ANNUAL REVIEW 1 October 2008–30 September 2009

ANNUAL REVIEW 2009

The Wellcome Trust We are a global charity 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.

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MAKING A DIFFERENCE EXECUTIVE BOARD BOARD OF GOVERNORS We are grateful to everyone who agreed The Wellcome Trust Annual Review is All images are courtesy of Wellcome Images to be reviewed in this issue, everyone distributed via a mailing list held by the (images.wellcome.ac.uk) except as follows: The Wellcome Trust’s mission is to p. 3: 1 (K Hodivala-Dilke and M Stone); pp. 6–7: 1 who supplied images or gave us Wellcome Trust. If you would like to be foster and promote research with the Director of the Wellcome Trust Chairman (Dr Linda Stannard, UCT/SPL), 2 (Arran Lewis), permission for their images to be used, added to the list, or if you have a 3 (Anthea Sieveking); p. 8 (David Gregory and Debbie aim of improving human and animal Ted Bianco and the many members of Wellcome colleague who would like to receive the Marshall); p. 10: 2 (Annie Cavanagh); p. 12 (Robert health. During 2005–2010, Pears/iStockphoto); p. 13 (BSIP VEM/SPL); p. 15 Director of Technology Transfer Deputy Chairman Trust staff who helped to produce this Wellcome Trust Annual Review, please our aims are: (Anna Tanczos); p. 17 (SPL); p. 18: 2 (Caroline Penn); volume. contact: p. 19: 1 (Dr Linda Stannard, UCT/SPL), 2 (Pasquale John Cooper Advancing knowledge: To support Sorrentino/SPL); p. 20: 1 (Ida Ma, Novartis Institute for UKCMRI Chief Operating Officer Editor Publishing Department Tropical Diseases), 2 (Chris de Bode/Panos); p. 21: 1 research to increase understanding Peter Davies and Interim Chief Executive Officer Ian Jones, Isinglass Consultancy Wellcome Trust (Western Ophthalmic Hospital/SPL), 2 (Warwick Design of health and disease, and its societal Consultants); p. 22: 1 (Annie Cavanagh); p. 26: 1 Christopher Fairburn FREEPOST context Simon Jeffreys Project Manager (Natural History Museum); p. 27: 1, 2 (Blink Films); RLYJ-UJHU-EKHJ p. 29 (Andrew Whittuck); p. 32: 1 (Daan van Aalten); Chief Operating Officer Lucy Moore Using knowledge: To support the Slough SL3 0EN p. 35 (Volker Brinkmann); p. 36 (Membrane Protein Laboratory); p. 41: 1 (Anna Tanczos); p. 45 development and use of knowledge David Lynn Roderick Kent Writers T +44 (0)20 7611 8651 (Annie Cavanagh, Wellcome Images); p. 46: top to create health benefit Head of Strategic Planning and Policy Penny Bailey (Anton Enwright), middle (Annie Cavanagh), bottom Eliza Manningham-Buller F +44 (0)20 7611 8242 Ian Jones (Benedict Campbell); p. 47: top (Yorgos Nikas), Engaging society: To engage with Clare Matterson E [email protected] middle (iStockphoto); p. 50 (Simon Clark). 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p. 5 THE YEAR IN REVIEW

Director’s statement 2 Advancing knowledge 4 Using knowledge 16

p. 7 p. 22 Engaging society 24 Developing people 30 Facilitating research 36 Developing our organisation 40 Corporate activities 2008/09 41 Financial summary 2008/09 42 p. 20 p. 26 Funding developments 2008/09 44 Streams funding 2008/09 46 Technology Transfer 48 Wellcome Trust Genome Campus 49 Public Engagement 50 p. 29 p. 33 51 Advisory committees 52

p. 34

p. 38 2 | AdvancingDirector’s statement knowledge

Five years of progress

As we reach the end of our five-year health and disease – including diabetes, for the disease and adopted globally. In Strategic Plan, we can celebrate cancer and malaria – exceeding its target Vietnam, meanwhile, researchers have much success and look forward to of 375 structures. In 2007, we committed completed an important phase II clinical exciting new directions. £16 million to enable the Consortium to trial of a new vaccine, solve an additional 600 structures. This developed with funding from our The end of 2009 sees not only the end of will further our understanding of these Technology Transfer division. The vaccine a year’s activities but also the fruition of a proteins and supply new targets for proved both safe and effective in eliciting five-year Strategic Plan that began in therapeutic intervention. good immune responses in children, 2005. In that Plan, we set out that we encouraging results that can pave the wanted our funding to lead to increased Advances in genomics have also made way for larger phase III clinical trials. understanding of health and disease, possible projects such as the Cancer and its societal context, and to use that Genome Project, an ambitious initiative In Kenya, researchers at the KEMRI– knowledge to develop improved health to map the individual mutations involved Wellcome Trust Research Programme benefits. I feel that we have met those in many different types of cancer. An found that invasive bacterial infections, aims. The last five years have seen our early success was the discovery of BRAF most of which could be prevented with funding contribute to some vital as an important gene involved in malignant existing vaccines, were the leading breakthroughs in biology and medicine melanoma and a high proportion of other cause of death among children at a rural and the pursuit of much inspirational cancers. The Project has also made Kenyan hospital. The findings highlighted science. significant progress in distinguishing the the neglected threat of bacterial disease ‘driver’ mutations that cause cancer from to public health and the need to One of our biggest areas of success the ‘passenger’ mutations that are a overcome the political and financial continues to be in genetics and genomics. result of it. barriers to widespread use of vaccines. As DNA-sequencing technology continues Researchers at the Programme have to improve at a remarkable rate, we have The Wellcome Trust Sanger Institute plays also demonstrated that vaccinating seen studies take advantage of the Human a key role in many of these projects and against Haemophilus influenzae serotype Genome Project since the completion of continues to be a leading light in the b (Hib), which can lead to meningitis and the first whole-genome draft in 2000. genomics field. In addition to its work in pneumonia and causes 400 000 deaths Chief among these is the advent of human genetics, it has completed a per year globally, reduces the number of genome-wide association studies, in number of important genome sequences, cases of Hib disease by 88 per cent. The particular the work of the Wellcome Trust notably the parasites Trypanosoma brucei Kenyan Ministry of Health subsequently Case Control Consortium. By examining and Leishmania, which cause two of the committed to funding an ongoing the whole genomes of thousands of major diseases in low-income countries, nationwide immunisation programme. patients, the Consortium has been able sleeping sickness (human african to identify genetic variants associated trypanosomiasis) and leishmaniasis. In , we have seen some with common diseases, including significant breakthroughs in our disease, diabetes and rheumatoid arthritis, These sequences are among the understanding how the brain functions, as well as other characteristics such as important breakthroughs our funded which could prove crucial to treating weight and height. These are providing scientists have made in infectious disease neurological and psychiatric diseases. insights into the mechanisms of disease, research. We are particularly proud of the Ray Dolan’s group at the opening up new avenues of research into work of our Major Overseas Programmes, Wellcome Trust Centre for Neuroimaging their causes and possible treatments. which have pioneered many life-saving at University College London, for example, treatments for major diseases in low- is using functional imaging to reveal the Crucial to our understanding of biological and middle-income countries. Our Major brain centres involved in decision making mechanisms is knowing the shape of a Overseas Programme in Thailand, for and other cognitive processes. Other protein and how this affects its function. example, established the use of artemisinin brain imaging research at the University Over the last four years, the Structural combination therapies for the treatment of Cambridge and the Institute of Genomics Consortium has determined of malaria. In 2006, these were Psychiatry at King’s College London has the three-dimensional structures of over recommended by the World Health revealed distinctive brain activity in 450 proteins with relevance to human Organization as the frontline treatment people with psychological conditions

IMAGES 1 Blood vessel grown into a melanoma, to which 2 The Trust ran an event at the House of Commons to Trust-supported research has linked the BRAF gene. promote new Darwin initiatives to MPs and peers. AdvancingDirector’s knowledge statement | 3

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years, has been open to researchers since delighted to open the doors to Wellcome 2007, producing beams of very bright Collection, our public venue at 183 light that allow scientists to look at the Euston Road. In the relatively short time atomic structures of molecules. since its opening, Wellcome Collection Meanwhile, UK Biobank, launched in has garnered critical acclaim and 2006, is well on the way towards attracted large visitor numbers with its achieving its aim of gathering, storing unique mix of science and art. It clearly and protecting the world’s largest bank illustrates the strong appetite of people of blood and DNA samples, and health to explore the connections between information, collected from 500 000 science, medicine and wider culture. volunteers in the UK aged between 40 and 69. By following this group over Looking forward, we are adding support 1 many years, it will provide researchers for the world’s best biomedical with a unique resource for studying the investigators to take risks and innovate such as obsessive–compulsive disorder roles of genes, lifestyle and environment to answer the most challenging research and depression. in disease. questions. We will also expand our support for translational research to help In 2007, Trust-funded researchers at the While our Strategic Plan primarily to bring new medical products and University of Edinburgh successfully focused on the practical benefits of our technologies closer to clinical use. And reversed the autism-like symptoms of advancing knowledge, one of our core we will outline several strategic ‘themes’ Rett syndrome in mice. This suggested goals remains to inspire members of the to identify important global challenges for that the effects of Rett are not public, particularly children, with the research community to respond to. permanently wired into the brain and scientific knowledge. Key to this is the These will link the diverse areas of raises hopes that a range of human development of teachers, who will go on biomedical science, ethics, history of neurodevelopmental disorders may be to inspire today’s young people, giving medicine, public engagement and policy reversible. In London, researchers at the them the confidence to understand, issues that are so important to the Trust. Institute of Psychiatry have developed a debate and question issues surrounding All our work is done in partnership, with highly effective form of cognitive therapy science. In 2006, we helped to establish governments, with other funders and, that has helped individuals suffering from the National Science Learning Centre to most importantly of all, with the post-traumatic stress disorder, including provide teachers and other educators universities, research institutes and survivors of the 7/7 London terrorist with access to the resources and individual and teams of researchers who attacks and the Omagh bombing. expertise to get to grips with the enable us to achieve our mission. Many complexities of contemporary science. thanks to you all. We are proud to have supported some This was taken a step further last year of the biggest science projects in the UK with the launch of Project Enthuse, over the last few years. The Diamond which offers bursaries to help to train the Mark Walport synchrotron, the largest scientific UK’s science teachers in the latest Director infrastructure project in the UK for 40 scientific discoveries. In 2007, we were January 2010

HIGHLIGHTS OF THE YEAR

• Genome-wide association studies • Genome of schistosome parasite • Innovative live surgery broadcast identify scores of loci involved in sequenced. w p. 13 attracts 3.5m viewers. w p. 25 common diseases. w p. 6 • Promising antimalarial enters drug • Darwin-inspired teaching resources • Spores found to be critical to spread development pipeline. w p. 20 supplied to thousands of UK schools. of C. difficile. w p. 10 w p. 26 • Phase I trial confirms safety of • New genes causing commonest form neoglycoside antibiotic. w p. 22 • Structure of membrane transporter of motor neurone disease identified. protein determined at Diamond w p. 11 synchrotron. w p. 37 Researchers Helen Saibil and use cryo-electron microscopy to work out structures of bacterial protein complexes. Advancing knowledge | 5

Advancing knowledge

Supporting research to increase understanding of health and disease, and its societal context

An inside job

Advanced imaging techniques are Now, for the first time, Professor Saibil’s The structure reveals how 14 copies of providing a glimpse of important group has visualised a polypeptide three different proteins come together bacterial ‘nanomachines’. bound to a chaperone complex as it to form a two-chambered, double- begins to fold, as well as when it has walled channel.2 It is open on the inside Within the cell, proteins typically reached its final conformation. of the cell but squeezed shut on the operate as part of large multisubunit outside. Importantly, its structure is quite assemblies – nanomachines capable This work exploited a variation of the different from other characterised export of performing sophisticated molecular GroEL–GroES system used by the systems. Ultimately, an understanding of engineering. Researchers at University bacteriophage T4 (a bacterial virus). its structure could aid the development College London and Birkbeck, University A key T4 protein (gp23) is too large to of agents to block the spread of of London have used cryo-electron fit within the standard GroEL–GroES antibiotic resistance. microscopy to work out the structures complex. To accommodate gp23, GroES and possible mechanisms of action is replaced by a related but larger protein 1 Clare DK et al. 2009;457(7225):107–10. of two important bacterial protein known as gp31, which is encoded 2 Fronzes R et al. Science 2009;323(5911):266–8. complexes. within the T4 genome. The cryo-electron microscopy revealed that, even with this Cryo-electron microscopy – electron larger chaperone, the folding chamber is microscopy at extremely low strained and deformed by the presence temperatures – can provide a ‘snapshot’ of gp23 within it. of structures within their natural environments. Helen Saibil has used Gabriel Waksman and colleagues, the technique to piece together the meanwhile, have been tackling a structures of the bacterial ‘chaperones’ massive protein complex situated in GroEL and GroES, which together the bacterial membrane – actually form a barrel-like chamber within which spanning the two membranes that make polypeptides fold up into their correct up the surface coat of Gram-negative shapes. bacteria. This ‘type IV’ secretion system is particularly significant as it is the route by which plasmids encoding antibiotic resistance factors and other important molecules are exported from the cell. 6 | Advancing knowledge

Coming up trumps Close association

Genome-wide studies have identified individual effect. Indeed, a significant Follow-up of genome-wide analyses hundreds of disease associations. fraction of the genetic contribution to can reveal disease mechanisms – disease remains unaccounted for. and even possible environmental Set up in 2007, the Wellcome Trust Case Furthermore, only rarely has the precise influences on disease. Control Consortium has pioneered a new genetic risk factor (the ‘causal variant’) wave of large-scale, high-throughput been identified. In some cases, a single Genome-wide studies identify genome-wide association studies. These association may actually be a composite associations between a disease and a studies have identified several hundred of several genetic variants lying close genetic marker, but only rarely is that genetic sites influencing (‘associated together (as seen in rheumatoid arthritis).7 marker itself the factor affecting risk. with’) common diseases. Looking More likely, it just happens to be close to forward, next-generation sequencing To winkle out the remaining genetic (and hence inherited with) the true culprit. technologies are providing the tools to factors – and to move from an At the Cambridge Institute of Medical identify many more. association to a causal variant – a much Research, Linda Wicker and John Todd’s more detailed view of human genetic groups are homing in on ‘causal variants’ Genome-wide studies have continued to variation is needed. This is the goal in type 1 diabetes. develop at an astonishing rate. As well as of the , which being applied to a wider range of is using next-generation sequencing One way to connect the two is to look for conditions, such as Alzheimer’s disease,1 technologies to provide a high-resolution nearby genes that could plausibly affect they are also being used to explore view of variation. A stepping-stone a disease. As type 1 diabetes is caused physiological traits relevant to disease, towards this goal was the sequencing by a self-directed immune response, such as blood lipid2 or blood glucose3 of the first individual African genome, in Linda Wicker, John Todd and colleagues levels or blood pressure.4 Extensive a collaboration between the Wellcome focused on a likely candidate gene international collaborations have enabled Trust Sanger Institute and the next- (encoding a protein known as IL2RA data to be pooled, which has enabled generation sequencing company or CD25) involved in immune system even more risk loci to be identified (see Illumina.8 function.1 page 8). With new statistical and methodological Genetic variants around the IL2RA gene While each individual association has tools also being developed (see page 33), affected how much IL2RA protein was value, collectively they may shed further these resources will continue to drive present on the surface of a key set of light on disease processes. Studies of rapid progress in the genetic dissection immune cells. Moreover, the variants Crohn’s disease, for example, implicated of common diseases. previously linked to diabetes had the autophagy (breakdown and disposal of greatest effect on IL2RA levels. Hence, cell structures) as an important disease This research was supported by the Wellcome Trust variation in IL2RA levels affecting the process.5 Studies of autoimmune and other funders. function of these immune cells is likely to conditions have revealed that many risk 1 Harold D et al. Nat Genet 2009;41(10):1088–93. underlie the increased risk of diabetes. Erratum in: Nat Genet 2009;41(10):1156. loci are shared between diseases.6 In type 1 diabetes, genetic discoveries are 2 Prokopenko I et al. Nat Genet 2009;41(1):77–81. Adopting a different strategy, John Todd, shedding light on environmental 3 Soranzo N et al. Nat Genet 2009;41(11):1182–90. Sergey Nejentsev and collaborators influences on disease (see right). 4 Newton-Cheh C et al. Nat Genet 2009;41(6):666–76. at Roche-454 used next-generation 5 Parkes M et al. Nat Genet 2007;39(7):830–2. techniques to sequence ten genes The studies also provide clues to the implicated in type 1 diabetes in nearly 6 Barton A et al. Hum Mol Genet 2009;18(13):2518–22. ‘genetic architecture’ of disease. Most 1000 patients and controls.2 conditions are influenced by a large 7 Orozco G et al. Hum Mol Genet 2009;18(14):2693–9. number of genes, mostly of small 8 Bentley DR et al. Nature 2008;456(7218):53–9.

IMAGE Millions of samples can be genotyped in high-throughput facilities. Advancing knowledge | 7

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Mind your language

This deep sequencing revealed fine- Genes affecting reading and language Rather than affecting reading and writing grained variation that could be tested for skills may be having a wide impact. skills, mutations of FOXP2 – identified by its association with disease. Professor Monaco and Dr Fisher in 2001 On rare occasions, a reading or language – cause a rare severe speech disorder. In The strongest association was seen impairment results from mutation of a a recent investigation of genes regulated with four variants around the IFIH1 gene, single gene. Usually, though, many by FOXP2, Dr Fisher identified a gene, encoding the MDA5 protein, which genes are likely to be involved. As work CNTNAP2, encoding a protein present in is involved in the interferon response by Tony Monaco and Simon Fisher at the the membranes of neurons, where it to enteroviruses – common RNA Wellcome Trust Centre for Human mediates interactions with other cells. viruses already suggested as possible Genetics in Oxford is revealing, both may Variants of CNTNAP2, Dr Fisher and environmental factors in some cases reflect aberrant wiring of the nervous Professor Monaco discovered, are of type 1 diabetes. Interestingly, all four system. associated with common forms of lowered the risk of disease (i.e. they were specific language impairment.3 protective) and disrupted the MDA5 Dyslexia is common, affecting around protein. This suggests that ‘normal’ 10 per cent of the population. Professor CNTNAP2 has also been implicated in immune responses to enteroviruses may Monaco has obtained compelling language delay in autism. Possibly, increase the risk of beta cell damage, evidence that a gene known as certain variants of CNTNAP2 increase leading to type 1 diabetes. KIAA0319 is a risk factor for the the risk of language abnormalities, while condition. The genetic variant most different genes contribute more to other In separate work, Professor Todd and strongly associated with dyslexia is in the deficits seen in autism. David van Heel at Barts and The London control region of the gene. It contains a School of Medicine and Dentistry have binding site for a gene-silencing protein, As FOXP2 also affects the development found that some diabetes risk alleles also which significantly reducesKIAA0319 of neuronal pathways, these studies predispose to coeliac disease (and vice activity.1 highlight the importance of nervous versa), suggesting a strong biological link system wiring to the development of between the two.3 Dietary antigens are Why low levels of KIAA0319 protein language and reading skills. It remains a known to trigger an immune response predispose to dyslexia is not clear. The significant challenge to identify exactly that affects gut tissue in coeliac disease, protein is present on the surface of cells how gene variation (and environmental but beta cells may also be affected, and seems to help neurons to migrate to factors) influence neural wiring and leading to type 1 diabetes. their correct locations in the cerebral complex skills such as language and cortex during development of the brain. reading. This research was supported by the Wellcome Trust and other funders. Interestingly, a study of 6000 seven-to- 1 Dennis MY et al. PLoS Genet 2009;5(3):e1000436. 1 Dendrou CA et al. Nat Genet 2009;41(9):1011–5. nine-year-olds from the ALSPAC birth 2 Paracchini S et al. Am J Psychiatry 2 Nejentsev S et al. Science 2009;324(5925):387–9. cohort (see page 38) revealed that 2008;165(12):1576–84. 3 Smyth DJ et al. N Engl J Med 2008;359(26):2767–77. KIAA0319 was also associated with poor 3 Vernes SC et al. N Engl J Med 2008;359(22):2337–45. reading ability – but not other cognitive measures such as IQ – in the general population.2 As the variant is carried by around 15 per cent of people, it is likely to be having a significant impact, with diagnosed cases of dyslexia representing the extreme end of a spectrum of impairment.

IMAGES 1 Enteroviruses are thought to be involved in some cases of type 1 diabetes. 2 Abnormal wiring of neurons in the brain may underlie reading and language disorders. 3 A gene implicated in dyslexia may affect reading skills in the general population. 8 | Advancing knowledge

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Genomes shape up

Genome-wide studies are shedding The height we finally grow to appears to FTO remains the locus with the greatest light on the genetics of human size be influenced by multiple independent impact on weight, and its discovery has and shape, while follow-up studies pathways – trunk size, for example, is opened up a fertile area of research. are revealing more about the genes’ controlled independently of leg length There are hints that FTO may have an biological effects. (the main factor affecting height). effect on appetite. Studies of children’s Breakdowns such as this can suggest recorded calorie intake in the ALSPAC Genome-wide studies are revealing the which processes particular genes may cohort (see page 38), for example, found genetic architecture of complex or be affecting, and provide insight into a link between the FTO risk allele and ‘quantitative’ traits – where bone-related medical conditions such as increased calorie intake.6 characteristics vary over a range of osteoporosis and arthritis. values rather than in the ‘either/or’ By contrast, work on a mouse model fashion of classical Mendelian genetics. Another gene to emerge from the Case carrying an FTO mutation, developed by Human size and shape are both Control Consortium’s early work was Roger Cox, and archetypal quantitative traits and of FTO, the first gene found to affect body colleagues at MRC Harwell and the medical significance – not least because mass index in the general population. Wellcome Trust-funded OXION initiative, of the link between excess weight and This was followed up by the discovery suggests that FTO has a metabolic type 2 diabetes. that common variants around the MC4R effect. Unlike mice completely lacking locus, mutation of which causes severe FTO, these animals do not overeat but In 2007, the Wellcome Trust Case childhood obesity, also have an effect on are lean and have a high metabolic rate Control Consortium identified the first body weight.3 Two recent studies have – and hence are constantly burning off gene associated with height variation in advanced this area considerably. more energy.7 Notably, the work the general population, HMGA2. More suggests that interfering with FTO could recently, further analysis revealed 20 Pooling of data from 15 studies, offer a way to control obesity. other loci affecting height, collectively including those conducted by the explaining around 3 per cent of height Consortium, confirmed the effects of Collectively, these studies illustrate how variation (or a 5 cm difference between FTO and MC4R but also identified six complex control of body form is. As all of people with mainly ‘short’ alleles and further loci affecting body weight. the genetic variations are of modest those with mainly ‘tall’ alleles).1 The loci Strikingly, several of these genes are effect size (and much of the genetic affect a wide range of pathways, active in the brain, highlighting the brain’s influence remains undiscovered), the including the well-studied ‘hedgehog’ key role in weight control.4 implications for individuals are generally signalling pathway, components of the still minor. Crucially, though, they provide extracellular matrix and pathways In terms of health, weight is not a route into the key pathways affecting implicated in cancer. Ultimately, the necessarily the best guide to someone’s health-related traits in the general number of genes affecting height is likely medical prospects – the size and population. to run into the hundreds. location of fat deposits are of more critical importance. A pooling of data This research was supported by the Wellcome One way in which genes can affect from 16 genome-wide association Trust and other funders. height is by influencing skeletal growth. studies has now identified two loci 1 Weedon MN et al. Nat Genet 2008;40(5):575–83. In a study of 20 000 individuals from the specifically affecting waist circumference 2 Soranzo N et al. PLoS Genet 2009;5(4):e1000445. UK and the Netherlands, Panos and one affecting waist-to-hip ratio in 3 Loos RJ et al. Nat Genet 2008;40(6):768–75. 5 Deloukas at the Wellcome Trust Sanger women. In these cases, it appears that 4 Willer CJ et al. Nat Genet 2009;41(1):25–34. Institute and colleagues identified the genetic effects may be on the 5 Lindgren CM et al. PLoS Genet 2009;5(6):e1000508. genetic variants affecting height and development and metabolism of fat skeletal frame size. Several genes were rather than the brain’s energy balance. 6 Timpson NJ et al. Am J Clin Nutr 2008;88(4):971–8. found to affect traits such as trunk 7 Church C et al. PLoS Genet 2009;5(8):e1000599. length, hip axis length and femur length.2

IMAGE Adipose tissue, the amount and distribution of which is affected by genetic variants. Advancing knowledge | 9

History in the genome

The ‘domestication’ of sheep gamekeeper twist, one of their roles is to Sheep and goats were originally retroviruses is revealing the history block infection by pathogenic retroviruses. domesticated for their meat, probably on of sheep domestication. For example, one endogenous relative of multiple occasions in south-west Asia. JSRV produces a slightly modified After spreading throughout Europe, Sheep were among the first animals to envelope protein that intermingles with the these animals were largely supplanted by be domesticated, some 9000 years ago, protein produced by the invading virus. In a second wave of animals selected for as a source initially of meat and later of doing so, it prevents the virus protein from wool production. Some ‘primitive’ types secondary products such as wool. As being processed through the cell’s clung on at the fringes on expansion or Charles Darwin appreciated 150 years intracellular protein trafficking system, so escaped and survived as feral animals. ago, domestication dramatically alters the cell cannot release new virus particles.2 evolution. More recently, Massimo By looking at the pattern of endogenous Palmarini’s research into sheep Even more surprisingly, Professor retroviruses in 133 breeds of sheep, retroviruses at the University of Glasgow Palmarini and colleagues in Texas have Professor Palmarini has been able to is providing a fascinating glimpse of shown that endogenous retroviruses determine the relatedness of breeds and evolution both ancient and modern in play a key role in sheep reproduction, hence their likely domestication history.4 this important livestock species. being essential for the development of Some elements show distinct geographic the placenta.3 Viral envelope proteins patterns: enJSRV-18, for example, is Like all mammals, sheep can be infected are very effective at sticking cells together found in Soay sheep, now confined mainly by retroviruses – viruses that have RNA and promoting cell fusion. They may be to the island of St Kilda, and Mediterranean as their genetic material. Their RNA is being put to work in the formation of mouflon. In fact, Soay, mouflon of Sardinia, copied into DNA, which then integrates multinucleate cells in the placenta, which Corsica and Cyprus, and Scandinavian into the genome, where it directs the depends on cell fusion. During evolution, breeds appear to be the last relics of the production of virus particles. Occasionally it is possible that viral defence was their first great wave of domesticated sheep, a retrovirus genome can become ‘trapped’ first role, but they were later co-opted to largely displaced by ‘modern’ breeds. in the host genome: it no longer makes support reproduction. the virus but is passed on from generation The work also sheds light on an ‘outlier’ to generation in the host DNA. Such Aside from their biological role, among UK sheep: the ‘Jacob’ sheep, elements are known as endogenous endogenous retroviruses are also useful named after the Biblical story of Jacob, retroviruses. They are surprisingly tools for tracking evolutionary changes. who was given every “speckled and common: the human genome, for Because mutations steadily accumulate spotted” sheep from his father-in-law, example, contains many thousands. in their DNA sequences, it is possible to Laban. One theory is that it was imported estimate how long they have been from Norse countries; another suggestion Professor Palmarini is particularly resident in the sheep genome. is that it was washed up after the sinking interested in a retrovirus known as of the Spanish Armada. The genetic Jaagsiekte sheep retrovirus (JSRV) and Of the 27 endogenous retroviruses evidence confirms its status as an oddity, its endogenous relatives. JSRV causes a related to JSRV, some are very ancient, related to Asian breeds. form of lung cancer in sheep. As well as dating back to the time when sheep and having veterinary importance, it is also a goat lineages were diverging (5–7 million This research was supported by the Wellcome Trust valuable model system for understanding years ago). Two entered the genome and other funders. the interplay between infectious and around the time different sheep species 1 Arnaud F et al. PLoS Pathog 2007;3(11):e170. 1 endogenous retroviruses. were appearing, around 3 million years 2 Arnaud F et al. J Virol 2007;81(20):11441–51. ago. These elements became fixed in the 3 Dunlap KA et al. Proc Natl Acad Sci USA Remarkably, endogenous retroviruses genome when domestication began. 2006;103(39):14390–5. are not simply carried around as ‘junk’ And one element seems to have entered 4 Chessa B et al. Science 2009;324(5926):532–6. but have evolved to play important roles the sheep genome within the past two in host cells. In a poacher-turned- centuries.

IMAGE Retroviruses can be used to study the evolution of domesticated sheep. 10 | Advancing knowledge

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Better late than never Spore draw

What happens when the brain that the brain is still processing The spore is Clostridium difficile’s changes its mind? information even as movement is being secret weapon – but may also be its triggered. Together, the two researchers Achilles heel. Controlling movement is central to developed a model that predicts that if human life. Although models have this ‘late’ information contradicts earlier Clostridium difficile has become one of come up with good explanations of input sufficiently strongly, it is possible the most worrisome public health threats how movement decisions are made in that an alternative threshold is reached, of the 21st century. Commonly seen in the brain, none can explain one crucial leading the brain to send a second healthcare settings, cases have leapt aspect: how we change our mind. By signal that countermands the first – tenfold in the last decade. C. difficile is both exploiting ingenious mechanical tools, resulting in a change of mind. highly infectious and difficult to eradicate at the University of – traits that, research at the Wellcome Cambridge has come up with a possible To test this idea, a system was set up in Trust Sanger Institute has revealed, are solution to this conundrum. which volunteers had to decide in which linked to the durability of its spores. direction a set of spots was moving Humans show astonishing motor control across a screen – with extra random To get a better picture of C. difficile skills: although a computer can beat the spots making it difficult to judge.1 transmission, Trevor Lawley, Gordon world’s best chess player, none comes Subjects had to choose left or right, Dougan and colleagues have established close to an average five-year-old’s ability by moving a robotic handle. Crucially, a model hospital environment with mice to move a pawn. These skills rely on our around 10–15 per cent of the time, as ‘patients’. When C. difficile was ability to integrate sensory information subjects headed in one direction before introduced, it colonised the intestines of from multiple sources. veering toward the other – changing mice without causing any symptoms. their mind. The mice shed spores, but did not infect But sensory information is inherently others living with them. However, when ambiguous (‘noisy’). To cope with this Significantly, these changes of mind treated with antibiotics, the mice become noise, the brain adopts a statistical usually corrected a wrong choice highly infectious ‘supershedders’, approach. A decision to move is thought – suggesting that additional active releasing vast numbers of spores that to be based on the rapid accumulation processing of information had led to a rapidly spread disease through the of noisy information until it hits a better decision. mouse community.1 threshold, triggering action. Even though based on an artificial The sudden change occurs because This model has stood up well to testing, situation with a simple binary choice, the antibiotic treatment kills most of the but has one obvious flaw: it cannot findings may well be broadly applicable. naturally occurring bacteria in the gut, account for changes of mind – once the Even though processing is so rapid it opening up an environment that threshold has been reached, movement happens below the level of conscious C. difficile can rapidly colonise. When is inevitable. awareness, it is plausible that similar antibiotic treatment is halted, the gut mechanisms are at work when we bacteria recover and displace C. difficile Working with Michael Shadlen from experience the cognitive sensation of (although some animals remain the University of Washington in Seattle, changing our mind. supershedders for several months). Professor Wolpert has come up with a way round this problem. Because of 1 Resulaj A et al. Nature 2009;461(7261):263–6. The work highlights the importance of lags in the motor system, it is possible non-pathogenic gut bacteria in keeping

IMAGES 1 Daniel Wolpert at the . 2 Clostridium difficile. Advancing knowledge | 11

Spore draw AGGREGATE LEADs

C. difficile under control. In theory, The genetic basis of amyotrophic Although TDP-43 mutations are rare, manipulating the gut’s microbial lateral sclerosis is gradually being TDP-43 protein is deposited in 90 per ecosystem – promoting the growth of unpicked. cent of all people with ALS and is the harmless bacteria – could provide a way single biggest clue to the cause of motor to manage C. difficile. Indeed, the gut Amyotrophic lateral sclerosis (ALS) neurone disease. bacteria present in mouse faecal material is the most common form of motor can be used to inoculate animals and neurone disease. It causes a relentlessly The discovery of TARDBP also led suppress C. difficile. Although this is not progressive muscle paralysis as motor Professor Shaw’s group to consider a practical option for people, it may be neurones degenerate, and is invariably similar proteins as possible causes possible to identify which bacterial fatal. Around 10 per cent of cases run of ALS in other families. This hunch species are most effective at suppressing in families, with the remainder occurring proved correct, with the subsequent C. difficile and use them in a form of sporadically. For the past 15 years identification of a mutation in a gene ‘bacterial therapy’. mutations in just one gene, SOD1, known as FUS.3 Screening other have been linked to ALS, but SOD1 unexplained cases revealed a further The Sanger Institute team has also been explains only a fraction of cases and seven families with FUS mutations. able to purify spores, enabling a the mechanisms of disease remained proteomic analysis to be carried out (in frustratingly unclear. In the past 18 Normally, TDP-43 and FUS proteins conjunction with Jyoti Choudhary and months, Chris Shaw at King’s College are found in the nucleus. The effects of the Sanger mass spectrometry team). London and colleagues have identified mutations in their respective genes are This has revealed hundreds of spore- two further genes that cause ALS when strikingly similar, both leading to large associated polypeptides, many seen mutated, shedding more light on this protein aggregations. The pathological across the Clostridium family but some distressing condition. effects of TDP-43 could be due to the specific toC. difficile.2 Ultimately, a build-up of toxic deposits in the cell, greater understanding of the make-up of Inside the motor neurones of people with but equally could be due to loss of the spore will provide leads towards ALS are characteristic clumps of protein normal TDP-43 function in the nucleus. better diagnostics and vaccines. that have been tagged for recycling but The latest discoveries have provided have not been broken down. The main powerful biological tools to explore The team is also looking at how spores constituent of these clumps is a protein underlying disease mechanisms and are affected by widely used disinfectant known as TDP-43, and in 2008 distinguish between these possibilities. techniques. While spores are eradicated Professor Shaw’s group discovered by highly oxidising approaches such as mutations in the gene encoding TDP-43, This research was supported by the Wellcome Trust vapourised hydrogen peroxide (‘deep TARDBP, in a familial case of ALS.1 and other funders. clean’), many cleansing products have Screening for changes in this gene 1 Sreedharan J et al. Science 2008;319(5870):1668–72. worryingly little effect. Collaborations are revealed mutations in one large family 2 Rutherford NJ et al. PLoS Genet 2008;4(9):e1000193. 2 now being established with hospitals to and two sporadic cases. Follow-up 3 Vance C et al. Science 2009;323(5918):1208–11. identify ways to use the new findings to work by many other groups has track and, it is hoped, to block the confirmed thatTARDBP mutations are spread of C. difficile. a significant cause of ALS.

1 Lawley TD et al. Infect Immun 2009;77(9):3661–9. 2 Lawley TD et al. J Bacteriol 2009;191(17):5377–86.

IMAGE Chris Shaw of King’s College London. 12 | Advancing knowledge

Tracking calcium All in the brain

An understanding of calcium Their reseach has shown that InsP3 Infections can cause a variety of dynamics in the cell may point the receptors are initially randomly physical symptoms, but they also way toward new therapeutics. distributed in the ER membrane. When make us feel bad. How these feelings

InsP3 first binds, receptors aggregate are triggered in the brain is now Calcium signalling underpins everything into small clusters, which alters their becoming clear.

from fertilisation to muscle contraction. sensitivity to both InsP3 and calcium. The Several groups’ work this year has signal generated will therefore depend Ever since the Ancient Greeks, the mind

significantly advanced our understanding on levels of InsP3 and calcium (and other and emotions have been cordoned off

of how calcium flows are finely tuned in inputs). InsP3 can thus generate a from the body. Recently, however, there the cell. hierarchical set of responses – initially has been a flourishing of research into from single channels, then puffs from the neural correlates of emotions and Three small chemical messengers are clusters of channels and then waves as ‘subjective’ feelings. In work begun at 2 crucial to calcium signalling: two (InsP3 multiple puffs coalesce. University College London and continued and cADPR) trigger release from at the , Hugo endoplasmic reticulum (ER) stores; a Ultimately, modulating calcium signalling Critchley and Neil Harrison are examining third, NAADP, was discovered only could be a way to modify the behaviour how in the body affects recently but has turned out to be the of cells involved in disease processes. mood and brain function. most potent stimulant of calcium release. The receptors that mediate calcium release are obvious targets. Working with We all recognise the sensation of feeling Antony Galione and John Parrington in Professor Taylor and others, Barry Potter ‘under the weather’ when laid low by an Oxford, Mark Evans in Edinburgh and in Bath has developed a range of infection. Yet while the immune system’s colleagues in the USA and China have chemical analogues that mimic or interfere response to infection receives close made an important step forward in with the triggers of calcium signals; these scrutiny, much less attention is given understanding the NAADP system, agents have been used to provide to the attendant mental symptoms identifying its receptor and the location of detailed insight into the mechanics of – collectively known as ‘sickness 1 3 the NAADP-sensitive calcium store. InsP3 receptor activation. Working with behaviour’. Surprisingly, calcium is released from groups in Germany, Professor Potter has acidic compartments such as lysosomes, also designed other agents to block To get a better handle on the brain’s not previously known as major calcium NAADP signalling and modulate the response to systemic infection, Professor stores. This initial burst of calcium can activation of T cells4 – opening up a Critchley, Dr Harrison and their colleagues trigger further calcium release through possible route to the treatment of have explored the effects of artificially

the InsP3 and cADPR systems, autoimmune diseases. induced inflammation on brain activity, amplifying the original signal. brain function and mood. Volunteers were This research was supported by the Wellcome Trust injected with either typhoid vaccine, to Calcium is a versatile signalling system: and other funders. induce inflammation, or a saline placebo, a wide range of signals can be generated, 1 Calcraft PJ et al. Nature 2009;459(7246):596–600. then given a battery of tests while their from local ‘puffs’ to global ‘waves’ 2 Taufiq-Ur-Rahman et al. Nature 2009;458(7238): brain activity was being monitored by spreading across the cell. Colin Taylor in 655–9. functional magnetic resonance imaging. Cambridge and colleagues have found 3 Rossi AM et al. Nat Chem Biol 2009;5(9):631–9.

that ‘tuning’ of InsP3 receptors can 4 Dammermann W et al. Proc Natl Acad Sci USA Participants who received the vaccine generate complex spatiotemporal 2009;106(26):10678–83. suffered a notable deterioration of patterns of calcium release. mood.1 Functional imaging revealed corresponding changes in brain activity:

IMAGE ‘Sickness behaviour’ illustrates how systemic infection can affect the brain. Advancing knowledge | 13

images of emotional faces, for example, triggered abnormally high activity in an area of the brain known to be involved in depression, while connectivity between this area and other regions of the brain was reduced. Such findings could explain why feeling ill has much in common with feeling depressed.

In addition, participants suffered greater fatigue, confusion and impaired concentration when undertaking a Fluke of nature cognitively demanding task. Doing the test activated ‘interoceptive’ brain regions – those implicated in sensations The genome sequence of a matched in multiple combinations – of internal body states.2 The extent to schistosome parasite is of interest to possibly a mechanism to increase which these areas were activated was a medical researchers and evolutionary protein variability and help the parasite good match for the levels of fatigue and biologists alike. to evade the host immune system. confusion reported. Those who did well on the test tended to recruit additional Schistosomes – flukes or parasitic A detailed analysis of the genome has prefrontal areas of the cortex. flatworms – are responsible for a huge identified many possible avenues for global health burden. Over 200 million drug development, such as proteins not The results thus provide direct evidence cases of schistosomiasis occur every seen in vertebrates and new members of of how an immune response can year, disabling millions and killing protein families typically targeted by influence brain activity, performance and hundreds of thousands. The genome drugs. Indeed, some S. mansoni subjective feelings. In the long term, an sequence of Schistosoma mansoni, proteins resemble those for which understanding of these processes may sequenced by Matt Berriman and potential drugs already exist. suggest ways to overcome the negative colleagues at the Wellcome Trust Sanger impact of infection on our brains and Institute,1 is suggesting new ways to Schistosomes are an important behaviour. break the transmission cycle but is also evolutionary stepping-stone. Comparisons providing clues to pivotal stages of with more simple organisms such as sea 1 Harrison NA et al. Biol Psychiatry 2009;66(5):407–14. evolution: the development of organs anemones have shed light on the new 2 Harrison NA et al. Biol Psychiatry 2009;66(5):415–22. and of the bilateral body plan. genetic features that led to anatomical innovations maintained throughout the The S. mansoni genome consists of some evolution of higher animals – such as the 360 million bases, and shows some three-layered body plan and the formation curious features. Within its 12 000 genes, of organs. Similarly, comparisons up the the gaps in its coding regions (introns) are family tree are providing insight into the small near the starts of genes and much steps needed to create the complex larger towards their ends. The genome anatomical structures seen in higher sequence also revealed families of genes animals. with very small exons (chunks of coding sequence) that seem to be mixed and 1 Berriman M et al. Nature 2009;460(7253):352–8.

IMAGE The head of the parasitic flatwormSchistosoma mansoni. 14 | Advancing knowledge

New funding

New genome-wide Pandemic influenza Neurodegenerative studies disease

Anorexia nervosa, dengue fever and In partnership with other UK agencies, Three research programmes tackling tuberculosis in Russia are among the the Wellcome Trust has moved rapidly Alzheimer’s disease, Parkinson’s conditions to be studied in ten new to support research on pandemic disease and motor neurone disease genome-wide association studies H1N1 swine flu. have received a total of £17 million receiving a total of £10 million funding. Strategic Award funding through a In May 2009, the Trust convened a neurodegenerative disease partnership David Collier of the Institute of Psychiatry workshop with the Medical Research with the Medical Research Council is working with the Wellcome Trust Case Council (MRC), the UK Department of (MRC). Control Consortium and international Health and others to identify research collaborators to explore the genetic risk priorities and opportunities during an The multidisciplinary collaborations aim factors associated with anorexia nervosa. unfolding influenza pandemic. to provide a better understanding of the causes and mechanisms of disease, in a Cameron Simmons (University of After ‘fast-track’ peer review, two bid to improve early diagnosis and identify Oxford) is jointly leading a programme programmes were jointly funded by the new therapeutic leads. with Martin Hibberd (Genome Institute Trust and the MRC. Led by Andrew of Singapore) and Anavaj Sakuntabhai Hayward at University College London, The Alzheimer’s programme will be led by (Pasteur Institute) to identify the genetic the ‘FluWatch’ programme, awarded Peter St George-Hyslop of the Cambridge basis of dengue shock syndrome, a £2.1 million, will examine the spread and Institute for Medical Research. life-threatening complication of dengue impact of swine flu in up to 10 000 Investigators from Cambridge, Bristol, virus infection that particularly affects the individuals in 4000 households, providing Germany and Canada will use innovative young. Studies in Vietnam will test the a detailed view of flu in the community. tools from physics, chemistry and biology theory that susceptibility is due to host to investigate how the accumulation of genetic variation. The Mechanisms of Severe Acute amyloid beta and tau proteins leads to the Influenza Consortium (MOSAIC), led by death of brain cells in Alzheimer’s and Sergey Nejentsev at the University of Peter Openshaw of Imperial College related neurodegenerative diseases. Cambridge is working with the Wellcome London, has been awarded £2.7m. It will Trust Sanger Institute and the TB- study up to 500 cases to try to unpick Chris Shaw of the MRC Centre for EUROGEN consortium to identify genetic both host and viral factors contributing to Neurodegeneration Research, King’s risk factors affecting susceptibility to disease severity. College London, will head a programme mycobacterial infection and progression based on recent advances in to TB. A second workshop, with the MRC, the understanding the genetic causes of Biotechnology and Biological Sciences motor neurone disease (see page 11). The Other studies to be carried out under Research Council and the UK Department collaboration includes investigators from the umbrella of the Wellcome Trust Case for Environment, Food and Rural Affairs, King’s, University of California San Diego, Control Consortium will examine host focused on veterinary swine flu. A £1.7m Cambridge, Dundee and Manchester. control of HIV, renal transplant failures consortium grant was subsequently and pre-eclampsia, while the Sanger awarded to fund the COSI (Combating The Parkinson’s disease programme will Institute has received support for core Swine Influenza) initiative. A collaboration be led by Nicholas Wood, John Hardy and genotyping facilities. led by James Woods at the University of Anthony Schapira of the Institute of Cambridge will monitor the spread of Neurology, University College London Other studies will tackle congenital heart pandemic H1N1 swine flu in the UK pig (UCL), working with researchers from disease, complications of pregnancy and industry, while Ian Brown at the Dundee, Sheffield and UCL. Its goal will be childhood kidney cancer. Veterinary Laboratories Agency to generate a better understanding of Weybridge and colleagues will examine genetic risk factors in Parkinson’s disease. the virus’s effect on pigs.

IMAGE Influenza virus. Advancing knowledge | 15

1

Biomedical ethics A SELECTION OF NOTABLE GRANTS AWARDED IN 2008/09

John Harris and Sir PROGRAMME GRANTS STATISTICAL GENETICS Professor Gil McVean (): of the University of Manchester INFLUENZA Analysis of data from the 1000 Genomes Professor Wendy Barclay (Imperial College have been awarded a £0.8 million Project. Strategic Award in Biomedical London): Interferons, innate immune responses and clinical disease during influenza infection. Ethics to establish a programme of CHILD DEVELOPMENT Professor Edward Sonuga-Barke (University work focused on the human body. ADOLESCENT HEALTH of Southampton): Use of white noise to improve Professor Cesar Victora (Federal University concentration of children with attention of Pelotas, Brazil): Using three birth cohorts to The work, to be undertaken in problems. explore the impact of early life events on collaboration with Sarah Cunningham- adolescent health and wellbeing. Burley at the University of Edinburgh, Professor Robert Unwin (University College PROTEIN TRANSLATION will cover five main themes: human London) and Scott Wildman (Royal Veterinary Professor Christopher Proud (University of biomaterials and the uses of human College): ATP signalling in the kidney. Southampton): Control of elongation factors organs and tissues; ‘genethics’, the eEF2K and eEF2. ethical issues surrounding human HUMAN GENETICS Ed Hollox (University of Leicester): Population BIOBANKING genetics and genome sequencing; variability of the copy number variable FGFR3 Professor Zhengming Chen (University of reproductive technologies, including gene. Oxford): Support for the Kadoorie Biobank current technologies such as pre- Study of 515 000 Chinese people aged 35–74. implantation genetic diagnosis and Peter Lawrence (University of Cambridge): NEUROSCIENCE emerging techniques such as gamete Planar cell polarity and cell migration in Professor Jon Driver (University College production from stem cells; Drosophila. London): How sensory processing is affected by enhancement (physical and mental); crosstalk with other regions of the brain. and bioethical methods, including ENVIRONMENT Melvyn Hillsdon (): ‘Four HUMAN GENETICS philosophical enquiry. Hundred Area Study’, evaluating the impact of Professor Sir Walter Bodmer (University of the built environment on physical activity in 400 Oxford): Identifying genes that affect the sites around the UK. John Harris is the Sir David Alliance structure of faces of people in the British Isles. Professor of Bioethics at the University SCHIZOPHRENIA PROJECT GRANTS of Manchester. Sir John Sulston was Professor David Porteous (University of the founder Director of the Wellcome MICROBIOLOGY Edinburgh): Structure and function of the DISC1 Trust Sanger Institute and was awarded Professor Gad Frankel (Imperial College schizophrenia susceptibility factor. the 2002 Nobel Prize for Physiology or London): How effector proteins enable pathogenic E. coli to adhere to mucosal INFLAMMATION Medicine. This programme of research surfaces. Professor Maria Belvisi (Imperial College will form part of Manchester’s Institute London): Theophylline as a possible therapy for for Science, Ethics and Innovation, PSYCHOLOGY chronic cough. launched in 2008. Matt Field (University of Liverpool): Motivational processes and their links with alcohol abuse. STRATEGIC AWARD IN THE HISTORY OF MEDICINE Smaller Biomedical Ethics Enhancement EPIGENETICS MODERN HISTORY Branwen Hennig (London School of Hygiene Awards were made to Malcolm Dando Nick Hopwood (University of Cambridge): and Tropical Medicine): Diet, malnutrition and at the University of Bradford (‘dual-use’ Health, fertility and reproduction in the 20th the epigenetic status of young babies in the century. applications of biomedical research), Gambia. Susan Golombok at the University of HISTORY OF MEDICINE PROGRAMME VASCULAR BIOLOGY Cambridge (assisted reproduction and GRANT new family make-ups) and Michael Professor Salvador Moncada (University College London): Nitric oxide and the ANCIENT HISTORY Parker at the University of Oxford antioxidant status of vascular endothelial cells. Professor Philip Van der Eijk (Newcastle (ethics of collaborative global health University): English translations of Galen’s research). works. 16 | Using knowledge

Gordon Hamilton of Keele University. Using knowledge | 17

Using knowledge

Supporting the development and use of knowledge to create health benefit

An attractive solution

Pheromone traps may be a way to The strategy adopted by Dr Hamilton leks in the field, and worked equally well control Leishmania-transmitting and his team has been to exploit the with both mechanical and sticky traps. sand flies. natural communication systems that They also showed that lek sites treated affect sand fly behaviour – specifically, with insecticide attracted and killed Among parasites transmitted by insects, their reproduction. Male sand flies significantly greater numbers of females single-celled protozoans of the genus aggregate on and around host animals, than control sites. Leishmania are second only to malaria releasing chemical pheromones that in terms of their impact on health. In attract females and other males to The results suggest that a ‘lure-and- some cases, the parasites cause the the mating and blood-feeding site kill’ strategy centred on synthetic sex potentially fatal visceral leishmaniasis, (‘lek’). With Technology Transfer pheromone could be an affordable which affects some half a million people funding, Dr Hamilton and his colleague and practical approach to lowering a year. One way to mitigate their effects Krishnakumari Bandi have been able transmission of visceral leishmaniasis, may be innovative ‘pheromone traps’ to synthesise the male sand fly sex complementing the high-cost, long-term being developed by Gordon Hamilton pheromone from intermediates that are alternatives of potential new drugs and a and colleagues at Keele University and easily and cheaply obtained from plant Leishmania vaccine. the Fundação Oswaldo Cruz in Brazil. sources. 1 Bray DP et al. J Med Entomol 2009;46(3):428–34. In South America, Leishmania infantum The synthetic pheromone attracted chagasi is transmitted by sand flies female sand flies in the laboratory, and (Lutzomyia longipalpis). As with in a recent field trial, Dr Hamilton, Daniel mosquitoes and malaria, it is only Bray and Reginaldo Brazil extended this females that take blood meals and work to show that pheromone-baited transmit the parasite. If feeding on traps successfully attracted both female humans could be reduced, the risk of and male sand flies.1 Dispensers were infection would be decreased. set up to release the pheromone in similar quantities to those seen around

IMAGE Single-celled Leishmania parasites. 18 | Using knowledge

1 1 2

A serious drug problem

Poor-quality antimalarial drugs and revealed that a worrying 78 per cent of fakes included detectable amounts of artemisinin-resistant parasites are a artesunate use was as a monotherapy.2 artemisinin. Meanwhile, in Africa a team dangerous combination. In north-western Thailand, by contrast, including staff from the Wellcome Trust’s artesunate remains highly efficacious Major Overseas Programme in Kenya Artemisinin-based combination after 13 years of combination therapy.3 tested more than 1000 antimalarial therapies are the treatments of choice samples from 21 districts in Tanzania. for uncomplicated malaria. One of the Mathematical modelling suggests Overall, an alarming 12 per cent were advantages of artemisinins is the speed that high coverage with combination substandard – a figure that reached with which they kill malaria parasites, therapies could eliminate resistant 24 per cent for quinine products.7 clearing infections within a couple of parasites and prevent their wider days. Unfortunately, following anecdotal dissemination. However, there is a sting Researchers have called for more reports of a decline in efficacy, Nick in the tail. Their use would impose further attention to be given to pharmaceutical White and colleagues at the Wellcome strong selection pressures on parasites, quality monitoring, and a set of Trust South-east Asia Major Overseas and if the containment programme guidelines has been proposed that Programme’s Tropical Research Network did not achieve elimination then any could be applied to obtain objective have found clear evidence of reduced remaining parasite, the ‘last man information through medicine quality parasite sensitivity to artesunate in standing’, would be the most resistant surveys and to improve reporting to western Cambodia – a potentially – and malaria could become even more assess the impact of interventions.8 catastrophic development if resistant difficult to treat.4 parasites spread more widely. To catalyse action specifically against the Resistance may also derive from trade in counterfeit , the Trust Professor White and colleagues the widespread use of poor-quality organised a workshop with the American compared treatment with either antimalarial drugs. Often these are Pharmaceutical Group, bringing together artesunate alone or with mefloquine the products of a deadly counterfeit a range of stakeholders and opinion in western Cambodia – a past hotbed drug trade. But even genuine drugs formers to discuss the problem and of antimalarial resistance – and north- may be low-quality, because of poor ways in which it might be tackled. west Thailand. Disturbingly, it took manufacturing or storage. The South- almost twice as long to clear parasites east Asia Network’s centre in Laos This research was supported by the Wellcome Trust in Cambodia, and nearly one in three has shown that both genuine but and other funders. patients receiving artesunate alone poor-quality and counterfeit drugs are 1 Dondorp AM et al. N Engl J Med 2009;361(5):455–67. suffered a recurrence of infection.1 an important cause of unnecessary 2 Yeung S et al. Malar J 2008;7:96. 5 suffering and even death. 3 Carrara VI et al. PLoS One 2009;4(2):e4551. The rise of resistance is probably linked 4 Maude RJ et al. Malar J 2009;8:31. to the extensive use of artesunate alone The scale of the problem is of significant 5 Keoluangkhot V et al. Am J Trop Med Hyg in this region over several decades. concern. A recent random sampling 2008;78(4):552–5. Although Cambodian government policy of pharmacies in Laos found that 88 6 Sengaloundeth S et al. Malar J 2009;8:172. is to use combination therapies, work per cent of those stocking artesunate carried out with the London School were selling counterfeit versions of the 7 Kaur H et al. PLoS One 2008;3(10):e3403. of Hygiene and Tropical Medicine drug.6 Worryingly, 15 per cent of the 8 Newton PN et al. PLoS Med 2009;6(3):e52.

IMAGES 1 Holograms have been used to make it harder to produce fake packaging for antimalarials. 2 Drug sales in rural Africa. Using knowledge | 19

1

Clean air acts

Simple methods may be able to The research revealed striking cut drastically the spread of TB in differences in the transmission of TB healthcare settings. from different patients.1 Nearly all guinea pig infections (98 per cent) could Back in the 1950s, Riley and Wells be traced to just 8.5 per cent of the undertook a classic series of patients. Importantly, the vast majority experiments exposing guinea pigs to air of transmission was from patients with from a ward of tuberculosis patients. The multidrug-resistant TB inadequately 2 animals succumbed to TB, convincingly treated with first-line therapy – an all-too- demonstrating that the disease was common situation in many low-income spread through airborne particles. With countries, where access to diagnostic Providing there is adequate mixing of TB undergoing an alarming resurgence, tests for drug resistance is poor or air, they offer an important new tool particularly in low-income countries, Rod absent. for preventing the transmission of Escombe (a Research Training in drug-resistant TB. Their use has now Clinical Tropical Medicine) and Carlton The results highlight the importance of been recommended in World Health Evans (a Research Career Development early identification of high-risk patients Organization policy on TB control in Fellow in Clinical Tropical Medicine) at carrying multidrug-resistant TB, treating healthcare facilities and other settings. , with them appropriately and establishing collaborators in Peru and elsewhere, are infection control measures to prevent 1 Escombe AR et al. PLoS Med 2008;5(9):e188. revisiting these studies and developing TB transmission in the first place. 2 Escombe AR et al. PLoS Med 2009;6(3):e43. practical interventions that could slash Such measures need not necessarily the spread of TB. be expensive. Dr Escombe’s previous research showed that as simple a To get a better handle on TB measure as increasing natural ventilation transmission, air from a TB ward in – opening doors and windows – can Lima, Peru was channelled to guinea produce high rates of air exchange likely pig colonies established on the roof of to reduce TB transmission in healthcare the hospital. Using genetic fingerprinting settings. techniques to trace the origins of each animal infection, the researchers Another possible solution is to sterilise were able to investigate effects of HIV the air in hospital wards and clinics, by infection and TB drug resistance on TB placing ultraviolet lights in the upper transmission. part of the room. In Peru, upper-room ultraviolet lights were found to cut TB transmission to guinea pigs by 70 per cent – the first demonstration of their effectiveness against TB in a clinical setting.2 As ultraviolet lights are relatively easy to install and require little maintenance, they are well suited to use in resource-poor settings.

IMAGES 1 Mycobacterium tuberculosis. 2 TB is a particular problem in impoverished areas of Peru. 20 | Using knowledge

1 1 2

Priming the pipeline Stronger bonds

A promising antimalarial is on course A simple intervention can strengthen to enter the Medicines for Malaria bonds between parent and child even Venture drug development pipeline. in an impoverished setting.

With resistance to artemisinin-based The quality of the relationship between drugs a growing concern (see page The NITD concentrates on early stages infant and caregiver (usually a mother) in 18), there remains a need to pursue of drug discovery, identifying and the early years of life can have a long-term new pharmacological leads in the chemically refining potential new agents, impact. If a secure attachment develops, battle against malaria. With Technology and carrying out preclinical studies to infants are more likely to forge good Transfer funding, the Novartis Institute test for efficacy and toxicity in animal relationships with their peers and develop for Tropical Diseases in Singapore models. as socially and emotionally well-adjusted is testing a range of possible new children, and are less likely to develop compounds, with a view to passing on Its most promising antimalarial mental health problems as they grow the most promising to the Medicines for compound emerged from a screen older. A clinical trial involving researchers Malaria Venture (MMV) – a public–private of a large library of natural products in Reading, Oxford and South Africa has partnership based in Switzerland that held by the Novartis parent company. now shown that a simple intervention has also received funding from the The compound was lethal to cultured delivered by local people without medical Wellcome Trust. Encouragingly, the first parasites, and in vivo tests after chemical training can significantly enhance the compound is due to make the transition optimisation have confirmed its potency. mother–infant relationship.1 to the MMV pipeline. Three doses rapidly and completely eliminated malaria parasites in infected The trial was carried out in Khayelitsha, a The Novartis Institute for Tropical mice – far exceeding the ‘gold standard’ sprawling township of more than a million Diseases (NITD), a public–private for efficacy at this stage of development. inhabitants on the outskirts of Cape Town. partnership between Novartis and the In a pilot study, mother–child attachment Singapore Economic Development The next step is to file for ‘investigational had been improved when new mothers Board, was set up in 2002. Its aim is to new drug’ status late in 2010, which received professional support and develop small-molecule therapeutics would enable the compound to be guidance on parenting. In the latest work, for infectious diseases of low-income registered for clinical trials. MMV and a randomised controlled trial tested countries, principally dengue, NITD will jointly manage the clinical whether a similar intervention delivered by tuberculosis and malaria. It works on development, and phase I clinical trials lay community workers, intended to compounds originating within Novartis could start in the first half of 2011. promote sensitive parenting and foster as well as others identified in academic secure infant attachment to mothers, had research. a similar beneficial effect.

IMAGES 1 The chemical structure of the spiroindolone, NITD609, a preclinical candidate for malaria. 2 A simple intervention can improve mother–child bonding even in impoverished settings. Using knowledge | 21

1

Better by design

Award-winning products could The study involved nearly 450 pregnant significantly improve treatment of two mothers, half of whom received support common medical conditions. and parenting guidance (based on World Health Organization recommendations) Cataracts and broken bones are both together with specific measures to common medical problems. Two encourage sensitive, responsive products developed in Nottingham with interactions, and half received standard Technology Transfer support promise to antenatal and postnatal care. Compared improve their treatment significantly, and 2 with mothers in the standard care have been recognised with prestigious condition, those who received the awards for innovation. intervention were significantly more Also developed in Nottingham, a new sensitive in interactions with their infants An injectable bone scaffold, designed disposable blade designed specifically at six and 12 months. At 18 months, a to promote bone healing after fractures, for cataract surgery could have global significantly greater proportion of infants won an Orthopaedic Innovation application. Although practised in the intervention group were rated as Award at the national Medical Futures thousands of times daily, cataract ‘securely attached’ (74 per cent versus Awards. Developed by RegenTec, a surgery is a relatively crude procedure 63 per cent). Some benefits to mothers’ biotechnology spin-off company set up in which a circle is cut in the eye’s lens mental health were seen at six months, by Kevin Shakesheff from the University capsule with a needle and forceps. John but not at later stages. of Nottingham, it is a toothpaste-like Stokes, a Consultant Ophthalmologist substance at room temperature. It at Nottingham University Hospitals NHS Although similar interventions have been can be injected into bone fractures, Trust, has worked with Warwick Design shown to work in high-income countries, hardening into a matrix that supports the Consultants to develop a disposable this is the first study to demonstrate regrowth of bone and associated blood device with a standardised blade that benefits in a socioeconomically deprived vessels and other tissues. can make precise circular cuts. low-income country. Given its simplicity, it is potentially a sustainable intervention In time, it may also be possible to The prototype device was awarded for vulnerable populations even in highly integrate factors that encourage the the Medical Devices prize at the deprived settings. growth of particular types of cell, to National NHS Innovation Awards. As an boost the regenerative process, and to affordable and simple-to-use device, it 1 Cooper PJ et al. BMJ 2009;338:b974. use the matrix in combination with stem may also ultimately benefit the 1.5 million cell therapies. The company hopes to people a year in low-income countries launch a marketable product within 18 who lose their sight to untreated months. cataracts.

IMAGES 1 A cataract in an eye. 2 The device for making precise cuts in the cornea. 22 | Using knowledge

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Adapt and survive Newborn need

Chemical modification of In the phase I trial, the safety of the Despite antiretroviral rollout compromised antibiotics is giving leading candidate was tested in a small programmes, not all young infants in them a new lease of life. randomised placebo-controlled trial. South Africa are getting the treatment No ill-effects were seen, paving the way they need. Aminoglycosides have been used for for phase II trials in 2010, starting with many years to treat a range of bacterial complicated urinary tract infections. South Africa is home to one in seven infections. As with all antibiotics, though, of the world’s HIV-infected population. the emergence of drug-resistant There is reason to be optimistic that While children under 16 make up just strains is a significant and growing neoglycosides will overcome the hurdles 6 per cent of this total, they account problem. Using an understanding of the of phase II and III trials. For antibiotics, for 12 per cent of new infections and drugs’ structure and the mechanisms the jump from animal to human studies 13 per cent of HIV-related deaths. As of resistance, Achaogen Inc. has is not so great, as the target – the Marie-Louise Newell and colleagues’ been chemically modifying existing bacterium – is the same in both cases. work at the Africa Centre for Health and aminoglycosides in a systematic manner Moreover, a great deal is already known Population Studies in KwaZulu-Natal has in order to work round resistance. about the safety and effectiveness of revealed, even when antiretroviral drugs The first fruits of this endeavour, a aminoglycosides, which will be relevant are available they are not always finding ‘neoglycoside’, recently came through a to the development of their relatives. their way to the very youngest infants.1 highly successful phase I trial. The results of the phase I trial were released at The Africa Centre maintains a long- the 49th Annual Interscience Conference on running demographic surveillance Aminoglycosides are broad-spectrum Antimicrobial Agents and Chemotherapy (ICAAC) antibiotics. Achaogen’s principal targets Annual Meeting in San Francisco, September 2009 system in the subdistrict of Hlabisa, are multidrug-resistant Gram-negative (www.achaogen.com/news). a particularly deprived rural area with bacteria, including intestinal pathogens a high incidence of HIV. It has been such as E. coli, Pseudomonas actively involved in South Africa’s rollout aeruginosa and MRSA. of antiretroviral drugs, and is thus well- placed to assess how rollout is achieved Aminoglycosides are complex organic in practice. molecules produced by a range of bacteria. Although highly effective, The Africa Centre researchers found that their use is being curtailed by the around 350 children under 16 had been development of resistance. To maintain started on antiretrovirals by the beginning their efficacy, Achaogen has made a of 2008; of these, 245 were under ten range of chemical modifications to the but just two were under one year of age. sites on the molecules known to be Modelling of the population suggested targeted by resistance mechanisms. that there were likely to be more than Preclinical studies have shown that this 2500 HIV-infected children under ten in is a successful strategy for overcoming the area, at least 521 of whom would resistance while maintaining the agents’ need immediate treatment. antibacterial properties.

IMAGES 1 MRSA, an important target for neoglycosides. 2 The Africa Centre’s Marie-Louise Newell. Using knowledge | 23

New funding A SELECTION OF NOTABLE GRANTS AWARDED IN 2008/09

MEDICAL ENGINEERING Vaccine Professor Ross Ethier (Imperial College London): Enhanced implants and surgical development techniques for osteoarthritis.

Furthermore, if antiretrovirals were The Wellcome Trust and Merck & Co., Professor John Fisher (University of Leeds): available to prevent mother-to-child Inc. have jointly committed £90 million Regenerative and replacement technologies for transmission, the annual number of infant to establish new laboratories to later life. infections could be halved. develop affordable vaccines for Professor Reza Razavi (King’s College diseases affecting low-income London): Improved medical imaging for The group has worked with the local countries. cardiovascular, psychiatric and other conditions. Department of Health to improve the Professor Lionel Tarassenko (University of identification of HIV-infected children so As well as developing new vaccines in Oxford): Technological approaches to more treatment can start within the first year areas of unmet need, the MSD– individualised medical treatment. of life. Up to June 2008, around 470 Wellcome Trust Hilleman Laboratories TRANSLATION AWARDS children were being treated. Over the will also optimise existing vaccines, a following year, the numbers doubled valuable way of increasing the impact of TYPHOID FEVER Laura Martin (Novartis Vaccines Institute for and around 1000 are now receiving vaccination in resource-limited settings. Global Health): Conjugate vaccine against antiretrovirals. typhoid fever. The venture is the first time a research 1 Cooke GS et al. PLoS One 2009;4(9):e7101. charity and a pharmaceutical company DIARRHOEA Professor Chris Probert (University of Bristol): have jointly formed a separate entity Development of a diarrhoea diagnostic device. with equally shared funding and decision- making rights. The Hilleman Laboratories PRE-ECLAMPSIA will operate on a not-for-profit basis but Louise Kenny (University College Cork): A metabolite biomarker-based screening test for will be run as a business enterprise. The pre-eclampsia. £90m investment will be made over seven years and will support around 60 staff. SEEDING DRUG DISCOVERY CANCER The Laboratories will be based in India, Professor Caroline Springer (Institute of providing access to a wide range of Cancer Research): Inhibitors of lysyl oxidase and treatment of metastatic cancer. expertise in vaccine research, policy and manufacturing. The venture’s Chief HEPATITIS C VIRUS Executive Officer will be Altaf Lal, who Neil Thompson (Astex Therapeutics Ltd): has spent 20 years working at the US Fragment-based drug discovery for hepatitis C. Centers for Disease Control and BACTERIAL INFECTION Prevention. Dr Lal is currently based at Professor Peter Andrew (University of the US Embassy in India. Leicester): Inhibitors of the pneumococcal toxin, pneumolysin. The new venture is named in honour of the pioneering vaccine scientist Maurice Hilleman, who is credited with the development of more than 30 licensed vaccines, including products for measles, mumps and hepatitis B, during a career that included nearly 30 years at Merck.

IMAGE The Africa Centre is situated in the heart of rural KwaZulu-Natal. 24 | Using knowledge

Channel 4’s Krishnan Guru-Murthy prepares for Surgery Live. Engaging society | 25

Engaging society

Engaging with society to foster an informed climate within which biomedical research can flourish

Reality surgery

Three-and-a-half million viewers Funded by a Wellcome Trust People More than 5000 people joined the watched surgeons operating on live Award, the collaboration between the Facebook group, while the Twitter television. Wellcome Trust, Channel 4 and Windfall group was the leading ‘trending topic’ Films, an independent production by the final night. Users are continuing Over four evenings in May 2009, 3.5m company, built on the popularity of ‘Live to debate medical issues, to which viewers tuned into Channel 4 to watch Surgery’ – two events held at Wellcome clinical practitioners have spontaneously The Operation: Surgery Live. This Collection in 2007, in which the audience participated. pioneering broadcast project took watched open-heart surgery live via a television viewers live into the operating satellite link. The Operation was just one of the theatre to watch leading surgeons innovative events and exhibitions perform life-saving operations, including The Operation: Surgery Live aimed to organised by Wellcome Collection during brain and open-heart surgery. The four expose a wider audience to modern the year. History, science, medicine surgeons – who routinely talk medical surgery, remove some of the mystique and art were juxtaposed in a series students through procedures during surrounding it, and inspire young people of imaginative and critically praised operations – answered questions from to consider careers in surgery. exhibitions, including War and Medicine the public while they worked. (“historically fascinating, scientifically A special area on Channel 4’s website informative and ethically challenging” – A live video link from the operating encouraged visitors to set up discussion Rachel Campbell-Johnston, the Times) theatre was played to a full house at the groups on Facebook and Twitter. and Exquisite Bodies (“I greatly enjoyed Wellcome Collection auditorium each Viewers at home could put questions this exhibition and regret only that it is not evening. The evenings were hosted by about the procedures to the surgical twice the size” – Brian Sewell, Evening Channel 4’s Krishnan Guru-Murthy, with team during the broadcasts by phone, Standard). a second surgeon on hand to answer email and Twitter. www.channel4.com/explore/surgerylive/ questions when the operating surgeon www.facebook.com/group.php?gid=91972614803 was too busy. twitter.com/surgerylive 26 | Engaging society

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200 not out

Every state school in the UK benefited I’m a Worm, Get Me Out of Here explores forums, video blogs, mobile updates and from evolution-based teaching natural selection for 11–14-year-olds. live events. resources during Darwin200 year. Brine Date for 14–16-year-olds looks at sexual selection in brine shrimp. And The The Routes drama was serialised in Darwin200 was a national programme X-Bacteria for post-16 students tracks Channel 4’s ‘3-minute wonder’ of events that took place during 2009, the development of antibiotic resistance primetime slot. As of October 2009, the to celebrate the 200th anniversary in bacteria. A total of 8570 kits had been Routes website had been visited by over of Charles Darwin’s birth in February sent to schools by October 2009. 132 000 people, and the Sneeze 1809 and the 150th anniversary of the minigame had been played a staggering publication of On the Origin of Species The National Centre for Biotechnology 20m times. Routes was nominated for a in November 1859. The Wellcome Trust Education at the University of Reading was Children’s BAFTA award and four British joined in the celebrations, supporting a granted a Society Award to develop a Interactive Media Awards. range of education and other projects resource enabling science teachers to use exploring Darwin’s theories and their modern methods of DNA data analysis, so As part of Darwin200, the Trust part- importance for science today. that they can teach 16–19-year-old biology funded an exhibition at the Fitzwilliam students about the latest molecular Museum in Cambridge exploring the To give school students an understanding evidence for evolution. DNA to Darwin cultural resonance of Darwin’s theories. of the long-lasting legacy of Darwin’s work, examines links between DNA and evolution Endless Forms: Charles Darwin, natural the Trust commissioned a programme of in a range of case studies, such as lactose science and the visual arts, held from free science activities for school students tolerance in humans and antibiotic June to October 2009, brought together aged five to 19. In March 2009, every state resistance in MRSA. A course run by the nearly 200 exhibits from around the primary school in the UK was sent a Great enables world, highlighting artistic responses to Plant Hunt Treasure Chest, produced by teachers to get the most from the resource. Darwin’s work, including imaginings of the Royal Botanic Gardens, Kew. prehistoric Earth and evocations of a The Trust also commissioned a five-minute troubled life dominated by the struggle Each chest contained a mini seed bank, animation that formed the centrepiece of for existence. plant press, plant identikit, books, and Sir David Attenborough’s award-winning exciting classroom and outdoor activities. BBC1 documentary, Charles Darwin and Fittingly, the Natural History Museum’s In May 2009, children took part in Great the Tree of Life, broadcast in February £78m Darwin Centre, to which the Trust Plant Hunt Week – a week-long search 2009 and watched by 6.3 million contributed £10m, was opened during for ten common species of plants. viewers. The animation is featured on the Darwin200. The dramatic eight-storey Participants recorded when and where Wellcome Trust’s Tree of Life microsite, cocoon-shaped building encased in the plants flowered, learning key scientific along with an interactive fly-through glass has doubled the size of the skills in the process. To date over 10 000 explaining the evolutionary links between Museum’s laboratory areas, and holds teachers have signed up to stay updated living things and activities encouraging 17m entomology specimens and 3m on the project and ‘the hunt goes on’ secondary school students to explore botany specimens. Museum visitors can into 2010. these concepts. now watch scientists in action, and even ask them about the work they are doing. Survival Rivals, a set of free science kits Routes, developed by Oil Productions for commissioned by the Trust for UK state the Trust and Channel 4 Education, was www.wellcometreeoflife.org www.nhm.ac.uk/visit-us/galleries/orange-zone/ secondary schools, encourages a ground-breaking eight-week exploration darwin-centre students to explore the ideas behind of genetics and bioethics using a variety www.darwinendlessforms.org. Darwin’s famous theories and how they of platforms – including an online www.greatplanthunt.org continue to underpin biological and documentary, minigames and puzzles, www.survivalrivals.org www.dnadarwin.org medical research today. a murder-mystery drama, discussion www.routesgame.com

IMAGES 1 Inside the Natural History Museum’s Darwin Centre. 2 Sir David Attenborough helps to launch the Wellcome Trust’s Darwin200 schools materials. Engaging society | 27

1

Run for your life

The televised race for survival Leading reproductive scientists helped between millions of human-sized to develop the programme, and the sperm cells attracted 1.5 million Channel 4 website published a peer- viewers. reviewed document of the science behind the programme – the first time In The Great Sperm Race, a documentary a television programme treatment has part-funded by a Wellcome Trust been through a scientific peer-review Broadcast Award and screened on process. 2 Channel 4 in March 2009, the microscopic world of sperm and egg was The website also features The Great scaled up 34 000 times to human size. Sperm Race game, funded by a The film explores the genesis of this Wellcome Trust People Award. The piece, and of another new work by Using computer graphics and game was widely distributed on gaming McGregor for the Royal Ballet premiered actors representing sperm cells, websites and social media networks, at Covent Garden three weeks later. The the programme portrayed the huge and had been played more than 3.5m film was screened on ITV’sSouth Bank challenges sperm face in the hostile times by October 2009. Show in January 2010. environment of the female reproductive tract, assaulted on every side by Another notable Broadcast Development www.channel4.com/programmes/ powerful acids, white blood cells and Award was made to Nigel Wattis of the-great-sperm-race other ‘hostile combatants’. Mindful Films, for a film based on www.randomdance.org/wayne_mcgregor choreographer Wayne McGregor’s Millions of human-sized contenders three-week residence at the University of raced to fertilise an egg, negotiating California San Diego. McGregor worked some of the world’s most striking intensively with cognitive scientists, landscapes, including a valley in the exploring the mental processes Canadian Rockies and buildings on associated with creativity. The resulting London’s South Bank. new work was staged at Sadler’s Wells in London in October 2009 as part of the centenary celebrations of the Ballets Russes.

IMAGES 1, 2 Actors took on the role of sperm in The Great Sperm Race. 28 | Engaging society

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Home win The best of times, the worst of times

A public engagement project in Kenya In March 2009, the team held a A play telling the stories of children has helped to dispel some of the participatory planning workshop on dialysis has won a prestigious myths surrounding medical research. attended by local science teachers, national award. scientists and a representative from the The KEMRI–Wellcome Trust Research District Education Office to plan school For the Best was based on the physical Programme in Kenya includes a major activities. Suggested activities included entrapment and vivid imaginative travels site at the coastal town of Kilifi, carrying school trips to the Programme, visits by experienced by children on dialysis. It out research into malaria and other scientists to schools, a football game was developed by artist Mark Storor, in infectious diseases affecting children. pitting scientists against students, and collaboration with Anna Ledgard, from Researchers at Kilifi were keen to give an inter-school science competition. the stories, pictures, songs and poems local students an insight into their As not all students could visit, students created by children attending the dialysis work, and into the process and goals from three schools filmed Kilifi’s research unit at Evelina Children’s Hospital and of biomedical research more generally. facilities and produced a ‘virtual tour’ to children at two primary schools. Thanks to an International Engagement be shown in schools. Award, they were able to develop Funded by a Wellcome Trust Arts Award, and pilot school activities that have The activities ran for six months, and For the Best won the 2009 Theatre helped to forge better links with the a follow-up survey found significant Management Association Theatre Award local community and even encouraged changes in knowledge and attitudes. The for Best Show for Children and Young students to consider a career in medical intervention with the biggest impact was People, placing it alongside the work of research. the school visits by Kenyan scientists, major national theatre institutions. It was with whom students could identify most seen by 1800 people during its run at the The Kenya Programme is an international closely. Their support and enthusiasm Unicorn Theatre in London during June institute, including a number of significantly motivated students to take 2009. researchers from Kenya and East an interest in science – and in some Africa. Local residents participate in cases consider scientific careers. The play received almost universal critical much of its research, the fruits of which acclaim. The Guardian described it as have influenced healthcare in Kenya a “devastating theatrical journey that and throughout Africa. However, local throws dazzling light on the idea of illness awareness of its work is limited. as metaphor” and an “extraordinary, fierce and moving show”. InTime Out’s In an initial survey, the project team, words, it was “as magical as the circus led by Alun Iwan Davies, discovered and as epic as Greek tragedy”. And that many students were unsure about Whatsonstage.com deemed it “possibly the purpose of the Programme. Some the most extraordinary show currently thought its main role was to treat playing in London”. the sick. Others mentioned rumours circulating in the community that revealed significant misconceptions (and even bizarre suggestions that researchers were devil worshippers).

IMAGES 1 ‘Home-grown’ researchers can act as role models for African children. 2 Primary school children helped to develop For the Best. Engaging society | 29

New funding A SELECTION OF NOTABLE GRANTS AWARDED IN 2008/09

CHELTENHAM ENGAGING SCIENCE CAPITAL AWARDS Caroline Worthington (Florence Nightingale FESTIVALS Museum): Reinvigorating the Museum for the centenary of Florence Nightingale’s death in Some of the children were also involved A Society Award will see biomedical 2010. in the performance, leading the audience science embedded across the full John Lippiett (Mary Rose Trust): in small groups through a series of range of Cheltenham Festival events. Reconstructing the Barber Surgeon’s cabin and installations to the theatre’s main arena. the secondary collection of the Mary Rose in its There, six professional performers acted The Cheltenham Music Festival was new museum. out the children’s descriptions of their launched in 1945 and a Literature Pamela Willis (Museum of the Order of St illness and its impact on their families. Festival in 1949. Its Jazz Festival began John): Enhancing the visitor experience and in 1996 and the Cheltenham Science highlighting the Order’s contribution to the A family of four are supported by a nurse, Festival in 2002. Collectively, the history of medicine. who moves in with them, underscoring Festivals now attract some 150 000 INTERNATIONAL ENGAGEMENT AWARDS the omnipresence of the illness: a black- visitors each year. Informal links between Paul Nampala (Makerere University, Uganda): eyed creature stalks them, the dark the Festivals were solidified in 2006, Pairing Ugandan MPs with health researchers. shadow that lives with them permanently. when they collectively came together Children on dialysis are living with the under the ‘Cheltenham Festivals’ Gabriel Harp (Srishti School of Art, Design and Technology, India): Using cultural artefacts to real possibility of dying, if donor organs umbrella. catalyse discussions among public health are not available. Death, suggests one, researchers and policy makers. is simply “a door in a room that we have One of the strengths of this arrangement not yet noticed and won’t until our eyes has been the mixing of participants from SOCIETY AWARD adjust to the dark”. The play does not a wide range of backgrounds. To build HUMAN GENETICS shy away from this stark fact – any more on this interdisciplinarity, Cheltenham Peter Finegold (Nowgen: A Centre for Genetics in Healthcare): Bringing modern genetic than do the stories and pictures of the Festivals have been awarded a methods such as genome-wide association children for whom it is an everyday part £200 000 Society Award, which will studies into the classroom. of life. support efforts to embed biomedical themes across the full range of Festivals. PEOPLE AWARD REPRODUCTION A Biosciences Project Manager will be Jen Topping (Channel 4): Flash-based game for Great Sperm Race website. appointed to coordinate planning across the Festivals, and to turn the many LARGE ARTS AWARD creative ideas generated during planning DEMENTIA into reality. The support will also enhance Sherry Neyhus (Opera Group): The Lion’s Face, audience reach by touring and an opera exploring social, emotional and education/outreach projects, better use physical aspects of dementia. of technology, and additional work with SMALL ARTS AWARD media and broadcast partners. FORENSIC SCIENCE Adrian Jackson (Cardboard Citizens): The long-term aim of the three-year Mincemeat, a play and coroner’s inquests project is to embed planning practices inspired by the use of the corpse of a so that scientific themes become a homeless man during World War II.

permanent feature across all HISTORY OF MEDICINE PUBLIC Cheltenham Festivals. ENGAGEMENT SMALLPOX Andrew Chater and Sanjoy Bhattacharya (Wellcome Trust Centre for the History of Medicine at UCL): A video-rich web resource on the history of smallpox, to be hosted on Timelines TV.

IMAGE A scene from For the Best. 30 | Using knowledge

New Sir Thomas Bowden and Erie Boorman. Developing people | 31

Developing people

Fostering a research community and individual researchers who can contribute to the advancement and use of knowledge

Giant steps Mind, body, medicine

Two Wellcome Trust-funded students Uniquely, his Fellowship will allow him the Wellcome Trust grantholder Philip from Oxford have secured prestigious flexibility to network between these sites, van der Eijk has been awarded a Sir Henry Wellcome Fellowships. developing a set of multidisciplinary skills prestigious Alexander von Humboldt that will complete his conversion from Professorship. Wellcome Trust Four-year PhD chemist to molecular virologist. Programmes have proved highly Professor van der Eijk was formerly popular, and competition for places is By contrast, Erie Boorman is establishing Director of the Wellcome Trust-funded intense. Launched in 2006, Sir Henry a niche in the field of decision making Northern Centre for the History of Wellcome Fellowships are likewise and cognitive neuroscience. After his Medicine, a partnership between highly competitive, providing newly degree at Stanford, Dr Boorman studied Newcastle and Durham Universities. He qualified postdoctoral researchers with for a Master’s under Matthew Rushworth has received many grants from the Trust, unprecedented freedom and funds to and Heidi Johansen-Berg as part of his including a University Award in 1994, establish their research. Making the four-year PhD in Oxford. after which he took up a personal Chair transition from four-year student to of Greek at Newcastle. fellow, two researchers from Oxford are Dr Boorman has applied functional taking advantage of their Fellowships imaging techniques to study brain The Humboldt Professorship, worth to establish international networks and activity during decision making, as well €3.5 million (around £3.1m), is awarded develop their skills base. as new anatomical methods to image to scientists and scholars outside cortical circuits.3,4 Such work is providing Germany, enabling them to carry out a After a Master’s in chemistry at the a fascinating picture of activity in the large-scale research project at a German University of St Andrews, Thomas brain as it weighs up different options. university. One of the most prestigious Bowden joined the Trust-funded His goal now is to add to this portfolio European academic prizes, it is awarded Four-year PhD Programme in Structural of skills, such as machine learning to up to ten researchers each year, Biology at the University of Oxford, and neuro-economics, to integrate usually in the fields of natural sciences, undertaking his work in the labs of computational and psychological medicine and mathematics. Professor Dave Stuart and Yvonne Jones perspectives. International collaborations van der Eijk is the first recipient from the in the Wellcome Trust Centre for Human will again be important, with his humanities. Genetics. Here, he has specialised in Fellowship split between Oxford and the the binding of viruses to host cells1,2 – California Institute of Technology. Professor van der Eijk’s field of interest an area he is taking forward in his is the dialogue between medicine and Fellowship. His focus will be 1 Bowden TA et al. J Virol 2008;82(23):11628–36. philosophy, the mind–body interface, the bunyaviruses such as Crimean–Congo 2 Bowden TA et al. Nat Struct Mol Biol transfer of medical knowledge, and the haemorrhagic fever virus, which have 2008;15(6):567–72. relationship between medicine, moral extremely high mortality rates. 3 Boorman ED et al. Neuron 2009;62(5):733–43. values and religion. An expert in Ancient 4 Boorman ED et al. Curr Biol 2007;17(16):1426–31. Greece and classical antiquity, in 2009 While an undergraduate, Dr Bowden he was awarded a History of Medicine spent time in labs at the Scripps programme grant, which is supporting Research Institute at La Jolla, California, an ambitious project to provide scholarly which will also be his base for part of his translations of Galen’s writings. Despite Fellowship. He has also established Galen’s seminal position in medical collaborations with teams at St Andrews history, much of his work has never been and the Max Planck Institute of satisfactorily translated. in Martinsried, Germany. 32 | Developing people

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Sugar STRUCTURES Data detective

The sugars attached to proteins are The work funded through the Fellowship With the right methods, electronic surprisingly important across many renewal will build on what was initially health records can establish the true areas of biology. a side project in his laboratory. As impact of adverse drug reactions. well as being used to make polymers, Daan van Aalten, whose Senior N-acetylglucosamine is also added to Despite their benefits, all drugs have Research Fellowship was renewed this proteins, modifying their activities. side-effects and their use always reflects year, has established himself as a leading Most excitingly, it appears that a balance between benefits and figure in ‘glycobiology’ – studies of sugar N-acetylglucosamine is added to the drawbacks. At the London School of molecules and the polymers made same sites as phosphate groups (serine Hygiene and Tropical Medicine, Liam from them. From the protective coats and threonine residues), a modification Smeeth, a Wellcome Trust Senior of yeast and bacteria, he has moved used to control the activity of many Research Fellow in Clinical Science, is on to processes happening within the cellular proteins. N-acetylglucosamine analysing data from electronic health cell – where addition of sugar molecules appears to be an additional part of records to gain a clearer picture of to proteins is playing an unexpectedly this control system, competing for the adverse reactions to a range of widely important role in the life of the cell. same target sites. N-acetylglucosamine used medications. modification may therefore figure in many Professor van Aalten began work on key cellular processes, from cell division Clinical trials are designed to assess drug chitin, possibly the most common and cancer to control of insulin secretion. efficacy and safety. However, no clinical natural product on Earth. A long polymer trial can include all possible patient types of a single sugar (N-acetylglucosamine), Having worked out the structures of the or pick up very rare (but serious) reactions. chitin makes up the shells of a multitude enzymes that carry out this reversible Thus even once a drug is in widespread of animals, from lobsters to locusts. modification,2,3 Professor van Aalten has use, ongoing assessment of its effects is More importantly, from a medical point of designed highly specific small-molecule needed. One way in which this can be done view, chitin is also found in the cell wall of inhibitors that are being used to dissect is through use of computerised health fungi that infect people. the role of this sugar modification in a records. Of particular value is the General range of cellular processes. Practice Research Database (GPRD), In the first five years of his Fellowship, which includes completely anonymous Professor van Aalten has worked 1 Dorfmueller HC et al. J Am Chem Soc medical records for over 3.6 million out the structures of key enzymes in 2006;128(51):16484–5. patients registered at almost 500 general chitin metabolism, identified natural 2 Rao FV et al. EMBO J 2006;25(7):1569–78. practice surgeries. products that inhibit these enzymes and 3 Clarke AJ et al. EMBO J 2008;27(20):2780–8. developed small chemical molecules Even with this amount of data on tap, there with similar inhibitory properties.1 is a need to be cautious about associations. Spectacular progress in this area is To minimise confounding factors, Professor being taken forward through Technology Smeeth has adopted an approach in which Transfer Seeding Drug Discovery people act as their own controls, comparing funding. periods before and after the initiation of drug use (while controlling for factors such as the resulting age difference).

His analyses have explained some otherwise puzzling findings. For example, some diabetes medicines appeared to

IMAGE Structure of ‘GlcNAcstatin’, a highly specific enzyme inhibitor. Developing people | 33

1 2

Do the math

increase the risk of fractures, but only in Sophisticated statistical analyses Statistical tools also come into play after women and only of certain bones – are extracting even more information an association has been confirmed. patterns that were difficult to explain. from genome-wide data. Individual loci may actually encompass Professor Smeeth’s much larger analysis several independent genetic influences, (more than 1800 patients who used the Genome-wide association studies or may exert their effects in combination drugs and also had fractures) confirmed generate an avalanche of data – but the with other loci or with environmental the association was present for both ‘wet experiments’ are only half of the factors. sexes and that a wide range of bones story. Perhaps the greatest challenge is were affected.1 in processing the data and extracting as Cecilia Lindgren, awarded a Research much information of biological relevance Career Development Fellowship this A similar approach revealed that as possible. Two Wellcome Trust fellows year, is applying statistical analyses antipsychotics, usually used to treat are playing important roles in this to obtain a better understanding of schizophrenia, were associated with an analysis. biological processes involved in the increased risk of stroke – particularly in development of type 2 diabetes and patients with dementia.2 Simply put, association studies identify obesity. Based at the Wellcome Trust genetic variants that are more common Centre for Human Genetics in Oxford, Such studies are not always purveyors of in study populations than in controls. Dr Lindgren has played a major part bad news, however. Analysis of GPRD This statistical association requires very in the Wellcome Trust Case Control data found no evidence that women careful scrutiny. If the bar of statistical Consortium’s studies.3,4,5 given new bisphosphonate drugs for significance is set too high, important osteoporosis were at higher risk of loci might be omitted. Set the bar too This work has highlighted genetic effects abnormal heart rhythms.3 And a mammoth low and all key loci will be captured – but on overall obesity (as defined by body analysis of nearly 130 000 patients and so too will many irrelevant markers that mass index) as well as risk factors for 600 000 controls cleared statins of show an unequal distribution just by diabetes. However, it is not just body involvement in a range of serious chance. Unfortunately, most loci have weight per se that is the problem – it conditions (such as cancer), as some small effects, so distinguishing ‘real’ and is how and where excess fat is stored. high-profile studies had alleged.4 spurious signals is a challenging task. Dr Lindgren now aims to use genome- wide data to identify more of the factors Professor Smeeth’s studies illustrate how At Newcastle University, Heather Cordell, influencing the distribution of fat in analysis of data held in electronic patient whose Senior Research Fellowship the body, particularly in the abdomen records can improve patient care. As well was renewed this year, is working with (central obesity). She also intends to as posing technical and confidentiality statisticians and geneticists to develop follow up the most interesting leads to challenges, though, there is also a need new statistical techniques for genome- see how they affect body physiology and for rigorous statistical and methodological wide data analysis. As well as pooling ultimately disease processes. approaches to ensure that data analyses data to increase sample size, it is also do actually provide meaningful results. possible to take account of factors such This research was supported by the Wellcome Trust as underlying population structure, and other funders. This research was supported by the Wellcome Trust the nature of the controls, family 1 Cordell HJ. Genomics 2009;93(1):5–9. and other funders. relationships and inheritance patterns at 2 Biernacka JM, Cordell HJ. Eur J Hum Genet 1 Douglas IJ et al. PLoS Med 2009;6(9):e1000154. particular loci.1,2 2009;17(5):644–50. 2 Smeeth L et al. Br J Clin Pharmacol 3 Lindgren CM et al. PLoS Genet 2009;5(6):e1000508. 2009;67(1):99–109. 4 Timpson NJ et al. Diabetes 2009;58(2):505–10. 3 Douglas IJ, Smeeth L. BMJ 2008;337:a1227. 5 Loos RJ et al. Nat Genet 2008;40(6):768–75. 4 Grosso A et al. PLoS One 2009;4(3):e4720.

IMAGES 1 Liam Smeeth of the London School of Hygiene and Tropical Medicine. 2 Cecilia Lindgren, a new Research Career Development Fellow. 34 | Developing people

Animal flu VOLUME CONTROL

A new veterinary fellow is looking at In 2007, he moved to the Cambridge An understanding of the pathways of the transmission of influenza viruses Veterinary School, working under the immune cell activation will provide in livestock. umbrella of the Cambridge Infectious opportunities to boost – or block – Diseases Consortium, led by James immune responses. The H1N1 swine flu pandemic and Wood. Here, Dr Murcia has switched persistent fears of an H5N1 avian flu his attention to influenza viruses, Immune responses depend on the outbreak have brought influenza A collaborating with the Wellcome Trust activation of certain key defence cells, viruses into sharp focus. These viruses Sanger Institute to establish an influenza such as dendritic cells, macrophages affect a range of animals, and as part virus genome-sequencing pipeline (part and neutrophils. Sometimes – after of the Wellcome Trust’s new veterinary of a programme funded by the Trust). vaccination, for example – immune initiative, Pablo Murcia will be using a responses need to be boosted; if postdoctoral fellowship to investigate As well as having veterinary importance, inflammatory conditions develop, genetic variation in influenza viruses and this work is also relevant to human though, they need to be suppressed. At its effects on virus transmission. influenza. It is not yet clear how viral the Semmelweis University in Hungary, genetic variation within an individual host International Senior Research Fellow Originally from Buenos Aires, Argentina, affects the spread of influenza through Attila Mócsai is unpicking the pathways Dr Murcia trained as a vet, graduating a population. Working on horses and of immune cell activation – work that in 1998. A research project during his pigs, Dr Murcia will monitor the spread of may provide methods to fine-tune the degree ignited an interest in virology infections and investigate this variation strength of immune responses. and he went on to undertake an MSc within individual animals by sequencing in animal health while attached to the virus isolates in collaboration with the One way in which neutrophils are Department of Virology at the University Sanger Institute. He also plans to map activated is through a family of cell- of Buenos Aires. this genetic variation to the antigenic surface receptors that recognise variation seen in viral proteins. In antibody–antigen complexes. As well During this time, he encountered an addition, collaborations with world- as identifying which family members are outbreak of pulmonary tumours in leading researchers at Penn State important in both mouse and human sheep in Patagonia. Curious to know University in the USA will integrate these neutrophil activation,1 Dr Mócsai has more about the cause of the tumours, findings into models of flu transmission. explored the intracellular events that Jaagsiekte sheep retrovirus, Dr Murcia follow activation. got in touch with Massimo Palmarini This research was supported by the Wellcome Trust at the University of Glasgow (see page and other funders. Several triggers of neutrophils act 9). A fellowship from the American 1 Mura M et al. Proc Natl Acad Sci USA through an important signalling pathway 2004;101(30):11117–22. Society for Microbiology enabled him controlled by the Syk tyrosine kinase. to join Professor Palmarini’s lab, where 2 Murcia PR et al. J Virol 2007;81(4):1762–72. Downstream steps in this pathway, he worked on the sheep virus and however, are not well understood. Dr endogenous retroviruses.1,2 Mócsai has found that one form of phospholipase C (PLCγ2) is specifically involved in neutrophil activation triggered by immune complexes.2 Blocking PLCγ2 inhibited neutrophil activation – and also completely protected mice from inflammatory arthritis.

IMAGE H1N1 ‘swine flu’ may be transmitted from humans to pigs. Developing people | 35

New funding A SELECTION OF NOTABLE GRANTS AWARDED IN 2008/09

Principal SENIOR RESEARCH FELLOWSHIPS ASTHMA Research FELLOWS Professor Clare Lloyd (Imperial College London): Allergic airway inflammation and With collaborators in Germany, Three leading figures inUK science remodelling (renewal). Dr Mócsai has examined signalling have had their Principal Research STEM CELLS downstream of Syk in other situations. Fellowships renewed. Anton Wutz (University of Cambridge): In macrophages and dendritic cells, for Epigenetics and stable cell identity in example, activation of the Card9 adapter Principal Research Fellowships (PRFs) mammalian stem cells. through Syk has turned out to be the are the most senior of the Wellcome WELLCOME TRUST–NIH FOUR-YEAR crucial route by which adjuvants boost Trust’s personal support schemes, PHD STUDENTSHIP immune responses to vaccines based on providing seven years’ initial support and NEUROSCIENCE Mycobacterium tuberculosis antigens.3 a further five years’ funding after renewal. Alexander Domanski (University of Edinburgh): This year, the PRFs of Karl Friston, SynGAP regulation of circuit formation in the somatosensory cortex. Inflammatory responses to fungal Margaret (‘Scottie’) Robinson and Brian infections also involve Syk, but in this Spratt were all renewed. RESEARCH TRAINING FELLOWSHIPS case it has two distinct roles. Acting IN PUBLIC HEALTH AND TROPICAL through Card9, Syk is needed to initiate Professor Friston is Scientific Director of MEDICINE synthesis of a precursor of interleukin 1β, the Wellcome Trust Centre for MALARIA an essential trigger of inflammatory Neuroimaging at University College Emelda Aluoch Okiro (KEMRI–Wellcome Trust Research Programme, Kenya): Changes in responses. Syk is also needed to London. His work focuses on paediatric malaria hospitalisation in East Africa. activate the intracellular complex (the computational models of brain function. ‘inflammasome’) that processes this In 2003 he was awarded the Minerva VETERINARY MEDICINE precursor into active interleukin 1 , but ‘Golden Brain’ award and is one of Helen Higgins: Assessing veterinary surgeons’ β clinical beliefs in dairy cow preventive medicine. this role is independent of Card9.4 world’s top ten most cited . SENIOR RESEARCH FELLOWSHIP This research was supported by the Wellcome Trust A former Senior Research Fellow, IN CLINICAL SCIENCE and other funders. Professor Robinson is based at the ANAESTHESIOLOGY 1 Jakus Z et al. J Immunol 2008;180(1):618–29. University of Cambridge. She is a world Anthony Pickering (University of Bristol): 2 Jakus Z et al. J Exp Med 2009;206(3):577–93. leader in research into the trafficking of Modulation of pain pathways by noradrenaline. 3 Werninghaus K et al. J Exp Med 2009;206(1):89–97. material through the cell in clathrin- SIR HENRY POSTDOCTORAL 4 Gross O et al. Nature 2009;459(7245):433–6. coated vesicles. WELLCOME FELLOWSHIP DNA DAMAGE Professor Spratt was among the first Hannah Mischo (CRUK London Research researchers to be awarded a PRF by the Institute): Sen1 and prevention of DNA damage. Wellcome Trust. His research at Imperial HISTORY OF MEDICINE FELLOWSHIP College London focuses on bacterial evolution, population genetics and MUSIC James Kennaway (Durham University): Music molecular epidemiology. as a cause of ill-health.

BIOMEDICAL ETHICS FELLOWSHIP CLINICAL TRIALS Neema Sofaer (King’s College London): Post-trial access to trial drugs, healthcare and information.

IMAGE A neutrophil, a key player in innate immune responses. 36 | Using knowledge

Structure of the Mhp1 membrane protein. Caption here Facilitating research | 37

Facilitating research

Promoting the best conditions for research and the use of knowledge

Inside story European engagement

The structure of a bacterial membrane Of greatest interest, the structure Engagement with the EU has helped protein has revealed an elegant suggests a mechanism for the specific to keep key research alive. mechanism of cross-membrane transport of its substrate – confirming transport. the ‘alternating access’ model proposed European legislation can significantly many years ago for the action of affect research in UK institutions. By Membrane proteins make up around 25 membrane transporters. working with partners with similar per cent of all proteins (and 40 per cent interests and by providing evidence on of drug targets). Yet, because membrane Without substrate, a central chamber the likely impact of two EU directives – on proteins are so hard to work with, is exposed to the outside environment. medical imaging and the use of animals relatively few structural studies have When hydantoin engages, it triggers – the Trust has helped to ensure that the been carried out on them. A dedicated a conformational change that in effect needs of medical research are taken into Membrane Protein Laboratory, led by closes the door to the entry of further account in the EU legislative process. Imperial College London’s So Iwata, has molecules. A second shift in structure been set up with Wellcome Trust funding exposes hydantoin to the inside of The Physical Agents Directive aimed to at the Diamond synchrotron, to act as a the cell, where it is ejected and the protect the health of workers exposed resource to support structural studies of transporter reverts to its original to electromagnetic fields. As originally membrane proteins. Work on a bacterial structure. drafted, however, it would have had transporter illustrates the kind of insights serious consequences for both clinical that structural studies can provide. The structure is likely to have relevance and research use of magnetic resonance beyond the world of bacteria. Many imaging equipment. Following input Mhp1, a membrane protein from membrane transporters, in all kinds of from the Trust and others, the Directive Microbacterium liquifaciens, has a organisms, are thought to operate was postponed for four years and the ‘metabolic salvage’ function. It imports through the alternating access process of revision is now underway. derivatives of the organic molecule mechanism. This work should therefore hydantoin, which are used to make a aid understanding of other structures The Use of Animals in Research Directive variety of amino acids. It is an important that move molecules across would have significantly hindered the use ‘model’ structure as it is one of a large membranes. of non-human primates and re-use of class of similar transporters: more than animals in research, stifling vital research, 800 are known in total, from all classes This research was supported by the Wellcome Trust hindering medical progress and of life. Its structure was worked out at and other funders. undermining Europe’s commercial and the Membrane Protein Laboratory by 1 Weyand S et al. Science 2008;322(5902):709–13. scientific competitiveness. Unnecessary Professor Iwata in collaboration with bureaucratic requirements would Peter Henderson from the University of make research in Europe prohibitively Leeds and others.1 expensive, and potentially drive studies abroad to countries with lower standards of animal welfare.

The Trust worked with a large coalition of bodies to collate evidence for the European Parliament and Home Office and House of Lords reviews of the Directive. It is hoped the important revisions made to date will remain intact. 38 | Facilitating research

Growing UP Taming the ‘beastly science’

Studies on the ALSPAC birth cohort infants with diagnosed brain damage Sir Bernard Spilsbury almost single- are revealing a host of factors affecting were at risk of lower IQ, but so too were handedly created the field of forensic children’s mental development. those who had been resuscitated but not medicine. His story is inspirational but identified as affected.7 Although the IQ also a timely warning. Set up in 1991, the Avon Longitudinal differential was smaller, they are a much Study of Parents and Children (ALSPAC) larger group overall. Educated at Oxford and St Mary’s is one of the world’s largest and longest- Hospital, London, Spilsbury specialised running birth cohorts. It covers some Paul Ramchandani and colleagues have in the emerging science of forensic 14 000 children and their parents, found that paternal depression can affect medicine – the ‘beastly science’, as it providing researchers with a treasure children’s wellbeing.8 A comparison of the was then known. He became a nationally trove of data on many aspects of effects of prenatal and postnatal recognised figure following the childhood health and development. depression suggested that ‘environmental’ Dr Crippen case in 1910, in which he Several recent studies have made influences may be more significant than testified that the remains of a body buried important discoveries about ‘biological’ factors. in lime in Crippen’s basement belonged to environmental, family and genetic his wife, on the basis of a scar-bearing influences on children’s mental health Cohorts such as ALSPAC are particularly fragment of skin. Crippen was hanged and and development. useful for studying the interaction between Spilsbury became a national celebrity. genes and environment, as a wide variety Stan Zammit and colleagues in Bristol of ‘lifestyle’ data are collected and samples Spilsbury was a prolific worker. He have looked at a range of factors that are available for DNA analysis. Two studies undertook more than 25 000 post might be associated with subclinical looking for links between behaviour and mortems – up to a 1000 a year. Although psychotic episodes – possible warning genetic variants affecting serotonin best known for lurid high-profile cases – signs of increased risk of schizophrenia metabolism have generated contrasting Crippen, the ‘Brides in the Bath’ trial, the in adulthood. They identified links with results. Early life stress and MAOA-LPR Brighton trunk murders and others that impaired fetal growth,1 trauma at or interact to increase the risk of transfixed the British public – his work around the time of birth,2 maternal hyperactivity,9 but no effects were seen actually illustrated how mundane sudden smoking3 and events in childhood itself, for a second variant, HTTLPR.10 death usually was. such as bullying.4 This research was supported by the Wellcome Trust He studiously recorded notes on index Alan Emond and colleagues found an and other funders. cards, nearly 4000 of which were association between binge drinking in 1 Thomas K et al. Br J Psychiatry 2009;194(6):521–6. purchased by the in mothers and behavioural problems such 2 Zammit S et al. Br J Psychiatry 2009;195(4):294–300. 2008, while a further 3000 were donated as hyperactivity at age four (in girls) and 3 Zammit S et al. Psychol Med 2009;39(9):1457–67. in 2009. Together, the cards provide a 5 at age seven (in both sexes). They also 4 Schreier A et al. Arch Gen Psychiatry fascinating insight into death and its identified a link between lead levels in 2009;66(5):527–36. forensic investigation from 1905 to 1946 blood at 30 months and a range of 5 Sayal K et al. Pediatrics 2009;123(2):e289–96. (with the odd gap). indicators at age seven to eight, including 6 Chandramouli L et al. Arch Dis Child reading and writing ability, SATs results 2009;94(11):844–8. The cards tell of tragic suicide, failed and antisocial behaviour measures, even 7 Odd DE et al. Lancet 2009;373(9675):1615–22. abortions and medical mysteries that at lead levels well below the generally stumped Spilsbury (such as likely cases 6 8 Ramchandani PG et al. J Child Psychol Psychiatry recognised risk level. 2008;49(10):1069–78. of cot death). Each card tells of a life brought to an untimely end in sad, 9 Enoch MA et al. Genes Brain Behav 2009 9 Sep David Odd (a Wellcome Trust Training [Epub ahead of print]. Fellow) and colleagues have looked at 10 Araya R et al. Am J Med Genet B Neuropsychiatr links between resuscitation at birth and Genet 2009;150B(5):670–82. cognition at age eight. As expected, Facilitating research | 39

New funding A SELECTION OF NOTABLE GRANTS AWARDED IN 2008/09

African consortia BIOMEDICAL RESOURCES NEURAL NETWORKS Professor Angus Silver (University College London): An open source database for pathetic or sometimes downright bizarre More than 50 institutions from 18 biologically realistic neural network models. ways: 42-year-old Ada Farnden took African countries are participating YEAST BIOLOGY quinine to induce an abortion: in international consortia under Carol Munro (University of Aberdeen): Novel “Laundress, four children in six years. a £28 million initiative aimed at tools for functional genomics of Candida Took quinine in port wine at 11am. Taken strengthening research capacity albicans. ill soon afterwards”; five-year-old Louisa across Africa. TECHNOLOGY DEVELOPMENT GRANTS Messenger was a victim of “death from IN VIVO IMAGING poisoning by rhubarb”. The African Institutions Initiative is Alessandro Sardini (Imperial College): supporting seven new international and Instrumentation for fluorescent imaging in living The notes may have been intended for pan-African consortia. The partnerships animals. a textbook on forensic medicine, which – each led by an African institution – aim MUTATION DETECTION Spilsbury never got round to writing. to develop the capacity of institutions Professor Sir Alec Jeffreys (University of Instead, his life – professional and to support and conduct health-related Leicester): High-throughput screening for de personal – headed into inexorable research to enhance people’s health, novo point mutations in human genomic DNA. decline. He was badly affected by the lives and livelihoods. The consortia are EQUIPMENT death of two sons, in World War II and led by researchers in academic centres RADIOTHERAPY from TB. Always strong-willed, he in Côte d’Ivoire, Ghana (two), Kenya, Stewart Martin (University of Nottingham): became increasingly dogmatic. Malawi, Tanzania and Uganda. Experimental radiation biology irradiation facility.

During his life, Spilsbury encountered Although the consortia include partners EMBRYOLOGY Timothy Mohun (National Institute for Medical many suicide victims. His own life ended from high-income countries, the agenda Research): An imaging pipeline for screening the same way. In December 1947 he for each has been set by the African mouse embryos. went to his laboratory in University centres’ needs and priorities. Each College London, turned on a Bunsen consortium operates independently CELL BIOLOGY Adrien Kissenpfennig (Queen’s University burner and gassed himself to death. and sets its own priorities, for example Belfast): A flow cytometry cell sorter. investment in leadership training and Spilsbury undoubtedly transformed the professional development, support BRAIN IMAGING field of forensic medicine. Yet perhaps he for PhD and postdoctoral fellowships, Professor Paul Furlong (Aston University): A magnetoencephalography system for infants. has a second legacy: a warning of the improved infrastructure, competitive dangers of depending on personal grant schemes and purchase of up-to- Professor Ray Dolan (University College opinion, no matter how authoritative, date equipment. London): An upgrade of MRI scanners at the when the stakes are so high. Wellcome Trust Centre for Neuroimaging at UCL. Ultimately, the main aim is to build All of the Spilsbury cards have been catalogued sustainable local research capacity DATABASE and can be accessed through the Wellcome Gerrit Kleijwegt (European Bioinformatics Library’s Archives and Manuscripts catalogue across Africa, by strengthening Institute): A European Protein Data Bank. (library.wellcome.ac.uk); see www.timesonline.co. universities and research institutions uk/tol/news/science/article5429780.ece and enabling them to develop research RESEARCH RESOURCES IN for more on the Spilsbury papers. networks. In this way, more African MEDICAL HISTORY universities can become platforms for MEDICAL RECORDS internationally competitive research Mike Barfoot (University of Edinburgh): tackling locally relevant health Preservation of 20th-century case notes relating challenges. to tuberculosis and World War II injuries.

IMAGE Spilsbury’s index cards in the Wellcome Library. 40 | Developing our organisation

Developing our organisation

Using our resources efficiently and effectively

Operations and ENGAGING Fair shares education Communications

Two senior staff with a wealth of Video, tweets and blogs are all being A £1.2 billion investment in large experience in contrasting domains used to communicate the Trust’s work. multinational companies had have joined the Wellcome Trust. increased in value by 25 per cent by The internet has opened up many new the end of the year. Simon Jeffreys, the Wellcome Trust’s ways in which organisations can new Chief Operating Officer, is charged communicate with different audiences, Despite a challenging year, the Wellcome with ensuring that the organisation is run and the Wellcome Trust has moved to Trust’s investments achieved gains of as efficiently and effectively as possible. adopt these new approaches. £580 million (5 per cent) during 2008/09, Having joined the Trust in March 2009, and were valued at £13.0bn at he has assumed responsibility for For example, the news and features 30 September 2009. key business operations, including posted on the Trust’s main website can finance, grants management, facilities now be obtained by RSS feeds or by A significant contribution to this strong management, IT, human resources and signing up to an e-newsletter. This year performance came from investment in legal affairs. He has absorbed many of has also seen a rapid growth in the use of late 2008 and early 2009, when stock the responsibilities previously held by video features, available on the main markets were very weak, of £1.2bn in John Cooper, who has taken on the role websites and on dedicated Wellcome shares of 32 global companies. Such of Chief Operating Officer and Interim Trust and Wellcome Collection YouTube companies, each valued at a minimum Chief Executive of the UK Centre for channels, which both launched in of US$50bn, typically deliver strong Medical Research and Innovation. January 2009. The Trust also uses returns during difficult economic times, Twitter to provide brief up-to-the-minute and after the stock market decline, their Simon Jeffreys has spent most of information, and has accumulated more shares represented very good value. By his professional life at than 2000 followers. The audience for the end of the year, the value of these PricewaterhouseCoopers and its Wellcome Trust print publications such investments had already risen to £1.6bn, predecessor firms, latterly as chairman as Wellcome News and Big Picture has an increase of 25 per cent. of its global investment management also significantly increased both in terms practice and part of the firm’s global of print circulation numbers and online The fall in stock market prices also financial services leadership team. usage following their inclusion in ‘online enabled the Trust to acquire a range libraries’ such as Yudu, Scribd and Issuu. of other shares at favourable prices, Derek Bell, former Chief Executive of the including 3 per cent of the shares of Association for Science Education, took Other new developments include a Marks & Spencer plc. over as the Wellcome Trust’s Head of Facebook page for Wellcome Collection, Education in January 2009. which has attracted more than 1200 Shares now account for around members, while the Wellcome Library 38 per cent of the Trust’s investment Professor Bell will have responsibility has launched a blog that provides an portfolio, with holdings geographically for the Trust’s education strategy and informative guide to the Library’s activities, well diversified. A growing proportion further developing the Trust’s leading role purchases and holdings. The Library’s are managed from within the Trust itself. in UK science education. This work will fascinating Moving Image and Sound The ability of the Trust to invest directly focus on increasing opportunities and Collection also has its own ‘Wellcome in equity markets has been enhanced by strengthening the culture for continuing Film’ YouTube channel. the establishment of a Public Securities professional development for science Execution team led by Tim Johnston, teachers. In addition, Professor Bell will www.twitter.com/wellcometrust previously at Goldman Sachs and a www.youtube.com/wellcometrust look at how research can best be used www.scribd.com/Wellcome Trust number of hedge funds. to support education policy making and issuu.com/wellcome-trust teaching practice. www.twitter.com/explorewellcome Overview | 41

1

CORPORATE ACTIVITIES 2008/09

Governors and senior staff commissioned by the Trust, the Medical The Wellcome Trust’s Director, Mark Research Council and the Academy of Walport, received a knighthood in the Medical Sciences that assessed the 2009 New Year’s Honours List for returns achieved from investment in services to medical research. Sir Mark research into cardiovascular disease and was appointed chair of the Science and mental health. Learning Expert Group established by the UK Department of Business, Internally, work began on a new Strategic 2 Innovation and Skills as part of its Plan, to follow the Trust’s previous science and society strategy. Strategic Plan 2005–2010: Making a difference. Peter Davies, a senior limited partner at With support from the Trust and other Lansdowne Partners, joined the Board of Priority areas bodies in the UK and USA, Professor Governors in September 2009. Simon The Trust reacted swiftly in response Sir Andrew Haines from the London Jeffreys was recruited to run the Trust’s to the H1N1 swine flu epidemic. An School of Hygiene and Tropical Medicine business operations, Derek Bell ongoing programme of work on global led a study investigating the potential assumed responsibility for the Trust’s influenza in human and animal health health benefits of reducing greenhouse education work and Tim Johnston joined was rapidly refocused on pandemic gas emissions to help combat the Investment team (see left). H1N1 after the outbreak was detected in climate change. Its findings informed February 2009. In spring 2009, a series discussions at the UN Climate Change Research environment of workshops were held with key UK Conference in Copenhagen, December The Human Fertilisation and Embryology funding and public health bodies, leading 2009. (HFE) Act was granted Royal Assent in to the rapid appraisal and funding of a November 2008. The Trust had worked series of collaborative programmes (see The Trust also brought together leading with a range of partners to ensure that page 14). Scientific advisory meetings researchers and other groups to discuss discussions of potentially contentious on seasonal, avian and pandemic issues arising from genomic and issues such as hybrid embryos were influenza were organised to identify cohort-based studies. Oxford’s Ethox balanced and factual, and that due gaps in knowledge and research Centre has been commissioned to consideration was given to the potential priorities. This work, including vaccine, conduct a literature review in this area. medical benefits of research covered by drug development and epidemiology, the legislation. is feeding into the World Health In collaboration with the Bill and Melinda Organization’s public health research Gates Foundation, the Trust is Following a series of meetings with key agenda for influenza. The Trust hosted supporting a scoping exercise to explore stakeholders, in June 2009 the Trust a joint meeting with the WHO on novel the potential for an ‘international index published a set of guidelines on the use influenza vaccines and continues to for nutrition’, which would assess how of medical records in research. Towards play an active role in the development of well companies were meeting their Consensus for Best Practice: Use of international policy. corporate and social responsibilities, in patient records from general practice for high-, middle- and low-income research was endorsed by the British The Trust is also supporting the South countries. The Global Alliance for Medical Association and the Royal East Asia Infectious Disease Clinical Improved Nutrition in Geneva is exploring College of General Practitioners. Research Network, which aims to approaches that might encourage food enhance regional capacity in clinical and beverage industries to adopt best In November 2008, the Trust published research and patient management. The practice with regard to the nutritional Medical Research: What’s it worth?, Network’s activities cover pandemic value of their products. the results of a year-long study H1N1 and H5N1 influenza.

IMAGES 1 H1N1 influenza virus. 2 Simon Jeffreys, the Trust’s new Chief Operating Officer. 42 | Financial summary 2008/09

Financial summary 2008/09

BREAKDOWN OF WELLCOME TRUST CHARITABLE EXPENDITURE 2008/09 Total: £720m Total charitable expenditure for the year increased to £720 million (2007/08: £702m). This rise is BIOMEDICAL SCIENCE GRANTS DIRECT ACTIVITIES principally due to a number of large £454.5m £39.8m Strategic Awards and new initiatives launched during the year, such as in TECHNOLOGY TRANSFER SUPPORT COSTS medical engineering. GRANTS £39.8m £60.2m Careers MEDICINE, SOCIETY Expenditure on careers support totalled AND HISTORY GRANTS 1 £135.2m (2007/08: £147.3m); in £16.5m addition, a significant proportion of funds committed through the African WELLCOME TRUST Institutions Initiative is likely to be used to Genome Campus provide careers support. £109.6m2

1 History of medicine, biomedical ethics and International public engagement with science. Funding to Major Overseas Programmes 2 This consists of: Wellcome Trust Sanger Institute and to institutions outside the UK totalled £97.4m (including £18.1m from other funders); £103.2m. other Genome Campus activities £12.2m.

Infrastructure DIRECT ACTIVITIES: £39.8M Expenditure on buildings, refurbishment, equipment and resources amounted to Direct activities are those managed by Biomedical science £20.2m in 2008/09. This figure does not the Wellcome Trust itself or in £7.2m include the significant expenditure on partnership with others. These include: Technology Transfer £13.3m equipment or infrastructure provided as Wellcome Collection • Medicine, Society part of other Trust grants, nor the likely • directly managed public engagement and History expenditure on infrastructure through the activities £19.3m African Institutions Initiative. • scientific conferences.

NB: These categories are not exclusive: some grants (e.g. international fellowships and capital awards) fall into more than one category. In these CHARITABLE EXPENDITURE 2005–09 (£M) cases, sums awarded have been included in all relevant categories, to give a more realistic indication of expenditure in each area. 800 720 700 702

600 520 Support expenditure 484 500 483 Direct expenditure Wellcome Trust Sanger Institute 400 Grants awarded 300

200

100 Further information is provided in the Wellcome Trust’s 0 Annual Report and Financial Statements 2009, 2005 2006 2007 2008 2009 available at www.wellcome.ac.uk/publications. Financial summary 2008/09 | 43

FUNDING HIGHLIGHTS Investments

£49m £5m The Trust’s asset base was £13.0 billion at 30 September 2009, Core support for South-east Asia Oxford Centre for Neural Circuits representing a return of £580 million Major Overseas Programme and Behaviour or 5 per cent over the year. £45m £4.8m During a year of volatile global markets, Sainsbury–Wellcome Centre for Novartis Vaccines Institute for Global the Trust’s flexible and active Neural Circuits and Behaviour at UCL Health: typhoid fever vaccine management of its investment portfolio ensured that its asset base remained £28m £3.7m intact. The year was marked by African Institutions Initiative Core funding Wellcome Trust Centre significant acquisition of equities for Cell-Matrix Research including a 3 per cent stake in Marks & £26.9m Spencer (see page 40). Strong Medical engineering centres of £3.4m performance of these assets added more excellence1 Flu research consortia grants4 than £400m to the Trust’s asset base. Performance is well ahead of world £22.8m £2.9m markets over three-, five- and ten-year Research Career Development Joint Basic and Clinical PhD timeframes. Fellowship funding Programmes Management of risk continued to be a key £19.7m £2.5m focus amid uncertain market conditions. Aided by a variety of defensive strategies, Seeding Dug Discovery initiative Kadoorie Biobank Study the Trust’s exposure to risk has risen only awards slightly, and is significantly below that £2.4m seen in global equity markets. £15m South-east Asia Major Overseas New Senior Research Fellowship Programme: primaquine use in vivax A key factor in the success of the portfolio funding malaria is its global diversification. UK-based assets now represent just 13 per cent of the total £11.3m £2.3m portfolio, the largest constituent being long- Neurodegenerative Diseases Karonga Prevention Study, Malawi term holdings of £0.9bn in residential Initiative2 property in London and South-east £1.8m England. These prime real estate holdings £10m Medicine, Society and History have held their value well even during the Genome-wide association studies3 Capital Awards UK’s recent house price decline. To avoid the need to dispose of assets at £7.7m £1.1m low prices during volatile periods, the Trust Clinical PhD Programmes Enhancement Awards in maintains high levels of liquidity in order to Biomedical Ethics £7.2m meet its annual cash expenditure of over 1  £600m. A second AAA/Aaa bond issue in Principal Research Fellowship renewals Plus £13.5m from Engineering and Physical Sciences Research Council. May 2009 contributed to holdings in cash 2 Plus £5.7m from Medical Research Council. and short-term bonds of £1.8bn at 3  Including £4.8m support for the Wellcome Trust year-end. Sanger Institute. 4 Plus contributions from Biotechnology and Average annual returns since Wellcome plc Biological Sciences Research Council, Department for Environment, Food and Rural was floated in October 1985 have been Affairs and Medical Research Council. 14.5 per cent, well ahead of inflation and global equity returns. 44 | Financial summary 2008/09

Funding developments 2008/09

NEW FUNDING INITIATIVES

The Wellcome Trust reserves a ADVANCING KNOWLEDGE The Research and Development for significant part of its funding for Affordable Healthcare in India initiative will major initiatives and projects of • Insect Pollinators Initiative fund translational projects that deliver international significance. These • Genome-wide association studies safe and effective healthcare products for are generally supported through India, and potentially other markets, at The Wellcome Trust, the Biotechnology Strategic Awards, which, along with affordable costs. The five-year, £30m and Biological Sciences Research some other large or unusual awards, initiative will support all areas of Council, the Department for Environment, are considered by a Strategic technology development, including Food and Rural Affairs, the Natural Awards Committee. diagnostics, therapeutics, vaccines, Environment Research Council and the medical devices and regenerative Scottish Government launched an Insect Ongoing funding programmes are medicine. A significant proportion of the Pollinators Initiative to fund research into based around funding streams, programme should be conducted in the threats to bees and other insect covering core areas of biomedical India, although international pollinators and possible mitigation science and the medical humanities. collaborations may be eligible for support. strategies. Cutting across these streams are Companies, universities and not-for-profit funding programmes in Technology institutions are eligible to apply. A further round of funding was provided Transfer and Public Engagement. Each for genome-wide association studies. funding stream has associated with Projects could be carried out in ENGAGING SCIENCE it one or more Funding Committees, collaboration with the Wellcome Trust responsible for most funding decisions. Case Control Consortium or Science Media Production Strategy Committees advise the Trust •  independently (see page 6). studentships on needs and opportunities within specific areas: (1) Neuroscience and The Wellcome Trust and Imperial College Mental Health; (2) Molecular and USING KNOWLEDGE London are launching studentships to Physiological Sciences; (3) Pathogens, support biomedical students interested in and Public Health; (4) • Health Innovation Challenge Fund a career in science broadcasting. The Medical Humanities; (5) Technology themed call 18-month studentships will enable two Transfer; and (6) Public Engagement. • Research and Development for students to undertake a postgraduate Affordable Healthcare in India course in Science Media Production at The funding streams offer a variety Imperial, including a six-month placement The Department of Health and the of forms of support, such as project in the broadcast industry. Wellcome Trust invited the first funding and programme grants, and career proposals under the Health Innovation development awards. Technology Challenge Fund, launched to further the DEVELOPING PEOPLE Transfer funding comprises Translation development of innovative healthcare Awards and Strategic Translation products. Through the provision of Starter Grants for Clinical Lecturers Awards, as well as Strategic Translation •  ‘gap-bridging’ funding, this five-year, Wellcome Trust Postdoctoral Awards in Seeding Drug Discovery. •  £100 million initiative will stimulate the Training Fellowships for MB/PhD Public Engagement support is primarily delivery of technologies, products and Graduates through the Engaging Science interventions having clinical applicability in Wellcome–Beit Prize Fellowships programme, which includes Society •  and beyond the NHS within three to five Wellcome Trust–MIT Postdoctoral Awards, People Awards, International •  years. The first themed call, providing Fellowships Engagement Awards and Small and total funding of up to £20m, focused on Wellcome Trust–DBT India Alliance Large Arts Awards. •  the clinical application of genetic fellowships discoveries. Occasional large capital awards are made to support nationally or internationally important developments. Financial summary 2008/09 | 45

FUNDING ANALYSIS

The Trust and the Academy of Medical Three fellowship schemes have been Total no. of grant applications 3138 Sciences launched a Starter Grants for launched by the Wellcome Trust–DBT Total no. of grants awarded 1104 Total value of applications considered £1.4bn Clinical Lecturers scheme, providing up India Alliance, an £80m partnership Total value of grants awarded £531m to £30 000 over two years, to support between the government of India and the No. of programme grants awarded 38 clinicians’ research early in their careers. Wellcome Trust. Funding is available for No. of PRFs awarded/renewed1 3 Early Career Fellowships, Intermediate No. of SRFs awarded/renewed 22 New Postdoctoral Training Fellowships Fellowships and Senior Fellowships. The No. of intermediate fellowships awarded 8 for MB/PhD Graduates provide up to first awards have been made to No. of training (junior) fellowships awarded 44 four years’ support, and enable fellows successful applicants in each scheme. No. of PhD studentships awarded 184 to undertake a period of postdoctoral research and continue their clinical FUNDING RATES Number Value FACILITATING RESEARCH training. Project grants 23% 21% Programme grants 46% 42% Health Research Capacity New Wellcome–Beit Prize Fellowships •  New PRFs (full app.) 0% 0% Strengthening initiative have been launched. The £25 000 SRFs (full app. Basic) 16% 20% SRFs (full app. Clinical) 30% 29% awards, which replace the Beit Memorial The Health Research Capacity SRFs (full app. Tropical) 0% 0% Fellowships for Medical Research, will be Strengthening initiative, a partnership SRFs (full app. International) 9% 8% made annually to each of four selected between the Trust and the UK Intermediate fellowships 11% 9% scientists awarded a Research Career Department for International Training (junior) fellowships 26% 26% Development Fellowship or Intermediate Development, is supporting two bodies History of Medicine Strategic Clinical Fellowship. Each prize will be awarding grants in Kenya and Malawi. and Enhancement Awards 100% 69% made in addition to the fellowship The Consortium for National Health History of Medicine ad hoc 40% 24% support and can be used flexibly in Research in Kenya and the National History of Medicine outreach 33% 15% support of fellows’ research. Research Council of Malawi have Research Resources in Medical History 48% 20% received £10m each over five years to Biomedical Ethics 39% 29% The Wellcome Trust and the make awards according to their national People Awards 22% 21% Massachusetts Institute of Technology research and training priorities. Schemes Society Awards 50% 54% (MIT) launched a new fellowship scheme have been launched for Centres of Arts Large Awards 13% 13% to promote interdisciplinary science. The Research Excellence, Research Group Arts Small Awards 14% 13% Wellcome Trust–MIT Postdoctoral Leaders, Research Training Fellows and Total no. of institutions receiving Fellowship scheme provides four years’ Research Placements. funding in 2008/09 (UK) 88 support for research at the interface of Total no. of institutions receiving biology/medicine and mathematics, funding in 2008/09 (non-UK) 73 engineering, or computer, physical or OUTSTANDING LIABILITIES chemical sciences. Fellows will spend Total grants commitments2 £1.41bn two to three years at MIT and one to two No. of countries receiving funding 74 years in the UK. Fellows currently supported 802 Researchers currently supported 3459 Total no. of institutions receiving funding (UK) 106 Total no. of institutions receiving funding (non-UK) 125

1 Includes PRF programme grant renewals. 2 As at 30 September 2009. PRF: Principal Research Fellowship SRF: Senior Research Fellowship

IMAGE Microparticle drug delivery. 46 | Streams funding 2008/09

Streams funding 2008/09

Number of grants awarded 185 Value of grants awarded £82.5m Number of programme grants awarded 12 Value of programme grants awarded £14.8m New and renewed Principal and Senior 8 MOLECULES, GENES AND CELLS Research Fellowships The Molecules, Genes and Cells stream supports high-quality research that will OTHER MAJOR AWARDS further our understanding of the • £5.7m Core support for Wellcome Trust Centres for Cell-Matrix Research and fundamental biology and specialist Research, and functions of molecular, cellular and • £5.2m Genome-wide association studies genetic processes, and their role in • £2.6m Strategic Award (type 2 diabetes; Mark McCarthy) health and disease. • £2.5m Strategic Award (enzyme regulation; Ashok Venkitaraman) • £2.5m Capital Award to UK Health Protection Agency for pilot manufacturing facility

Number of grants awarded 173 Value of grants awarded £64.3m Number of programme grants awarded 9 Value of programme grants awarded £11.8m New and renewed Principal and Senior 7 Immunology and Research Fellowships Infectious Disease The Immunology and Infectious Disease OTHER MAJOR AWARDS stream aims to increase our knowledge • £49.2m Core support for South-east Asia Major Overseas Programme and understanding of the infectious • £3.4m H1N1 influenza fast-track funding organisms that cause disease in humans • £2.8m UK Centres for Clinical Tropical Medicine and animals, and of the immune systems that fight these organisms.

Number of grants awarded 121 Value of grants awarded £53.3m Number of programme grants awarded 8 Value of programme grants awarded £11.3m New and renewed Principal and Senior 6 Neuroscience and Research Fellowships Mental Health

The Neuroscience and Mental Health OTHER MAJOR AWARDS funding stream aims to support high- • £45m Sainsbury–Wellcome Centre for Neural Circuits and Behaviour at UCL quality research into the function of the • £11.3m Strategic Awards in Neurodegenerative Diseases nervous system in health and disease. • £7.7m Clinical PhD Programmes • £5m Oxford Centre for Neural Circuits and Behaviour • £2.9m Joint Basic and Clinical PhD Programmes Streams funding 2008/09 | 47

Number of grants awarded 80 Value of grants awarded £26.9m Number of programme grants awarded 4 Value of programme grants awarded £4.7m New and renewed Principal and Senior 4 Physiological Sciences Research Fellowships The Physiological Sciences funding stream aims to support high-quality basic and clinical research relevant to the understanding of biological processes at the cell, organ, system and whole-animal levels in health and disease.

Number of grants awarded 45 Value of grants awarded £23.4m Number of programme grants awarded 4 Value of programme grants awarded £9.0m New and renewed Principal and Senior 0 Populations and Research Fellowships Public Health

The Populations and Public Health OTHER MAJOR AWARDS stream supports research to improve • £27.7m African Institutions Initiative understanding of the determinants of • £5m DfID Health Research Capacity Strengthening Initiative in Malawi, Kenya disease and quality of life in populations, • £1.8m UK Biobank and to provide a sound evidence base to inform decisions in public health and healthcare delivery.

Number of grants awarded 151 Value of grants awarded £10.4m Number of programme grants awarded 1 Value of programme grants awarded £0.4m

Medical Humanities OTHER MAJOR AWARDS The Medical Humanities stream aims to • £0.8m Strategic Award in Biomedical Ethics enhance understanding of the historical and social context of medicine and biomedical science. It supports research in history of medicine and biomedical ethics, and encourages use of findings, for example to inform public policy making. 48 | Technology Transfer

Technology Transfer

Technology Transfer at the Wellcome improve diagnosis and treatment of a of lysyl oxidase, an enzyme associated Trust seeks to maximise the impact range of cardiovascular and psychiatric with metastatic growth of cancers. And of research innovations on health conditions. David Madge and colleagues at Xention by facilitating their development to Ltd are developing small-molecule a point at which they can be further With a motto of ‘50 more years after 50’, inhibitors of cardiac ion currents to treat developed by the market. John Fisher and colleagues at Leeds are atrial fibrillation. working on a range of regenerative and Unmet medical needs in low- and replacement technologies to mitigate In diagnostics, Louise Kenny of middle-income countries were a major the effects of ageing. Finally, Lionel University College Cork received a focus of the year, with the launch of Tarassenko in Oxford is leading a varied Translation Award to support early a vaccine development venture in programme of work using technological research aimed as developing a partnership with Merck and an affordable solutions to provide more individualised biomarker-based assay for pre- healthcare initiative in India. In the UK, healthcare. eclampsia, the most common serious four medical engineering centres of complication of pregnancy. At the excellence were funded, alongside Medical engineering was also a theme of University of Bristol, Chris Probert is translational projects in a range of areas several Translation Awards made during refining a device for diagnosing the including cancer, infectious disease and the year. Mihailo Ristic from Imperial, for causes of diarrhoea to enable its routine prosthetics. example, is developing an MRI-guided use in clinical settings. endoscope, while Chris Toumazou is Vaccines represent one of the most designing a bio-artificial pancreas for Among other notable awards, Lisbeth cost-effective ways to relieve the health type 1 diabetes. Illum and colleagues at Critical burden imposed by infectious diseases. Pharmaceuticals Ltd are developing a Yet for many diseases affecting low- and In the Seeding Drug Discovery initiative, human growth hormone nasal spray for middle-income countries, no vaccines several awards went to projects children with growth hormone deficiency, exist or they are not optimised for locally tackling infectious diseases. Peter and Julian Yates and colleagues at the prevalent strains. To address this need, Andrew of the University of Leicester is are designing a the Trust has launched a new vaccine developing drugs against pneumolysin, rapid manufacturing system for facial development initiative in partnership with a toxin responsible for much of the soft tissue prostheses. Merck, to be run as an independent not- tissue damage seen in pneumococcal for-profit enterprise in India (see page 23). infections. Johan Neyts of the Rega In all, Strategic Translation Awards worth Institute for Medical Research, Leuven, £8m were made to four projects, and The Medical Engineering Initiative, Belgium, is working on agents to combat Translation Awards totalling £13m were launched in 2008 in partnership with dengue virus, while Neil Thompson and made to 16 projects. Initial applications the Engineering and Physical Sciences colleagues at Astex Therapeutics Ltd are were considered in the Affordable Research Council, made four awards using an innovative fragment-based drug Healthcare Initiative, while the first call for totalling £40.4 million, to Imperial College discovery approach to identify inhibitors proposals was made in the £20m Health London, King’s College London, the of hepatitis C virus. Innovation Challenge Fund, a partnership University of Leeds and the University of with the UK Department of Health. The Oxford. Seeding Drug Discovery awards were first awards under these initiatives are also made in other areas of medical expected in 2010. The Imperial centre, led by Ross Ethier need. Clive Robinson of St George’s, and colleagues, aims to develop better University of London, is developing a implants and surgical techniques for new class of drugs that target the root people with osteoarthritis. At King’s cause of asthma and allergic diseases. College, Reza Razavi and colleagues Caroline Springer of the Institute of are refining imaging technologies, to Cancer Research is developing inhibitors

IMAGE Optical motion tracking in Ross Ethier’s lab at Imperial College London. Wellcome Trust Genome Campus | 49

Wellcome Trust Genome Campus

The Wellcome Trust Genome Campus disease. Interactions with pathogens – Advanced Courses and Scientific at Hinxton, near Cambridge, is home natural selection in action – were also Conferences to the Wellcome Trust Sanger Institute, explored in work on Chlamydia and The Advanced Courses and Scientific the Wellcome Trust Conference Centre Candida. Each shows extensive gene Conferences programmes have been and Wellcome Trust Advanced Courses. loss, but with very different outcomes: combined into one department. spread of undetectable Chlamydia and Appropriately for the 150th anniversary loss of virulence for Candida. The Advanced Courses programme ran of Darwin’s On the Origin of Species, 22 courses in Hinxton, Thailand, Malawi, evolutionary processes were a strong The platforms to knock out genes in the Uruguay and Kenya. New courses theme of the Sanger Institute’s research mouse genome and to characterise their teaching practical laboratory skills were in 2009. The strengths of the Institute’s effects have ramped up significantly this held, including ‘Genetic Manipulation of research were also reflected in the year. Sanger Institute researchers have ES Cells’. A new IT-based course was scientific conferences and courses produced more than 5000 mutant mouse developed, ‘Genomic Epidemiology of organised at the Genome Campus. embryonic stem cell lines, as part of Malaria’, which will be run in Bangkok major international programmes. More in 2010. This year, Sanger Institute researchers than 300 mutant mice are being directly measured the rate of mutation extensively characterised. Consistent Of particular note was the ‘Molecular – the driving force of evolution – in the with the Sanger philosophy of sharing Approaches to Clinical Microbiology’ human genome. Strikingly, other biological resources, these cells and course, held at the Malawi–Liverpool– discoveries raised interesting evolutionary mice are made freely available to the Wellcome Trust Clinical Research questions, such as why 4 per cent of academic community. They have also Programme, which attracted participants people from the Indian subcontinent been used by Institute researchers, from clinical diagnostics and research carry a mutation that appeared 30 000 leading to the discovery of the first departments all over Africa. This course years ago and significantly increases the microRNA mutation causing deafness in will be further developed and held in risk of heart disease, and why more than the mouse (a change also implicated in other African countries. 200 human genes can apparently be human hearing loss). inactivated without any effect on health. The Scientific Conferences programme Several Sanger Institute scientists have held 26 events ranging from large-scale Studies of variation in the human been formally recognised this year. Karen conferences to summer schools, genome – the legacy of our evolution Steel was elected a Fellow of the Royal workshops and invitation-only retreats. – aim to identify loci involved in disease. Society, was made a The annual ‘Genomic Disorders’ meeting As well as co-leading the 1000 Genomes Fellow of the American Academy of continues to grow in popularity, while the Project and the project generating the Microbiology, has been largest event during the year was the first sequence of an African genome elected to the Fellowship of the UK ‘Genomics of Common Diseases’ (page 6), Sanger Institute researchers Academy of Medical Sciences, and both conference. The ‘2nd Summer School of played leadership roles in a new map of Richard Durbin and Mike Stratton have Human Genomics’ was also very popular, structural variation and a host of studies been elected as members of the European with international tutors providing intensive linking human genetic variants to disease Molecular Biology Organisation. tuition to promising PhD students. (page 6). In cancer genetics, the first risk genes involved in testicular cancer were Conference Centre Future plans are to expand the number identified. In 2008/09 the Conference Centre of conferences held in Hinxton, creating generated sales of just under £2.4 million. an internationally renowned scientific Work on Clostridium difficile(page 10) Approximately 80 per cent of events programme fostering discussion, debate and Schistosoma mansoni (page 13) related to scientific research, with the and collaboration in the latest cutting-edge reflects two facets of the Sanger remainder being run for commercial areas of research, innovation and ideas. Institute’s commitment to infectious purposes.

IMAGE Genome Campus by night. 50 | Public engagement

PUBLIC ENGAGEMENT

The Wellcome Trust’s Public Broadcast Development Awards: Two issues of the Big Picture schools Engagement activities aim to engage 21 awards (up to £10 000) were made to resource were published during the year with society to foster a climate within support the development of broadcast – Health and Climate Change and Music, which biomedical science can proposals with a link to biomedical science. Mind and Medicine – while a special flourish. issue on influenza was published in International Engagement Awards: September 2009. A more thematic approach was adopted 17 small awards (up to £30 000) were during the year, starting with a themed made under the new International Supporting researchers and broadcast Society Awards call for proposals on Engagement Awards programme. In Six training workshops on narrative skills genetic variation and health. Darwin addition to this, one large award was were run for UK Trust-funded researchers, celebrations were a major theme of the made to the Wellcome Trust Major in addition to a refresher event for year (see page 26), and the experience Overseas Programme in South Africa previous attendees. An international gained in this work and other large-scale to support the development of its engagement workshop was held in ventures such as Wellcome Collection is in-country programme. South Africa, principally for international feeding into further initiatives integrating engagement grantholders but also to commissioned work and response- Capital Awards: Three major capital help to develop an international mode funding, starting with a six-month awards were made, to the Florence community of practitioners in low- season of activity exploring the theme of Nightingale Museum, the Mary Rose income countries. identity. Trust and the Museum of the Order of St John. A bursary scheme was launched to Grants enable practising biomedical scientists A total of 98 grants were awarded under Education to undertake a postgraduate qualification the £3.3 million Engaging Science initiative, The Trust’s nationally significant role in in Science Media Production at Imperial and 41 grants under the broadcast and science education was reflected in the College London, along with a six-month international engagement schemes. appointment of Sir Mark Walport as chair industry placement. of the UK government’s Science and Society Awards: Ten of these large Learning Expert Group. Derek Bell joined A number of projects supported by awards (over £30 000) were made for a the Trust from the Association for broadcast awards won prizes during the range of important activities. Support Science Education to lead the Trust’s year, most notably Here’s Johnny (Kat was provided to the Cheltenham education work, the centrepiece of Mansoor), which won two Grierson Festivals (see page 29), the Naked which is an ambitious project to identify Awards (Best Documentary on the Arts Scientists and a partnership aiming to options for the future shape of UK and the Bloomberg Award For Best integrate human genomics into the science education. Newcomer), and The English Surgeon, school curriculum. which won nine awards, including the The National Science Learning Centre Best International Feature Documentary People Awards: There were 45 awards had another successful year, providing at Hotdocs in 2008. (up to £30 000) made to support a 6519 training days, while the now formal diverse range of activities, including network of regional Science Learning Book Prize performances, exhibitions, talks, Centres contributed to almost 20 000 The £25 000 Wellcome Trust Book Prize conferences, debates and training days. In all, 73 per cent of UK was launched in October 2008. The annual documentaries. secondary schools and 17 per cent of Prize will be awarded to the year’s primary schools have had participants outstanding work of fiction or non-fiction Arts Awards: 38 small grants (up to attending training at a centre. on a theme linked to health, illness or £30 000) and two large grants (over medicine. Comedian and writer Jo Brand £30 000) were awarded. chaired the judging panel for the 2009 award.

IMAGE Henry Marsh, who features in the award-winning documentary The English Surgeon. Wellcome Collection | 51

1 2

WELLCOME COLLECTION

Wellcome Collection is a free public others. Packed Lunches will now The Wellcome Library blog was launched venue hosting events and permanent become a regular part of the Wellcome in October 2008, and attracted 24 000 and temporary exhibitions. It also Collection programme, and the two visits from some 139 countries. houses the Wellcome Library, the pilots have been released as podcasts. Wellcome Trust Centre for the History The most eye-catching addition to the of Medicine at UCL, a Conference Some 1800 visitors attended a ‘Quacks Library’s collections was ‘Acts of Mercy’, Centre, a forum and events space, a and Cures’ evening in July 2009. a series of four large paintings by bookshop and a café. Attractions included a re-creation of a Frederick Cayley Robinson, previously Victorian medical show, diagnoses by hung in the Middlesex Hospital. Two of Wellcome Collection attracted over 19th-, 20th- and 21st-century doctors, the paintings now grace the Library’s 335 000 visits during 2008/09, as well as Ben Goldacre, the Guardian’s entrance hall. exceeding last year’s figures. In October ‘Bad Science’ columnist, talking about 2009, it reached a total of 750 000 visits the placebo effect. Over 100 hours of medical films since its opening in June 2007, and is were digitised during the year and expecting its millionth visit in the summer On Saturday 20 June 2009, Wellcome can be viewed at of 2010. This steady increase is Collection held a Midsummer Picnic on www.youtube.com/wellcomefilm. encouraging, particularly as visitor the theme of collecting and collectors at numbers to new museums typically Cumberland Market in Somers Town, in Wellcome Images decline after initial interest. partnership with West Euston Time The Wellcome Image Awards – which Bank, a local community volunteer recognise the most informative, striking Temporary exhibitions group. Some 300 people participated in and technically excellent recent Wellcome Collection’s four temporary the event, part of the Trust’s community acquisitions by Wellcome Images – exhibitions during 2008/09 attracted engagement programme. celebrated their tenth round. The winners almost 122 000 visits. War and Medicine were featured on national TV news and in considered the constantly evolving Wellcome Collection Club many newspapers. relationship between warfare and The Wellcome Collection Club, which medicine; Madness & Modernity looked offers a stylish, comfortable room with An exhibition of 150 photographs of China at how madness and art interacted in refreshment facilities for members to taken by Victorian photographer John Vienna at the turn of the 20th century; relax in, along with monthly Club socials Thomson, part of the Wellcome Images Bobby Baker’s Diary Drawings charted and private exhibition views, now has collections, opened in April 2009 in Beijing the artist’s struggle with mental illness; around 500 members. and will tour other venues in China. and Exquisite Bodies explored anatomical wax models from the Victorian era. The Wellcome Library Conference Centre exhibitions received widespread press The Library received over 38 000 visits – The Conference Centre continues coverage. Guardian critic Stuart Jeffries, a 15 per cent increase on last year. The to thrive, bringing in a revenue of visiting War and Medicine in November ‘Insights’ visits continued to flourish, with £1.45 million for the year and generating 2008, noted: “Thanks to the Wellcome new themes ‘Caricatures and Cartoons’, a trading surplus of £0.7m. Collection, I am once more in serious ‘Fascinating Faces’, ‘Medi-cinema’ and danger of learning something.” ‘Native Americans’ joining the programme Business during the year. Another new theme, Blackwell bookshop was named by Time Events ‘Anatomies of London’, was chosen by Out as one of its top five museum June 2009 saw two lunchtime ‘Packed Time Out as one of the ten best events bookshops of the year. Both the Lunch’ pilot events, where visitors bring taking place during the ‘Story of London’ bookshop and Peyton and Byrne café their own lunch and listen to stimulating festival in June 2009. have continued to be popular talks by scientists, medics, artists and destinations for visitors.

IMAGES 1 Wellcome Collection’s Midsummer Picnic at Cumberland Market, London. 2 Anatomical wax Venus from the Exquisite Bodies exhibition. 52 | Advisory committees

Advisory committees

The Wellcome Trust is indebted to the many researchers who gave up their time to sit on our advisory committees, and to the thousands of scientific referees, in the UK and overseas, who provide comments on grant applications. The following pages list the external members of our advisory committees during 2008/09.

Advisory Committee for the M Semple Professor D Wassenaar Wellcome Trust–National The Experience Corps Ltd University of KwaZulu-Natal, South Africa Institutes of Health Four-year PhD Dr H J Spiers H Whittall Studentship Programme University College London Nuffield Council on Bioethics Dr G Felsenfeld Dr R J T Wingate Dr G Widdershoven (Chair) National Institutes of Health, Bethesda, USA King’s College London Maastricht University, the Netherlands Dr J Clarke Professor S Yearley Dr Michael Wilks University of Cambridge University of Edinburgh British Medical Association Dr D C Douek National Institutes of Health, Bethesda, USA Basic Science Clinical Interview Committee Dr M M S Heck Interview Committee Professor B P Morgan University of Edinburgh Professor M J Humphries (Chair) Cardiff University Professor A J King (Chair) University of Manchester Professor C Boshoff University of Oxford Professor R C Allshire University College London Dr M J Lenardo University of Edinburgh Professor R J M Franklin National Institutes of Health, Bethesda, USA Professor N J Buckley University of Cambridge Professor C J McBain King’s College London Professor F Karet National Institutes of Health, Bethesda, USA Professor P R Burton University of Cambridge Dr S Muller University of Leicester Dr P Klenerman University of Glasgow Professor A Galione University of Oxford Dr P Schwartzberg University of Oxford Professor F Y Liew National Institutes of Health, Bethesda, USA Professor C Kleanthous University of Glasgow Dr J R Sellers University of York Professor P H Maxwell National Institutes of Health, Bethesda, USA Professor L M Machesky Imperial College London Dr J-P Vincent CRUK Beatson Institute for Cancer Research, Professor E Simpson National Institute for Medical Research, Glasgow Imperial College London Medical Research Council, London Professor R C Miall Professor A Thrasher Dr T Wolfsberg University of Birmingham University College London National Institutes of Health, Bethesda, USA Professor G R Screaton Professor B Walker Imperial College London University of Edinburgh Arts Award Professor C M R Turner Funding Committee University of Glasgow Cognitive and Higher Professor H Nicholson Professor S W Wilson Systems Funding Committee (Chair) Royal Holloway, University of London University College London Professor J P Aggleton M Crimmin (Chair) Cardiff University Royal Society of Arts Biomedical Ethics Professor T Griffiths K Khan Funding Committee Newcastle University London Organising Committee of the Professor A Webster Olympic & Paralympic Games Professor P J Harrison (Chair) University of York University of Oxford L Le Feuvre Professor R Brownsword Curator and writer Professor D K Jones King’s College London Cardiff University Dr R Levinson Professor M Dixon-Woods University of London Professor G E Lewis University of Leicester University of Bristol Dr G Lewis Professor E H Matthews Poet Professor A C Nobre Dr J McMillan University of Cambridge Dr F McKee University of Hull Writer and curator Professor J O’Keefe Professor N Pfeffer University College London R Mortimer London Metropolitan University Film maker Dr A Owen Dr R Simpson University of Cambridge Dr S Ochugboju Durham University Biomedical scientist/international science Professor I Robertson communicator Dr J H Solbakk Trinity College Dublin, Ireland University of Oslo, Norway Advisory committess | 53

History of Medicine International Engagement Funding Professor G Miesenboeck Funding Committee Committee University of Oxford Professor S King Professor D Wassenaar Professor R Miles (Chair) Oxford Brookes University (Chair) University of KwaZulu-Natal, INSERM, University of Paris, France South Africa Professor P Biller Professor T Owens University of York Professor W Graham University of Southern Denmark, Odense, University of Aberdeen Denmark Dr L T Kassell University of Cambridge Dr A Jesani Professor D Rubinsztein Anusandhan Trust, Mumbai, India University of Cambridge Professor H Marland University of Warwick Dr L Massani Professor A Stephenson Fundação Oswaldo Cruz, Rio de Janeiro, Brazil University of London Dr T Rütten Newcastle University O Obyerodhyambo Professor L Wilkinson Family Health International, Nairobi, Kenya Cardiff University Dr S Shamdasani University College London Dr D J A Wyllie Library Advisory Committee University of Edinburgh Professor L T Weaver University of Glasgow J Wilkinson (Chair) University of Manchester Molecular and Physiological Dr J Welshman Sciences Strategy Committee Lancaster University Dr T Boon Science Museum Professor P M Stewart Professor M Worboys (Chair) University of Birmingham University of Manchester A S Byatt Arts Council England Professor D M Altshuler Massachusetts General Hospital, Boston, USA Immunology and Infectious Disease A Fleming Funding Committee Freelance working in film and video Dr C D Austin National Human Genome Research Institute, Professor D Goldblatt A Green Bethesda, USA (Joint Chair) Institute of Child Health, London National Library of Wales, Aberystwyth Professor A Bradley Professor F C Odds Dr N D Hopwood Wellcome Trust Sanger Institute, Cambridge (Joint Chair) University of Aberdeen University of Cambridge Professor G Fitzgerald Professor J Allen University of Pennsylvania, Philadelphia, USA University of Edinburgh Medical Humanities Strategy Committee Professor M J Humphries Dr A A Antson University of Manchester University of York Professor T Treasure (Chair) University College London Professor A J Hunter Professor A Bjorkman GlaxoSmithKline Karolinska Institute, Stockholm, Sweden Professor N L G Eastman St George’s Hospital Medical School, London Professor A I Lamond Professor A Craig University of Dundee Liverpool School of Tropical Medicine Professor H M Evans Durham University Dr S E Lewis Professor P Craig University of California, Berkeley, USA University of Salford Professor K W M Fulford University of Warwick Professor P Maxwell Professor P R Crocker University College London University of Dundee Professor B Hurwitz King’s College London Professor J Smith Professor P Garside University of Cambridge University of Strathclyde Professor M A Jackson University of Exeter Dr F Geissmann Molecules, Genes and Cells King’s College London Professor S King Funding Committee Oxford Brookes University Professor H Jenkinson Professor A I Lamond University of Bristol Professor G Richardson (Chair) University of Dundee King’s College London Professor P J Lehner Professor K R Ayscough Cambridge Institute for Medical Research Professor A Webster University of Sheffield University of York Professor G F H Medley Professor P Beales University of Warwick University College London Molecular and Cellular Professor C D O’Connor Neuroscience Funding Committee Professor N Brockdorff University of Southampton University of Oxford Professor D M Turnbull Professor P Openshaw (Chair) Newcastle University Professor S Brunak National Heart and Lung Institute, London Technical University of Denmark Professor M E Cheetham Professor M Palmarini University College London Professor N J Bulleid University of Glasgow University of Glasgow Professor C H Davies Professor R Randall GlaxoSmithKline Dr R M Cooke University of St Andrews GlaxoSmithKline Professor A Graham Dr G Rudenko King’s College London Professor J Errington University of Oxford Newcastle University Professor C Holt Professor E Schurr University of Cambridge Dr A P Gould Montréal General Hospital, Canada National Institute for Medical Research, London Dr L Lagnado Professor R Shattock Medical Research Council, Cambridge Professor T Hyman St George’s Hospital Medical School, Max Planck Institute for Molecular Biology and University of London Professor K Martin Genetics, Dresden, Germany Institute of Neuroinformatics, Zurich, Switzerland 54 | Advisory committees

Professor J Iredale Professor P T LoVerde Professor C King University of Edinburgh University of Texas, San Antonio, USA Case Western Reserve University, Cleveland, USA Professor M Jobling Professor S Macintyre University of Leicester University of Glasgow Professor A Lopez University of Queensland, Herston, Australia Professor G Murphy Professor B P Morgan University of Cambridge Cardiff University Dr Z Matthews University of Southampton Professor N D Perkins Professor F C Odds University of Bristol University of Aberdeen Professor A D Morris University of Dundee Professor B V L Potter Professor M E J Woolhouse University of Bath University of Edinburgh Professor B S Ramakrishna Christian Medical College and Hospital, Professor E J Robertson Vellore, India University of Oxford Physiological Sciences Funding Committee Professor T Smith Professor M C Seabra Swiss Tropical Institute, Basel, Switzerland Imperial College London Professor P Maxwell (Chair) University College London Professor J Volmink Professor C W J Smith Stellenbosch University, Cape Town, University of Cambridge Professor P-O Berggren South Africa Karolinska Institute, Stockholm, Sweden Neuroscience and Mental Professor K M Channon Principal Research Fellowship Health Strategy Committee University of Oxford Interview Committee Professor M C Raff Professor H T Cook Professor D Ish-Horowicz (Chair) University College London Imperial College London (Chair) Cancer Research UK Professor J P Aggleton Professor M Gautel Professor C Frith Cardiff University King’s College London University College London Professor K H Ashe Professor C Godson Professor T Hunter University of Minnesota, Minneapolis, USA University College Dublin The Salk Institute for Biological Studies, Professor D J Kupfer Professor A J Knox San Diego, USA University of Pittsburgh, USA University of Nottingham Dr P Marrack Professor M H Sheng Professor N W Morrell Howard Hughes Medical Institute, Denver, USA Massachusetts Institute of Technology, University of Cambridge Cambridge, USA Dr A M Prentice Public Engagement Strategy Professor W Singer London School of Hygiene and Committee Max Planck Institute for Brain Research, Tropical Medicine Professor F Balkwill Frankfurt am Main, Germany Professor N J Samani (Chair) University of London Professor A Toga University of Leicester Q Cooper UCLA School of Medicine, Los Angeles, USA Professor I Sargent Writer and broadcaster Professor S Tonegawa University of Oxford Professor S King Massachusetts Institute of Technology, Professor J Seckl Oxford Brookes University Cambridge, USA University of Edinburgh Professor H Nicholson Professor D M Turnbull Professor D G Thompson Royal Holloway, University of London Newcastle University Hope Hospital, Manchester Professor N S Rose Professor A Tinker London School of Economics Pathogens, Immunology and University College London Population Health Strategy J Sjøvoll Committee Professor S G Ward Framwellgate School Durham University of Bath Dr R M Atlas T Smit (Chair) University of Louisville, Kentucky, USA Eden Project Populations and Public Health Professor Z A Bhutta Dr S Webster Funding Committee Aga Khan University Hospital, Karachi, Pakistan Imperial College London Professor N Chaturvedi Dr F Binka (Chair) Imperial College London University of Ghana, Legon, Ghana Public Health and Tropical Professor M L Barreto Medicine Interview Committee Professor B R Bloom Federal University of Bahia, Brazil Harvard School of Public Health, Boston, USA Professor P T LoVerde Professor C Brayne (Chair) University of Texas, San Antonio, USA Professor P R Burton University of Cambridge University of Leicester Professor M J Cardosa Professor U D’Alessandro Universiti Malaysia Sarawak, Malaysia Professor N Chaturvedi Prince Leopold Institute of Tropical Medicine, Imperial College London Professor M Caulfield Belgium Barts and The London, Queen Mary’s School of Professor P J Donnelly Professor G P Garnett Medicine and Dentistry University of Oxford Imperial College London Professor K K Cheng Professor G Dougan Professor A O House University of Birmingham Wellcome Trust Sanger Institute, Cambridge University of Leeds Professor A Lalvani Professor S B J Ebrahim Professor T H Jafar Imperial College London London School of Hygiene and Aga Khan University, Karachi, Pakistan Tropical Medicine Professor L Richter Professor A M Johnson Human Sciences Research Council, Professor D Goldblatt University College London South Africa Institute of Child Health, London Advisory committees | 55

Professor G Tomson Sir Henry Wellcome Postdoctoral Professor J H Darbyshire Karolinska Institute, Stockholm, Sweden Fellowship Interview Committee MRC Clinical Trials Unit, London Dr F Wabwire-Mangen Professor J C Smith Dr P Deloukas Makerere University, Uganda (Chair) University of Cambridge Wellcome Trust Sanger Institute, Cambridge Professor M Wahlgren Professor J C Buckingham Professor M Egger Karolinska Institute, Stockholm, Sweden Imperial College London University of Bern, Switzerland Professor D A Cantrell Professor C P Farrington R&D for Affordable Healthcare University of Dundee Open University in India Committee Professor A C Dolphin Professor R J Hayes Dr R Parekh University College London London School of Hygiene and Tropical Medicine (Chair) Advent Venture Partners Professor W C Earnshaw Professor J L Hutton Dr A Allsop University of Edinburgh University of Warwick AstraZeneca Professor K Gull Professor M Khoury S Bayman University of Oxford Centers for Disease Control and Prevention, Stonebridge International, USA Atlanta, USA Professor A D Hingorani Professor G Dougan University College London Professor D A Lawlor Wellcome Trust Sanger Institute, Cambridge University of Bristol Professor S C R Williams Dr R Kumar King’s College London Professor M McCarthy Dr Reddy’s Laboratories, Hyderabad, India University of Oxford Professor Sir Ravinder N Maini Society Awards Funding Committee Professor D J Porteous Imperial College London University of Edinburgh Dr S Webster Dr C Newton (Chair) Imperial College London Professor M J Prince BioFocus DPI King’s College London R Gould Professor S Reddy Theatre director and producer Professor J N Weber Public Health Foundation of India, New Delhi, India Imperial College School of Medicine, London Dr A McFarlane Professor K Vijayraghavan The Royal Botanic Gardens, Kew B Zaba National Centre for Biological Sciences, London School of Hygiene and Tropical Sir Nick Partridge Bangalore, India Medicine Terrence Higgins Trust Dr A Wood Professor D J Porteous Eli Lilly Technology Transfer Challenge University of Edinburgh Committee Dr S Preston Research Resources in Medical Dr T Bianco Durham University History Funding Committee (Chair) Wellcome Trust Dr J Thomas Professor M A Jackson Dr N Booth Open University (Chair) University of Exeter Department of Health Dr M Whitby J Andrews Professor W N Charman Red, Green & Blue Co. Ltd Newcastle University Monash University, Melbourne, Australia N Bell Dr S Chatfield Standing Advisory Group on Ethics The National Archives Health Protection Agency Professor S Holm Professor A Borsay Dr M Claybourn (Chair) Cardiff University University of Wales, Swansea AstraZeneca Professor B Greenwood I Milne Dr L Fass London School of Hygiene and Tropical Medicine Royal College of Physicians of Edinburgh GE Healthcare Professor G Laurie A Walker Professor M Feldmann University of Edinburgh British Library University College London Professor T W Meade Dr G C Forrest London School of Hygiene and Tropical Medicine Seeding Drug Discovery Genosis Ltd Funding Committee K Whitehorn Dr A Hudson Freelance journalist Professor W N Charman Pharma research consultant (Chair) Monash University, Melbourne, Australia Dr K Johnson Study Design Expert Group Dr C Bountra Index Ventures University of Oxford Professor P R Burton Dr F D King (Chair) University of Leicester Dr P England University College London ProXara Biotechnology Limited Dr R Apweiler Dr G Lawton European Bioinformatics Institute, Hinxton Professor J Griffin Lectus Therapeutics Ltd Numerate Inc. Professor H Colhoun Dr W Luyten University of Dundee Dr F D King PharmaDM University College London Professor R Collins Professor E Mathiowitz University of Oxford Dr T J Rink Brown University, Providence, USA Board member, Adnexus Therapeutics Inc., Professor N Craddock Dr G Michel Sepracor Inc. and Santhera Pharmaceuticals Cardiff University Foundation of New Innovative Diagnostics, Professor J Danesh Switzerland University of Cambridge The Wellcome Trust Acknowledgements

MAKING A DIFFERENCE EXECUTIVE BOARD BOARD OF GOVERNORS We are grateful to everyone who agreed The Wellcome Trust Annual Review is All images are courtesy of Wellcome Images to be reviewed in this issue, everyone distributed via a mailing list held by the (images.wellcome.ac.uk) except as follows: The Wellcome Trust’s mission is to Mark Walport William Castell p. 3: 1 (K Hodivala-Dilke and M Stone); pp. 6–7: 1 who supplied images or gave us Wellcome Trust. If you would like to be foster and promote research with the Director of the Wellcome Trust Chairman (Dr Linda Stannard, UCT/SPL), 2 (Arran Lewis), permission for their images to be used, added to the list, or if you have a 3 (Anthea Sieveking); p. 8 (David Gregory and Debbie aim of improving human and animal Ted Bianco Adrian Bird and the many members of Wellcome colleague who would like to receive the Marshall); p. 10: 2 (Annie Cavanagh); p. 12 (Robert health. During 2005–2010, Pears/iStockphoto); p. 13 (BSIP VEM/SPL); p. 15 Director of Technology Transfer Deputy Chairman Trust staff who helped to produce this Wellcome Trust Annual Review, please our aims are: (Anna Tanczos); p. 17 (SPL); p. 18: 2 (Caroline Penn); volume. contact: p. 19: 1 (Dr Linda Stannard, UCT/SPL), 2 (Pasquale John Cooper Kay Davies Advancing knowledge: To support Sorrentino/SPL); p. 20: 1 (Ida Ma, Novartis Institute for UKCMRI Chief Operating Officer Editor Publishing Department Tropical Diseases), 2 (Chris de Bode/Panos); p. 21: 1 research to increase understanding Peter Davies and Interim Chief Executive Officer Ian Jones, Isinglass Consultancy Wellcome Trust (Western Ophthalmic Hospital/SPL), 2 (Warwick Design of health and disease, and its societal Consultants); p. 22: 1 (Annie Cavanagh); p. 26: 1 Christopher Fairburn FREEPOST context Simon Jeffreys Project Manager (Natural History Museum); p. 27: 1, 2 (Blink Films); RLYJ-UJHU-EKHJ p. 29 (Andrew Whittuck); p. 32: 1 (Daan van Aalten); Chief Operating Officer Richard Hynes Lucy Moore Using knowledge: To support the Slough SL3 0EN p. 35 (Volker Brinkmann); p. 36 (Membrane Protein Laboratory); p. 41: 1 (Anna Tanczos); p. 45 development and use of knowledge David Lynn Roderick Kent Writers T +44 (0)20 7611 8651 (Annie Cavanagh, Wellcome Images); p. 46: top to create health benefit Head of Strategic Planning and Policy Penny Bailey (Anton Enwright), middle (Annie Cavanagh), bottom Eliza Manningham-Buller F +44 (0)20 7611 8242 Ian Jones (Benedict Campbell); p. 47: top (Yorgos Nikas), Engaging society: To engage with Clare Matterson E [email protected] middle (iStockphoto); p. 50 (Simon Clark). Peter Rigby Mun-Keat Looi society to foster an informed climate Director of Medicine, www.wellcome.ac.uk/publications within which biomedical research Society and History Peter Smith Assistant editor can flourish Tom Freeman ISBN 978 1 84129 084 3 Alan Schafer Edward Walker-Arnott Developing people: To foster a research Director of Science Funding Design The Wellcome Trust is a charity community and individual researchers Anja Fouad registered in England, no. 210183. Its John Stewart As at January 2010 who can contribute to the advancement sole trustee is The Wellcome Trust Head of Legal and Company Secretary Photography and use of knowledge Limited, a company registered in David Sayer Danny Truell England, no. 2711000, whose registered Facilitating research: To promote the Chief Investment Officer Publisher office is at 215 Euston Road, London best conditions for research and the Hugh Blackbourn NW1 2BE, UK. use of knowledge As at January 2010 Comments on the Wellcome Trust First published by the Wellcome Trust, Developing our organisation: To use Annual Review are welcomed and 2010. our resources efficiently and effectively. should be sent to: © The trustee of the Wellcome Trust, Hugh Blackbourn London. www.wellcome.ac.uk/strategicplan. 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Dr R Parekh THEMED COMMITTEE MEETINGS Medicine, Society and History Advent Venture Partners HELD IN 2008/09 Capital Awards Dr J Rasmussen J Vitmayer CNS consultant African Institutions Initiative (Chair) Horniman Museum, London Dr F Sams-Dodd Professor M Tanner Professor A G Balls Neurofit SAS, France (Chair) Swiss Tropical Institute, Basel, International Centre for Life, Newcastle upon Switzerland Tyne Professor M Singer University College London Dr S Bennett S MacDonald World Health Organization, Geneva, Switzerland University College London Dr M Skingle GlaxoSmithKline Dr R I Glass Professor C Rapley National Institutes for Health, Bethesda, USA Science Museum, London Professor C Toumazou Imperial College London Professor M Hommel Professor K Vogel Pasteur Institute, Paris, France Deutsches Hygiene-Museum, Dresden, Germany Technology Transfer Professor C Mgone Strategy Panel European and Developing Countries Clinical Trials Partnership, the Hague, the Netherlands Neurodegenerative Diseases Dr T J Rink Initiative (Chair) Board member, Adnexus Therapeutics Professor S Reddy Inc., Sepracor Inc. and Santhera Public Health Foundation of India, New Delhi, India Professor Lord Stewart Sutherland Pharmaceuticals (Chair) Dr J Hills Genome-wide Association Studies Professor M Flint Beal Bristol-Myers Squibb Weill Medical College of Cornell University, Professor S Chanock New York, USA Professor L Tarassenko (Chair) National Cancer Institute, Bethesda, USA University of Oxford Professor K Fox Professor M Boehnke Cardiff University; member of MRC Dr A Wood University of Michigan, Ann Arbor, USA and Mental Health Board Eli Lilly Professor N Cox Professor C Kennard University of Chicago, USA Imperial College London; member of MRC Veterinary Fellowships Professor D Goldstein Neurosciences and Mental Health Board Interview Committee Duke University, North Carolina, USA Professor L J Launer Professor E Simpson Professor M Pericak-Vance National Institute of Aging, Bethesda, USA (Chair) Imperial College London University of Miami, USA Professor G E Rees Professor A W C A Cornelissen Professor Dr H Schunkert University College London; member of MRC University of Utrecht, the Netherlands University of Schleswig-Holstein, Lubeck, Germany Neurosciences and Mental Health Board Professor R M Elliott Professor J Todd Professor M Sendtner University of St Andrews Cambridge Institute for Medical Research University of Wurzburg, Germany Professor J L Fitzpatrick Professor A Toga Moredun Research Institute, Penicuik Medical Engineering Initiative UCLA School of Medicine, Los Angeles, USA Professor I R Hart Professor C Lee Professor F Van Leuven University of London (Chair) Royal College of Surgeons, Dublin, Ireland Katholieke Universiteit Leuven, Belgium Professor A R McLean Col Dr K Friedl Professor H Wekerle University of Oxford US Army, Fort Detrick, USA Max Planck Institute of Neurobiology, Planegg- Professor M Shirley Martinsreid, Germany Professor M Nerlich Institute for Animal Health, Pirbright University Hospital Regensburg, Germany Dr J A Parrish MD Center for Integration of Medicine and Innovative Technology, Boston, USA Dr H Rosen MD Onsite Neonatal Partners Inc., Voorhees, USA Professor C Sheppard National University of Singapore, Singapore Dr U Steinseifer Helmholtz-Institute, Aachen, Germany WELLCOME TRUST ANNUAL REVIEW 1 October 2008–30 September 2009

ANNUAL REVIEW 2009

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