, bringing a rise in superbugs bacteria resistant to drugs. Knowing about quorum-sensing, however, can offer hope. It is possible

to interfere with the communication between individual bacterial cells in order to ensure that they live out their days without getting too dangerous. As each species has its own language, we can befuddle one without disturbing the rest. on the other hand, we could interfere with helpful bacteria to increase the volume of their conversation and increase their activity. When it comes to life on Earth, we like to think that the bigger the brain, the better. Bacteria might be small but they communicate in more than one language, they strategise, they coordinate their efforts, they have thrived in places you wouldnt even go for a dare. It seems clear they still have a lesson or two for us big-headed folk.

The Science Writing Prize

In 2011, the Wellcome Trust, in partnership with the Guardian and Observer, set about trying to find the next generation of undiscovered writing talent. The competition was open to all nonprofessional science writers in the UK and was split into two categories: one for professional scientists (postgraduate or higher) and the second for those with a non-professional interest in science, including undergraduates. We had a fantastic response, with over 800 entries from a range of people: PhDs and undergraduates, a retiree, a 12-year-old and even a lifeguard who gave the beach as his place of work. The competition was judged by: Alan Rusbridger, Editor-inchief of Guardian News & Media; Robin McKie, Science Editor of the Observer; Sir Mark Walport, Director of the Wellcome Trust; Clare Matterson, Director of Medical Humanities and Engagement at the Wellcome Trust; and Dara O Briain, broadcaster and comedian. Awards were made in October.

28 | Wellcome NEWS

DEATH BY HYPoCHoNDRIA: THE NoCEBo EFFECT

By Penny Sarchet, winner of the professional category.
Can just telling a man he has cancer kill him? In 1992 the Southern Medical Journal reported the case of a man who in 1973 had been diagnosed with cancer and given just months to live. After his death, however, his autopsy showed that the tumour in his liver had not grown. His intern, Clifton Meador, didnt believe hed died of cancer: I do not know the pathologic cause of his death, he wrote. Could it be that, instead of the cancer, it was his expectation of death that killed him? Advocates of the nocebo effect claim this death was an extreme example of the phenomenon the flipside to the better-known placebo effect. While an inert sugar pill (placebo) can make you feel better, warnings of fictional side-effects (nocebo) can make you feel those too. This is a common problem in pharmaceutical trials and a 1980s study found that heart patients were far more likely to suffer side-effects from their blood-thinning medication if they had first been warned of the medications side-effects. This poses an ethical quandary: should doctors warn patients about side-effects if doing so makes them more likely to arise? The nocebo effect can also be highly infectious. In 1962, 62 workers at a uS dressmaking factory were suddenly stricken with headaches, nausea and rashes, and the outbreak was blamed upon an insect arriving from England in a delivery of cloth. No insect was ever found, and mass psychogenic illnesses like these occur worldwide, usually affecting close communities and spreading most rapidly to female individuals who have seen someone else suffering from the condition. until recently, we knew very little about how the nocebo effect works. Now, however, a number of scientists are beginning to make headway. A study in February 2011 led by oxfords Professor Irene Tracey showed that when volunteers feel nocebo pain, corresponding brain activity is detectable in an MRI scanner. This shows that, at the neurological level at least, these volunteers really are responding to actual, non-imaginary, pain. Fabrizio Benedetti, of the university of Turin, and his colleagues have managed to determine one of the neurochemicals responsible for converting the expectation of pain into this genuine pain perception. The chemical is called cholecystokinin and carries messages between nerve cells. When drugs are used to block cholecystokinin from functioning, patients feel no nocebo pain, despite being just as anxious. The findings of Benedetti and Tracey not only offer the first glimpses into the neurology underlying the nocebo effect, but also have very real medical implications. Benedettis work on blocking cholecystokinin could pave the way for techniques that remove nocebo outcomes from medical procedures, as well as hinting at more general treatments for both pain and anxiety. The findings of Traceys team carry startling implications for the way we practise modern medicine. By monitoring pain levels in volunteers who had been given a strong opioid painkiller, they found that telling a volunteer the drug had now worn off was enough for a persons pain to return to the level it was at before they were given the drug. This indicates that a patients negative expectations have the power to undermine the effectiveness of a treatment, and suggests that doctors would do well to treat the beliefs of their patients, not just their physical symptoms. This places a spotlight on doctor patient relationships. Todays society is litigious and sceptical, and if doctors overemphasise side-effects to their patients to avoid being sued, or patients mistrust their doctors chosen course of action, the nocebo effect can cause a treatment to fail before it has begun. It also introduces a paradox we must believe in our doctors if we are to gain

the full benefits of their prescribed treatments, but if we trust in them too strongly, we can die from their pronouncements. Today, many of the fastest-growing illnesses are relatively new and characterised solely by a collection of complaints. Chronic fatigue syndrome, food allergies and back pain could easily be real physiological illnesses in some people and nocebo-induced conditions in others. More than a century ago, doctors found they could induce a hay fever sufferers wheezing by exposure to an artificial rose. observations like these suggest we should think twice before overmedicalising the human experience. our day-to-day worrying should be regarded as such, not built up into psychological syndromes with suites of symptoms, and the health warnings that accompany new products should be narrow and accurate, not vague and general in order to waive the manufacturers liability. As scientists begin to determine how the nocebo effect works, we would do well to use their findings to manage that most 21st-century of all diseases anxiety.

Winter 2011 | 29

STRUCTURAL BIOLOGY STRuCTuRAL GENETICS CoNSoRTIuM

WELCoME To THE FoLD

Integral membrane proteins, tucked away in the membranes of cells and organelles, are vital for all kinds of cell processes, yet little is known about their three-dimensional structure and function. The Structural Genomics Consortium released its first structure of a human membrane protein earlier in the year, and has big plans for more. By Chrissie Giles.
x-ray crystallography is not a pursuit for the impatient. When John Kendrew published the three-dimensional structure of myoglobin in 1958 the first protein structure determined by x-ray crystallography it was a paper 22 years in the making. Today, patience remains a virtue for structural biologists. Each of the thousands of protein structures determined since the 1960s is testimony to hours spent in the lab, perfecting protocols and tweaking methodologies. Painstaking trial and error is the only way to produce protein crystals that are stable enough to be placed in a beam of x-rays and have their structure elucidated. The results of this toil are brightly coloured models of ribbons and loops, twisting and turning, showing how proteins fold up in three dimensions. The structures give clues to what the proteins do in the organism and can be used by researchers to design drugs to act on specific proteins and change how they work. part of the protein that crossed the membrane like a belt around the proteins waist, says Liz but this makes crystallisation hard. To grow crystals, neighbouring protein molecules must be in close contact, so you have to rely on other parts of proteins to make contact with each other, Liz explains.

A banking bonus
The Protein Data Bank, an online repository for protein structures, reflects this difficulty. Currently it holds some 58 000 soluble protein structures but only around 300 integral membrane proteins. of these, just 20 or so are human. This is disproportionately low, given that an estimated 15 to 39 per cent of the 23 000 or so human proteins are integral membrane proteins. In May 2011, the SGC deposited protein number 1126 to the data bank: ABCB10, a human mitochondrial ABC transporter (www. thesgc.org/structures/ details?pdbid=2YL4/). Not only was it the first structure of a human ABC (ATPbinding cassette) transporter to be released, but it is also the first human integral membrane protein to be solved by the SGC taking just under two years. We treated this as a test case, Liz says. From a list of 186 human integral membrane proteins we wanted to see if we could produce proteins in quantity

Above: Dr Liz Carpenter of SGC Oxford. Qiuhong Lee

Getting plenty of protein

When the Structural Genomics Consortium (SGC), an international publicprivate partnership to determine the structures of medically important proteins, began in 2004 it aimed to bank 386 three-dimensional structures in three years. It, in fact, solved over 450 in this time. Its 1000th protein structure was deposited in 2010, a year ahead of schedule. The vast majority of the structures cracked by the SGC so far are of soluble human proteins, which, while still fiddly, can generally be manipulated in the lab to form crystals. Trickier are so-called integral membrane proteins,
30 | Wellcome NEWS

which act as gatekeepers for the cells. These are the channels, transporters and receptors that help substances and signals get into and out of the cell across the membrane. Embedded in the fatty membrane of cells and organelles, these proteins are harder to produce in sufficient amounts, and difficult to purify and to crystallise. Dr Liz Carpenter, Principal Investigator of the Integral Membrane Protein Group at SGC oxford explains: The membrane is very hydrophobic, or oily, inside. The proteins sit in this lipid bilayer, and only parts of their surface are hydrophilic [attracted to water and more soluble in it]. Purification and crystallisation need to occur in a water-rich environment, so the membrane proteins have to be extracted from the fatty bosom of the bilayer using detergent. The detergent coats the

The structures give clues to what the proteins do in the organism and can be used to design drugs to act on specific proteins.

and get their structures. The 186 proteins were from six families of integral membrane proteins. These include ion channels, proteins that form pores to allow charged particles to pass through a membrane, the family that Lizs team is focusing on. Weve screened the 186 proteins and have so far found three that we could crystallise, and from these, we went on to solve the ABC transporter. Not unusually for the membrane protein field, the team didnt know what the protein did when they solved its structure.

In search of a role
From the sequence of amino acids that make up the protein, the team knew it was an ABC transporter, one of four types found in human mitochondria. Previous research indicates a possible role for this protein in oxidative stress and protection of the heart. The transporters cargo remains a mystery, but suggestions include substances involved in iron metabolism, short proteins called peptides, bile salts and lipids. Rather than wait until these findings were published in a journal, Lizs team released the structure and information on how to purify and crystallise it to the public straight away online in accordance with the SGCs ethos of open access. This gave other

labs across the world working on membrane proteins access to information that could prove invaluable for their own research, saving time, effort and manpower. She and her team are now finalising their paper on the protein and its role. They are also back to the list of 186 proteins working on the next structure, determined to solve more human membrane protein structures. With computer modelling of structures possible, is crystallography really the most pragmatic approach to working out how proteins fold? You can build a model from the protein sequence, says Liz, but these dont give enough accuracy for working out which small-molecule drugs may bind to the protein, and where. Knowing this information is vital if this research is to be translated into therapies. Membrane proteins are targets for a large number of pharmaceuticals currently on the market. Many are on the cell surface, and are accessible to small molecules, Dr Rob Cooke, formerly of GSK and a Director of the SGC, and now with Heptares Therapeutics, explains. A membrane protein often provides the first response to a signal from the environment, so by manipulating their activity you can affect the cells signalling pathways.

pharmaceutical research. The challenge has been to extend them to integral membrane proteins, which are of interest for a number of areas, neuroscience in particular, says Rob. But obtaining their structures is finally allowing this to happen. Companies dont want just one structure but a series of different protein structures that they can test with their new molecule, says Liz. For this you need a very stable, reliable way of making protein crystals that will diffract at high resolution and can be crystallised with the small molecule. Were still a long way from this kind of screening being possible. Knowing a structure can also boost our understanding of the wider role of a particular protein in the body. The SGCs work on a family of enzymes called kinases is a case in point. The kinase work stimulated a huge amount of research in other areas, says Liz. Challenging though the field is, she wouldnt work on anything else. If you want to know how cells work, then you need to know how molecules work, she says. As I tell students, this isnt the easiest field in the world but its all worth it when you make something that no one has ever seen before.
In September 2011, the SCGs funders, which include the Wellcome Trust, committed nearly $50m (32m) in funding to sustain another four years of operations. For more, see www.thesgc.org or www.sgc.ox.ac.uk.

From structures to drugs

Equipped with a proteins threedimensional structure, designing small-molecule drugs for them becomes feasible. Ever since the anti-influenza drugs Tamiflu and Relenza were discovered around 20 years ago using structure-based approaches, these methods have become increasingly common in

Left: The ABC10 structure solved by Liz Carpenter and colleagues. Created using ICM Browser from MolSoft LLC

Winter 2011 | 31

fROM ThE ARChIVE

SANDALS

RED oR DEAD HIV/AIDS SANDALS

32 | Wellcome NEWS

William Schupbach presents some AIDS awareness memorabilia from the Wellcome Library. What is it?
A pair of sandals made in Spain around 1994.

Why are they so special?

They include the red ribbon that was introduced in 1991 to declare solidarity with people with HIV/AIDS. Such ribbons were first used in 1979: yellow, for the uS hostages in Iran. This was revived in 1991 for victims of the Gulf War, and the red ribbon appeared along with it for people with AIDS. The link is significant because the red ribbon presented patients as victims rather than culprits, in an attempt to combat the blame and stigmatisation they experienced. But there is more to it. The brand name on these sandals is Red or Dead. That phrase referred originally to Red Indians (native Americans), and from the 1950s to the McCarthyite anticommunist sentiment Better Dead than Red. This associated the design firm doubly with a liberal outlook, and using the red AIDS ribbon provided the brand with a third level of emphasis.

Can I see them?

Yes, they can be seen in the Wellcome Library in London by anybody, on request. If you need to handle them, you will be supplied with white cotton gloves to keep them clean.

Want to know more?

Read Sander L Gilmans essay What is the color of the gonorrhea ribbon? Stigma, sexual diseases, and popular culture in the twenty-first century, in his book Diseases and Diagnoses: The second age of biology.

Find out more at catalogue.wellcome.ac.uk/search~S8/ o32355i

Winter 2011 | 33

Theres no such thing as a non-science story

QuENTIN CooPER, BRoADCASTER AND JouRNALIST
cience is part of absolutely everything. I hate science being confined to science programmes and science festivals and science pages. To me, science isnt a domain but a way of looking at things. After starting my career as a news trainee with the BBC I went on to present the arts programme Kaleidoscope. Interestingly for me, when I interviewed a photographer, visual artist or film maker nobody ever asked what my qualifications were, they just accepted I was there. For the first three years that I presented Material World, at least half of the interviewees wanted to know if I had a scientific background. As it happens I do, but its interesting that we have this strange attitude that unless youre a scientist youre not allowed to talk to other scientists. During that time I never looked at an arts story as more interesting than a science story, or vice versa, I just asked, is it a story first of all? Why do we have to apply labels rather than asking if its an interesting story? In my opinion, theres no such thing as a non-science story. I dont like the way the boundary around science applies to festivals either. Ive done events at science festivals that have gone really well, but Im convinced that, within a five-mile radius of the venue, there are thousands of people who would love the event but who would never walk through the door because its in a science festival. This is one of the things I like about Cheltenham: that the festivals of jazz, music, science and literature are linked. Im involved in Laboratory, a project to get biomedical science across the four festivals. A think-tank including writers, musicians and scientists creates highly innovative events both in content and style that cross boundaries and I think theres a great deal of potential for it to go further. Sometimes its said that science is unappealing to certain audiences, but I believe that people care passionately about it. They may not know theyre caring about science, or may resent the label, but there are always amazing stories. Are any topics too difficult? I dont think so. You can be lazy and concentrate on stories about dinosaurs or space, but even something about a new laminate or property of a material can be interesting if you think hard about the best way to pitch it. I find it ridiculous that we say we dont like science. We dont like the difficult bits, the complicated equations, but there are difficult bits in everything even the plots of soap operas. Science isnt always easy, but these kinds of objections arent anti-science, just anti-difficult. As told to Chrissie Giles.

APPLIANCE oF SCIENCE

Find out more about Cheltenham Festival at www.cheltenhamfestivals.com. Quentin Cooper will be hosting The Thing Is at Wellcome Collection on 27 January and 22 February.

34 | Wellcome NEWS

DIARY Courses, conferences and workshops

Wellcome Trust Genome Campus, Hinxton, unless otherwise specified. For more, see www.wellcome.ac.uk/ advancedcourses and www.wellcome.ac.uk/conferences Mouse Models of Disease: Linking in vivo observations to pathology endpoints Conference, 13 February 2012 Therapeutic Applications of Computational Biology and Chemistry (TACBAC) 2012 Conference, 1214 March 2012 Perspectives in Clinical Proteomics 2012 Conference, 1415 March 2012 Perspectives in Clinical Proteomics 2012 Workshop, 1517 March 2012 Genomic Disorders 2012 Conference, 2124 March 2012 Working with the Human Genome Sequence Workshop, Instituto de Higiene, Montevideo, uruguay, 1619 April 2012 Genomic Epidemiology in Africa Course, MalawiLiverpoolWellcome Trust Clinical Research Programme, Blantyre, Malawi, 611 May 2012 Exploring Human HostMicrobiome Interactions in Health and Disease Conference, 810 May 2012 Virus Discovery in the Clinical Setting Course, 1318 May 2012 Working with the Human Genome Sequence Workshop, 1416 May 2012 Genomic Epidemiology of Malaria 2012 Conference, 1013 June 2012

Wellcome Trust Genome Campus

Practical Aspects of Small Molecule Drug Discovery

At the interface of biology, chemistry and pharmacology. This Wellcome Trust Advanced Course aims to give researchers of any discipline a broad introduction to the theoretical, practical and organisational aspects of small molecule drug discovery. Held on 1722 June 2012. Apply by 5 March 2012. Full details at: www.wellcome.ac.uk/advancedcourses

Wellcome Collection events and exhibitions

Euston Road, London. www.wellcomecollection.org Miracles & Charms Exhibitions, until 26 February 2012 Medicine Man and Medicine Now Permanent exhibitions Event listings See website for details

IN YouR NExT ISSuE

Matt Parker talks maths and comedy, plus updates on our funding and research activities.

Winter 2011 | 35

two free exhibitions

Endlessly imaginative
Sunday Telegraph

Impossible to convey the subtleties of these two shows with words

lOndOniST

Time OuT AND TimeS

Critics choice

MEXICAN MIRACLE PAINTINGS AND LONDONS LOST CHARMS, EXPLORING FAITH, HOPE AND CHANCE UNTIL 26 FEbRUARy

TUESDAYSUNDAY (UNTIL 18.00), CLOSED MONDAY LATE-NIGHT THURSDAY (UNTIL 22.00) EUSTON, EUSTON SqUARE 183 EUSTON ROAD, NW1

www.wellcomecollection.org/miracles | A free destination for the incurably curious

Wellcome Collection is part of the Wellcome Trust. 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-5261.3/11-2011/MD