Wellcome News 57 (december 2008)

ISSUE 57 DECEMBER 2008

Double-acts On the front line of twin research In sequence The Sanger Institute’s Richard Durbin CSI: 1910 Forensic archives – Spilsbury vs Crippen

Wellcome News

Editorial

Wellcome News is published four times a year and is available free of charge. To subscribe, contact: Publishing Department Wellcome Trust FREEPOST RLYJ-UJHU-EKHJ Slough SL3 0BP T +44 (0)20 7611 8651 F +44 (0)20 7611 8242 E [email protected] or go to: www.wellcome.ac.uk/wellcomenews We positively encourage letters to the Editor and suggestions for future articles. Please contact: The Editor Wellcome News Wellcome Trust Gibbs Building 215 Euston Road London NW1 2BE E [email protected] Editor Chrissie Giles Writers Craig Brierley, Mike Findlay, Chrissie Giles, Mun-Keat Looi, Michael Regnier Design Cosima Dinkel Assistant Editor Tom Freeman Photography David Sayer Publisher Hugh Blackbourn All images, unless otherwise stated, are from the Wellcome Library. Copies of images can be obtained through Wellcome Images (http://images.wellcome.ac.uk).

The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. 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, 2008. © The trustee of the Wellcome Trust. The Wellcome Trust is a charity registered in England, no. 210183. Its sole trustee is The Wellcome Trust Limited, a company registered in England, no. 2711000, whose registered office is at 215 Euston Road, London NW1 2BE, UK. PU-4334/12K/12-2008/CD Cover: A Wellcome Collection event in November 2008 explored what it means to be a twin. See pages 4–5.

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

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Clinical researchers – medically trained scientists working in health research – operate at the critical interface between research and clinical practice. They help to connect basic research with the pathways that take us from the diagnosis and understanding of disease to the design and trial of new interventions and preventative strategies. Yet in spite of the huge opportunities for clinical research, there has been a long-standing decline in clinicians opting for a career in academia. This was due to a lack of clarity about career pathways for young clinicians with academic interests, and a lack of suitable training posts. Now, with the reestablishment of clear and flexible academic career pathways and the funding of new training posts, there is evidence that the decline is being reversed. At the Wellcome Trust, we are ‘doing our bit’ to enhance training opportunities for clinical scientists by expanding and refining our investment in training schemes at every level of support. Recognising the need to get more clinicians through basic research training, we have established integrated PhD programmes targeted at clinicians. These fellowships provide structured research training at the PhD level, borrowing from our experience of training basic research scientists. In 2008 we awarded 13 PhD programmes, seven of which are dedicated solely to those with medical qualifications, and two of which are available for those with or without medical qualifications. We also awarded four programmes in translational medicine and therapeutics that aim to reverse the decline in clinical pharmacology, a key area for the development and optimal use of drugs.

But this is only the start. One of the major problems faced by clinical researchers post-PhD is to maintain research momentum while undergoing speciality professional training. Clinicians do not have the flexibility to undertake multiple postdoctoral posts and must juggle research time with the demands of ongoing medical training. For these individuals, the Department of Health in England and the devolved administrations, working with the universities, have established new clinical lectureship posts. These are structured so that half of the individual’s time can be spent in academic activity and half in clinical training. But these lectureships are highly competitive, and success is less likely if clinicians do not have the financial support to gather the data required for a successful application. That is where we come in. Starter Grants for Clinical Lecturers, funded by the Trust and offered in partnership with the Academy of Medical Sciences, support clinicians post-PhD for up to two years, allowing them to develop their own research programmes and obtain the crucial pilot data needed to apply for longer-term funding. We have also developed a new postdoctoral fellowship programme for clinical scientists, aimed specifically at talented clinicians who have completed their PhD at a very early stage, either before or as an integrated part of their medical degree. Our Postdoctoral Training Fellowships for MB/PhD graduates provide flexible opportunities for postdoctoral research, providing salary and research costs, and support to allow reintegration back into postgraduate medical training afterwards. Through these and our other training schemes, we aim to develop a cadre of the best clinical researchers who will go on to make outstanding contributions. We hope that many will ultimately compete for our Senior Research Fellowships and similar schemes from other research funders. Indeed, the current generation of clinical academic leaders includes several former Wellcome Trust Senior Research Fellows. It is a hugely exciting time for medical research and we aim to be able to support the best scientists who will advance our knowledge of both health and disease and will translate that knowledge into health benefit.

Mark Walport Director of the Wellcome Trust

In this issue News........................... 2–3 Funding........................6–7 Research................... 8–11 Features Seeing doubles.........4–5 Highly cited.................. 9 Crippen’s nemesis..... 12 Noticeboard.................. 13

Investigate Bernard Spilsbury’s filing cabinet of horrors (top), let Michelle Teng explain how nematode worms could help with drug screening (above left), explore the neuroscience of disturbing art (above), read about Richard Durbin’s genomesequencing work (far left), discover cortisol’s role in teenage antisocial behaviour (near left), and more… WellcomeNews | Issue 57

News Sharing Science

Educating Darwin

Scene from the Research film, part of the Sharing Science series.

A series of six short films called Sharing Science opens up the lives and work of Dundee scientists to the general public. The films have been produced by artist Gordon Dawson, working with researchers from the Wellcome Trust Centre for Gene Regulation and Expression, part of the College of Life Sciences at the University of Dundee.

The films explore what it is that researchers do in the lab, as well as giving viewers a taste of the pioneering Centre, which opened in November 2007. The Research film follows a Principal Investigator at the Centre, Dr Sonia Rocha, as two years of her and her team’s work comes to fruition in the form of a protein gel showing a particularly important result. To view the films, see http://gre.lifesci. dundee.ac.uk/sharing_science/.

Paranoid thoughts A new book by Wellcome Trust Research Career Development Fellow Dr Daniel Freeman and his brother Jason argues that paranoia is extremely common, and is on the increase.

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For a decade Dr Freeman has been conducting pioneering research into paranoia at the Institute of Psychiatry, King’s College London. He has shown that levels of paranoia and mistrust are much higher than previously suspected – one in four people in the general public has regular paranoid thoughts. “We seem to have entered an age of paranoia,” says Dr Freeman. “And the indications are that things may only get worse.” He thinks that much needs to be done to stem the rise in paranoia, both across society and in individuals. “Dealing with paranoia at an individual level is relatively straightforward through techniques such as cognitive behavioural therapy,” he says. “But if we are really to get to the root of the problem, we need urgent action at a wider level. We need a range of policies to raise public awareness of paranoia, to train therapists and tackle the effects of potentially damaging social and economic trends.” Paranoia: The 21st century fear, published by Oxford University Press, is out now in hardback. www.paranoidthoughts.com

We have commissioned a programme of free education projects to celebrate the 200th anniversary of Charles Darwin’s birth and the 150th anniversary of the publication of On the Origin of Species in 2009. With the Royal Botanic Gardens, Kew, we have developed the Great Plant Hunt, and will be sending a treasure chest to every UK primary school. The chests will contain lesson resources, books and a mini seedbanking kit to inspire children as they collect and study plant samples from their local environment. Survival Rivals is a series of experiment kits for secondary schools, illustrating Darwin’s key ideas. Experiments such as ‘Brine Date’, which looks at sexual selection in brine shrimp, and ‘I’m a Worm, Get Me Out of Here’, which examines natural selection, offer fun new ways for teachers to engage their classes with science. The aim is for these to become an integral part of science teaching in the UK, enabling pupils to relate Darwin’s work to contemporary science. The resources will be available from March 2009. Among other Trust projects to celebrate Darwin 200 is Evolving Words – a set of poetry workshops for teens and young adults – and a series of events at Wellcome Collection to examine the relevance of Darwin’s ideas for society today. www.greatplanthunt.org www.survivalrivals.org www.wellcome.ac.uk/darwin200

HFE Act becomes law We were pleased to see the Human Fertilisation and Embryology Act gain royal assent in November 2008, having worked with other medical research organisations to support the Act’s research provisions. MPs and peers received Wellcome Trust briefing material on the issues, and we arranged meetings between scientists and MPs. We also commissioned a special supplement on stem cells in The Times, and Wellcome Collection hosted a debate between leading scientists, ethicists and religious figures. Provisions of the Act, as passed, will ensure that all avenues of stem cell research can be pursued within a transparent and ethically robust framework, which will enable the UK to remain at the forefront of stem cell research. www.wellcome.ac.uk/hfe

Animal protection

Wellcome Collection events

Prizes and appointments Dr Sarah Reece, Wellcome Trust Career Development Fellow at the University of Edinburgh, has been awarded one of four 2008 L’Oreal UK and Ireland Fellowships for Women in Science, which support outstanding female postdoctoral researchers.

The revised Directive on the Protection of Animals Used in Scientific Procedures was published by the European Commission on 5 November. We are concerned that this Directive proposes significant, unnecessary bureaucracy and restrictions to research, which not only fail to enhance animal welfare but also threaten the UK’s economic competitiveness in basic research. We are working with other stakeholders to influence UK and European policy makers to ensure that the regulations promote animal welfare, while enabling important biomedical research to continue.

Among the upcoming events at Wellcome Collection is ‘Changing Places’, part of a series of events exploring identity and change. The event, which takes place on 29 January 2009, will focus on ideas of gender and features two transsexual speakers who have undergone transitions from male to female and female to male: respectively, Sarah Muirhead-Allwood, orthopaedic surgeon at the Royal National Orthopaedic Hospital, and Stephen Whittle OBE, Professor of Equalities Law, Manchester Metropolitan University. On 30–31 January, join experts from the worlds of neuroscience, psychology, visual culture and history for the ‘Remembering War’ symposium. This will explore issues surrounding war and memory, including whether we should try to remember or forget experiences of war, and whether literature, film or art can ever truly reflect its horror. Anyone can share their own war memories online – whether they are personal experiences or memorable movies – at www.wellcomecollection.org/ rememberingwar. The event is in support of Wellcome Collection’s War and Medicine exhibition (see back cover).

Professor Adrian Bird, Deputy Chairman of the Trust’s Board of Governors, is the 2008 recipient of the Charles Leopold Mayer Prize, awarded by the French Academy of Sciences for his work in biology. The Heart, the book to accompany the Wellcome Collection exhibition of the same name, has won first prize in the popular medicine category of the 2008 British Medical Association book competition. Wellcome Collection’s Head of Public Programmes, Ken Arnold, has become the Museum Association’s first research associate. In this unpaid position he will be investigating the role and significance of exhibitions and events in museums.

Drawing conclusions The Big Draw – the national annual campaign to get people drawing – was launched at a festival held at University College London and Wellcome Collection on 26–28 September 2008. Over 5000 people visited Wellcome Collection over the weekend, making it the biggest event there so far.

Among the highlights were Nathan ‘Flutebox’ Lee (a beatboxing flautist) and illustrator Steven Appleby, who joined forces in a fascinating mix of imagery, science and sound. For more pictures and videos of the event see www.wellcomecollection.org/ drawingonlife.

Participants in activities at the launch of The Big Draw.

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Seeing doubles

A twin-only meeting in support of Wellcome Collection’s ‘Divided Yet Whole’ event brought together twins from the TwinsUK registry.

Every year, researchers at the Department of Twin Research, King’s College London, play host to around 1000 twin visits. Chrissie Giles went along with her identical twin, Katie, to see what it’s like to be at the sharp end of a scientific study. I’m sat in a narrow consulting room, gripping as hard as I can on a strange piece of equipment I’m told is called a hand dynamometer. Across the desk, my twin sister, Katie, is doing the same, her face screwed up in determination to grip harder than me. The research nurse tells us that, according to the chart on the wall, we’re both distinctly average at gripping. The dynamometer was just the start. By the end of our half-day visit to the Department of Twin Research, based at St Thomas’ Hospital in London, we’d undergone a barrage of tests. We’d been weighed and measured, bled, had our inner arms exposed to the chemical responsible for burning in chillies, and been asked to judge which of a selection of well-known melodies had out-of-tune notes included. My sister and I volunteered to be part of TwinsUK several years ago. The only adult twin registry in the UK, TwinsUK contains clinical, demographic and lifestyle data from around 11 000 mostly female identical and non-identical twin pairs aged between 16 and 100, who have been randomly sampled from the UK population. Much of the information is collected during visits to the Department, and this was our first trip there. Typically, visitors undergo a number of checks, including height, weight, blood pressure and lung function tests, ECG, 4 | WellcomeNews | Issue 57

bone mineral density scans, eye tests, facial photographs and cognitive tests. They are also fitted with a monitor to measure physical activity and heart activity over a week, and some have biopsies taken from muscle, fat and skin, or moles. My sister has an ECG while I remove anything metallic from my person and climb on to the DXA (dual energy X-ray absorptiometry) bone scanner. I have to lie still for almost 10 minutes as the machine moves up and down my body, and the table I’m lying on glides silently from side to side. Then we swap places. During the visit we also complete a series of questionnaires, which are similar to those sent every year to the twins on the register. These questionnaires often cover an intriguing mix of subjects: everything from obsessive–compulsive behaviour, through religious beliefs, to personal experience of baldness. As the researchers stick identification stickers on the blood tubes and paperwork, they explain that the information and samples are being collected as part of the Healthy Ageing Twin Study. Funded by the Wellcome Trust, this study is designed to explore the genetic aspects of common diseases of ageing such as osteoporosis, osteoarthritis and obesity, as well as those affecting the cardiovascular system and the eye.

It is one of over 20 different funded projects underway within the Department of Twin Research, which is staffed by over 40 researchers (including nurses, statisticians and laboratory personnel) – a marked change from the Department’s modest beginnings in 1992. “From a small grant with two staff we originally looked at whether osteoporosis is genetic or not, since then our study has expanded slowly and steadily,” says Tim Spector, Professor of Genetic Epidemiology at King’s College London, Consultant Rheumatologist and Director of the Department. “Twins were coming in for one test and we realised it would be more costeffective to do a range of tests in one visit. No other unit in the country is doing this.”

It seems that nothing is off-limits to what can be genetically programmed: from political views to religion… you feel like nothing is sacrosanct. As the Department began with a focus on osteoporosis and osteoarthritis (diseases of ageing that tend to affect women more than men), almost 80 per cent of the 11 000 twins on the register are female. Now, the Department welcomes twin volunteers of either sex, from the age of 16. Over the past 15 years, the researchers have studied the influence of genes on all kinds of diseases, characteristics and behaviours (see box for a selection of key findings). Over 3000 such phenotypes are under investigation.

“The last 15 years has really been sorting out the nature/nurture debate,” says Professor Spector. “The default position now is that everything is partly genetic until proven otherwise. It seems that nothing is off-limits to what can be genetically programmed: from political views to religion…you feel like nothing is sacrosanct.” Now, the direction of twin research is reflecting wider changes in the field of genetics. According to Professor Spector, the Department’s next phase of research is to find the genes responsible for various diseases or characteristics. To do this, researchers will use the latest technologies, allowing large-scale genetic association studies that can flag most of an individual’s 23 000 genes. It was researchers at the Department who performed the first genome-wide association scan for osteoporosis. They found two genes that increase a person’s risk of the disease 1.5-fold when present together. These genes are common and are thought to occur in around a quarter of women. Another recent study found that 14 per cent of men carry two genes that increase the chance of baldness seven-fold. Another development is the emergence of the study of epigenetics, heritable changes in the way genes work that are independent from the DNA sequence itself. To explore epigenetics, twin researchers are now focusing on the differences between identical twins, a contrast to ‘traditional’ twin research, which had always been about comparing the similarities of identical twins with those of non-identical twins. “Epigenetics is where identical twins come into their own,” says Professor Spector. “Preliminary results show tiny [epigenetic] differences between identical twins, and we’re looking at whether these changes are systematic, random or influenced by environment, and whether they change as people age.” The researchers are looking across the genome to see whether twins have the same changes at sites called CpG islands – areas on the DNA chain where a guanine base directly follows a cytosine. At these sites, a small chemical group can be added in a process called methylation. The team will explore whether these changes affect particular genes’ being ‘on’ or ‘off’, and will study whether the methylation status of these sites changes as twins get older. With these changes in mind, does Professor Spector ever see a time where twin research is no longer relevant? “Twin research is constantly changing. The nature versus nurture aspect will eventually have answered every question you could ever ask,” he says. “However, I think using the twin model

In your genes? Work at the Department of Twin Research has increased our understanding of the genetic basis of many diseases of ageing, including osteoporosis and osteoarthritis. It has also shown that genetic factors play a part in a wide range of characteristics and behaviours – ranging from diet choices to the number of sexual partners a female has, from male-pattern baldness to becoming self-employed. Other selected findings include: • moderate drinking (an average of eight units of alcohol a week) appears to keep brittle bones at bay in women • body odour is largely genetic and unique to individuals • having a high number of moles, exercising in your free time, and high vitamin D levels are all linked to delayed to study other areas like epigenetics, copy number variation [genetic mutations involving the gain or loss of chunks of DNA, some of which are associated with disease] and even trials exploring individual genetic responses is going to keep twin researchers happy, certainly for the next 50 years.” As part of securing the UK’s future as a leading place for twin research, Professor Spector is currently in discussions with the Department of Health to try to get an official twin register for the UK, which is one of the only northern European countries not to have one. Back in the consulting room, our tests are finished. It’s with an odd sense of detachment that we pore over the printouts from the bone scanner, which reveal gawkylooking skeletons surrounded by fuzzy

ageing (defined as having longer telomeres – the DNA caps that protect the ends of chromosomes from damage) • obesity and cigarette smoking accelerate human ageing (as measured by telomere length) • short-sightedness, cold intolerance, back pain and musical pitch recognition are predominantly genetic. The Wellcome Trust has supported the Department and its core work on the TwinsUK resource since its launch in 1993. Other Trust-funded projects currently underway include studies covering the genetics of shortsightedness, how obesity genes are expressed differently in fat, muscle and blood, and the genes involved in age-related telomere variation. outlines of flesh. The detail is quite amazing, and the printouts give us information on not just our bone density but also the fat and lean mass of each body part, limb by limb. We learn that our bone densities are within normal levels and that we are not at an increased risk of fracture. As Katie and I wander along the bright corridors of St Thomas’, we enjoy a glow of satisfaction at having done our bit for medical science, and imagine the future publications in which the data from our tests might feature. However, as interesting as it’s been, and despite the researchers’ reassurances, I’m still left with a sense of discomfort – it will take me some time to accept that my left arm has 4.1 per cent more fat than my right, and that I’m only average at gripping. www.twinsuk.ac.uk

Chrissie Giles (right) and her sister Katie.

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Funding Tackling trypanosomiasis Two awards made through our Immunology and Infectious Disease stream will help researchers to take on trypanosomes – the parasites responsible for human African trypanosomiasis – on two fronts. A project grant has been awarded to Dr Klaus Ersfeld, University of Hull, to study the trypanosome’s motor proteins. These proteins guide the movement of chromosomes as one parasite divides into two daughter parasites, and so are vital for parasite division. Professor Michael Ferguson and colleagues from the University of Dundee have been awarded a programme grant to investigate the process by which Trypanosoma brucei (below) builds its surface coat, which, constantly changing, allows the parasite to evade the host’s immune system. If the research groups can unravel how these proteins work, it may be possible to design drugs to disrupt the parasite processes of division and disguise. The drugs currently in use against human African trypanosomiasis are extremely toxic and difficult to administer, and there is currently no vaccine for the disease, which is 100 per cent fatal if not detected and treated in time.

Branislav Ostojic/iStockphoto

Sexual attitudes We are co-funding Britain’s third National Survey of Sexual Attitudes and Lifestyles, due to be carried out in 2010. The survey, NATSAL III, will capture the views and experiences of some 15 000 men and women aged between 16 and 74, randomly selected from England, Wales and Scotland. The 2010 survey follows two similar surveys carried out in 1990 and 2000, the first of which was also funded by us. The new survey will be based on methods used in the earlier surveys, and will feature new elements such as the collection of anonymised biological data on sexually transmitted infections and sex hormones.

Capital ideas We have awarded almost £30 million in Capital Award funding to nine of the UK’s leading universities, to help them to create new internationally competitive research facilities. Launched in 2007, our Capital Awards in Biomedical Sciences provide substantial funding for large-scale projects – either new builds or refurbishments – in partnership with the host institution. This initiative follows the successful Joint Infrastructure and Science Research Innovation Fund partnerships. Universities from across the UK have secured awards of between £1.1m and £6m under the scheme. Recipients include Professor Ed Watkins at the Mood Disorders Centre, University of Exeter, who has been awarded £3.6m for a new translational research facility, and Professor Irene Leigh at the University of Dundee, who has received £3.5m to develop a Centre for Molecular Medicine. 6 | WellcomeNews | Issue 57

Professor Anne Johnson, Director of the University College London Division of Population Health, says: “The 1990 and 2000 NATSAL surveys provided a wealth of information on sexual lifestyles, the risk of sexually transmitted infections, as well as the use and preferences for sexual health services. "The data have been widely used to guide policy for sexual health education and services in Britain. We are delighted at the award of the funding and hope the 2010 survey will help improve sexual health promotion and treatment services.”

Working with the media The other Capital Award recipients are: Professor Brian Sutton, King’s College London; Professor Jennifer Kirkham, University of Leeds; Professor Mike Barer, University of Leicester; Professor Janet Hemingway, Liverpool School of Tropical Medicine; Professor Jeff Errington, Newcastle University; Professor Nicholas Rawlins, University of Oxford; and Professor James Naismith, University of St Andrews.

Capital Awards support construction or refurbishment projects.

Do you want help publicising your work? Looking for tips on how to deal with journalists? Take a look at the new ‘Wellcome Trust Guide to Working with the Media’. This booklet gives you an idea of what to expect when working with media professionals, and includes practical tips for print and broadcast interviews alongside guidance on getting your story across and managing controversy. For your free copy, or for any other advice on mediarelated issues, contact our Media Office on 020 7611 8866 or email [email protected].

Making an IMPACT

Engineering success

The first patient has been treated in the CMV~IMPACT study, a Trust-funded clinical trial designed to demonstrate the effectiveness of a new type of cell therapy used to treat infections in people receiving bone marrow transplants. Cell Medica, a company that works on developing and delivering cellular immunotherapy to treat infectious disease, has already demonstrated that so-called immunoprophylactic adoptive cell therapy (IMPACT) can be used to prevent infections in people who undergo bone marrow transplants. The company has now set up the CMV~IMPACT study, which we have funded through a Translation Award, to begin to establish the therapy as routine clinical practice around the world. The trial will include 110 patients across 11 UK hospitals and is expected to be completed within two years.

The Medical Engineering scheme – a £45 million fund set up by the Engineering and Physical Sciences Research Council and us for multidisciplinary projects – has had an overwhelming response, with 45 preliminary applications received. The scheme was launched in March 2008. A shortlist of proposals is now under review, and the awards will be announced in spring 2009. “Each of these major awards will establish a medical engineering hub that will drive innovation by putting clinicians, biomedical research scientists and engineers together in labs to solve the big challenges in medicine today. Their solutions could be new devices, imaging, nanotechnology, software or something we can’t yet predict,” said Richard Seabrook, Wellcome Trust Head of Business Development. “What’s clear is that there is a rich pool of researchers more than willing to cooperate in this field. We believe a multidisciplinary approach stands a better chance of generating innovation in healthcare, so we need to address how to support more of these collaborations.” Applications for the fund are now closed, but other medical engineering projects may be eligible to apply for funding through our technology transfer or biomedical science funding areas. www.wellcome.ac.uk/funding

American adventure

Howard Hughes (HHMI Archives) and Henry Wellcome.

We have teamed up with two major institutions in the USA to offer postdoctoral researchers and PhD students the chance to undertake international collaborative research projects across the Atlantic. The Wellcome Trust and Howard Hughes Medical Institute (HHMI) Exchange Programme has been introduced to promote international collaborations among scientists funded by the Trust or the HHMI. These awards give opportunities for postdoctoral researchers in some key Trust and HHMI labs to carry out collaborative research for periods from three months to one year. Applications can be made at any time and decisions will normally be made within six weeks of receipt. For more information and an application form for eligible Trust-funded researchers, see www.wellcome.ac.uk/hhmi. Wellcome Trust and National Institutes of Health (NIH) Four-year PhD Studentships allow the most promising postgraduate students to undertake international, collaborative four-year PhD training based in both an academic institution in the UK/ Republic of Ireland and the intramural campus of the NIH at Bethesda, USA. Applications have closed for this year. For more details on the annual scheme, see www.wellcome.ac.uk/wtnih

Small Arts Awards

Butterfly wing. Franziska Schenk

We have funded a number of Small Arts Awards. These include Marie Curie and the Discovery of Radium, a multilanguage project for schools by Théâtre Sans Frontières and Newcastle’s Centre for Life, investigating the story of Marie Curie’s groundbreaking research. Elsewhere, visual artist Franziska Schenk will work with cutting-edge biomimetic paint technology to create artworks inspired by the eyespots of butterfly wings and Darwin’s theories of eye development. Photographer Karen Hitchlock and writer Rose Flint are developing a series of portraits exploring the experiences of children and families affected by cleft lip and/or palate. The portraits will be exhibited in three regional hospitals and at national and international conferences. www.wellcome.ac.uk/arts

Internationally engaging

People Awards

Our International Engagement Awards fund projects that encourage public engagement with health research in developing countries. After an impressive response to the first ever round of funding, we funded 15 projects. Of these, three are in Uganda, complementing other projects underway to build strong public engagement practice in the East Africa region. In Uganda, the awards were made to: Pontiano Kaleebu (Uganda Virus Research Institute, Entebbe), to address communication gaps and needs in HIV prevention research within Lake Victoria fishing communities; Dan Kaye (Makerere University, Kampala), to engage the public in global health research and help the university become a leading institution for public engagement; and Duncan Dallas and Patrice Mawa (Cafes Scientifiques UK and Uganda Virus Research Institute), to establish cafes scientifiques for adults and for schools in Uganda.

Among the People Awards we have recently funded is Superfoods Explained, a project looking to help people with learning difficulties make informed choices about shopping and eating. The Garden Science Trust will bring people together with scientists from the Institute of Food Research to design practical activities explaining the science behind different foods and their roles in preventing disease.

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Research Art that irks

Rewiring the brain

‘Jesmond Barn’ by Debbie Ayles, who received a Wellcome Trust Sciart award in 2004.

For some people, certain paintings are uncomfortable to look at, and can even cause headaches and seizures. To find out why, Dominic Fernandez and Professor Arnold Wilkins at the University of Essex have studied works of art and natural scenes.

They found that ‘uncomfortable’ images included stripes at the width we’re most visually sensitive to (as seen in Debbie Ayles’s migraine-inspired ‘Jesmond Barn’, above).

Not-so-blind date

Gene links

Anthea Sieveking

A study offers new evidence that some populations may choose their partner based on differences in the major histocompatibility complex (MHC) – an important set of immune system genes. Professor Peter Donnelly from the Wellcome Trust Centre for Human Genetics in Oxford and colleagues found that American couples from the muchstudied samples of the Human Polymorphism Study Centre (based in Paris) favoured MHCdissimilar mates, though this was not the case with African couples. Chaix R et al. Is mate choice in humans MHC-dependent? PLoS Genet 2008;4(9):e1000184.

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Fernandez D and Wilkins AJ. Uncomfortable images in art and nature. Perception 2008;37:1098–113.

A common variant of a gene thought to be associated with dyslexia is also linked to poor reading ability in the general population, a study led by Dr Silvia Paracchini from the Wellcome Trust Centre for Human Genetics, University of Oxford, has shown. Other work, by researchers from the Universities of Edinburgh, Aberdeen and Oxford, has identified a variant in the GRIK4 glutamate receptor gene that reduces the risk of developing bipolar disorder. Lastly, a gene called PLCL1 is associated with variation in hip bone size – a risk factor for low-trauma hip fracture. That’s according to the results of the first genome-wide association study for this phenotype, carried out by an international team of researchers.

Learning from experience can change the connections among nerve cells within the brain, altering how stimuli are perceived and processed. Trust-funded researchers at King’s College London have explored what this change looks like at the cellular level. The researchers worked with rats, which use their whiskers to sense their environment. They trimmed some of the whiskers on both sides of the rats, which meant that one part of the brain received no sensory input while neighbouring areas received normal stimulation. The authors compared the connections among the nerves in both areas of the brain two to six weeks later. Computer analysis of 3D images let them track the parts of nerve ells that send and receive signals in response to the whiskers. The lack of sensation had little effect on the parts of the cell that receive signals from the whiskers. But things were different in the cell axons, which transmit signals. In brain areas that received input from the whiskers, more of the axons were in close proximity to the receiving cells. Oddly, however, this proximity didn’t foster more connections between the sending and receiving cells. The authors suggest that this reflects the difference between learning capacity and actual learning. Areas of the brain that receive input from the whiskers have a higher capacity to form connections among nerve cells owing to the close proximity. But that capacity will only be used if the nerves have something important to say. Cheetham CE et al. Altered sensory experience induces targeted rewiring of local excitatory connections in mature neocortex. J Neurosci 2008;28(37):9249–60.

Paracchini S et al. Association of the KIAA0319 dyslexia susceptibility gene with reading skills in the general population. Am J Psychiatry 2008 [Epub ahead of print]. Pickard BS et al. A common variant in the 3'UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder. Proc Natl Acad Sci USA 2008;105(39):14940–5. Liu YZ et al. Identification of PLCL1 gene for hip bone size variation in females in a genome-wide association study. PLoS ONE 2008;3(9):e3160.

Pyramidal neurons forming a network in the brain. Dr Jonathan Clarke

Highly cited Richard Durbin helped to develop the confocal microscope and was one of the ‘founding fathers’ of the Wellcome Trust Sanger Institute. Now he is Europe’s most highly cited researcher. Ian Jones talked to him. Dr Richard Durbin at the Wellcome Trust Sanger Institute.

Founded in 1992, the Sanger Institute has grown into one of the world’s leading centres of genome-based research. There at the beginning was Richard Durbin, whose background in mathematics and computing has proved essential to the Sanger’s processing and analysis of genome data. “I’d worked with John Sulston at the LMB [the MRC Laboratory of Molecular Biology] in Cambridge,” he explains. “When he moved to Hinxton to establish the Sanger Institute he asked me to join him.” Having grown disillusioned with his area of research at the time, neural nets – “I wanted to model nervous systems but it was diverging from science: it wasn’t the brain” – he leapt at the opportunity. Beginning with the Human Genome Project, Dr Durbin has witnessed at first hand the extraordinary growth of DNA sequencing. In 1992, the Sanger Institute’s output was around 100 000 base pairs a day. During the heyday of the Human Genome Project in 2000, this had jumped to 10 million base pairs. And in 2008, thanks to ‘next-generation’ sequencing machines, the Institute has been churning out an astonishing 10 billion base pairs – equivalent to three human genomes – every day. Dr Durbin has had the challenging role not only of ensuring that the Sanger Institute can cope with this ever-increasing flood of data but also of discerning meaning in its endless streams of As, Cs, Gs and Ts. Where are the genes? Where are the control regions? Where are the conserved sequences – those seen across a range of species? Where is the variation – the bits that differ between people?

The fundamental nature of these questions, and the value of the software tools used to answer them, has involved Dr Durbin in numerous projects – from the analysis of the human genome to the development of widely used software tools such as Ensembl, Pfam (protein families) and WormBase (a nematode worm genome database). All have generated influential scientific papers. Indeed, a recent analysis by ScienceWatch ranked Dr Durbin as Europe’s most highly cited researcher. “It was a bit of a surprise,” he admits. “I was amused more than anything. It’s somewhat artificial. It hasn’t changed my life!” In reality, he says, he was lucky enough to be a member of several multidisciplinary consortia, each with several key contributors. Dr Durbin is likely to rack up more citations thanks to his involvement in the 1000 Genomes Project, a US$50 million partnership between the Sanger Institute and centres in the USA, China and Germany, funded by the Wellcome Trust and others, which will provide a more detailed picture of human genetic variation. The Human Genome Project produced a reference sequence while follow-ups such as the International HapMap Project have begun to identify the sites at which human genomes differ. Added to this has been the flow of information from ‘personal genomics’ projects, such as the sequencing of the genomes of James Watson and Craig Venter. Yet the picture of rare human genetic variation is obscure – even though, as many genome-wide studies have shown recently, it accounts for a significant proportion of the risk factors for common diseases. To tackle this problem, the 1000 Genomes Project will

analyse the genomes of a further 1000 people – generating a staggering 6 trillion base pairs of sequence information. Indeed, suggests Dr Durbin, sequence productivity is following its own version of ‘Moore’s law’ – the observation that computer memory capacity doubles roughly every 18 months. In fact, with nextgeneration sequencers, doubling time has actually got faster. This is having a profound influence: “I think we’re witnessing a shift in how science is done,” suggests Dr Durbin. “Sequencing machines are beginning to infiltrate labs. And doing sequence-based studies is becoming affordably cheap.” Just as recombinant DNA technologies were rapidly picked up in the early 1980s, so other fields will adopt genomic tools. An ecologist studying a population of birds, for example, could soon be integrating genomic analyses of individuals within that population. Indeed, Dr Durbin sees genomebased approaches putting the genes into population genetics: traditionally, the field has treated them mostly as theoretical concepts. “Genetics in the 20th century was mainly indirect – it was hard to observe genes directly. Since about 2000 you can easily look at whole genomes, you can look directly at the scale of human genes in individuals.” Population-based studies with genome-wide breadth are a real possibility – the beginnings of which can perhaps be seen in metagenomic studies of bacterial populations. Such studies have the advantage of generating huge amounts of data – an advantage, that is, if you have someone like Richard Durbin to make sense of them. WellcomeNews | Issue 57 | 9

Maternal mental health

Mother and child in Pakistan. N Durrell McKenna

A programme that trained community health workers in rural Pakistan to identify and treat the symptoms of depression in pregnant women has had dramatic results. The UK and Pakistani researchers, led by former Wellcome Trust Career Development Fellow in Tropical Health Professor Atif Rahman, trained ‘Lady Health Workers’ (who provide preventative healthcare to pregnant women and newborns) to identify symptoms of depression. Around 900 women were enrolled on the study, half of whom

Antibiotics against MRSA

Cortisol in the act received a programme based on cognitive behavioural therapy for their depression, while the remainder received standard care. The therapy included both sessions with the health workers and techniques that could be practised at home in between the sessions. At both six months and a year after the start of therapy, the incidence of depression in the treatment group was half that of controls. The treatment also helped postnatal care: the mothers who underwent therapy were more likely to ensure their children were fully immunised, and their children had reduced rates of diarrhoea. These mothers were more likely to be using contraception, which decreases infant mortality by increasing the time between childbirth. The team stresses the importance of “the development of an evidence-base for costeffective interventions that can be scaled up in resource-poor settings”. Rahman A et al. Cognitive behaviour therapy-based intervention by community health workers for mothers with depression and their infants in rural Pakistan: a cluster-randomised controlled trial. Lancet 2008;372:902–9.

Investigating implantation

A new class of drugs that kill methicillinresistant and multidrug-resistant Staphylococcus aureus (MRSA) in the lab has been discovered, and could form the basis of new treatments to fight the infection, according to research published in the journal Science. Scientists from Prolysis, a British drug discovery and development company, and their colleagues created a class of drugs that selectively block the action of FtsZ, a protein that bacteria need to grow. The drugs kill a range of bacteria, including MRSA. “There’s still a lot of work to be done in terms of development and clinical studies, but we’re hopeful that in just a few years, we’ll see therapies based on this innovative approach in widespread use,” said Lloyd Czaplewski, Director of Research at Prolysis. The research was part-funded by our Seeding Drug Discovery programme.

A new study has revealed, for the first time, the process that governs the implantation of embryos in the human uterus. This should increase understanding of why some embryos fail to implant – a leading cause of infertility. The researchers, from Oxford and King’s College London, found that the embryo and uterine lining ‘talk’ to each other on the molecular level when the embryo lands on the uterus wall. After this, cells from the embryo begin to invade the uterine lining, eventually connecting with the mother’s blood vessels to form the placenta. Two proteins – Rac1 and RhoA – control the invasion; Rac1 stimulates cells in the uterine lining to move, allowing the embryo to invade and implant properly, while RhoA inhibits this. The researchers found that if the balance of the two is altered, the cells of the uterine lining don’t migrate and the embryo doesn’t implant. “We believe this controlled balance of the two proteins is critical for successful implantation of the embryo,” said Professor Helen J Mardon from the Nuffield Department of Obstetrics and Gynaecology at the University of Oxford, who led the study.

Haydon DJ et al. An inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science 2008;321(5896):1673–5.

Grewal S et al. Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration. Proc Natl Acad Sci USA 2008;105(42):16189–94.

Clusters of MRSA bacteria. Annie Cavanagh

10 | WellcomeNews | Issue 57

Trust-funded research at the University of Cambridge has identified a link between reduced levels of the stress hormone cortisol and antisocial behaviour in male adolescents. The study shows that, when under stress, adolescents with severe antisocial behaviour exhibit a different change in cortisol levels compared with those without antisocial behaviour. The findings suggest that, in some cases, antisocial behaviour may be affected by an individual’s biological make-up, just as some people are more vulnerable to depression or anxiety. Cortisol levels in the body usually increase when people undergo a stressful experience. Cortisol enhances memory formation and is thought to make people behave more cautiously and to help regulate emotions, particularly temper and violent impulses. In the study, young men from schools, pupil referral units and the Youth Offending Service took part in a stressful experiment designed to induce frustration. While the average adolescent showed large increases in cortisol levels during the experiment, levels actually decreased in those with severe antisocial behaviour. “If we can figure out precisely what underlies the inability to show a normal stress response, we may be able to design new treatments for severe behaviour problems,” said Dr Graeme Fairchild from Cambridge, who led the research. Fairchild G et al. Cortisol diurnal rhythm and stress reactivity in male adolescents with early-onset or adolescence-onset conduct disorder. Biol Psychiatry 2008;64(7):599–606.

iStockphoto

Genes and social habits An international team including Trustfunded researchers from the University of Leicester has studied patterns of sex-specific inheritance, and discovered that societal structure leaves its mark on our genes. Parts of the human genome are inherited only through one parent: mitochondrial DNA comes from the mother, while fathers always contribute a Y chromosome to their sons. Previous genetic studies in large populations suggest that, on average, mitochondrial DNA types are more geographically spread, and thus that women move around more. The researchers developed a mathematical formula that relates differences in sexspecific and regular DNA to population size and migration. They sampled a number of populations in Central Asia, including Tajiks, Kazakhs, Karakalpaks, Kyrgyz and Turkmen. Traditionally, most of these groups consist of herders organised into paternal descent groups that choose brides outside of their own social group. The Tajiks, in contrast, place equal importance upon male and female lines, and marry within their own social group, often to cousins. The authors found the signature of the two different social organisations in the genomes of the current members of each society. As expected, the women seemed to move around more among the herders, as they live in their husbands’ villages, far from their birthplaces. But more surprisingly, the calculations suggest that there is a larger effective population of women compared with men in these populations – meaning that, within populations, men are more genetically related than expected, because of the importance of paternal descent in their social organisation. Since humans aren’t the only ones with complex social dynamics, the methods in this study may also be useful for studying the ecology of animal species. Ségurel L et al. Sex-specific genetic structure and social organization in Central Asia: insights from a multi-locus study. PLoS Genet 2008;4(9):e1000200.

Q&A What did you find? We generated a library of genetic variants of the MIP-1ß peptide, in which we mutagenised nearly every amino acid residue. Each mutant was tested in the feeding assay, and we identified 13 residues involved in the activation of human chemokine receptor 5 (CCR5), the receptor responsible for HIV entry into cells which also binds its native agonist, MIP-1ß. Of these 13 residues, we found four that had not been described before, despite detailed mutagenesis work in the 1990s.

How could this assay be used in the future?

Michelle Teng, now at MedImmune, Inc. in Cambridge.

In studies of G-protein-coupled receptors (important targets of many human diseases) and their ligands, Dr Michelle Teng – then working at the Wellcome Trust Sanger Institute – and colleagues have developed assays using the nematode worm Caenorhabditis elegans. In 2006, they showed that worms expressing human receptors in their sensory neurons can ‘taste’ and deliberately avoid soluble forms of the receptor’s ligand. Now, the team has developed a feeding assay that can be used to test variants of the ligand. What’s new for this paper? We’ve taken advantage of the fact that C. elegans eat bacteria. We give the worms a strain of E. coli called OP50. It’s like cat food to them – they’d rather be eating something else, but we use it as it stops them growing too fast. This time, we’ve expressed the ligand in the bacteria. As our earlier paper showed that worms can taste soluble ligand, we reasoned they should be able to taste it when expressed in E. coli.

How does this feeding assay work? We give the worms a choice between bacteria that express the test ligand (MIP1ß) and bacteria that express something that does not trigger an avoidance response. We found that the worms specifically avoid eating the bugs that express the ligand; they only eat it when other food sources run out.

The beauty of this system is that you don’t have to purify the mutated ligand, you just express it in bacteria – so it’s a really fast method for structure–function studies. You get a narrowed-down list of residues that are important in the receptor–agonist interaction, which you can then test in more conventional assays. The assay could, in the future, facilitate the discovery of agonists from libraries of bacteria expressing different ligands, so it has potential for drug screening. The proteins/peptides we (and others) have expressed in bacteria are functionally active, so we could apply this feeding assay system to other ligands and other transgenic worms. I certainly hope other groups will try out the system.

How has the Trust helped you? The Trust funded my postdoctoral fellowship at the Sanger, and my PhD, through a Wellcome Trust Prize Studentship. The Trust support is especially helpful as it allows postdocs to pursue their ideas in an independent fashion. If I wasn’t at the Sanger, I don’t think I would have been given the opportunity to develop a wacky idea and then work on it for three or four years.

What do you do outside of the lab? I’m an endorphin addict: I have a black belt in tae kwon do and do lots of yoga, running and climbing. Teng MS et al. Control of feeding behavior in C. elegans by human G protein-coupled receptors permits screening for agonist-expressing bacteria. Proc Natl Acad Sci USA 2008;105(39):14826–31.

Kyrgyz people in front of a yurt. Laure Ségurel

WellcomeNews | Issue 57 | 11

Title

Crippen’s nemesis: the father of forensics Dusty old index cards may be a far cry from the glamorous TV world of CSI, but when they shed new light on one of the first and most controversial figures in forensic science, it’s enough to make Mike Findlay drop the remote control and head to the Wellcome Library. In August 2008, the Wellcome Library’s Senior Archivist Chris Hilton secured at auction the last remaining index cards of the late Sir Bernard Spilsbury, known as ‘the father of modern forensics’. Spilsbury was a famous figure in forensic medicine in the early 20th century. He appeared as a prosecution witness in many high-profile murder trials, including the notorious Dr Crippen case. He also performed autopsies in many other cases of accidental or unexpected death or suicide, which form the basis of the material purchased by the Wellcome Library. Over the course of his career he undertook more than 25 000 post mortems – between 750 and 1000 per year. Spilsbury was born in Bath in 1877. He gained entry to Magdalen College, Oxford, to study natural science with the intention of going into medicine. With his father’s gift of a microscope, the impressionable young man took an interest in pathology. Spilsbury shot to fame during the highly publicised 1910 trial of Dr Hawley Crippen, an American physician who was hanged in London for his wife’s murder. When Mrs Crippen disappeared, two letters signed by her announced her resignation from the Music Hall Ladies Guild, saying she had been summoned to the USA on a family matter. The letters were not, however, in her writing. Dr Crippen told a family friend that his wife had been taken ill in the USA and was not expected to live. A little later, this friend received a telegraph stating that Mrs Crippen had indeed died. Friends of the Crippens, alarmed, approached Scotland Yard to investigate. Panicked, Crippen and his mistress fled to Canada. Chief Inspector Walter Dew searched the Crippen household to discover human remains buried in lime in the coal cellar; he boarded a faster ship and arrested the pair at sea. At trial, Spilsbury argued that a scar on a small piece of skin from the remains pointed to their being Mrs Crippen’s. Despite the defence stating that no link could be proven, Spilsbury was insistent. Crippen was convicted and hanged. 12 | WellcomeNews | Issue 57

The case set the tone for a colourful career in forensic medicine. Spilsbury gave evidence in numerous other high-profile trials, including the ‘Brides in the Bath’ murders, where three women were drowned in their baths – each had been married to George Joseph Smith. In a theatrical display, Spilsbury laid out a bathtub in the Old Bailey courtroom and explained how Smith could have whipped each woman under the water, causing them to pass out and drown. Forensic medicine was often frowned upon by the medical and legal professions, but Spilsbury was instrumental in changing its perceptions for generations to follow. His presentational skills brought a star quality to the courtroom. According to Colin Evans, author of The Father of Forensics, he was “toweringly handsome, immaculately turned out, with a fresh red carnation on his buttonhole”. Critics of Spilsbury cast doubt over his ability, particularly given his lack of academic attainment. He has been accused of being behind several miscarriages of justice. The recent Five documentary Dr Crippen explored how the case has recently been

Bernard Spilsbury by George Belcher, 1928.

reopened, speculating that his wife’s death was an accident or that the body discovered in the coal cellar was that of a man – calling Spilsbury’s method into question. In later life, Spilsbury was estranged from his wife and in poor health. In 1947, following the deaths of two of his sons, he committed suicide in his laboratory by coal-gas poisoning, a method he had often encountered in his work. Despite this bleak and dramatic end, there is no doubt that Spilsbury paved the way for modern CSI. Although his official career is well documented in materials at the National Archives and in the press, no significant collections of personal papers, apart from these handwritten cards, are known to have survived. Discovered in a lost cabinet, they may help to explain the father of forensics – so maybe it is time to swap the sofa for the filing cabinet.

Index cards in Spilsbury’s filing cabinet.

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