ELOETUTANA EIW1Otbr20–0Spebr2007 WELLCOME TRUST ANNUAL REVIEW 1 October 2006–30 September

ANNUAL REVIEW 2007

The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £500 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. www.wellcome.ac.uk THE WELLCOME TRUST The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, and supports public debate about biomedical research and its impact on health and wellbeing.

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CONTENTS BOARD OF GOVERNORS 2 Director’s statement William Castell Chairman Achieving our objectives Adrian Bird 4 Advancing knowledge Deputy Chairman 16 Using knowledge Kay Davies 24 Engaging society Christopher Fairburn 30 Developing people Patricia Hodgson 36 Facilitating research Richard Hynes 40 Developing our organisation Peter Rigby The year in review Alastair Ross Goobey* 41 Corporate activities Peter Smith 42 Financial summary 2006/07 Edward Walker-Arnott 44 Funding developments 2006/07 As at January 2008

46 Streams funding 2006/07 *While finalising this publication, we were saddened to learn that Alastair Ross Goobey had died, following a 48 Technology Transfer long illness. Alastair was an outstanding Governor and extraordinary friend of the Wellcome Trust. A Governor 49 Wellcome Trust Genome Campus since 2002, his advice was instrumental in helping to develop the investments of the Trust. He took a 50 Public Engagement great interest in all aspects of our activities and will be 51 Wellcome Collection sadly missed by those who worked with him. 52 Advisory committees

Images This Annual Review covers the 1 A trypanosome parasite. 3 Examining material in 5 The Beagle 2 spacecraft. Wellcome Trust’s financial year, from 2 Stephen Fry in the Wellcome Library. 6 The Africa Centre for 1 October 2006 to 30 September 2007. Wellcome Collection. 4 Malaria parasites inside Health and Population red blood cells. Studies. CONTENTS 1

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EXECUTIVE BOARD MAKING A DIFFERENCE Developing people: To foster a Mark Walport The Wellcome Trust’s mission is research community and individual Director of the Wellcome Trust to foster and promote research with researchers who can contribute to the advancement and use of knowledge Ted Bianco the aim of improving human and animal Director of Technology Transfer health. During 2005–2010, Facilitating research: To promote the our aims are: best conditions for research and the John Cooper use of knowledge Director of Resources Advancing knowledge: To support research to increase understanding Developing our organisation: To use David Lynn of health and disease, and its our resources efficiently and effectively. Head of Strategic Planning and Policy societal context Clare Matterson Using knowledge: To support the Director of Medicine, development and use of knowledge Society and History to create health benefit David Phillipps Engaging society: To engage with Director of Finance society to foster an informed climate Alan Schafer within which biomedical research Head of Molecular and can flourish Physiological Sciences John Stewart Head of Legal and Company Secretary Danny Truell Chief Investment Officer

As at January 2008

Strategic Plan updates, summarising progress in achieving specific objectives during 2006/07, can be found at www.wellcome.ac.uk/strategicplan. DIRECTOR’S STATEMENT 2

BEING BOLD

Sometimes big is definitely better…

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One of the benefits of having significant Crucially, this work has only been made The Consortium was not the only sums to award in grants is the possible by the availability of a dense notable ‘big science’ achievement of the opportunity to make major investments – map of genetic markers – an outcome of year. January 2007 saw the opening of to think big. We have been in the the Human Genome Project, the the Diamond synchrotron, a joint venture fortunate position of being able to do sequencing of which identified sites of with the UK Government (page 37). This that while maintaining our core support single-letter variation in the human initiative, the largest scientific for curiosity-driven investigator-led genetic code (so-called single nucleotide infrastructure project in the UK for 40 proposals. But rather than do ‘more of polymorphisms, SNPs). Recognising the years, has been many years in gestation the same’ we have consciously set aside value of SNPs as genetic markers, we and it gives me great pleasure to see large sums to be spent on the truly supported the SNP Consortium, a such a world-class facility up and running. innovative, large-scale projects that will public–private partnership that mapped The value of structural approaches, have enduring impact. This year we can hundreds of thousands of SNPs across where Diamond will have its biggest see how this policy has borne fruit the genome and made them freely biological impact, is amply illustrated by magnificently. available for use in research. the continuing success of the Structural The undoubted highlight has been the From the SNP Consortium emerged the Genomics Consortium (page 37). stream of papers emerging from the International HapMap Project, to which Another public–private partnership, and Wellcome Trust Case Control we have also contributed support. The based on an international collaboration Consortium (page 6). Identifying genes HapMap Project is characterising human involving the UK, Canada and Sweden, associated with common diseases has genetic variation across different human the Structural Genomics Consortium has been a goal of human geneticists for populations. It is variation between confounded sceptics – easily surpassing decades, yet with a few notable individuals that will underpin differing its targets. Protein structures, again exceptions progress has been susceptibilities to disease. freely released into the public domain, frustratingly slow. It has taken advances While SNPs still appear to be the main have given insight into fundamental in technology, methodology and source of human genetic variation, copy biological questions and are also of statistical tools to arrive at a situation number variation is also turning out to be direct practical benefit, stimulating new where reliable associations can now be significant (pages 6–7). Blocks of DNA may drug development. identified. be missing or present in different numbers Large-scale high-throughput More than 30 genes have been of copies in different people. We are now approaches are one of the strengths of pinpointed by the Consortium using this discovering that this feature is more the Wellcome Trust Sanger Institute. It approach, and others are likely to be common than we thought, is distinct continues to play a key role in unravelling confirmed by more detailed follow-up from SNP variation, and impacts on the mysteries of the human genome – an work. They are providing valuable leads health. In a new venture funded this year, entity that is more complex than anyone for researchers investigating the biology the Case Control Consortium will be had thought when the sequencing of these conditions, and have opened up searching for copy number variation as a project was launched (pages 6–7). The a host of new therapeutic targets. possible factor in common diseases. Sanger Institute has also shown how

Images 1 Buildings housing the Wellcome Trust 3 Dr Mark Walport with Stephen Fry (left) and Sanger Institute. Trust Deputy Chairman Professor Martin 2 Structure of JMJD2A demethylase enzyme, Bobrow (right) at the opening of Wellcome determined by the Structural Genomics Collection. Consortium. 4 Lung cancer cells in culture. DIRECTOR’S STATEMENT 3

HIGHLIGHTS OF THE YEAR

much can be gained from comparative This trend towards ‘big science’ is sure genomics – identifying key differences to continue. Progress continues on the between strains and different but related UK Biobank project, which with data on species (pages 10–11). 500 000 people will provide an unrivalled The Cancer Genome Project, a resource for epidemiological research. partnership between the Sanger Institute This year we have promoted more and the Institute of Cancer Research, is imaginative thinking around electronic another ambitious initiative that continues patient records, where the UK’s national to generate important information infrastructure provides a huge (page 7). An early success was its opportunity for health research. The discovery of BRAF as a key gene technical and logistical challenges are involved in malignant melanoma. It now significant but this is an opportunity that must not be let slip away. looks as if BRAF may be exceptional in 4 causing such a high proportion of these The great advances made by large- cancers. An exhaustive trawl of kinase scale initiatives should not cause us to genes in a range of human tumours has lose sight of the high-quality research • Wellcome Trust Case Control revealed great diversity in the mutations being carried out by individual research Consortium finds 30 genes present in cancers. Not all the groups. The work of Professor Adrian associated with common mutations are necessarily contributing Bird and colleagues in Edinburgh and diseases. to cancer growth, and it is a significant researchers at the Behavioural and • Wellcome Trust Sanger Institute challenge distinguishing the ‘drivers’ Clinical Neuroscience Institute in researchers discover further from the ‘passengers’. Cambridge shows how studies of complexity in the human genome. Another key factor in the success of the animal models can shed light on key Case Control Consortium was the biological processes. In elegantly • Cancer Genome Project identifies network of collaborating groups across conceived experiments, Professor ‘driver’ and ‘passenger’ mutations the UK that made it possible. Bird’s group has shown that the autism- in systematic analysis of kinase like symptoms of a mouse model of Collaboration has always been central genes in human cancers. to research but now there is even more Rett syndrome can be reversed through to be gained from pooling expertise, use of agents affecting the methylation • Autism-like symptoms reversed in experience and materials. Crucially, state of DNA. The Cambridge group mouse model of Rett syndrome. discovered that unusual patterns of results in one cohort could be compared • Predisposition to impulsive with those obtained in others, thus dopamine receptor activity in the brain behaviour and drug addiction confirming that the observed effects are were associated with both impulsive linked to pre-existing dopamine reproducible – an issue that has dogged behaviour and susceptibility to cocaine human genetics for years. addiction in rats. receptor abnormalities. Collaboration has also been an important Discussion of this year’s highlights • Key promoter of inflammatory feature of our Major Overseas would not be complete without mention bowel disease identified. Programmes. It is striking to see how our of the opening of Wellcome Collection, • Diamond synchrotron opens to its centres in the Far East have established our new public venue at 183 Euston productive links both within their host Road, London. It has proved a huge first users. success, in terms of both critical countries and with others in the region – • Risk of mother-to-child and globally (pages 20–21 and 31). acclaim and visitor numbers. Its unique mix of science and art, old and new, transmission of HIV found to be Combating threats such as H5N1 avian lowest in exclusively breastfed calls for a coherent joined-up clearly illustrates the connections infants. approach – the pathogens concerned between science, medicine and wider are no respecters of national borders. culture. It, too, demonstrates that an • Typhoid vaccine successfully imaginative idea, conceived and And by sharing results, as has completes phase I trial in Vietnam. happened with steroid treatment of delivered on a grand scale, can deliver meningitis, researchers can tackle rich rewards. • Wellcome Collection opens to the public. questions that none alone could Dr Mark Walport possibly have answered. Director January 2008

ADVANCING KNOWLEDGE Supporting research to increase understanding of health and disease, and its societal context. ADVANCING KNOWLEDGE 6

A CASE FOR RETHINKING CELEBRATION THE GENOME The Wellcome Trust Case Control Consortium has identified The more the human genome is genes involved in a host of common diseases. studied, the more surprises emerge.

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The past couple of decades have In essence, case–control approaches When the first draft of the human seen enormous efforts made to look for genetic variations that are more genome was completed, Sir John identify genes increasing our common in people with a given condition Sulston argued that it was a susceptibility to common diseases. than in matched healthy individuals. beginning not an end. The wave of Whole-genome scans now enable The Consortium used the approach on unexpected discoveries that have the entire genome to be screened a variety of conditions. This work, and followed have vindicated that view. for possible contributory factors. follow-up by individual disease groups And it is fitting that the Wellcome Unfortunately, the field has been and collaborators, has now identified Trust Sanger Institute has been at blighted by ‘false positives’ – more than 30 genetic factors contributing the forefront of efforts to understand statistical associations discovered to diseases including heart disease, the genome – as illustrated by its in one population but not apparent type 1 and type 2 diabetes, Crohn’s work on conserved regions and copy in another. Now, though, an disease, rheumatoid arthritis and number variation. approach spearheaded by the ankylosing spondylitis. The number of The ENCODE (Encyclopedia of DNA Wellcome Trust Case Control genes continues to increase with more Elements) project is an international Consortium is finally generating detailed data analysis and follow-up. collaboration analysing in detail 1 per robust data. Interestingly, the approach also led to cent of the human genome. This analysis The Consortium is making use of the the identification of genes associated has thrown up a whole host of surprising dense map of genetic markers with other characteristics, such as findings – from the unexpectedly large produced by the SNP Consortium and weight and height. proportion of the genome copied into its follow-up, the International HapMap Because so many factors affect RNA to the seemingly almost random Project. Advances in technology have common diseases, and a single gene distribution of gene control regions. enabled high-throughput analysis of will generally have only a small effect, The ENCODE project, to which Sanger hundreds of thousands of such markers the identification of susceptibility genes Institute researchers Dr Manolis in large numbers of individuals. will have limited value in the prediction Dermitzakis and Dr Tim Hubbard made The Consortium also depended on of disease in individuals. Far more key contributions, is challenging received coordination among the UK’s leading important is the insight provided into wisdom about how genes and genomes researchers (and groups abroad). mechanisms of disease, opening up are organised – highlighting how much Crucially, genetic associations identified new avenues of research into causes is still to be learned about genome in one population could be tested in and possible treatments. function and evolution. other, increasing confidence that an Wellcome Trust Case Control Consortium. Last year, Dr Matt Hurles and colleagues association is real. Genome-wide association study of 14,000 cases discovered surprisingly high levels of of seven common diseases and 3,000 shared copy number variation – blocks of DNA controls. Nature 2007;447(7145):661–78.

Images 1 Human variation: 2 Human chromosomes. 4 Prostate cancer cells. genetic differences 3 A dividing HeLa cell, influence our with DNA stained blue. susceptibility to disease. ADVANCING KNOWLEDGE 7

DRIVING MISREGULATION Mining the human genome reveals far more ‘cancer genes’ than expected.

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present in different numbers, or missing All cancers occur due to necessarily mean that it is contributing entirely, in different people. Further abnormalities in DNA sequence. to uncontrolled cell growth. Indeed, analysis by Dr Dermitzakis, Dr Hurles The steady accumulation of these most changes appear to be and colleagues has revealed that copy abnormalities throughout life ‘passenger’ mutations incidental to number variation does not necessarily ultimately means that one in three tumour development. But the correlate with another source of human people in the Western world researchers highlighted 158 mutations genetic variation, single nucleotide develops cancer. This year, the in 120 kinase genes as possible polymorphisms (SNPs). Hence SNP- Cancer Genome Project – an ‘drivers’ of disease. based searches for disease-linked international collaboration led by Although it adds considerably to the variants may miss out on predispositions Professor Michael Stratton and 350 genes previously implicated in caused by changes in copy number. colleagues at the Wellcome Trust cancer, the study highlights how And research continues to identify Sanger Institute – has dramatically genetically complex even a single conditions influenced by copy number expanded the database of known tumour is. And as each tumour type variation. In one of the few studies to cancer genes, adding significantly to turned out to have a wide range of date of its clinical consquences, our understanding of cancer biology driver mutations, no obvious drug Professor Tim Aitman and colleagues and fuelling research into the targets emerged for particular cancers. discovered a link between copy development of new treatments. Nevertheless, the study has opened up number variation affecting the FCGR3B The project set about probing the a whole host of new molecular gene and susceptibility to autoimmune genetic make-up of cells taken from pathways to investigate and drug diseases – but only those affecting the 210 different human cancers. The targets to explore. whole body rather than specific organs. study focused on the genes encoding Greenman C et al. Patterns of somatic mutation ENCODE Project Consortium. Identification and all 518 known human protein kinases, in human cancer genomes. Nature analysis of functional elements in 1% of the human enzymes that regulate other proteins 2007;446(7132):153–8. genome by the ENCODE pilot project. Nature through the addition of a phosphate 2007;447(7146):799–816. residue. These key molecular players Stranger BE et al. Relative impact of nucleotide and copy number variation on gene expression can have a strong influence on cell phenotypes. Science 2007;315(5813):848–53. growth and division and if not working Fanciulli M et al. FCGR3B copy number variation properly can trigger tumour is associated with susceptibility to systemic, but development. not organ-specific, autoimmunity. Nat Genet 2007;39(6):721–3. The molecular scrutiny revealed over 1000 different mutations. However, the ENCODE is funded by the National Human Genome Research Institute. presence of a mutation does not ADVANCING KNOWLEDGE 8

RETT REVERSAL PAIN-FREE LIVING Studies in mice suggest that autism-like A rare defect in pain perception conditions may be reversible. points the way to new analgesics.

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Rett syndrome is an autism-like This implies that the effects of the Rett Pain is an important protective disorder caused by the mutation of a syndrome mutation are not permanently mechanism, but there are many single gene – MECP2. Although the wired into the brain. If this is also true in occasions when we would prefer not function of nerve cells is clearly people, it might be possible to reverse to experience it. Chronic pain, in affected, they do not die as in the symptoms of Rett syndrome by particular, can make a life a misery neurodegenerative conditions such reactivating the MECP2 gene (although and is difficult to control. Studies of as Alzheimer’s. A key question, then, the approach used in mice is not one families with a total lack of pain is: can the brain’s developmental applicable to people). sensation, led by Dr Geoffrey Woods abnormalities be reversed? Working More generally, the study raises of the University of Cambridge, have with a mouse model, Professor hopes that a range of human identified a key mechanism in pain Adrian Bird and colleagues at the neurodevelopmental disorders might detection and may offer a new route University of Edinburgh have be reversible. to effective pain relief. uncovered remarkable evidence Six children from three related families that they can. Guy J et al. Reversal of neurological defects in a mouse model of Rett syndrome. Science from northern Pakistan came to the Professor Bird’s team has been 2007;315(5815):1143–7. attention of researchers because of studying the MECP2 gene for several their extraordinary abilities to tolerate years. It encodes a protein that normally painful experiences. regulates the activity of other genes. Superficially, there was nothing wrong Mutations in the gene affect around with their peripheral and central 1 in 10 000 girls, and also causes nervous systems and they seemed in distressing physical symptoms, good health in spite of a catalogue of including loss of movement, abnormal cuts, bruises and breaks they had breathing patterns and difficulty with endured throughout childhood. speech. Many children display an By studying the affected family abnormal, stiff-legged gait and some network, the researchers were able to become confined to a wheelchair. home in on the genetic basis for this Professor Bird’s team created a mouse condition. The disorder was associated model of this disease by silencing the with a region of chromosome 2 expression of MECP2. To their surprise, containing SCN9A, a gene that the Rett-like symptoms these mice encodes a voltage-gated sodium developed disappeared when the gene channel found on pain-responsive was reactivated. neurons. Sequence analysis of this

Images 1 A laboratory mouse: mice are helping to 3 Visualising pain: an artwork by Deborah reveal the mysteries of Rett syndrome. Padfield. 2 A network of neurons in the brain: miswiring 4 A section through pain-sensing neurons. may cause conditions such as Rett 5 Appetising meals: the hormone leptin may syndrome. influence the desirability of food. ADVANCING KNOWLEDGE 9

APPETITE FOR DECONSTRUCTION How does the brain integrate the factors that control our appetite?

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gene in the affected individuals revealed What controls how much we eat? The enhances ‘fullness’ signals in the three distinct mutations. In vitro regulation of food intake is complex, hypothalamus but also influences the experiments demonstrated that these but it has become clear that a specific desirability of food. mutations shut down these sodium brain area, the hypothalamus, plays a Exactly how leptin acts on brain cells is channels completely. key role in integrating hormonal unclear, but work from Professor This raises the possibility that variation signals from body tissues. But as Dominic Withers, Professor Mike in SCN9A might account for differences Dr Sadaf Farooqi, Dr Paul Fletcher Ashford and others provides clues to in pain tolerance between individuals. and colleagues have discovered, the cellular systems that might respond Furthermore, since the individuals with other brain areas are also influenced to leptin and nutrients in the regulation loss-of-function mutations in this gene by hormones. of food intake and energy balance. are otherwise healthy, a drug that could The hormone leptin is known to be a The enzyme AMP-activated protein selectively target this sodium channel powerful regulator of feeding – without kinase (AMPK) is thought to be a master has the potential to produce pain relief it, mice (and people) eat voraciously and ‘energy sensor’, the body’s fuel gauge. without affecting other aspects of become morbidly obese. Leptin is Research on two knockout mouse nervous system function. produced by fat cells, and is a signal for strains lacking AMPK in either of two Cox JJ et al. An SCN9A channelopathy causes starvation, as falling levels trigger an key cell populations in the hypothalamus congenital inability to experience pain. Nature increase in food intake. suggests a more complicated picture. 2006;444(7121):894–8. Leptin acts directly on the hypothalamus One strain became obese, but the other but, as the researchers discovered, this remained lean. Both strains remained is not its only target in the brain. In sensitive to leptin, but showed abnormal studies of brain activity in two individuals glucose sensing by neurons. Therefore, lacking leptin, before and after leptin while AMPK is an important sensor of therapy, leptin enhanced the response some types of nutrients, it does not to ‘fullness’ signals after food, but also appear to be the master regulator of had an effect in the brain’s reward areas energy homeostasis in the hypothalamus. – the pathways associated with Farooqi IS et al. Leptin regulates striatal regions pleasurable sensations. and human eating behavior. Science 2007;317(5843):1355. Crucially, in the leptin-deficient state the Claret M et al. AMPK is essential for energy patients recorded higher activity in homeostasis regulation and glucose sensing by reward pathways when shown pictures POMC and AgRP neurons. J Clin Invest of food, and they rated them as 2007;117(8):2325–36. more desirable. Thus leptin not only ADVANCING KNOWLEDGE 10

COMPARE AND CONTRAST 1: 2: PARASITES BACTERIA Comparisons between genome sequences can reveal …and are providing new insights why some bacteria are deadlier than others… into parasite biology.

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While a complete genome sequence environmental organism, and its The genome of Plasmodium often reveals much about an genomic characteristics are quite falciparum, the most deadly malaria organism, more can be learned from distinct from relatives such as parasite, was sequenced in 2002. comparisons with close relatives. C. difficile. It has a very stable genome, But the laboratory strain sequenced They can pinpoint genetic features unlike C. difficile, which seems to have is likely to differ from those present linked to pathogenic properties and hoovered up DNA from many bacteria. in the wild. Moreover, as with shed light on evolution, as illustrated Rather than constantly adapting to a humans, it will be crucial to unpick by work from Professor Julian living host, it relies on opportunism – the impact of genetic variation in Parkhill and colleagues at the a sudden lethal strike followed by natural populations. A first step Wellcome Trust Sanger Institute. leisurely digestion. towards this goal has been taken by Dr Matt Berriman and colleagues at Yersinia enterocolitica is a gut-dwelling Different strains of C. botulinum are the Wellcome Trust Sanger Institute. mild microbial pathogen. Its relatives only tenuously related. Indeed, the In a second project they have used Y. pseudotuberculosis and Y. pestis are concept of a bacterial species is comparisons of related species to much nastier, causing gastroenteritis increasingly hard to nail down. Some investigate another important and bubonic plague respectively. A bacteria, such as Streptococcus parasite, Leishmania. three-way comparison of their genomes pneumoniae, seem to have a has revealed genes associated with life ‘supragenome’ – a large pool of genes The malaria project compiled new in the gut (unlike its relatives, Y. pestis only a subset of which are found in any sequences for a parasite obtained lives in the bloodstream) and with one strain. directly from a patient in Ghana, a different clinical symptoms. Interestingly, Thomson NR et al. The complete genome laboratory isolate and the chimpanzee Y. pseudotuberculosis lacks clusters sequence and comparative genome analysis of parasite P. reichenowi. These were of metabolic genes present in the high pathogenicity Yersinia enterocolitica compared with the fully sequenced strain 8081. PLoS Genet 2006;2(12):e206. Y. enterocolitica, suggesting that they P. falciparum reference genome. occupy distinct niches within the gut. Sebaihia M et al. Genome sequence of a proteolytic (Group I) Clostridium botulinum strain In this and two other studies published Y. pestis is thought to have evolved very Hall A and comparative analysis of the clostridial simultaneously, some 27 000 sites of genomes. Genome Res 2007;17(7):1082–92. recently, and is in the process of shedding variation were identified in the genome. genes not needed in its new habitat. As Hiller NL et al. Comparative genomic analyses of Analysis of these sites sheds light on a result, it is becoming more deadly. seventeen Streptococcus pneumoniae strains: insights into the pneumococcal supragenome. genes involved in the parasite’s arms Clostridium botulinum produces the J Bacteriol 2007;189(22):8186–95. race with the host. Parasite molecules world’s most lethal toxin (2 kg could kill that are exposed to our immune system everyone on the planet). Although it can need to change rapidly for the parasite infect the body, it is primarily an to avoid detection. Analysing DNA

Images 1 Clostridium difficile, a 2 Malaria parasites inside microbe with a highly red blood cells. dynamic genome. 3 A bloodstream-stage trypanosome parasite. ADVANCING KNOWLEDGE 11

A DEADLY MOSAIC

Trypanosomes are adept at changing their surface structures. Their trick is to create a multitude of mosaic genes.

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variation reveals those molecules that Trypanosomes, single-celled This enormous capacity to create mosaic are interacting with the immune system parasites infecting people and genes theoretically enables the parasite and therefore represent possible livestock, cause enormous to create far more surface forms than vaccine targets. deprivation throughout Africa. Their previously thought. New mosaic forms The Leishmania project compared resilience to host immune responses can appear within a few weeks of new sequences for L. infantum and stems from their extraordinarily infection, and they may even enable the L. braziliensis with the published variable surface coat – as soon as parasite to reinfect people who have genome of L. major. These parasites the immune system has geared up developed immunity to existing strains. cause different forms of disease, so the to attack one form, another type Other work from the Glasgow group has genome comparisons reveal genetic appears and proliferates, leading to identified an unusual method of DNA features that may be linked to particular wave after wave of infection. The repair, which could contribute to the clinical symptoms. sequencing of the trypanosome DNA-shuffling process creating mosaic genome suggested unexpected The genomes turn out to have genes. And a mathematical study ways in which the parasite might be suggests that it is the parasite itself, remarkably similar structures – only generating this diversity, and about 200 genes really differ in their rather than pressures from the immune research from Professor Dave Barry system, that generates waves of presence or absence between the and colleagues at the Wellcome three genomes. The main genetic infection in a host. The parasite has Trust Centre for Molecular thus evolved mechanisms to prolong changes seem to arise from gene loss Parasitology in Glasgow has or inactivation. Changes in a small infections, through a series of mini- revealed new insights into these infections, rather than immediately number of genes may therefore be deadly masters of disguise. having a big impact on the nature of overwhelming a host – thereby disease, though other effects – such as A key finding from the trypanosome increasing its chances of transmission. differences in gene activity or gene genome project was the discovery of Marcello L, Barry JD. Analysis of the VSG gene copy number – could also be many hundreds of damaged genes silent archive in Trypanosoma brucei reveals that coding for the main trypanosome mosaic gene expression is prominent in antigenic significant. variation and is favored by archive substructure. surface protein. Professor Barry and Jeffares DC et al. Genome variation and evolution Genome Res 2007;17(9):1344–52. of the malaria parasite Plasmodium falciparum. colleagues have found that these Burton P et al. Ku-independent end-joining in Nat Genet 2007;39(1):120–5. Errata in: Nat Genet damaged genes are used as a source Trypanosoma brucei cell extracts relies upon 2007;39(4):567, Nat Genet 2007;39(3):422. of spare parts for functional genes. sequence microhomology. Eukaryot Cell Peacock CS et al. Comparative genomic analysis Small sections are included in active 2007;6(10):1773–81. of three Leishmania species that cause diverse genes, altering the structure of the Lythgoe KA et al. Parasite-intrinsic factors can human disease. Nat Genet 2007;39(7):839–47. protein displayed on the cell surface. explain ordered progression of trypanosome antigenic variation. Proc Natl Acad Sci USA 2007;104(19):8095–100. ADVANCING KNOWLEDGE 12

ADDICTION SEEING THE PREDICTION UNCONSCIOUS A study with rats suggests that some individuals are The unconscious brain may be more likely to become hooked on drugs than others. guiding our actions more than we think.

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A long-running debate has focused particular dopamine receptors. They Non-invasive imaging techniques on the possible predisposition of then looked to see which factors were are revealing the brain in action, and people to drug addiction. Genetic associated with high drug consumption. how brain activity maps to studies are not clear-cut, and Since the rats had not previously been conscious awareness (or lack of it). although particular types of exposed to the drug, any associations And research is revealing some behaviour and brain activity are seen would be a potential cause rather than unnerving aspects of conscious and in addiction, these could be a consequence of drug taking. unconscious thought. consequence rather than a cause of It is already known that visual images drug taking. A neat experiment in The studies revealed that addiction can be registered in the brain even when rats, however, provides strong correlated with both impulsive observers are not aware of them. Now evidence that susceptibility to behaviour and low availability of Professor Geraint Rees and colleagues addiction has a biological dopamine receptors in key areas of the at the Wellcome Trust Centre for component. brain. A defect in dopamine receptor activity in the brain could therefore be Neuroimaging have shown that the The dopamine or ‘reward’ brain system a risk factor for drug consumption – in processing of such unconsciously is well known to be involved in addiction. humans as well as rats. recognised images is strongly affected It is also implicated in certain behaviours, by attention. Dalley JW et al. Nucleus accumbens D2/3 including impulsivity, the tendency to receptors predict trait impulsivity and cocaine When subjects engaged in a demanding respond prematurely without adequate reinforcement. Science 2007;315(5816): task were also presented with images 1267–70. reflection. Potentially, then, individual that were rendered invisible (by use of a variations affecting the dopamine masking technique), brain responses system could predispose to addiction to these images changed according to through their effects on behaviour. the attentional demands of the task. To test this idea, a group including So the allocation of attention to a visual Professor Trevor Robbins, Dr Jeffrey stimulus does not depend on its Dalley and Professor Barry Everitt in conscious detection. Cambridge monitored drug As well as handling inputs – sensory consumption in rats provided with perceptions of the world – access to the addictive drug cocaine. consciousness also shapes our actions. Before exposure, they measured the But perhaps not as much as we might animals’ tendency to impulsive think. The frontal lobes of the brain are behaviour and used brain-imaging considered to be critical for initiating techniques to quantify levels of voluntary actions.

Images 1 Visualising dopamine D2/D3 receptor 4 Decisions, decisions: does the density in regions of the brain. subconscious influence us more than we 2 Cocaine: susceptibility to addiction may lie, think? in part, in our genes. 5 Dutch art flourished in the 17th century, 3 Part of the frontal lobe (red) involved in alongside commerce and science. automatic suppression of reflex responses. Engraving by C de Passe after M de Vos. ADVANCING KNOWLEDGE 13

GOING DUTCH

Did Dutch trade kick-start the scientific revolution?

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Yet when Dr Petroc Sumner, Professor Something resembling modern Republic during its golden age of Masud Husain and colleagues studied science first emerged in Europe 1581–1695 – was the key driver of the two individuals with localised lesions in four-and-a-half centuries ago. The scientific revolution. key regions of the prefrontal cortex, they new emphasis on observation and At the time, Professor Cook suggests, found that automatic, unconscious experiment is often portrayed as the factors driving Dutch expansionism responses that normally suppress part of the wider intellectual were seen as precisely those unwanted actions were impaired as well. flowering of the European underpinning the new science. The Similarly, Dr Hakwan Lau and Professor Renaissance, yet that movement’s knowledge economy of the day placed Richard Passingham have found that adherence to classical knowledge a high value on objective description the prefrontal cortex can also engage in was antithetical to the empiricism at and accumulation of knowledge, subconscious processing. In their the heart of the new thinking. Now, through observation and experiment. studies, volunteers were subconsciously Professor Hal Cook, Director of the And they went hand in hand with a primed before undertaking a task Wellcome Trust Centre for the scientific methodology that sought requiring conscious thought, the prime History of Medicine at UCL, has rational explanations for observable being either compatible or incompatible proposed a radical new interpretation: phenomena. with the task. Even though subjects it was commerce that really powered the scientific revolution. Indeed, Professor Cook argues, this had no conscious knowledge of the pragmatism became firmly instilled in prime, incompatible primes disrupted Until now, historians have linked the Dutch culture and thinking. Its medicine their thinking. Furthermore, brain imaging birth of modern science to religion – a focused not on arcane theories of revealed activity in the prefrontal cortex retreat from superstition and the rise of causes but on careful description and when an incompatible prime was Protestantism, with its more direct, treatment. The result was an explosion presented, implying that it is engaged in humanistic interpretation of religious in science, botany, medicine, natural subconscious processing of information. texts – alongside the emergence of a history and the arts. Bahrami B et al. Attentional load modulates natural philosophy emphasising responses of human primary visual cortex to knowledge gained by experiment. The At least some reviewers were convinced: invisible stimuli. Curr Biol 2007;17(6):509–13. rise of the international trading “Cook is deeply persuasive that science Sumner P et al. Human medial frontal cortex economy during the same period has and commerce are epistemologically mediates unconscious inhibition of voluntary generally been seen as independent. linked through materialist necessity in action. Neuron 2007;54(5):697–711. this magisterial scholarly analysis,” said Lau HC, Passingham RE. Unconscious activation In Matters of Exchange, Professor the Journal of the American Medical of the cognitive control system in the human Cook argues that, far from being merely Association. “Altogether an enriching prefrontal cortex. J Neurosci coincidental, the new global commercial 2007;27(21):5805–11. tome,” added the New England Journal culture – seen most clearly in the Dutch of Medicine. ADVANCING KNOWLEDGE 14

NEW FUNDING

Africa Centre The brain of the beholder Copybook project

A £16.8 million award to the Africa A £1 million Strategic Award is The Wellcome Trust Case Control Centre for Health and Population supporting an innovative Consortium is turning its attention Studies will see it continue its critical multidisciplinary programme in to copy number variation. research on HIV. ‘neuroaesthetics’. The Wellcome Trust Case Control The Africa Centre, based in KwaZulu- Professor Semir Zeki from University Consortium demonstrated the value Natal in South Africa, is one of the College London (UCL) aims to bring of coordinated efforts to scan entire leading African HIV research institutes. neuroscience into areas normally seen genomes for disease susceptibility Led by Professor Marie-Louise Newell, as the territory of artists and genes (see page 6). It focused on it has established one of the continent’s philosophers. Can we measure beauty simple variation – single nucleotide most comprehensive demographic objectively? How are beauty and love polymorphisms (SNPs) – but copy surveillance systems, covering 90 000 related? What does it mean to be number variation also affects health people in mainly rural locations, and happy? What is creativity? (see pages 6–7). With £7.7 million has done much to document the extent With this new funding, Professor Zeki follow-up funding from the Wellcome and impact of HIV and AIDS on South hopes to attract students and Trust, the Consortium is now sweeping African people (see page 19). researchers from the sciences, arts and the genome for disease-associated The population is particularly badly humanities into taking up truly copy number variation. affected by HIV – around one in four interdisciplinary research. Their work Copy number variation is much less well people in the local community is HIV will be overseen by an advisory board understood than SNPs, but positive. The infection’s impact is that includes author Dame Antonia understanding is developing rapidly. The compounded by poverty, migration and Byatt, doctor, broadcaster and opera Consortium is using newly developed lack of access to effective treatments. director Sir Jonathan Miller, and the tools to carry out high-throughput With renewed five-year core funding, Director of the Courtauld Institute of analyses of 19 000 samples from eight the Africa Centre is well placed to focus Art, Dr Deborah Swallow. diseases (the seven diseases from the on monitoring and evaluating the Anti- With Professor Ray Dolan, Director of main study, plus breast cancer), to Retroviral Treatment Programme for the Wellcome Trust Centre for search for changes in copy number HIV, which is currently being rolled out, Neuroimaging at UCL, Professor Zeki associated with disease. and assessing the impact of will bring an experimental It will also be dissecting in more detail simultaneous epidemics of HIV, neurobiological approach to profound some of the genomic regions identified sexually transmitted infections and issues that have taxed thinkers for in the first phase, which appear to tuberculosis. The Africa Centre also centuries. The results not only will include more than one genetic factor aims to identify the best ways to deliver increase our knowledge about the influencing health. HIV-related healthcare in a low-income workings of the human brain but also As in phase 1, data and software tools rural setting. should offer fascinating insights into will be made freely available to the Opened in 1997, the Africa Centre is a human nature and how we view research community – emphasising the collaboration between the University of ourselves. value of not only the Consortium’s KwaZulu-Natal, the South African scientific discoveries but also its Medical Research Council and the ‘pathfinder’ role, developing tools and Wellcome Trust. techniques to accelerate research. ADVANCING KNOWLEDGE 15

A new view of cells A selection of notable grants awarded in 2006/07.

STRATEGIC AWARD DEVELOPMENTAL BIOLOGY AGEING Dr James Briscoe (National Institute for Professor Linda Partridge (University College Medical Research) and Dr Karen Page London) The biological mechanisms of cellular (University College London) Mathematical and bodily ageing. models of Sonic Hedgehog signalling in the neural tube. PROGRAMME GRANTS ORGAN DEVELOPMENT FAT DISTRIBUTION Professor Elizabeth A Jones (University of Professor Keith Frayn (University of Oxford) Warwick) Purinergic (ATP-based) and lipid The impact of fat deposition in different parts of signalling in Xenopus kidney development. the body and its harmful (or beneficial) effects on metabolic disease. RECOMBINATION Professor Sir Alec Jeffreys (University of GERM CELLS Leicester) Analysing recombination hotspots Professor Azim Surani (University of using single-molecule methods in individual Cambridge) The epigenetic mechanisms of sperm. germ cell specification in mice. MALARIA A new Wellcome Trust Centre for GONADOTROPHINS Gene Regulation and Expression is Professor John M Kelly (London School of Professor Ilpo Huhtaniemi (Imperial College Hygiene and Tropical Medicine) Plasmodium being established at the University London) Further studies of luteinising falciparum centromere function. of Dundee. hormone’s action on gonadal and other tissues. INNATE IMMUNITY The discovery that humans have a Professor Anthony Segal (University College METABOLISM surprisingly small number of genes London) Innate immunity and inflammatory Professor Paul Stewart (University of bowel disease. highlighted how important control of Birmingham) Novel regulators of corticosteroid gene activity is in human biology. An hormone metabolism and possible links to EPIDEMIOLOGY exquisitely complex set of interactions polycystic ovary syndrome and metabolic Professor Sarah Cleaveland (University of conditions. Edinburgh) Zoonotic pathogens in linked ensures that genes are only active in human and animal populations in rural Kenya. the right cells and at the right times. Professor Jonathan Seckl (University of Edinburgh) 11beta hydroxysteroid PROJECT GRANTS (COGNITIVE The Dundee Centre, funded by a dehydrogenase type 1 and atherosclerosis SYSTEMS FORESIGHT AWARDS) £5 million Strategic Award to Principal risk. ATTENTION Research Fellow Professor Angus BACTERIAL SECRETION Professor Tom Troscianko (University of Lamond and colleagues, will build on Professor Gabriel Waksman (Birkbeck, Bristol) and Professor David Hogg (University the expertise of a number of groups University of London) Structural studies of of Leeds) Developing a computer algorithm bacterial type IV secretion systems. modelling attention by studying human working on different aspects of gene attention in a realistic setting (in partnership control, including transcription, splicing INTRACELLULAR TRANSPORT with the EPSRC). and chromosome dynamics. Dr Murray Stewart (MRC Laboratory of Molecular Biology, Cambridge) Structural SPATIAL NAVIGATION It aims to pioneer a new approach in studies of factors needed for import and export Professor Lars Chittka (Queen Mary, cell biology by bringing together of material into and out of the nucleus. University of London) Studying bee foraging to gain insight into navigation strategies (in advanced imaging and proteomics PROJECT GRANTS partnership with the BBSRC and the EPSRC). technologies, combined with enhanced PAIN HISTORY OF MEDICINE data analysis tools, to provide a Professor John N Wood (University College PROGRAMME GRANT London) Regulation of Nav1.7, an ion channel quantitative understanding of gene HISTORY OF MEDICINE regulation and chromosome biology at recently found to have a role in pain detection (see pages 8–9). Professor Mark Jackson (University of Exeter) the single-cell level. The history of stress. LUNG DEVELOPMENT It also plans to establish a collaborative, Dr John Owers-Bradley (University of BIOMEDICAL ETHICS PROJECT GRANT multidisciplinary environment in which Nottingham) and Professor Michael BIOMEDICAL ETHICS to train young scientists. Silverman (University of Leicester) Measuring Professor Stefan Priebe (Queen Mary, alveolar growth and development in childhood University of London) The ethics of financial by helium-3 magnetic resonance. incentives to promote medicine taking.

Details of all grants made can be found in Grants Awarded 2006/07, available on the Wellcome Trust website.

USING KNOWLEDGE Supporting the development and use of knowledge to create health benefit. USING KNOWLEDGE 18

BLOOD NET TIES BENEFITS A better understanding of blood disorders is leading Making bednets available for free has to improved diagnosis and targeted therapies. greatly increased their use in Kenya.

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For over a century, clinicians have trial, Professor Green’s group was also More than a million children die of recognised a number of diseases, able to identify previously unrecognised malaria in Africa each year. This now termed the myeloproliferative disease variants and produce a new number could be dramatically slashed disorders (MPDs), in which the bone molecular classification of the MPDs. if more children slept beneath marrow goes into overdrive and Gradually, other genetic causes are insecticide-treated bednets. Take-up produces too many red blood cells, being unpicked. In 2007, for example, has been limited, however. Now, white blood cells or platelets. Work Professor Green’s group found a new Professor Bob Snow and colleagues from the group of Professor Tony set of JAK2 mutations and identified a at the Kenya Medical Research Green, at the University of novel variant of polycythaemia vera. Institute–Wellcome Trust Research Cambridge, is now revealing the Together, these findings have made a Programme in Kenya have shown molecular defects underlying these dramatic impact on clinical that free supply of bednets can disorders, and laying the foundation management. A widely used molecular make a huge impact on coverage – for more rational diagnosis and test is already allowing simple and particularly among the poor. treatment. more accurate diagnosis. The Although the benefits of treated All the various types of blood cell identification of molecular lesions not bednets are well-established, how best originate from blood stem cells. only provides a more logical basis for to encourage their use is less clear. As Mutations affecting blood stem cells grouping patients, but also provides well as the cost implications, there have are thought to result in a number of targets for novel therapies. Several been concerns that free bednets will blood disorders, including the MPD. JAK2 inhibitors are being developed not be valued or used. A common and the results of initial clinical studies However, the origins of the MPDs compromise is for bednets to be made are eagerly awaited. (polycythaemia vera, essential by local suppliers and sold at a thrombocythaemia and idiopathic Baxter EJ et al. Acquired mutation of the tyrosine subsidised price. kinase JAK2 in human myeloproliferative myelofibrosis) remained obscure until disorders. Lancet 2005;365(9464):1054–61. But even low-cost bednets may be out 2005, when several groups, including Erratum in: Lancet 2005;366(9480):122. of reach of many. Dr Abdisalan Noor (a Professor Green’s, reported mutations Campbell PJ et al. Definition of subtypes of Wellcome Trust Research Training in a gene called JAK2. Surprisingly a essential thrombocythaemia and relation to Fellow) and Professor Snow therefore single JAK2 mutation was found in the polycythaemia vera based on JAK2 V617F set out to examine how coverage was mutation status: a prospective study. Lancet majority of people with polycythaemia 2005;366(9501):1945–53. affected by cost in Kenya. In 2004, nets vera and in around half of those with were available only through the Scott LM et al. JAK2 exon 12 mutations in essential thrombocythaemia or polycythemia vera and idiopathic erythrocytosis. commercial sector. By 2005, a campaign idiopathic myelofibrosis. By analysing N Engl J Med 2007;356(5):459–68. was making subsidised nets available. patient samples from a large clinical

Images 1 Cross-section of a small 2 Bednets: free 4 Mothers breastfeeding blood vessel containing distribution greatly young infants in sub- red blood cells and a increases their use. Saharan Africa. white blood cell. 3 A malaria-transmitting mosquito after a meal of blood. USING KNOWLEDGE 19

BREAST IS DEFINITELY BEST Exclusive breastfeeding could significantly reduce the risk of HIV transmission in Africa.

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And in 2006, a mass free distribution In developing countries, where most contrast, may damage the intestine, programme began. babies depend on breast milk for allowing HIV to pass into the In 2004, bednet use was just 7 per cent. their survival, HIV transmission from bloodstream more effectively. By 2005, this had risen to 24 per cent. mother to child during breastfeeding UNICEF, the World Health Organization But in 2006, it had leapt to 66 per cent. is common. Intriguingly, however, and UNAIDS have already revised their And while bednet use in 2004 was researchers at the Africa Centre for guidelines on infant feeding to reflect dominated by richer families, almost no Health and Population Studies in these findings. This could dramatically difference between socioeconomic South Africa have found that HIV reduce the vertical transmission of HIV groups was seen in 2006. transmission is far lower if mothers from mother to child on the African feed their children exclusively with continent and beyond. Another study has stressed the benefits breast milk for the first six months of providing bednets to older children Coovadia HM et al. Mother-to-child transmission than if they also introduce formula of HIV-1 infection during exclusive breastfeeding and adults too. Using the latest models milk or solids at this early stage. in the first 6 months of life: an intervention cohort of mosquito behaviour and mortality, study. Lancet 2007;369(9567):1107–16. Research Career Development Fellow In a study of more than 2000 new Dr Gerry Killeen and colleagues argue mothers in rural and urban areas, that this would kill adult mosquitoes Professor Hoosen Coovadia and directly or force them to undertake colleagues found that there was a 4 per longer, more hazardous foraging cent risk of postnatal HIV transmission expeditions in search of their next feed. between the ages of six weeks and six months to babies fed on breast milk Noor AM et al. Increasing coverage and decreasing inequity in insecticide-treated bed net alone. Infants who received a mixture of use among rural Kenyan children. PLoS Med breast milk and formula were nearly 2007;4(8):e255. twice as likely to be infected as those Killeen G et al. Preventing childhood malaria in receiving breast milk only. Alarmingly, Africa by protecting adults from mosquitoes with those given both breast milk and solids insecticide-treated nets. PLoS Med 2007;4(7):e229. were almost 11 times likelier than the breast-only group to acquire infection. This unexpected benefit of breast milk may come about because it strengthens the baby’s gut lining. The larger, more complex proteins found in formula, animal milk and solids, by USING KNOWLEDGE 20

KILL OR FEVERISH CURE ACTIVITY Survivors of H5N1 infection may hold the secret Dengue is beginning to receive to others’ survival. the attention it deserves.

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The Spanish flu epidemic of 1918 protection against other H5N1 strains. Symptoms of dengue vary from mild killed millions. Doctors had no A set of monoclonal antibodies of fever through to life-threatening treatments to offer, but among the varying specificity might therefore offer dengue shock syndrome or severe remedies tried was blood transfusion an additional weapon against avian flu. dengue. A resurgence of dengue in from survivors to patients. This may Or, in an emergency, transfusions from tropical regions is reawakening well have reduced mortality – and flu survivors might enhance survival, as interest in the disease. In Vietnam, researchers at the Hospital for in the Spanish flu pandemic. researchers are dissecting the clinical Tropical Diseases and the Wellcome The Vietnam group is also studying syndrome and the body’s response Trust’s South-east Asia Programme the body’s response to H5N1, to to the virus to identify possible links in Vietnam have found that an find out why the virus is so deadly. to severe disease. They are also part updated approach might offer Animal studies have suggested that of international collaborations protection from H5N1 avian flu. severe disease is linked to rapid tackling this growing menace. H5N1 kills a high proportion of people it virus multiplication (high viral load) Over the past 30 years, dengue has infects. But some survive, and in their and excessive release of cytokines, emerged as a major threat to health bloodstream are antibodies that may molecules that signal between in tropical regions. It affects around 100 prevent the virus infecting cells. To test immune cells. A comparison of patients million people a year, with several this idea, Dr Tran Tinh Hien, Dr with H5N1 and human flu conducted hundred thousand experiencing the Cameron Simmons, Professor Jeremy by Dr Menno de Jong, Dr Simmons more severe form of dengue. and Dr Hien confirmed that human Farrar and colleagues in Vietnam took Several distinct strains of dengue virus H5N1 infection is associated with blood samples from H5N1 survivors exist, but the immune response to the very high viral loads and a massive and, in collaboration with Professor virus is complex and poorly cytokine response. Antonio Lanzavecchia in Switzerland understood. In infants, for example, Dr and Dr Kanta Subbarao in the USA, This suggests that early prevention Cameron Simmons and colleagues at developed monoclonal antibody cell of viral multiplication, and possibly the Wellcome Trust’s South-east Asia lines making anti-H5N1 antibody. management of the cytokine response, Programme in Vietnam have found that A well as binding tightly to H5N1 in should be priorities in treatment low levels of maternal antibodies biochemical assays, some of these of H5N1. correlate reasonably (but not monoclonal antibodies were able to Simmons CP et al. Prophylactic and therapeutic absolutely) with disease severity but, protect mice from infection and kept efficacy of human monoclonal antibodies against surprisingly, the link between viral load mice alive after exposure to a lethal H5N1 influenza. PLoS Med 2007;4(5):e178. and disease is weak at best. These dose of virus. Antibodies protected well de Jong MD et al. Fatal outcome of human influenza results could have significant A (H5N1) is associated with high viral load and against the strain of H5N1 people had hypercytokinemia. Nat Med 2006;12(10):1203–7. implications for vaccine development. been exposed to, but also offered

Images 1 Influenza virus particles 2 Hn, an 11-year-old girl 4 Slum conditions in on cells lining the who survived avian flu Vietnam: tainted water airways of the lung. infection, with her supplies promote the parents. spread of typhoid fever. 3 Dengue virus. 5 Public water supply in Bangladesh. USING KNOWLEDGE 21

TYPHOID TRIAL A vaccine for typhoid fever has completed a phase II trial.

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Similarly, collaborative studies with Dr Responsible for around 200 000 received vaccine and 50 placebo. Kerstin Luhn and others in Oxford have deaths a year, typhoid fever is a There were no serious adverse events found unusual patterns of regulatory T major global health problem. in the treated group, who showed cell activity in dengue. As in avian flu A new vaccine developed with significantly higher antibody responses (see left), disease seems to be triggered Wellcome Trust Technology to bacterial antigens. Previous trials in by excessive cytokine release. One Transfer funding has recently the UK, USA and in adults in Vietnam possibility is that this over-reaction completed a phase II clinical trial, have also shown that the vaccine is arises from defective regulatory T cell involving children aged between five safe and immunogenic. activity. Yet regulatory T cells turned out and 14 in Vietnam. Encouragingly, Although a phase II trial does not to be present and active in dengue – the vaccine was both safe and necessarily mean that the vaccine will but seemed to be overwhelmed by the elicited good immune responses in protect against infection, the better- strength of the response triggered by the vaccinated children. than-expected results boost the virus. The vaccine has been developed by confidence that the vaccine will be Emphasis is also being placed on Emergent Biosolutions Inc., a US- effective in the field and pave the way coordinated global responses. Professor based vaccine and therapeutic for larger phase III trials. Jeremy Farrar is playing an active role in company. It is a single-dose drinkable DENCO, a global dengue clinical vaccine based on a live attenuated research network, supported by the strain of Salmonella typhi, the European Commission and the bacterium that causes typhoid fever. Wellcome Trust, which brings together The strain has two genes deleted, clinical aspects with basic science, which abolishes its ability to cause epidemiology and public health, disease. Early development of the spanning countries in South-east Asia, vaccine was carried out by Reading- South America and Europe, and with based company Microscience, close links to the World Health which later became part of Organization. Emergent Biosolutions. Simmons CP et al. Maternal antibody and viral The latest trial was carried out in factors in the pathogenesis of dengue virus in infants. J Infect Dis 2007;196(3):416–24. Vietnam, with support from Professor Jeremy Farrar and colleagues at the Lühn K et al. Increased frequencies of CD4+ CD25(high) regulatory T cells in acute dengue Wellcome Trust’s Major Overseas infection. J Exp Med 2007;204(5):979–85. Programme. In a double-blind Farrar J et al. Towards a global dengue research randomised control trial, 101 children agenda. Trop Med Int Health 2007;12(6):695–9. USING KNOWLEDGE 22

BEAGLE SUPER- BONUS ANTIBIOTICS Like a phoenix from the flames, Beagle 2 lives again – Engineering new antibiotics may or at least its technology does. create a new tool against C. difficile.

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Among the instruments on board the Dr Liz Corbett, at the London School of MRSA and Clostridium difficile are Beagle 2 spacecraft was a prototype Hygiene and Tropical Medicine, to major headaches for the UK public miniaturised mass spectrometer, the develop and evaluate the technology health system, and bacteria are development of which was sponsored in a resource-poor setting. emerging that tolerate the few by the Wellcome Trust. The new TB kills around two million people every effective antibiotics still available. technology, it was thought, would year, mainly in developing countries. New approaches are urgently also filter through to other lab Globally, one person in three is thought needed, and the engineered equipment. Indeed, it now has a to be infected with M. tuberculosis. lantibiotics being developed by potentially life-saving terrestrial But widely used methods for detecting Novacta Biosystems with Wellcome application – as a new tool to infection, based on culture of sputum Trust Technology Transfer funding diagnose TB. samples, are neither quick nor may provide agents that not only kill Mass spectrometry is a popular particularly reliable. Speed is a crucial bacteria but also are less vulnerable laboratory technique for analysing factor. Conventional methods of to resistance. chemical structures. Mass spec diagnosis take weeks – by which time Lantibiotics (lanthionine-containing equipment, though, is large and bulky – patients with TB may be gravely ill, if peptide antibiotics) are produced by wholly impractical for a space mission. not dead, particularly if they are also certain Gram-positive bacteria and kill With Trust support, Professor Colin infected with HIV. other Gram-positive bacteria. They act Pillinger and Dr Geraint ‘Taff’ Morgan at The new device will provide results on lipid II, a precursor needed for the Open University set about within hours, so treatment can begin bacterial cell wall biosynthesis. miniaturising the technology so that it immediately. It will detect the presence Resistance is less likely to arise was suitable for interplanetary travel. of a complex lipid specific for because lipid II consists of several While the equipment never got to search M. tuberculosis; integrated software, components, and depends on the for Martian microbes, the Open being developed by the Bioinformatics coordinated activity of several genes. University team has adapted the Group at Cranfield University, will The Gram-positive bacterium C. difficile technology to identify chemical analyse results and determine disease causes serious gastrointestinal products characteristic of status. When the device has been symptoms that are potentially deadly in Mycobacterium tuberculosis, the cause shown to work under laboratory weak and elderly people. Although it of TB. Now, with £1.34 million conditions, it will be trialled in remains sensitive to drugs such as Technology Transfer funding, they have Zimbabwe, where Dr Corbett is based vancomycin, infections return in up to a teamed up with Wellcome Trust Senior and TB is rife. quarter of cases, through either Clinical Fellow in Tropical Medicine reinfection or incomplete eradication.

Images 1 The miniaturised mass 3 Clostridium difficile, spectrometer. a growing problem 2 The Beagle 2 in the UK. spacecraft. 4 A mock-up of the i-Snake next to a model heart. USING KNOWLEDGE 23

NEW FUNDING

A selection of notable grants A flexible friend awarded in 2006/07.

SEEDING DRUG DISCOVERY TRANSLATION AWARDS OBESITY Professor Stephen Bloom (Imperial College School of Medicine) Novel analogues of pancreatic polypeptide Y4 as antiobesity agents. ANTIBIOTICS Dr David Payne (GlaxoSmithKline) Novel antibacterials for Gram-negative pathogens. ANTIBIOTICS 3 4 Dr Lloyd Czaplewski (Prolysis Limited) Novel compounds to treat life-threatening, drug-resistant staphylococcal infections. MULTIPLE SCLEROSIS One reason why reinfection is so The ‘i-Snake’ surgical robot will take Dr Roland Kozlowski (Lectus Therapeutics common is that vancomycin is a non- keyhole surgery into previously Ltd) Novel Kv1.3 ion channel inhibitors for specific antibiotic that eliminates whole unexplored territory. the treatment of multiple sclerosis. swathes of gut bacteria, including Keyhole surgery was one of the great INFLAMMATION harmless bystanders. The gut is thus Professor David Ray (University of Manchester) medical advances of the 20th century. free territory for recolonisation. Refining glucocorticoid receptor agonists for Sophisticated surgical operations could the treatment of inflammatory conditions. Lantibiotics, by contrast, are potentially be carried out with comparatively little CANCER more specific. Moreover, because they trauma, and patients could rapidly Professor Ashok Venkitaraman (Sentinel Ltd) are peptides made by a commonly return to normal life. Refining cytotoxic compounds activated in used strain of bacteria, it is possible to hypoxic environments for use in glioblastoma But there are limits to the procedures engineer new peptides using genetic treatment. that can be carried out this way. The techniques. Through this approach, ‘i-Snake’, the brainchild of Professor OTHER TRANSLATION AWARDS Novacta, a spin-off from the John Innes Lord Darzi and Professor Guang-Zhong VACCINE DEVELOPMENT Centre in Norwich, has produced a Dr Andrew J Pollard (University of Oxford) Yang of Imperial College London, will be series of lead compounds highly A recombinant Opa protein vaccine for designed to take keyhole surgery into specific for C. difficile and with good meningococci. previously inaccessible new territories. pharmacological properties both in PRF PROGRAMME GRANT RENEWAL With £2.1 million of Technology Transfer cells and in animals. DEPRESSION funding, the multidisciplinary team is Professor Mark Williams (University of Oxford) With initial Technology Transfer funding, drawing inspiration from the world of Developing and testing cognitive behavioural Novacta has analysed several hundred herpetology, by developing a flexibly therapies for people at risk of suicide. compounds and assessed their effects jointed robot that will navigate its way PROJECT GRANTS on different strains of C. difficile and in through body spaces to hard-to-reach TUBERCULOSIS different infected animals. The success locations. Professor Juraj Ivanyi (King’s College of this research has led to £3.5 million As well as novel locomotory functions, London) and Dr Jenny Woof (University of follow-on funding to develop lead Dundee) Evaluating an engineered human the i-Snake’s pioneering engineering compounds by testing for safety and IgA antibody specific for the alpha-crystallin will also provide multiple sensing antigen of M. tuberculosis. toxicity, with the eventual aim of testing mechanisms and imaging tools at its a selected lead compound in a phase I MALIGNANT HYPERTHERMIA ‘head’, so it will be manoeuvrable with Professor Philip Hopkins (University of clinical trial. a high degree of precision. Therefore Leeds) A blood-based screening test for the surgeon will be able to visualise the malignant hyperthermia, an inherited abnormality of muscle metabolism. i-Snake’s journey and use a suite DEPRESSION surgical tools, located within its core, Professor Ricardo Araya (University of when it arrives at the site of the disease. Bristol) A trial of a psychological intervention Among many possible applications are for adolescent depression in poor areas of Santiago, Uruguay. clinical investigation of the alimentary tract or complex multi-vessel coronary Details of all grants made can be found in bypass surgery. Grants Awarded 2006/07, available on the Wellcome Trust website.

ENGAGING SOCIETY Engaging with society to foster an informed climate within which biomedical research can flourish. ENGAGING SOCIETY 26

A TASTY HEART TREAT STARTING Some 70 000 members of the public visited A Wellcome Collection exhibition Wellcome Collection in its first three months. explored the many meanings of the heart.

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Wellcome Collection, the new not usually known for its coverage of The Heart – the opening temporary £30 million visitor attraction from either art or science, devoted a double- exhibition in the new £30 million the Wellcome Trust, was opened at page spread to its delights. Wellcome Collection – explored the an evening gala reception on The nine-storey building houses three medical and cultural significance of 20 July 2007 by James Watson and galleries. The largest of these, on the the heart, through attractions as Stephen Fry – who enthused: “One ground floor, hosts temporary themed diverse as drawings of an ox heart of the most remarkable collections exhibitions, opening with The Heart by Leonardo da Vinci, prints by Andy of medical and physiological items (see right). Warhol and (for the non-squeamish) ever assembled is united with three live heart surgery. intelligent, inspiring and intriguing The other two galleries house two Curated by James Peto and Emily exhibitions to make as compelling a permanent exhibitions. Medicine Man, Jo Sargent, the exhibition encouraged visit as London has to offer.” previously shown at the British Museum, contains more than 500 audiences to contemplate the heart’s Wellcome Collection is the artefacts from Sir Henry Wellcome’s anatomical and symbolic power transformation of the Wellcome original collection, including a lock of through the ages. Building, the former headquarters of George III’s hair and Napoleon’s Medical understanding of the heart has the Wellcome Trust, at 183 Euston toothbrush. And Medicine Now developed considerably over time. Road, London. It provides stimulating explores contemporary medical topics Drawings by Leonardo da Vinci and insight into the human condition, such as obesity and genomes through mid-17th-century anatomical tables combining cultural, scientific and the eyes of scientists, artists and onto which entire human blood vessels artistic frames of reference. popular culture. were varnished illustrate early attempts “A new museum that is unashamedly The exhibitions are supplemented by a to understand its function. A modern ‘braining up’,” applauded Nigel lively programme of public events, perfusion machine is a reminder that we Richardson in the Daily Telegraph. “You where audiences can explore and now know enough to mimic the heart. will spill back on to the Euston Road debate current issues and ancient But the heart also has powerful cultural feeling both exhilarated and ever so mysteries of human wellbeing. symbolism. The ancient Egyptian Book slightly more intelligent.” All the visitor attractions have been of the Dead shows the heart being “A treasure,” agreed the Londonist positively received. Even the Peyton weighed against the ‘feather of truth’ in website: “London’s best new galleries and Byrne café gained rave reviews: order to determine the deceased’s in years.” Writing in the Independent, “This cheerful spot is welcome indeed,” suitability for the afterlife. Hearts also Janet Street-Porter called it: “One of concluded Jenni Muir in Time Out. appear on poignant 19th-century the most thought-provoking exhibitions playing cards. They are cut in half – one I've been to in years.” Even the Sun, half accompanied a child going to a

Images 1 Stephen Fry in the 3 ‘Our Lady of the Seven 5 Continuing the debate Medicine Now gallery in Sorrows’, an exhibit in (L–R): James Munro, Wellcome Collection. The Heart exhibition. Andy Davis and Gunes 2 Infant identification kit, in 4 Modern heart surgery, Taylor from Weston Wellcome Collection’s inside The Heart. College at the Debating Medicine Man exhibition. Matters national final. ENGAGING SOCIETY 27

MOTION CARRIED

Through Debating Matters, sixth formers rigorously debate contemporary real-world issues hitting the headlines.

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Foundling Hospital while the child’s More than 200 schools – 85 per cent and the audience. Students need not mother retained the other half so that from the state sector – and 2000 only to make a convincing case, but she might be able to reclaim her child in students have participated in the also to think on their feet. Time and later life. Debating Matters competition since time again, students have shown that That the heart continues to fascinate 2004, when the Wellcome Trust they can rise to the challenge. was evident from the 35 000 visitors provided funding to the Institute of The National Final 2006/07 took place who came specifically to see the Ideas through an Engaging Science at King’s College London and the exhibition. Some 200 attended the live Society Award. More than a third of National Portrait Gallery, with Mark broadcast of heart surgery from the schools had never previously Walport, Director of the Wellcome Papworth Hospital in July 2007 – been involved with debate. Trust, as one of the judges. Queen tickets for which sold out within a day. The Institute of Ideas and Pfizer Elizabeth’s Sixth Form College from the A notable visitor was Jennifer Sutton, Debating Matters competition was North East won the first prize, after a 23, from Ringwood, Hampshire – who piloted in 2003 and is now well close-fought round on human genetics, underwent a heart transplant at established as the country’s leading with Elfed High School from north Papworth in June 2007 and lent her schools debating competition. Sixth- Wales as runners-up. original heart to Wellcome Collection. form students in eight UK regions Students taking part have been Within weeks, she came to view the debate issues that impact on the world, enthusiastic. Ryan Devlin from organ that nearly killed her. and the way in which we understand Winstanley College, Wigan, said: and shape it. Many of these issues “School life completely changed when The multifaceted view of the heart was have a scientific strand to them. carried through to a successful we got involved with Debating Matters. symposium, ‘Matters of the Heart’, and In their preparation, students are Suddenly we were sitting around a book edited by James Peto, The expressly asked to find the evidence talking about huge global issues. It was Heart, published by Yale University they need to support their case. During revelatory.” Press. “In an age when research is the competition, judges from a range of increasingly sophisticated, and often professional backgrounds pose seemingly inaccessible,” said the questions and prompt students to Lancet in its review, “an intelligent develop and defend their arguments. impression of the cultural and social At the end, they offer critical but implications of these marvellous constructive feedback. achievements is uplifting and most The focus is on the quality of the uniquely welcome.” arguments and response to questions from the judges, the opposing team ENGAGING SOCIETY 28

ACTION AND HEROES OF INFLUENCE WAR New courses, a move into new areas and an expanded remit marked a A new docu-drama recounts a successful year for the National Science Learning Centre. remarkable mercy mission.

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In its second operational year, the Education and Leadership being The Relief of Belsen, a feature-length National Science Learning Centre in offered by the University of York. drama-documentary telling one of York delivered nearly 4000 training A Network Projects Director was the most extraordinary stories to days to more than 1500 teaching appointed in December 2006 to emerge from World War II, premiered staff, over 90 per cent of whom coordinate activities across the ten on 15 October 2007 on Channel 4. scored their experience as good or Science Learning Centres. The On 17 April 1945, a British ambulance excellent. National Centre also began developing unit accompanying the drive to Berlin As well as this practical support, the a bid, with the regional Centres, to was ordered instead to a newly Centre also fed into education policy create a united network of Science liberated prison camp in northern making, with its Director, Professor Learning Centres across England. Germany to handle an outbreak of John Holman, being appointed the UK The Centre has also worked closely typhus. That camp was Bergen-Belsen. Government’s National STEM Director with other key bodies in education, The arriving British unit found 40 000 in October 2006, with a remit to such as the Qualifications and prisoners starving and living in squalor, coordinate the UK’s science, Curriculum Authority, with which the including, in one hut designed for 100, technology, engineering and Centre ran a series of workshops on 1346 people – not counting the dead. mathematics (STEM) activities across curriculum development, and the schools and other centres of learning. Training and Development Agency Over the next few weeks, an international team of doctors, nurses, The National Science Learning Centre for Schools. former inmates, soldiers and local opened in 2005, part of a £51 million Professor Holman’s appointment as Germans, led by the medical corps of partnership with the Department for National STEM Director will help to the British Army, worked to try to save Children, Schools and Families to ensure that Science Learning Centres the dying prisoners of Belsen, while the provide high-quality continuing are integral to initiatives promoting war continued to rage throughout professional development opportunities STEM education. The STEM programme Europe. In the process, they created for science teachers and technicians. is underpinned by the STEM High Level the biggest hospital in Europe. As well as more training days, the Strategy Group, which offers advice to The Relief of Belsen tells this story, Centre also added 44 new courses, ministers on national priorities and using scripted drama, testimony and and now offers 76 in total. These range includes a representative from the extensive news footage from the 'horror from a summer school for newly Wellcome Trust. camp'. It received a Wellcome Trust qualified teachers through to Public Engagement Award in the ‘Leadership for Impact: New and History of Medicine to ensure its aspiring heads of science’, which will medical and historical authenticity. form one third of a new MA in Science

Images 1 A practical 2 Teachers share thoughts 4 A scene from The Relief demonstration at the during the course at of Belsen, screened on National Science York. Channel 4. Learning Centre in York. 3 Treating one of the 5 Part of the Centre of the patients at Belsen. Cell visitor attraction. ENGAGING SOCIETY 29

NEW FUNDING

A selection of notable grants Nuclear medicine awarded in 2006/07.

SOCIETY AWARDS FILM Jane Stephenson (Media Trust) ‘My Illness’: a series of 30-minute films on patients’ experiences of different illnesses. EDUCATION Dean Madden (University of Reading) ‘From DNA to Darwin’: education activities illustrating molecular evidence for evolution. PEOPLE AWARDS NEW MEDIA EDUCATION 445Kam Memarzia (PlayGen Ltd) An interactive video game for 12- to 16-year- olds about biomedical science at the nanoscale. It was made by the producers of the An innovative visitor centre situated THEATRE award-winning film Trafalgar Battle in a medical school will provide Mark Sands (Deafinitely Theatre) Surgeon, also part-funded by the Trust, young people with an exciting Playing God: a play about the ethical issues which was watched by some 1.4 million insight into medical science. surrounding cochlear implants for deaf viewers on Channel 4 in August 2005. children. The Centre of the Cell, recipient of a The critically acclaimed film, which £600 000 Public Engagement grant THE FACE garnered a 2005 Royal Television Helen Middleton-Price (Nowgen) from the Wellcome Trust, is sited within Society Award, examined the role of Sir A programme of events at the Manchester the research laboratories of Barts and Science Festival themed around the face. William Beatty, surgeon on HMS The London, Queen Mary’s School of Victory, and Navy doctors in the Battle ARTS AWARDS Medicine and Dentistry. It aims to of Trafalgar. THE BRAIN inspire and engage young people, and Tina Gonsalves, Chris Frith and Hugo Film-making can play an important role show more clearly how modern science Critchley raising awareness and interest in is underpinning today’s medical ‘Chameleon’: an interactive, audiovisual science and medicine. As well as these advances. installation, developed jointly by an artist, high-profile projects, the Trust has neuroscientists and computer scientists, The attraction, masterminded by exploring the communication of emotional funded many others that engage a Professor Fran Balkwill, a renowned states. variety of audiences. This area is poised cancer researcher and author of several INFECTIOUS DISEASE to become a bigger part of the Trust’s highly illustrated science books for Steve Ball (Birmingham Repertory Theatre) public engagement activities over the children, has attracted funding from The Speckled Monster: a site-specific, coming years. interactive theatre production and science several sources. The Trust’s education programme for young people, contribution is for the nucleus of the based on a historical local smallpox outbreak. cell, fittingly its central focus. It will HISTORY OF MEDICINE PUBLIC feature a mix of interactive games and ENGAGEMENT audiovisual shows, all highlighting the MENTAL ILLNESS central place of the cell in life, health Joe Matthews (Seneca Productions) and disease. A drama-documentary based on Bethlem Hospital. The Centre of the Cell aims to attract school visits from schools in the local area, one of the poorest parts of London. The hope is that the inspiring experience on offer will encourage young children to consider a career in Details of all grants made can be found in science and to think more deeply about Grants Awarded 2006/07, available on the the place of science in modern life. Wellcome Trust website. DEVELOPING PEOPLE Fostering a research community and individual researchers who can contribute to the advancement and use of knowledge. DEVELOPING PEOPLE 31

OF TYPHOID MODIFIED AND TOADS BY ASCENT A research programme in Thailand and Laos is helping Fruitful studies of DNA–protein to enhance regional research capacity. interactions are helping a young researcher up the career ladder.

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The South-east Asia Major Overseas understood. Studies have uncovered a How do histone proteins control Programme is based in Bangkok, surprisingly high incidence of typhoid gene activity? Dr Catherine Millar, a Thailand, and Ho Chi Minh City, fever, identified Staphylococcus aureus Wellcome Trust International Prize Vietnam. Satellite units exist in these as the main cause of septicaemia in the Travelling Fellow awarded a countries, with collaborations in under-ones, and revealed unexpectedly Research Career Development several nearby countries, including a high incidences of scrub typhus, Fellowship this year, is using yeast to long-standing partnership with Laos. murine typhus and leptospirosis. Such understand some of the intricacies information is important as it has of gene control. Sandwiched between Vietnam and guided changes in the use of suitable Thailand, Laos is a predominantly rural Dr Millar studied for her PhD in antibiotics. Although Laos does not yet country of around 6.5 million people. Professor Adrian Bird’s laboratory in have a serious problem with drug- Since 1999, the Thai unit has been Edinburgh, focusing on a protein resistant bacteria, nearby countries do collaborating with researchers at known as MBD4. and there is a risk that such strains will Mahosot Hospital, Vientiane. The be introduced or arise de novo. From Edinburgh, she moved to the research, which is led by clinicians laboratory of Professor Michael Dr Paul Newton, Dr Mayfong Mayxay But research extends beyond Grunstein at the University of California, (a former Wellcome Trust fellow) and infectious diseases: the Laos team Los Angeles. Her work there shifted to Dr Rattanaphone Phetsouvanh in recently came across cases of fatal the modification of histones and their Vientiane, concentrates on infectious heart damage in children who had possible role in controlling gene activity. diseases, to support evidence-based eaten the skin and eggs of a common clinical practice and health policy. toad, Bufo melanostictus. Interviews Dr Millar’s focus has been a variant of suggested that toad poisoning may be histone H2A known as Htz1 in yeast. Malaria has been a key priority. relatively common and a significant Although Htz1 is found mainly at An analysis of malarial parasites, public health issue. inactive genes, acetylation at one and cure rates in malaria patients, particular point is associated with active has revealed high levels of resistance Mayxay M et al. Combined molecular and clinical assessment of Plasmodium falciparum genes. Now in Manchester, Dr Millar is to chloroquine and sulphadoxine- antimalarial drug resistance in the Lao People’s using her Fellowship to establish a pyrimethamine. This, and other Democratic Republic (Laos). Am J Trop Med Hyg group to probe more deeply into Htz1 evidence, has led to the government of 2007;77(1):36–43. function. Laos changing treatment policy to Phetsouvanh R et al. Causes of community- Millar CB et al. Enhanced CpG mutability and artemisinin-based combination therapy. acquired bacteremia and patterns of antimicrobial resistance in Vientiane, Laos. Am J Trop Med Hyg tumorigenesis in MBD4-deficient mice. Science Bacterial infections have also been an 2006;75(5):978–85. 2002;297(5580):403–5. important focus. As in much of Asia, Keomany S et al. Toad poisoning in Laos. Millar CB et al. Acetylation of H2AZ Lys 14 is Am J Trop Med Hyg 2007;77(5):850–3. associated with genome-wide gene activity in the causes of fever in Laos are poorly yeast. Genes Dev 2006;20(6):711–22.

Images 1 Hmong farming women 2 Staphylococcus aureus, 3 Htz1 binding sites in Laos. the main cause of mapped using whole- septicaemia in genome microarrays. under-ones in Laos. Left: Dr Catherine Millar, a new Research Career Development Fellow at Manchester. DEVELOPING PEOPLE 32

GUT ONE, TWO, REACTION MANY How regulatory T cells orchestrate immune A single-gene disorder has proven responses in the gut is gradually being revealed. more tractable than a complex condition.

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The cells in the intestinal wall have a Of particular interest has been the Genetic studies can identify the tricky balancing act to perform. They discovery that, unlike most tissues, the factors underlying behavioural must generate an immune response gut does not depend only on regulatory conditions, providing clues to to defend the body against T cells from the thymus – it produces its underlying biological mechanisms. pathogens in the gut but must not own. This production is dependent on In a recent example, a team led by react to dietary antigens or the a classical regulatory T cell stimulus, Professor Jonathan Flint (recently symbiotic microbes that have made TGF-ß, and the vitamin A metabolite awarded a Principal Research it their home. Research led by retinoic acid. It also appears that Fellowship) identified a mutation Professor Fiona Powrie, Wellcome regulatory T cells occupy a distinct causing lissencephaly, a rare Trust Senior Research Fellow at the location in the gut tissue. condition in which the migration of University of Oxford, is piecing Professor Powrie’s group has also neurons through the brain is disrupted together the complex web of identified factors that may tip the during early development. But unlike interactions that maintain this intestinal balance towards over-reaction. single-gene disorders, genetic delicate balance. The cytokine IL-23, for example, seems analysis of complex behavioural traits remains challenging. It is becoming increasingly clear that to be specifically involved in promoting the gut’s immune mechanisms play a inflammatory reactions in the gut – and The lissencephaly story begins with a key role in our defence – but also is thus an exciting new target for IBD large-scale mutagenic study of mice, contribute to common medical therapies. and a search for animals with unusual complaints. Around 1 in 1000 people in Coombes JL et al. A functionally specialized behavioural traits. One such animal developed countries endures population of mucosal CD103+ DCs induces showed abnormalities in brain structure inflammatory bowel disease (IBD), where Foxp3+ regulatory T cells via a TGF-beta and and neuron migration similar to those retinoic acid-dependent mechanism. J Exp Med an overactive immune system ends up 2007;204(8):1757–64. seen in other strains with lissencephaly- damaging the body’s own tissues. Uhlig HH et al. Characterization of like features. The animal had acquired a A possible answer to the miseries of Foxp3+CD4+CD25+ and IL-10-secreting mutation in a tubulin gene, which CD4+CD25+ T cells during cure of colitis. affected its ability to make microtubules, IBD may lie with regulatory T cells: J Immunol 2007;177(9):5852–60. immune cells exciting great interest components of the cell’s internal Hue S et al. Interleukin-23 drives innate and skeleton. because of the ability to turn off T cell-mediated intestinal inflammation. J Exp Med unwanted immune responses. 2006;203(11):2473–83. The similarity between the mouse Professor Powrie’s research has Kullberg MC et al. IL-23 plays a key role in mutants led the team to screen for revealed much about how these cells Helicobacter hepaticus-induced T cell-dependent tubulin mutations in people with operate, both in normal health and in colitis. J Exp Med 2006;203(11):2485–94. lissencephaly of unknown cause. Two inflammatory conditions such as IBD. such individuals had mutations

Images 1 Professor Fiona Powrie, 3 Professor Jonathan 4 A typical site of a Senior Research Flint, a new Principal schistosome Fellow at the University Research Fellow at the transmission, Lake of Oxford. University of Oxford. Victoria in Uganda. 2 Intestinal bacteria. 5 The head of a schistosome parasite. DEVELOPING PEOPLE 33

A FLUKE OF NATURE Wide-scale programmes are underway to tackle schistosome parasites in Africa. But is the impact of such interventions fully understood?

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affecting the human version of the In Uganda, two Wellcome Trust- On the other hand, schistosome mouse tubulin gene. Follow-up studies funded fellows – Dr Simon Brooker infections are so common that they identified tubulin mutations in six and Dr Alison Elliott – are aiming to frequently overlap with other infections, more people with a range of neuro- find out more about the impact of such as HIV/AIDS or TB. HIV is known developmental conditions. schistosomes and their control. to accelerate TB disease, and Dr Elliott, who holds a Career Post in Clinical But unlike single-gene abnormalities, Control of infections calls for a good Tropical Medicine at the LSHTM, has genetic dissection of behavioural traits understanding of where they occur. discovered that schistosomes further or neuropsychiatric conditions remains Transmission will vary across a country, accelerate TB progression in HIV- difficult. For example, a large-scale and information is rarely available for infected individuals. whole-genome scan for factors every region. Nonetheless, by associated with neuroticism failed to combining field data with climate data Nevertheless, most helminth infections identify genes clearly associated with acquired from remote sensing systems, go unnoticed, as the parasite blocks the trait, even though twin studies imply spatial patterns can be modelled, the host’s immune response. And while that genes are important. Possibly, many helping to fill gaps in survey data. this might promote other infections, or rare interacting factors underlie such interfere with BCG vaccination, it may Using this approach, Dr Brooker, a traits – and hence very large studies will actually have benefits – protecting newly appointed Career Development be needed to identify them against severe malaria or allergic Fellow at the London School of Hygiene unambiguously. conditions. Dr Elliott is therefore leading and Tropical Medicine (LSHTM), and a clinical trial in Uganda examining the Keays DA et al. Mutations in alpha-tubulin cause colleagues have developed a predictive abnormal neuronal migration in mice and effects of de-worming treatments of map of infection risk. By reducing the lissencephaly in humans. Cell 2007;128(1):45–57. pregnant mothers and children on need for expensive field surveys, the Poirier K et al. Large spectrum of lissencephaly infection and responses to vaccination. and pachygyria phenotypes resulting from de approach has made national control novo missense mutations in tubulin alpha 1A efforts economically feasible, and has Clements AC et al. Bayesian geostatistical (TUBA1A). Hum Mutat 2007;28(11):1055–64. prediction of the intensity of infection with helped to guide control in Uganda, as Schistosoma mansoni in East Africa. Parasitology Shifman S et al. A whole genome association part of the Gates Foundation-financed 2006;133(Pt 6):711–9. study of neuroticism using DNA pooling. Mol Schistosome Control Initiative. Other Psychiatry 2007 [Epub ahead of print]. Kabatereine NB et al. Impact of a national work has evaluated the health impact helminth control programme on infection and and cost-effectiveness of control. morbidity in Ugandan schoolchildren. Bull World Health Organ 2007;85(2):91–9. Brown M et al. Schistosoma mansoni, nematode infections, and progression to active tuberculosis among HIV-1-infected Ugandans. Am J Trop Med Hyg 2006;74(5):819–25. DEVELOPING PEOPLE 34

THE H ASSEMBLING FACTOR A CAREER The complex role of factor H in kidney disease How proteins aggregate is the focus is gradually being unravelled. of a new Sir Henry Wellcome Fellow.

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The complement system is an when animals lacking factor H are given Sir Henry Wellcome Fellowships important part of the body’s anti-C5 antibody. As well as implicating were introduced in 2006 to provide defences against infection. It is C5 in the disease, these findings researchers early in their careers with based on a complex cascade of identify C5 as a potentially important a unique opportunity to develop their reactions that ultimately generates a drug target. research. Among the first batch of protein superstructure that destroys Factor H has also been linked to retinal successful applicants was invading cells. Given this firepower, degeneration and a rare kidney disease Dr Thomas Jahn, whose interests lie complement must be kept under of children, atypical haemolytic uraemic in the mechanisms driving abnormal tight control. The bloodstream syndrome (aHUS). The genetic factors folding of proteins implicated in protein factor H plays a crucial role driving the nephritis seen in mice neurodegenerative disorders such in this control, and deficiencies in its lacking factor H appear distinct from as Parkinson’s and Alzheimer’s activity have been linked to several those linked to aHUS. This appears to disease. diseases. At Imperial College reflect the impact of different mutations Dr Jahn studied biochemistry at the London, new Wellcome Trust Senior in the factor H gene. Indeed, when University of Halle, before being Research Fellow Dr Matthew transgenic mice were created with the awarded a place on the Four-year PhD Pickering has been clarifying the role aHUS version of the factor H gene, the Programme at the University of Leeds. of factor H in kidney disease. animals developed signs of aHUS. Under the supervision of Professors Exactly how factor H contributes to These mice are important as they Sheena Radford and Steve Homans, disease processes is not always clear. represent the first animal model of he used a variety of biophysical Using transgenic mice lacking factor H, aHUS. They pinpoint complement techniques to study the folding of beta- Dr Pickering has been teasing these activation on kidney endothelial cells as 2-microglobulin. processes apart. the key site of damage and open up the This protein shows a natural tendency Complement activation has been prospect of testing targeted therapies. to aggregate into fibrils similar to those implicated in an inflammatory kidney Pickering MC et al. Prevention of C5 activation seen in Alzheimer’s disease (amyloid disease, membranoproliferative ameliorates spontaneous and experimental fibrils), resulting in the disorder dialysis- glomerulonephritis type 2, also known glomerulonephritis in factor H-deficient mice. Proc related amyloidosis. The structural Natl Acad Sci USA 2006;103(25):9649–54. as dense deposit disease. The disease studies showed that beta-2- Pickering MC et al. Spontaneous hemolytic develops spontaneously in mice uremic syndrome triggered by complement factor microglobulin first converts into a lacking factor H. However, its severity is H lacking surface recognition domains. J Exp Med partially unfolded intermediate form that reduced in the absence of complement 2007;204(6):1249–56. has a high propensity to bind further protein C5. In addition, antibody- copies, polymerising into a fibril. triggered kidney disease is prevented

Images 1 Membranous 3 Dr Thomas Jahn, one of 4 An amyloid plaque, as glomerulonephritis. the first Sir Henry seen in Alzheimer’s 2 Dr Matthew Pickering, Wellcome Fellows. disease. a new Senior Research 5 Dairy cows. Fellow at Imperial College London. DEVELOPING PEOPLE 35

NEW FUNDING

A selection of notable grants Animal insights awarded in 2006/07.

PRINCIPAL RESEARCH FELLOWSHIPS T CELLS Professor Gillian Griffiths (University of Cambridge) Secretion mechanisms of cytotoxic T lymphocytes. ALZHEIMER’S DISEASE Professor Peter St George-Hyslop (University of Cambridge) Molecular and cellular studies of presenilins in Alzheimer’s and other diseases. SENIOR RESEARCH FELLOWSHIP IN 4 CLINICAL SCIENCE EPIDEMIOLOGY Professor Liam Smeeth (London School of Hygiene and Tropical Medicine) Making better With his new Fellowship providing Clinical veterinary research will use of computerised clinical data for £250 000 support over four years, benefit from a new £10.7 million epidemiological research. Dr Jahn is moving to the University of initiative. SENIOR RESEARCH FELLOWSHIPS IN Cambridge to study variants of alpha- BASIC BIOMEDICAL SCIENCE Veterinary research is important not just synuclein, a protein implicated in CELL BIOLOGY to the future health of animals. Diseases Parkinson’s disease. He plans to Dr Blanche Schwappach (University of that jump species from animals to combine biophysical analysis with Manchester) Assembly-dependent transport humans are a constant threat to human of multimeric membrane proteins to the cell studies of accumulation in the brain of health – SARS and H5N1 avian flu surface. living fruit fly, to try to identify being just two recent examples. biochemical features that are predictive VIROLOGY The Wellcome Trust’s new clinical Dr Ian Goodfellow (Imperial College London) of protein aggregation in living cells. The Mechanisms of norovirus replication. move to Cambridge will also facilitate veterinary initiative, being run in partnership with the seven UK INTERNATIONAL SENIOR RESEARCH collaboration with the groups of Dr FELLOWSHIP Michele Vendruscolo and Professor veterinary schools and coordinated by Professor Sandy Trees from the CELL SIGNALLING Christopher Dobson in the Department Dr Attila Remenyi (Eotvos Lorand University, of Chemistry. University of Liverpool, aims to create a Hungary) Protein scaffolds organising MAP- Jahn TR, Radford SE. Folding versus community of ‘clinically literate kinase-mediated signal transduction. aggregation: polypeptide conformations on researchers and research-literate RESEARCH CAREER DEVELOPMENT competing pathways. Arch Biochem Biophys clinicians’. FELLOWSHIP 2007;469(1):100–17. Funding of £7m will be used to create NEUROSCIENCE Smith AM et al. Direct observation of oligomeric three types of fellowship for different Dr James Kilner (University College London) species formed in the early stages of amyloid fibril Applying statistical approaches to the mirror formation using electrospray ionisation mass career stages: one-year Research Entry neuron system. spectrometry. J Mol Biol 2006;364(1):9–19. Fellowships, Integrated Training SIR HENRY WELLCOME Jahn TR et al. Amyloid formation under Fellowships towards a PhD, and POSTDOCTORAL FELLOWSHIP physiological conditions proceeds via a native-like Postdoctoral Fellowships. These folding intermediate. Nat Struct Mol Biol EMERGING INFECTION 2006;13(3):195–201. awards will be administered by the Dr Shelly Cook (Natural History Museum) Trust. Vector and host biology and genetic diversity The remaining £3.7m of funding will be of flaviviruses. available for small grants such as RESEARCH TRAINING FELLOWSHIPS laboratory animals training, vacation CHILD PSYCHOLOGY scholarships, intercalated awards and Dr Helen J Baker-Henningham (University of summer schools. the West Indies, Jamaica) Young children’s social and emotional competence. HISTORY OF MEDICINE FELLOWSHIP WOMEN’S HEALTH Dr Elizabeth Toon (University of Manchester) Screening and women’s health in the UK, 1960–2000. Details of all grants made can be found in Grants Awarded 2006/07, available on the Wellcome Trust website. FACILITATING RESEARCH Promoting the best conditions for research and the use of knowledge. FACILITATING RESARCH 37

STRUCTURAL SUCCESS LIGHT FANTASTIC The Structural Genomics Consortium is generating new drug leads The Diamond synchrotron is up as well as new knowledge. and running.

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The Structural Genomics This structural analysis will help to Welcoming its first users in January Consortium (SGC), operating out clarify the molecular basis of histone 2007, Diamond is the result of a of labs in Oxford, Toronto and modification, and may also be a decade-long £263 million Stockholm, is bringing a high- starting-point for the development of collaboration between the Wellcome throughput approach to protein chemical inhibitors. Trust and the UK Government. In structure determination. The SGC New chemical leads are also arising phase 1, seven beamlines were has significantly boosted the from work on PIM kinases, a class of established. Phase 2 will provide for numbers of structures being enzymes involved in cell signalling. another 15. Demand is already high – released, and is responsible for Structural studies revealed an unusual when active, beamlines are running almost one in four of all protein binding site for a particular class of 24 hours a day. structures going into public inhibitors (imidazo[1,2-b]pyridazines). Professor Dave Stuart at the Wellcome databases. And the freely released Unlike similar inhibitors, they block Trust Centre for Human Genetics in information is of value in both access of ATP to the enzyme’s active Oxford was the first to use the fundamental research and targeted site rather than competing directly at macromolecular structure beamline. drug development. the actual binding site. They are thus Professor Stuart is visualising the Modification of histones has emerged more selective inhibitors. One of the structure of ephrin receptors – proteins as an important mechanism controlling more active inhibitors suppressed the found on the surface of cells that guide gene activity. Accordingly, much growth of a variety of leukaemic cell migrating cells to their correct location. attention has been focused on the lines, illustrating their promise as Abnormal ephrin signalling has been enzymes that add or remove these targets for therapeutic intervention. implicated in several cancers. modifications. Of particular importance Diamond is also home to the Trust- is how the exquisite specificity of these Ng SS et al. Crystal structures of histone funded Membrane Protein Laboratory, enzymes is achieved. demethylase JMJD2A reveal basis for substrate run by Diamond Fellow Professor So specificity. Nature 2007;448(7149):87–91. A structural study of the JMJD2A Iwata, which is providing support for Pogacic V et al. Structural analysis identifies demethylase, which removes methyl imidazo[1,2-b]pyridazines as PIM kinase inhibitors researchers working with membrane groups from a pair of lysine residues on with in vitro antileukemic activity. Cancer Res proteins. Such proteins are central to histone H3, provides some answers. 2007;67(14):6916–24. many biological processes but are Stanley Ng, a graduate student at the difficult to crystallise, making structural SGC and the University of Oxford, studies problematic. determined the structure of the enzyme Outside biology, Diamond is being used bound to histones with different forms to study materials ranging from of methylated lysines. meteorites to ancient manuscripts.

Images 1 Structure of PIM1, with 2 An aerial view of the substrate, produced by Diamond synchrotron. the Structural Genomics Consortium. FACILITATING RESEARCH 38

TESTING TOMORROW’S CHANGING MEDICINES PRACTICE Clinical Research Facilities are being used to test Research at Clinical Research a variety of innovative therapies. Facilities can feed directly into healthcare delivery.

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The explosive growth of biomedical Preliminary results suggest that the Studies hosted at Clinical Research research over the past decades is technique is safe and feasible for use in Facilities (CRFs) reveal disease generating huge potential for the people and stimulates strong immune mechanisms and test experimental development of new treatments. responses. new therapies. Such work takes time Ensuring that this potential is Gene-based studies demand specially to influence practice, but some studies realised will call for concerted efforts trained support staff, found only in have more immediate impact. in translational research and Clinical Research Facilities. The same is The Southampton CRF has been experimental medicine. A key step in true of the challenging neurosurgery contributing to a multicentre trial this process will be early testing of research being carried out in assessing the value of early antibiotic new therapies, and Clinical Birmingham. A pioneering use in people with severe, acute Research Facilities are ideal sites in neurosurgical study is examining the necrotising pancreatitis. The trial found which to carry out this research. potential of deep-brain stimulation to no evidence of benefit in preventing Many kinds of approach are being reduce long-term dependence on infection or improving survival. The explored. Gene-based therapies have levodopa in Parkinson’s disease. This results have led to changes in local yet to realise the benefits initially hoped technique is also a possible treatment practice – helping to reduce antibiotic for, but research continues on possible for Tourette syndrome. usage and lessen the risks of hospital- strategies, particularly in the promising One of Manchester’s specialist areas is acquired infections. area of DNA vaccines. In Birmingham, magnetic resonance imaging, which Other work has led to validation of for example, a phase I study is being has many possible applications. For biomarkers of liver fibrosis identified at carried out of a cancer treatment based example, a study is using the technique the CRF. A non-invasive blood test, the on an engineered herpes simplex virus to optimise monoclonal antibody Enhanced Liver Fibrosis (ELF) Test, can producing granulocyte–macrophage therapy, seeking to improve the detect early stages of liver fibrosis – of colony-stimulating factor, which treatment of people with colorectal value, as the condition is potentially enhances the immune response cancer. reversible if caught early. The test is against cancer cells. cheaper than a liver biopsy. It received Meanwhile, in Southampton, highly regulatory approval in May 2007. promising results have been obtained Southampton has also become involved in a prostate cancer treatment, in which in substance abuse in sport. A growth an electroporation technique is used to hormone doping test, developed from deliver immune-stimulating DNA work carried out in the CRF, has vaccines. entered the validation process prior to commercial release.

Images 1 Studies in the 3 Cycling, a sport that has 4 The newly opened Manchester Clinical struggled to control building at the European Research Facility. drug use. Bioinformatics Institute. 2 Liver tissue affected by fibrosis. FACILITATING RESARCH 39

NEW FUNDING

A selection of notable grants Name that gene awarded in 2006/07.

STRATEGIC AWARDS TROPICAL MEDICINE Thailand Major Overseas Programme Re-housing the Programme’s offices and laboratories. MOUSE MODELS Immunity and Infection Genomics Consortium ENU mouse mutagenesis facility at the Australian National University, Canberra. CAPITAL AWARD CHROMOSOME BIOLOGY 3 Professor Kim Nasmyth (University of Oxford) A contribution towards the building costs of the Institute of Chromosome Biology. In Birmingham, research on a possible The challenging task of formalising TECHNOLOGY DEVELOPMENT GRANT blood test for bowel cancer has had human gene nomenclature is being SOFTWARE spin-off benefits in colonoscopy. taken on by the European Professor Peter Green (University of Bristol) Development of ClonalFrame software for Traditional colonoscopy is unpleasant Bioinformatics Institute. analysis of bacterial sequence data and and carries risks of gut damage. More The Human Genome Organisation’s association mapping. sophisticated technologies were thus Gene Nomenclature Committee (HGNC) EQUIPMENT GRANTS introduced for research studies and is the only authority worldwide providing RNAi shown to be significantly safer. They are unique, standardised nomenclature for Professor Andrew Sharrocks (University of now gradually being implemented Manchester) Establishing an RNAi facility. human genes – essential housekeeping across the NHS. to avoid confusion and promote data PROTEIN ANALYSIS The CRF in Cambridge has been used sharing. This year, Dr Ewan Birney of Professor Peter Tompa (Institute of to look after patients in a persistent Enzymology, Hungary) An AKTA protein the European Bioinformatics Institute purification system. vegetative state (PVS) following brain (EBI) and Dr Elspeth Bruford of BIOMEDICAL RESOURCES GRANT injury, who have been undergoing University College London were brain-imaging studies. The patients’ awarded a biomedical resources grant DEVELOPMENTAL BIOLOGY Professor Susan Lindsay responses to specific stimuli suggest to take on the task of assigning (University of Newcastle upon Tyne) that they retain conscious awareness – nomenclature to human genes, with and Professor Andrew Copp findings that could have significant the HGNC moving to the EBI. (Institute of Child Health, London) implications for PVS diagnosis. Human Developmental Biology Resource. Based at the Wellcome Trust Genome Dellinger EP et al. Early antibiotic treatment for RESEARCH RESOURCES IN MEDICAL severe acute necrotizing pancreatitis: a Campus at Hinxton, near Cambridge, HISTORY GRANT the EBI is a leading centre for analysis randomized, double-blind, placebo-controlled ARCHIVES study. Ann Surg 2007;245(5):674–83. and annotation of the human genome. Dr Andrew Grout (Edinburgh University Parkes J et al. European liver fibrosis (ELF) This year also saw the completion of Library) Widening access to University of markers accurately distinguish fibrosis severity in the Wellcome Trust-funded extension Edinburgh MD theses, 1726–1930. chronic hepatitis C (CHC); an external validation to the EBI building, the ‘East Wing’. study in a population-based cohort. Hepatology HISTORY OF MEDICINE PROJECT 2006;44(4) Suppl. 1:283A. The Trust funds other work at the EBI, GRANT Erotokritou-Mulligan I et al. Validation of the including the Ensembl genome browser ARCHIVES growth hormone (GH)-dependent marker method and Macromolecular Structure Dr John Lagnado (Biochemical Society) of detecting GH abuse in sport through the use of Database. Cataloguing the Biochemical Society archives, independent data sets. Growth Horm IGF Res including items belonging to Fred Sanger. 2007;17(5):416–23. Professor Janet Thornton of the EBI Owen AM et al. Detecting awareness in the is also involved in a £5.9 million vegetative state. Science 2006;313(5792):1402. Strategic Award on ageing and age-related disease, led by Professor Linda Partridge and colleagues at UCL.

Details of all grants made can be found in Grants Awarded 2006/07, available on the Wellcome Trust website. DEVELOPING OUR ORGANISATION Using our resources efficiently and effectively.

GROWTH PATTERNS TAKING THE TEMPERATURE NEW FACES Wellcome Trust assets grew An independent survey of opinion The Wellcome Trust has been to more than £15 billion during leaders and grantholders revealed reorganising – bringing in more the year. positive views, along with some scientific expertise and gearing up for suggestions for improvement. a new grants management system. Active management of a diversified investment portfolio led to further During 2007, the Trust commissioned This year saw a new senior scientific excellent growth in the Trust’s assets, Ipsos MORI to undertake an team put together, with considerable even during the credit squeeze in independent opinion audit of important experience in basic science and autumn 2007. During the year, the Trust stakeholders, to find out about translational medicine. Trust’s investment base rose by their perceptions of the Trust and its Professor Richard Morris joined the £1.7bn, from £13.4bn to £15.1bn. work. Ipsos MORI interviewed 51 Trust to take up a role as Head of The success of this year’s asset opinion formers (such as representatives Neuroscience and Mental Health, while management – a return of 17 per cent – from academia, government, other maintaining his group in Edinburgh. Alan continues a period of excellent funding organisations and the media) Schafer, new Head of Molecular and performance. Returns over the past and received over 1200 responses to Physiological Sciences, co-founded the three years have averaged 17.6 per cent, an online survey of grantholders. biotech company Hexagen, and has led and over the past five years 15.7 per The findings were extremely positive. GlaxoSmithKline’s Technology cent, against a net target of 6 per cent. Familiarity with the Trust’s core activities Development Department. Over each of the past five years, was high, and stakeholders associated Pat Goodwin remains Head of investment returns have exceeded values such as ‘excellence’, Pathogens, Immunology and Population £1bn; cumulative gains in the period ‘professional conduct’ and ‘dynamism’ Studies and Jimmy Whitworth Head of have been more than £8bn. with the Trust. Most said that they International Activities. Completing the Over the longer term, since the flotation would speak very favourably about the senior team, Catherine Quinn, previously of Wellcome plc in 1986, annual returns Trust and its activities. at the University of Oxford, is heading up have been 16.2 per cent, significantly There was a lower awareness of the a new Grants Management department. higher than global equity total returns Trust’s work outside biomedical research; The new Grant System being launched in and the Trust’s targets. some felt the Trust could do more to 2008 will provide grantholders with more At the same time, the Trust has been communicate its international activities. scope to manage grants and applications developing a number of sophisticated In terms of the future, there was a desire electronically. Nevertheless, applicants tools to monitor and manage risks to see more communication on the and grantholders clearly appreciate in its investment portfolio. This has Trust’s strategic direction and funding personal interactions with Trust staff, and significantly reduced volatility opportunities. Opinion leaders also the new structure is designed to provide of investment values over time. suggested that the Trust should consider a service better tailored to their needs. Returns quoted are nominal figures its niche in the light of the opportunities The reorganisation is part of an ongoing (i.e. before adjustment for inflation). and challenges arising from the changing scrutiny of operating costs to ensure biomedical research landscape, both in that the Trust is run efficiently while the UK and internationally. continuing to provide a high-quality service. OVERVIEW 41

CORPORATE ACTIVITIES 2006/07 A brief overview of the Wellcome Trust’s corporate activities over the year.

1 23

Governors and senior staff Wellcome Collection would have denied scientists a valuable Professor Richard Hynes, a Howard This year saw the opening of Wellcome research tool. Following input from the Hughes Medical Institute Investigator Collection, a major new public venue Trust and others, and a public at the Massachusetts Institute of located in the Trust’s former headquarters consultation that found general public Technology, was appointed a Governor building at 183 Euston Road (see pages support for hybrid use in medical in January 2007. Professor Adrian Bird 26 and 51). As well as exhibition and research, plans for a ban were dropped. was appointed Deputy Chairman, for a events space, it houses the Wellcome The potential to use electronic patient three-year term until 31 March 2010. Library, the Wellcome Trust Centre for records in research, through the Professor Ron Plasterk left the Board of the History of Medicine at UCL, and a Connecting for Health initiative, has been Governors, having taken up a new role new Conference Centre. a major focus during the year. Use of as the Dutch minister of research and Contributions to policy making patients’ medical information could universities. Professor Martin Bobrow, The Trust has worked with a range of prove invaluable in research, and is an Professor Sir Leszek Borysiewicz and partners to draw attention to the area in which the UK, with its nationwide Professor Dame Jean Thomas also left threats to research posed by the EU National Health Service, has a distinct the Board. Physical Agents (Electromagnetic advantage. A public consultation Dr Mark Walport’s position as Director of Fields) Directive. Approved by the commissioned by the Trust revealed the Wellcome Trust was extended for a European Commission in 2004, the that the public are positive about second term to 2013. Dr Walport and Directive was intended to protect participating in research and sharing the Chairman of the Wellcome Trust, workers exposed to electromagnetic personal data if effective systems are in Sir William Castell, were invited by the fields. However, the legislation could place to ensure informed consent, UK Government to join the Health also limit the use of magnetic anonymity and security of their data. Innovation Council. Chaired by Lord resonance imaging (MRI) for research, Data sharing and release remained a Darzi, the Council is charged with diagnosis and treatment. Unusually, in priority. This year saw the launch of UK promoting innovation, from discovery light of the evidence presented, the EC PubMed Central, set up by the Trust, as to take-up by health systems. announced in October 2007 that part of a group of leading UK research Dr Walport was also appointed to the implementation of the Directive would funders in partnership with the British board of the new Office for Strategic be delayed, to allow further discussion. Library. From 1 October 2006, it became Coordination of Health Research The Trust also provided MEPs with a formal condition that all research (OSCHR). Established after the 2006 access to information about the use of papers funded in whole or in part by the Cooksey Report, OSCHR is charged non-human primates in medical Trust must be made freely accessible. with developing a single integrated research. This followed a proposal that The Trust also announced a new data Health Research Strategy for England a timetable be set to phase out primate management and sharing policy. covering all areas of health research. use across the EU. Several senior staff joined during the The Trust contributed to the debate on year (see left). animal–human hybrid embryos. A UK Images Government White Paper revealed plans 1 Professor Adrian Bird, 3 Functional magnetic to outlaw such hybrids, a move that the Trust’s new Deputy resonance imaging, Chairman. an important research 2 Outside Wellcome and medical technology. Collection. FINANCIAL SUMMARY 2006/07 42

FINANCIAL SUMMARY 2006/07 In the year ending 30 September 2007, the Wellcome Trust’s total charitable expenditure was £519.8m.

Total charitable expenditure for the BREAKDOWN OF WELLCOME TRUST year grew slightly to £520 million CHARITABLE EXPENDITURE 2006/07 (2006: £484m), mainly due to higher Science Funding and Technology Transfer grants expenditure. Total: £519.8m The total grants awarded increased by GRANTS AWARDED £34m, owing to a small rise in funding BIOMEDICAL SCIENCE rates and the number of grants funded. £327.1m Expenditure on activities managed TECHNOLOGY TRANSFER directly by the Trust was similar to last £20.1m year’s figure. Support costs increased MEDICINE, SOCIETY AND slightly, mainly as a result of expenditure HISTORY1 on a new grants management system £12.0m and associated restructuring costs (see page 40). WELLCOME TRUST SANGER INSTITUTE Careers £72.9m Expenditure on careers support totalled £125.5m, an increase of £25m over OTHER EXPENDITURE 2005/06. Seven Principal Research DIRECT ACTIVITIES Fellowships were awarded or renewed £40.6m over the year. Funding for Senior SUPPORT COSTS Research Fellowships also increased, £47.1m and this was the first year of funding of Sir Henry Wellcome Fellowships for 1 History of medicine, biomedical ethics and public engagement with science funding. outstanding researchers at the beginning of their careers. International DIRECT ACTIVITIES: £40.6M Biomedical science Some £41.4m was awarded directly to Direct activities are those £6.6m researchers at overseas institutions. managed by the Wellcome Trust Technology Transfer Of this, £21.6m was for the support of itself or in partnership with others. £6.8m research at the Trust’s Major Overseas These include: Medicine, Society and History Programmes in South-east Asia Wellcome Trust Genome £18.0m (Thailand and Vietnam) and Africa Campus, excluding Wellcome Trust (Kenya, Malawi and South Africa). the Sanger Institute Genome Campus £9.2m A further £33.3m was awarded to Wellcome Library researchers at UK institutions for Directly managed public research to be carried out overseas. engagement activities Total international funding, £74.7m, Scientific conferences. was slightly higher than in 2005/06. Infrastructure SUPPORT COSTS: £47.1M Biomedical science Support specifically for buildings, Support costs include £22.9m refurbishment, equipment and expenditure required to run the Technology Transfer resources amounted to £13.4m. Wellcome Trust and Genome £3.2m This figure does not include the Campus, including the Sanger Medicine, Society and History £12.8m significant expenditure on equipment Institute. These include costs Wellcome Trust Genome or infrastructure provided as part of associated with administering Campus other Trust grants. grants and the wide range of £8.2m other activities carried out by the Trust.

The expenditure values used here are extracted from the Wellcome Trust’s Annual Report and Financial Statements 2007, which include a detailed breakdown of the Trust’s expenditure and investments during the year. The Annual Report is available at www.wellcome.ac.uk. FINANCIAL SUMMARY 2006/07 43

FUNDING HIGHLIGHTS INVESTMENTS 2006/07 £30m £5m The Trust’s asset base grew to New and renewed Principal Centre for Gene Regulation £15.1 billion during the year, with particularly strong returns from Research Fellowships and and Expression, University of Asian and emerging markets, programme support. Dundee. private equity and UK residential property assets. £16.8m £3.7m2 Renewal of funding for Africa Clinical veterinary research The Trust holds a world-class portfolio Centre. of investments widely diversified across initiative. asset type and geographical region. £7.7m1 £7.6m Rather than restrictive strategic Case Control Consortium Diagnostics for the Real World, benchmarks, the Trust’s approach to phase 2 funding. asset management is a flexible and for point-of-care diagnostics. dynamic approach, based on the £6.3m £2.1m identification of the best investment Capital Award for Institute of i-Snake robotic surgical tool. opportunities wherever and in whatever Chromosome Biology, form they may arise. A return of 17.0 per £0.6m cent in 2006/07 reflects the success of University of Oxford. Centre of the Cell. this commitment to excellence and focus £5.9m on absolute return. Strategic Award for research 1 Includes funds awarded to the Wellcome Trust Public equities enjoyed another strong on ageing and age-related Sanger Institute. year, with gains in excess of 40 per cent 2 Plus £7m in future financial years. in Asian and emerging markets. Holdings disease. in UK equities were again reduced, to £5m 14.7 per cent of total assets. More than half of the Trust’s portfolio is now held in Funding for first Sir Henry ‘alternative’ assets (hedge funds, buyout Wellcome Fellows. funds, venture, property and emerging market equities). The Trust’s commitment to hedge funds rose to £3.1bn. The Trust is also seeding Charitable expenditure 2003–07 (£m)* Grant liabilities 2003–07 (£m) up to US$550m in funds, principally 1168 500 1200 hedge funds, managed by New Smith 473 473 Capital Partners, and is taking a financial 446 444 1035 1023 1017 1040 interest in the group. 1000 400 The Trust remains a major investor in 344 private equity, with investments in over 800 500 partnerships and total commitments 300 in excess of £3.8bn. Net annual returns

600 have exceeded 21 per cent. The Trust’s property portfolio continued 200 400 to prosper, the 36 per cent gain in the value of residential property also

100 reflecting the benefits of active portfolio 200 management. Returns quoted are nominal figures (i.e. before 0 0 adjustment for inflation). 2003 2004 2005 2006 2007 2003 2004 2005 2006 2007 Direct expenditure Wellcome Trust Sanger Institute Grants awarded

*Excluding support costs. FUNDING DEVELOPMENTS 2006/07 44

FUNDING DEVELOPMENTS 2006/07 An overview of strategy development, new initiatives, significant changes to funding policies, and an analysis of the year’s funding.

The Wellcome Trust’s funding is NEW FUNDING INITIATIVES based around funding streams, covering core areas of biomedical DEVELOPING PEOPLE science and the medical humanities. US–UK funding partnerships Cutting across these streams are Translational medicine and therapeutics programme funding programmes in Technology Clinical veterinary research training initiative Transfer and Public Engagement GLOBAL HEALTH RESEARCH (see below). Research capacity strengthening in African institutions Each funding stream has associated Malawi and Kenya capacity development with it one or more Funding Committees, responsible for most funding decisions. Strategy Committees advise the Trust on needs and opportunities within specific areas: (1) Neuroscience and Mental Health; (2) Molecular and A new partnership between the GLOBAL HEALTH RESEARCH Physiological Sciences; (3) Pathogens, Wellcome Trust and the US National A major new initiative was launched in Immunology and Public Health; (4) Institutes of Health (NIH) enables 2007 to strengthen the institutional Medical Humanities; (5) Technology postgraduate students to undertake research base in Africa, particularly in Transfer; and (6) Public Engagement. four-year PhD training in centres in the universities. Funding will be provided to UK or Republic of Ireland and the NIH enhance research facilities in African The funding streams offer a variety of at Bethesda, Maryland. research centres that are part of forms of support, such as project and Through a new programme run in consortia or networks linked to leading programme grants, and career higher education institutions in the UK development awards. partnership with the Howard Hughes Medical Institute (HHMI), postdoctoral or elsewhere. Technology Transfer funding comprises researchers working with a major Trust Some £10m was also committed to Translation Awards and Strategic award holder can join the laboratory of health research capacity development Translation Awards, as well as Strategic an HHMI investigator for up to one year in Kenya and Malawi, with matching Translation Awards in Seeding Drug (and vice versa). funds from the UK Government’s Discovery. Public Engagement is Department for International supported primarily through the A new initiative will support interdisciplinary research training Development and £1m from the Engaging Science programme, which International Development Research includes Society Awards, People programmes for clinicians in translational medicine and Centre, Canada. Funding through this Awards and Arts Awards. Occasional initiative will become available in 2008 large Capital Awards are made to therapeutics. Programmes will enable clinicians to combine a rigorous and, unusually, local funding schemes support nationally or internationally will be established and administered important developments. grounding in the principles of translational medicine with research directly by national bodies. Strategic Awards and some other large opportunities that apply the latest The Trust also expanded its global or unusual awards are considered by a approaches to important clinical health fellowship schemes. The new Strategic Awards Committee. problems. Programmes will be Fellowships in Public Health and underpinned by partnerships between Tropical Medicine provide a complete UK academic institutions and industry. career ladder for researchers at A £10.7 million initiative in clinical academic institutions in developing countries. Immunology and veterinary research was launched, in Infectious Disease partnership with the seven UK FACILITATING RESEARCH Populations and veterinary schools. Funding of £7m will Public Health A new funding initiative was launched in be used to create fellowships at 2007 to support the development and Neuroscience and different career stages. The remaining Mental Health use of electronic patient record £3.7m will be available for small grants Physiological resources in health research, in such as vacation scholarships. Sciences partnership with the Economic and Molecules, Social Research Council, the Genes and Cells Engineering and Physical Sciences Medical Humanities Research Council and the Medical

Wellcome Trust funding streams. FUNDING DEVELOPMENTS 2006/07 45

FUNDING ANALYSIS

FACILITATING RESEARCH PUBLIC ENGAGEMENT Total no. of grant applications: 2603 Electronic patient records initiative Arts funding Total no. of grants awarded: 893 Capital funding initiative Broadcast Development Awards Public engagement ‘beacons’ Value of applications considered: £963m USING KNOWLEDGE Value of grants awarded: £370m Health Innovation Challenge Fund Adjuvants No. of programme grants awarded: 51 No. of PRFs awarded/renewed:1 9 No. of SRFs awarded/renewed: 27 No. of intermediate fellowships awarded: 34 No. of training (junior) fellowships awarded: 66 No. of PhD studentships supported: 98 Research Council. Proposals were MEDICAL HUMANITIES FUNDING RATES sought in three areas: health research A call for Strategic Award proposals in By no. By amount using electronic patient records and the medical humanities was launched, Project grants 26% 26% cohort databases, training to provide support for major ventures programmes and workshops, and exploring the human experience of Programme grants 59% 52% public engagement activities. medicine. New PRFs (full app.) 47% 57% A new capital funding scheme, to be The Trust’s Biomedical Ethics SRFs (full app. Basic) 17% 17% run every two years, will provide funds Programme was substantially revised, SRFs (full app. Clinical) 33% 32% for new buildings or refurbishment of with an immediate priority of building SRFs (full app. Tropical) 67% 75% existing laboratories. Up to £30m is capacity and quality by supporting SRFs (full app. International) 19% 26% available for the first round of funding. centres or collaborations. After this Intermediate fellows 10% 10% initial phase, attention will shift to A one-off call for proposals was Training (junior) fellows 19% 19% launched for genome-wide association fellowship and other support. Biomedical Ethics 23% 24% studies in common, complex disease, Capital funding is also available in these using DNA samples from existing areas (see above). History of Medicine 27% 21% disease collections or cohorts. A Research Resources scheme was launched to provide PUBLIC ENGAGEMENT in Medical History 45% 49% access to commercially produced gene A new Arts Awards scheme was Society Awards: Activities 12% 10% knockout mouse strains. This resource launched in 2007, building on the Society Awards: Research 25% 19% success of previous Pulse and Sciart will be coordinated by the European Large Arts Awards 7% 4% Mutant Mouse Archive. funding. Broadcast Development Awards were launched to enable early- Small Arts Awards 20% 23% USING KNOWLEDGE stage ideas for media projects to be Total no. of institutions The Trust committed £50m over five developed into full proposals that can receiving funding in 2006/07 (UK): 73 years to a new Health Innovation be used to secure further funding or a Total no. of institutions receiving Challenge Fund, with matching funding broadcasting platform. funding in 2006/07 (non-UK): 51 from the UK Department of Health. The The Trust also supported the £8m 2 £100m fund will be used to support the ONGOING LIABILITIES initiative launched by the UK higher Total grants liabilities: £1.040bn translation of research into new education funding councils and No. of countries receiving funding: 35 products and approaches to treat Research Councils UK to develop a Fellows currently supported: 754 disease. network of public engagement A specific initiative was launched to ‘beacons’. Researchers currently supported: 3228 promote research on vaccine Total no. of institutions receiving adjuvants, agents that improve the funding (UK): 87 body’s response to vaccines. This Total no. of institutions receiving initiative was open to researchers funding (non-UK): 138 outside the UK and scientists in 1 Includes PRF programme grant renewals. industry as well as academia. 2 Excludes supplementations and grants no longer required. PRF: Principal Research Fellowship SRF: Senior Research Fellowship STREAMS FUNDING 2006/07 46

STREAMS FUNDING 2006/07 1 October 2006 to 30 September 2007.

MOLECULES, GENES Total number of grants awarded 173 AND CELLS Value of grants awarded £90.1m The Molecules, Genes and Cells Number of programme grants awarded stream supports high-quality 16 research that will further our Value of programme grants awarded £19.3m understanding of the fundamental biology and specialist functions of OTHER MAJOR AWARDS: molecular, cellular and genetic • Follow-on funding for Wellcome Trust Case Control Consortium processes, and their role in health • £5m Strategic Award to the Centre for Gene Regulation and Expression, University of Dundee • £5.9m Strategic Award for the genomic and biochemical analysis of ageing, University College London and disease. • £6.3m Capital Award to the University of Oxford for Institute of Chromosome Biology

MAJOR PERSONAL SUPPORT AWARDS: • 2 new (plus 1 renewed) Principal Research Fellowships • 4 new (plus 5 renewed) Senior Research Fellowships • 5 new International Senior Research Fellowships

OTHER ACTIVITIES DURING YEAR: • Call for proposals for genome-wide association studies • Two calls for proposals for acquisition of mouse knockout lines

IMMUNOLOGY AND Total number of grants awarded 161 INFECTIOUS DISEASE Value of grants awarded £73.9m The Immunology and Infectious Number of programme grants awarded Disease stream aims to increase our 12 knowledge and understanding of the Value of programme grants awarded £15.2m infectious organisms that cause disease in humans and animals, and OTHER MAJOR AWARDS: of the immune systems that fight • £1.6m Strategic Award to the Centre for Immunity, Infection and Evolution, University of Edinburgh these organisms. • £2.1m Strategic Award to the Immunity and Infection Genomics Consortium • £1.2m Strategic Award to the Centre for Drug Discovery, Dundee

MAJOR PERSONAL SUPPORT AWARDS: • 1 new Principal Research Fellowship (plus 2 renewals of programme grants associated with PRFs) • 3 new (plus 3 renewed) Senior Research Fellowships

NEUROSCIENCE AND Total number of grants awarded 122 MENTAL HEALTH Value of grants awarded £43.5m The Neuroscience and Mental Health Number of programme grants awarded funding stream aims to support high- 6 quality research into the function of Value of programme grants awarded £7.3m the nervous system in health and disease. OTHER MAJOR AWARDS: • £1.1m Strategic Award in neuroaesthetics

MAJOR PERSONAL SUPPORT AWARDS: • 1 new Principal Research Fellowship (plus 2 renewals of programme grants associated with PRFs) • 1 new (plus 2 renewed) Senior Research Fellowships

OTHER ACTIVITIES DURING YEAR: • 3 Masterclasses in Clinical Neuroscience • 2 Cognitive Foresight project grants awarded in partnership with the Research Councils STREAMS FUNDING 2006/07 47

PHYSIOLOGICAL Total number of grants awarded 97 SCIENCES Value of grants awarded £38.4m The Physiological Sciences funding Number of programme grants awarded stream aims to support high-quality 12 basic and clinical research relevant Value of programme grants awarded £12.7m to the understanding of biological processes at the cell, organ, system MAJOR PERSONAL SUPPORT AWARDS: and whole-animal levels in health • 3 new Senior Research Fellowships and disease. OTHER ACTIVITIES DURING YEAR: • In vivo physiology and pharmacology techniques: acting to increase awareness and understanding

POPULATIONS AND PUBLIC Total number of grants awarded 46 HEALTH Value of grants awarded £16.3m The Populations and Public Health Number of programme grants awarded stream supports research to improve 4 understanding of the determinants Value of programme grants awarded £6.6m of disease and quality of life in populations, and to provide a sound OTHER MAJOR AWARDS: evidence base to inform decisions in • £3.7m Strategic Award for clinical veterinary research public health and healthcare • £1.6m Strategic Award to SPARTAC antiretroviral trial delivery. MAJOR PERSONAL SUPPORT AWARDS: • 2 new Senior Research Fellowships

OTHER ACTIVITIES DURING YEAR: • £16.8m Africa Centre renewal • £7m commitment for future fellowships in clinical veterinary medicine

MEDICAL HUMANITIES Total number of grants awarded 143 The Medical Humanities stream Value of grants awarded £12.0m aims to enhance understanding of Number of programme grants awarded the historical and social context of 1 medicine and biomedical science. It Value of programme grants awarded £0.5m supports research in history of medicine and biomedical ethics, OTHER MAJOR AWARDS: and encourages use of findings, for • 2 Enhancement Awards and 1 Strategic Award example to inform public policy making. MAJOR PERSONAL SUPPORT AWARDS • 3 University Awards

OTHER ACTIVITIES DURING YEAR: • Biomedical Ethics Summer School TECHNOLOGY TRANSFER 48

TECHNOLOGY TRANSFER Technology Transfer at the Wellcome Trust seeks to maximise the impact of research innovations on health by facilitating the development of early-stage technologies to a point at which they can be further developed by the market.

Over the past nine years, around 120 translational research projects from 50 institutions have been funded under Development Fund and Translation Award schemes. Many of these have raised additional investment and a number have already developed products. This year saw the first awards made in the Seeding Drug Discovery initiative. Support was also provided for development of a range of new technologies, in diagnostics, surgery and other areas.

Translation Awards support a diverse Strategic Translation Awards are The £91m Seeding Drug Discovery array of technologies, not only from designed to support translational initiative, launched in 2005, made ten biology but also from the physical research in areas of key importance to awards in its first two rounds of sciences and mathematics; they are the Wellcome Trust. Twelve funding. Eight awards were for full drug available to both academic institutions applications have been considered to discovery programmes in therapeutic and early-stage companies. Of 27 date, in diagnostics, vaccination, areas spanning bacterial infections, applications received from 17 regenerative medicine, genotyping cancer, amyloidosis, obesity, multiple institutions during 2006/07, 26 per cent technology and drug discovery. The sclerosis and inflammation. were awarded. The mean value of mean value of awards has been £3.2m The mean value of these awards has these awards has been £646 000 (range £1.3–8.1m). New awards were been £2.8m (range £1.3–4.0m) and the (range £240 000–1.0 million) and the made this year to two multidisciplinary average duration is 30 months (range average duration 25 months (range teams working at the interface between 24–36 months). Two smaller awards 10–36 months). The average time from engineering and medicine, tackling two were made to explore the feasibility of application to decision is around three important medical issues: diagnosis of novel approaches to the treatment of to four months. tuberculosis (page 22) and minimal aspergillosis and management of The projects address a wide range of invasive surgery (page 23). allergy. The scheme has continued to potential applications, including An award of £7.6m was made to Dr attract considerable interest from the therapeutics, vaccines, diagnostics, Helen Lee to support research and academic community and companies medical devices and enabling development into rapid diagnostics for alike, and the competition has been technologies. Examples include the infectious diseases. The programme, expanded to two rounds a year. development and evaluation of an based at the University of Cambridge Several companies that received injectable scaffold for reconstructive and within Diagnostics for the Real support during early validation of their surgery, preclinical and clinical studies World Ltd, builds on earlier work on a technology have had success in raising of a novel meningococcal vaccine, rapid test for chlamydia infection, later further funds. These include the start- clinical studies into the therapeutic applied to other sexually transmitted up companies Celltran Ltd, Senexsis management of inflammatory bowel infections and to trachoma. Dr Lee’s Ltd, Polytherics Ltd and Population disease, and research to improve the team is also working on proof-of- Genetics Technologies Ltd. Another reliability and safety of medicinal concept studies of a new DNA group of companies successfully infusions outside a clinical environment. amplification technology that could concluded terms under which they Other awards were for the offer an alternative to polymerase chain were acquired by public companies, development of a drug delivery system reaction chemistry for DNA detection including Paradigm Therapeutics Ltd, for the treatment of brain tumours, assays. DanioLabs Ltd and Oxxon research into a cell-based bandage for Therapeutics Ltd. Emergent the treatment of meniscal cartilage Biosolutions floated on the New York injuries, and DNA sequencing using Stock Exchange. Overall, Trust-funded single molecule tunnelling techniques. companies have raised over £155m to date. WELLCOME TRUST GENOME CAMPUS 49

WELLCOME TRUST GENOME CAMPUS The Wellcome Trust Genome Campus at Hinxton, near Cambridge, is home to the Wellcome Trust Sanger Institute, the Wellcome Trust Conference Centre and Wellcome Trust Advanced Courses.

The Wellcome Trust Sanger Institute continues to be highly productive, in terms of both genome sequencing and published outputs. The Advanced Courses programme has been expanding both its UK-based and international activities, while the Wellcome Trust Conference Centre has attracted leading speakers to a series of high-profile scientific events.

Wellcome Trust Sanger Institute the project to refine mapping of variants An IT training room was set up in Kilifi, The Sanger Institute has been further and to study copy number variation, an Kenya, at the Kenya Medical Research developing its emphasis on human area where the Institute is a world Institute–Wellcome Trust Research genetics over the last 12 months, leader (pages 6–7). Other papers Programme and a workshop, ‘Working culminating in the appointment of described genes involved in X-linked with Pathogen Genomes’, was held in Professor Leena Peltonen as Head of deficits in mental development, December 2006, with scientists Human Genetics. Professor Peltonen is diabetes and other common diseases. attending from all over Africa. an acknowledged leader in studies of As part of the development in Genome Next year will see new Advanced the molecular basis of both single-gene Campus conferences, Sanger Institute Courses in Hinxton on molecular disorders and more common complex staff organised international conferences virology, global analysis of fission yeast diseases. Professor Aarno Palotie also on hearing, mouse molecular genetics gene function, and small molecule drug joined the Sanger Institute, and these and DECIPHER, a database of sub- discovery, as well as the development appointments strengthen the Institute’s microscopic chromosomal anomalies of IT training rooms at the Wellcome research into human disease. implicated in disease or abnormal Trust Major Overseas Programmes in The Sanger Institute’s new strategy, development. This will be an area of Vietnam and Malawi. developed in 2006, sets out ways to growth in coming years. Meetings Programme and capitalise on the major contributions The Sanger Institute’s Public Conference Centre previously made to genome sequencing Engagement Programme opened its A total of 16 meetings were held at and high-throughput projects, with a new visitor space during the year and Hinxton as part of the Wellcome Trust special emphasis on genetic variation relaunched www.yourgenome.org. Meetings Programme in 2006/07. and its impact on health. Sanger It also made a major contribution to the Highlights included the ‘Genomics of researchers continued to publish in high- national travelling exhibition project Common Diseases’ conference held in impact scientific journals, appearing as Inside DNA: A genomic revolution, July 2007 jointly with Nature Genetics. authors on more than 260 original while continuing to develop resources This event showcased many of the research papers – an increase of 20 per and experiences for age 14+ students, research projects funded by the Case cent over 2005/06 – including 38 in for teachers and for adult groups. Control Consortium, with the auditorium Nature, Nature Genetics, Science or at full capacity. Proceedings of the National Academy Wellcome Trust Advanced Courses of Sciences (USA). These articles include The Wellcome Trust Advanced Courses Over £2 million of business was run many of the discoveries of the Cancer programme organised nine Advanced through the Conference Centre, almost Genome Project (see page 7), the Courses and six workshops at the three-quarters being aligned with the ENCODE Consortium (pages 6–7) and Wellcome Trust Genome Campus, and Trust’s mission and hence charged at pathogen sequencing projects (pages three workshops overseas. Two subsidised rates. The remaining 10–11). bioinformatics workshops were held at business filled gaps in the conference the IT training room previously set up at diary and generated sufficient profit to The Sanger Institute’s work with the the Institute of Hygiene in Montevideo, subsidise the scientific events. Wellcome Trust Case Control Consortium Uruguay. With the support of Sanger A study is currently underway to has resulted in major publications (page Institute instructors, previous participants 6). The Institute has received a major determine the options and cost plans are being encouraged to become the for expanding the conference facilities. award to undertake a second phase of trainers of the future. PUBLIC ENGAGEMENT 50

PUBLIC ENGAGEMENT The Wellcome Trust’s Public Engagement activities aim to engage with society to foster a climate within which biomedical science can flourish.

While the opening of Wellcome Collection was the highlight of the year in public engagement, grant-giving continued to be an area of significant activity. Planning began for work associated with Darwin anniversaries in 2009, and the year also saw the development of new strategies for education and broadcast.

Grants interpretations of their synaesthetic Species. Activities will include a series A total of 86 grants were awarded reactions to everyday sounds. of Darwin-inspired biomedical under the £3 million Engaging Science Capital Award: A grant of £600 000 experiments available to every funding programme and one capital was awarded to Professor Fran Balkwill schoolchild in the UK, a number of grant of £600 000 was made. to develop Centre of the Cell – a new broadcast and web projects, and a Society Awards: Six large awards interactive exhibition for children cultural initiative. (over £30 000) were made for a range located in east London (see page 29). The Trust has also begun to implement of important activities. One award was Education its new broadcast strategy, which will made to Dean Madden at the National In June 2007, the Trust approved a new combine training and development Centre for Biotechnology Education in Education Strategy. Central to this is the activities for scientists and Reading to provide practical desire to establish the Trust as a major broadcasters and provide a small bioinformatics activities enabling biology influence on school-focused education amount of highly targeted funding. students aged 16–19 to explore modern from primary stages onwards. In conjunction with the development evidence for evolution. In addition, four In September 2007, the Trust and the of a Trust-wide international strategy, awards were made to support academic a public engagement strand has been research about public engagement. US National Science Foundation hosted an international conference developed with a focus on developing People Awards: Some 48 awards examining ‘the national value of science countries. (up to £30 000) were made to support education’. The Trust is also supporting Supporting researchers a diverse range of activities, including a project examining the impact of Support for Wellcome Trust-funded performances, exhibitions, talks, assessment on science education at researchers expanded in 2007 with the conferences, debates and the end of Key Stage 2 (10–11-year- provision of a web resource, responsive documentaries. A notable award was olds). This work is being undertaken by support and training sessions. The to Deafinitely Theatre (above), the UK’s the Institute of Education and Ipsos Trust hosted two events for young only deaf-led professional theatre MORI. The study will also compare researchers explaining how to engage company, to develop a production that pupils’ and teachers’ attitudes and with different audiences, while Fellows explored issues surrounding cochlear learning outcomes in England with were able to attend a session on implants in a deaf child. those in Wales, which recently withdrew engaging and influencing people Arts Awards: In February 2007, the end of Key Stage 2 assessment. through use of narrative techniques. Wellcome Trust launched its new Arts Two issues of the Big Picture series, a The Trust has sought to improve Awards funding scheme to build on the publication for post-16 students and institutional support for researcher work of the Sciart and Pulse schemes. teachers, were published – on engagement through the Beacons Since its launch, 25 small grants (up to epidemics and evolution. Both for Public Engagement scheme, in £30 000) and three large grants have publications are available online. partnership with the UK Funding been awarded. One award was to Councils and RCUK (UK Research Samantha Moore to produce An Eyeful New developments The Trust has initiated a programme to Councils). The Trust also continues of Sound, a short animated documentary its support of the Researchers in film that explores synaesthesia, mark the bicentenary in 2009 of the birth of Charles Darwin and 150 years Residence scheme, in partnership incorporating conversations with with the RCUK. synaesthetes as well as visual since the publication of On the Origin of WELLCOME COLLECTION 51

WELLCOME COLLECTION Wellcome Collection is a free public venue hosting events and permanent and temporary exhibitions. It also houses the Wellcome Library, the Wellcome Trust Centre for the History of Medicine at UCL, a Conference Centre, a forum and events spaces, a bookshop and a café.

Wellcome Collection opened to the public on 21 June 2007. Formerly the headquarters of the Wellcome Trust, 183 Euston Road now houses more than 1300 medical, cultural and historical artefacts, including works by Antony Gormley, Marc Quinn and Pablo Picasso – all designed to stimulate dialogue between art, science, history and the public.

Exhibitions who described the lives of people Wellcome Images Wellcome Collection contains two with spinal cord injuries in his book Formerly known as the Medical permanent galleries charting the Still Lives. Photographic Library, Wellcome evolution of our cultural responses to Wellcome Library Images provides access to more than health, sickness and discovery. Medicine Wellcome Collection is also home to 100 000 items, from stunning modern Man, first hosted in the British Museum the Wellcome Library. With around images to the fascinating historical in 2003, exhibits objects from Sir Henry 2.5 million items, including 600 000 works held in the Wellcome Library. The Wellcome’s original collection. Medicine books and journals, an extensive range new Wellcome Images website Now explores issues in contemporary of manuscripts, and more than 100 000 includes much improved functionality. medicine, including malaria, obesity, paintings, prints and drawings, it is one Images are now freely available for genomics and cloning. of the world’s major resources for the download for personal, academic A large gallery on the ground floor study of the history of medicine. teaching or study use, under Creative Commons licences. hosts an ongoing programme of Following the move the Library began a thematic temporary exhibitions. It programme of events and talks, Members’ Club opened with The Heart (see pages including twice-monthly Insights visits, Wellcome Collection also includes a 26–27). Works by artists such as covering topics such as the life and Club. Members can take advantage of Spencer Tunick, Mauro Perucchetti, work of Henry Wellcome, the body in a stylish Club Room (offering WiFi and Gunther von Hagens, Antony Gormley history, Hinduism, Buddhism and refreshments), where they can meet and Marc Quinn are displayed around Jainism, and the preservation and other members and swap ideas, read, the building. conservation of books and manuscripts. bring guests or simply relax. Events In the first six months after reopening Conference Centre The exhibitions are supported by an (April–September 2007) the Library The Conference Centre – offering four ongoing programme of public events. registered more than 2000 new readers meeting rooms and a tiered 154-seat ‘Heartfelt Emotions’, a weekend – up 88 per cent from the previous year. auditorium for corporate and private symposium held on 7–8 September In all, nearly 11 000 visitors used the events – hosted 125 events. Initial user 2007, brought together neuroscientific, Library – an increase of 32 per cent feedback has been highly positive. clinical, behavioural, social, over 2005/06. Business epidemiological, historical and literary The booksellers Blackwell opened a expertise to explore the physical and ‘Uncover’, the touch-screen interactive in Wellcome Collection, proved popular, branch in Wellcome Collection in May metaphorical role of the heart in our 2007. It stocks a wide variety of books emotions. with visitors viewing some 38 000 Library images. Further insight into its on subjects including medicine, ‘Medicine and Literature’, a series of remarkable holdings appeared in Cures science, history and art, along with four free evening events, began in and Curiosities: Inside the Wellcome Wellcome Collection merchandise. September 2007, exploring different Library, a lavishly illustrated book Wellcome Collection’s café, run by forms of writing about medicine. edited by Tony Gould and with a Peyton and Byrne, opened in June Speakers included Michael Blastland, foreword by Sebastian Faulks, which 2007, and has enjoyed a number of author of a book, Joe, about his was published by Profile Books to favourable reviews. severely autistic son, and Jonathan Cole, commemorate the Library’s reopening. ADVISORY COMMITTEES 52

ADVISORY COMMITTEES

Arts Awards Funding Professor M Palmarini Clinical Interview Committee History of Medicine Committee (established University of Glasgow Professor D M Turnbull Funding Committee in December 2006) Professor C E Rudd (Chair) University of Newcastle Professor M A Jackson Dr H Nicholson Imperial College of Science, upon Tyne (Chair) University of Exeter (Chair) Royal Holloway, Technology and Medicine, London Professor C G Fairburn Dr J M T Ford University of London Professor R E Sockett University of Oxford J N P B Horden K Khan University of Nottingham Professor R Franklin Royal Holloway, London Organising Professor D Soldati-Favre University of Cambridge University of London Committee of the Olympic and University of Geneva, Switzerland Paralympic Games Professor F Karet Professor S King University of Cambridge Oxford Brookes University L Le Feuvre Basic Science Goldsmiths College, Interview Committee Professor D P Kelleher Professor H Marland Trinity College Dublin, Ireland University of Warwick University of London Professor G Banting R Levinson (Chair) University of Bristol Professor P Klenerman Dr T Ruetten University of Oxford University of Newcastle upon Tyne Institute of Education, Professor N J Buckley University of London University of Leeds Professor M Maze Dr T Tansey Imperial College of Science, University College London Dr G Lewis Professor P R Burton Technology and Medicine, London Dr F McKee (from December 2006) University Dr J Welshman of Leicester Professor B P Morgan Lancaster University R Mortimer Cardiff University Wonderdog Productions, London Professor A Galione Professor M Worboys Professor S H Sacks University of Manchester Dr S Ochugboju (from December 2006) University of Oxford Guy’s, King’s and St Thomas’ Immunology and Infectious Dr R J T Wingate School of Medicine, London Professor P W Ingham Disease Strategy Committee King’s College London University of Sheffield Professor E Simpson Professor R M Atlas Professor S Yearley (from December 2006) Imperial Professor A R Mayes (Chair) University of Louisville, University of Edinburgh College of Science, Technology University of Liverpool Kentucky, USA and Medicine, London Professor L H Pearl Professor V Chauhan Basic Immunology and Professor A Thrasher Infectious Disease University of London International Centre for Genetic Institute of Child Health, London Engineering and Biotechnology, Funding Committee Professor G R Screaton Professor P Woodruff New Delhi, India Professor AC Hayday (from December 2006) Imperial University of Sheffield (Chair) Guy’s, King’s and College of Science, Technology Professor D Colley University of Georgia, Athens, USA St Thomas’ School of Medicine, and Medicine, London Cognitive and Higher Systems London Professor D F Smith Funding Committee Professor G Dougan Wellcome Trust Sanger Institute, Professor P Crocker University of York Professor J N P Rawlins Cambridge University of Dundee Dr C M R Turner (Chair) University of Oxford Professor C C Goodnow Professor M Duszenko University of Glasgow Professor J P Aggleton Australian National University, University of Tübingen, Germany Professor M Yaniv Cardiff University Canberra, Australia Professor R M Elliott Pasteur Institute, Paris, France Professor D V M Bishop Professor A C Hayday University of Glasgow University of Oxford Guy’s, King’s and St Thomas’ Professor F Geissmann Biomedical Ethics Funding Committee Professor R J Dolan School of Medicine, London Hôpital Necker – Enfants Malades, Institute of Neurology, Professor N L G Eastman Professor P T LoVerde Paris, France University College London Southwest Foundation for Professor G Griffiths (Chair) St George’s Hospital Medical School, University Professor P A Garety Biomedical Research, University of Oxford of London Institute of Psychiatry, King’s San Antonio, USA Professor P D Griffiths College London Dr R E Ashcroft Professor H R P Miller Royal Free and University College Department of Biomedical Ethics, Professor R A Kauppinen Royal (Dick) School of Veterinary Hospital, London Queen Mary, University of London University of Birmingham Studies, University of Edinburgh Professor H Jenkinson Professor R E Brownsword Professor G Lewis Professor A B Rickinson University of Bristol King’s College London University of Bristol University of Birmingham Professor M J Keeling Dr P Martin Professor M J Morgan Professor M E J Woolhouse University of Warwick University of Nottingham City University, London University of Edinburgh Dr A Lalvani Dr R E Simpson Professor I Robertson Imperial College of Science, University of Durham Trinity College Dublin, Ireland Technology and Medicine, London Professor D Wassenaar Professor R Salmelin Dr B Luisi University of KwaZulu-Natal, Helsinki University of University of Cambridge South Africa Technology, Finland Professor R M Maizels Dr S Wilkinson Professor W Schultz University of Edinburgh University of Keele University of Cambridge Professor D O’Connor Professor A Thapar University of Southampton Cardiff University Professor F C Odds Professor J M Wardlaw University of Aberdeen University of Edinburgh ADVISORY COMMITTEES 53

The Wellcome Trust is committed to the principles of peer review. We are 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 2006/07.

Library Advisory Committee Professor R Miles Professor A B Tobin PhD Programmes Committee J Wilkinson INSERM U739, University of Paris, University of Leicester (established in December 2006) (Chair) The British Library, London France Professor R J White Professor E W Holmes Dr P Ayris Professor G Schiavo University of Glasgow (Chair) Agency for Science, (Vice-chair) University College Cancer Research UK, London Technology and Research, Molecules, Genes and Cells London Library Research Institute California, USA Strategy Committee A Fleming Professor K P Steel Professor D Ausiello Professor B Alberts Freelance Wellcome Trust Sanger Institute, Massachusetts General Hospital, Cambridge (Chair) University of California, Boston, USA Dr A Hardy San Francisco, USA Wellcome Trust Centre for the Professor D G Wilkinson Professor G Fitzgerald Professor D M Altshuler History of Medicine at UCL National Institute for Medical (from August 2007) University of Research, London Massachusetts General Hospital, Pennsylvania, Philadelphia, USA Dr N Hopwood Boston, USA University of Cambridge Dr L Wilkinson Professor P N Goodfellow Professor G Banting Cardiff University Professor B T Grenfell University of Bristol Medical Humanities Professor H J Willison Pennsylvania State University, Strategy Committee University of Glasgow Professor A Berns Pennsylvania, USA Professor R A Hope Netherlands Cancer Institute, Professor W G Haynes Molecules, Genes and Cells Amsterdam, The Netherlands (Chair) University of Oxford University of Iowa, Iowa City, USA Funding Committee Professor A Bradley Professor N Britten Dr M W Hentze Professor S G Oliver Wellcome Trust Sanger Institute, Peninsula Medical School, Exeter European Molecular Biology (Chair) University of Cambridge Cambridge Professor N L G Eastman Laboratory, Heidelberg, Germany Dr J A Armour Dr R Brent St George’s Hospital Medical Dr M J Lenardo University of Nottingham Molecular Sciences Institute, School, University of London National Institute of Allergy and Berkeley, USA Professor H M Evans Dr K Ayscough Infectious Diseases, Bethesda, University of Durham University of Sheffield Professor P N Goodfellow USA Professor K W M Fulford Professor P Beales Professor S G Oliver Professor M C Raff University of Warwick Institute of Child Health, London University of Cambridge (University University College London of Manchester to September 2007) Professor M A Jackson Professor N Brockdorff Professor A Toga University of Exeter Imperial College of Science, Professor P W J Rigby (from August 2007) UCLA School Technology and Medicine, London Institute of Cancer Research, of Medicine, Los Angeles, USA Professor H M King London University of Reading Professor L R Cardon Professor A P Waters University of Oxford Professor J M Thornton Leiden University Medical Centre, Professor G Richardson European Bioinformatics Institute, The Netherlands Queen Mary, University of London Dr R M Cooke GlaxoSmithKline Cambridge Professor T Treasure Physiological Sciences Funding Guy’s and St Thomas’ NHS Professor J A Errington Neuroscience and Mental Committee University of Newcastle upon Tyne Foundation Trust Health Strategy Committee Professor I C A F Robinson Dr A J Greenfield Professor D Purves (Chair) National Institute for Medical Molecular and Cellular Medical Research Council (Chair) Duke University, Research, London Neuroscience Funding Mammalian Genetics Unit Durham, USA Committee Professor K Channon Professor J Iredale Professor D M Clark University of Oxford Professor V H Perry University of Edinburgh Institute of Psychiatry, King’s Professor E R Chilvers (Chair) University of Southampton College London Professor J Ladbury University of Cambridge Professor P J Brophy University College London Professor D A S Compston Professor A F Dominiczak University of Edinburgh University of Cambridge Professor A I Lamond University of Glasgow Professor C Davies University of Dundee Professor V H Perry Professor M Gautel GlaxoSmithKline University of Southampton Professor G Murphy King’s College London Professor M Götz University of Cambridge Professor M C Raff Professor C Godson Institute of Stem Cell Research, Professor B Potter University College London Munich, Germany University College Dublin, Ireland University of Bath Professor J N P Rawlins Professor C F Inglehearn Professor S G Hillier Professor L M Roberts University of Oxford University of Leeds University of Edinburgh University of Warwick Professor A Toga Professor D M Kullman Professor A J Knox Professor E Robertson UCLA School of Medicine, Institute of Neurology, Nottingham City Hospital University of Oxford Los Angeles, USA University College London Professor L Lanyon Dr D L Stemple Professor D M Turnbull Professor S H Lovestone Royal Veterinary College, Wellcome Trust Sanger Institute, University of Newcastle upon Tyne Institute of Psychiatry, King’s University of London Cambridge College London Professor P H Maxwell Professor C E Sunkel Professor K Martin Imperial College of Science, Institute of Molecular and Cell Institute of Neuroinformatics, Technology and Medicine, London Biology, University of Porto, Zürich, Switzerland Portugal Professor S O’Rahilly University of Cambridge ADVISORY COMMITTEES 54

ADVISORY COMMITTEES

Professor M Perretti Professor K T Khaw Professor K Sykes Seeding Drug Discovery Barts and The London, Queen University of Cambridge University of Bristol Funding Committee Mary’s School of Medicine and Dr Z Matthews Dr G Watts Professor W Charman Dentistry, London University of Southampton BBC/Freelance (Chair) Monash University, Victoria, Professor G A Rutter Professor M McKee S Webster Australia University of Bristol London School of Hygiene and Imperial College of Science, Professor J Allen Professor J Seckl Tropical Medicine Technology and Medicine, London Conway Institute, University Queen’s Medical Research Dr C A Stoltenberg Professor Lord Robert Winston College Dublin, Ireland Institute, Edinburgh Norwegian Institute of Public Imperial College of Science, Professor K Altmann Professor D Thompson Health, Norway Technology and Medicine, London Swiss Federal Institute of University of Manchester Professor J Volmink Professor B Wynne Technology, Zürich, Switzerland Professor A Tinker Stellenbosch University, Cape Lancaster University Dr P England University College London Town, South Africa Proxara Biotechnology Limited, Professor A M Tomkins Public Health and Tropical St Albans Populations and Public Health Medicine Interview Committee Institute of Child Health, London Professor J H Griffin Strategy Committee Professor P T LoVerde (from March 2007) Numerate Inc., Physiological Sciences Professor L Peltonen-Palotie (Chair) Southwest Foundation San Bruno, USA Strategy Committee (Chair) University of Helsinki, for Biomedical Research, Dr F D King Professor P M Stewart Finland San Antonio, USA Dr T Rink (Chair) Birmingham University Professor F Binka Dr J Ashton Professor F M Ashcroft INDEPTH Network, Accra, Ghana (to March 2007) Sir Henry Wellcome University of Oxford Professor P J Donnelly Professor M J Cardosa Postdoctoral Fellowship Professor K R Chien University of Oxford Universiti Malaysia, Sarawak, Interview Committee University of California, Professor S B J Ebrahim Malaysia (established in December 2006) San Diego, USA London School of Hygiene and Professor K K Cheng Professor J C Smith Professor G Fitzgerald Tropical Medicine University of Birmingham (Chair) University of Cambridge University of Pennsylvania, Professor P Elliott Professor D Goldblatt Professor J C Buckingham Philadelphia, USA Imperial College of Science, Institute of Child Health, London Imperial College of Science, Professor J Hunter Technology and Medicine, London Professor L Richter Technology and Medicine, London GlaxoSmithKline Professor W Graham Human Sciences Research Professor D A Cantrell Professor J J Mullins University of Aberdeen Council, Dalbridge, South Africa University of Dundee University of Edinburgh Professor H Jaffe Professor G Tomson Professor N Chaturvedi Professor I C A F Robinson University of Oxford Karolinska Institute, Stockholm, Imperial College of Science, National Institute for Medical Dr S Macintyre Sweden Technology and Medicine, London Research, London University of Glasgow Dr F Wabwire-Mangen Professor A C Dolphin Makerere University, Kampala, University College London Populations and Public Health Principal Research Fellowship Uganda Professor W C Earnshaw Funding Committee Interview Committee University of Edinburgh Professor S B J Ebrahim Professor P W J Rigby Research Resources In Medical Professor K Gull (Chair) London School of Hygiene (Chair) Institute of Cancer History Funding Committee University of Oxford and Tropical Medicine Research, University of London Professor H King Professor M J Humphries Professor M Barreto Professor T E Wellems (Chair) University of Reading University of Manchester Instituto de Saude Coletiva, National Institute of Allergy and Dr J Andrews Federal University of Bahia, Brazil Infectious Diseases, Bethesda, University of Newcastle upon Tyne Society Activity Awards Professor C A Dezateux USA N Bell Funding Committee Institute of Child Health, London The National Archives, Richmond Public Engagement Strategy Professor R Millar Professor M Egger Committee Y M T Dahnsjö (Chair) University of York University of Bern, Switzerland South East Regional Office, Professor N J Rothwell Dr S Blakemore The National Trust Dr A Fontanet (Chair) University of Manchester University College London Pasteur Institute, Paris, France J Etherton Professor N L G Eastman Dr S Joss Valence House Museum, Professor G P Garnett St George’s Hospital Medical University of Westminster Dagenham Imperial College of Science, School, University of London Dr G Mulgan Technology and Medicine, London Professor M A Jackson C Fox Young Foundation, London University of Exeter Professor K Hill Institute of Ideas, London Dr M Parker Harvard Initiative for Global Health, H Lindsay Professor A Irwin University of Oxford USA London Metropolitan Archives Brunel University N Partridge Professor A O House Dr I Milne Professor M A Jackson Terrence Higgins Trust University of Leeds Royal College of Physicians, University of Exeter Dr S Preston Professor T H Jafar Edinburgh Professor R Millar University of Durham Aga Khan University, Karachi, University of York Pakistan M Whitby Dr R Persaud Red, Green and Blue Company Bethlem Royal and Maudsley Hospitals, London ADVISORY COMMITTEES 55

Society Research Awards Professor R W Snow Tropical and Clinical Funding Committee KEMRI–Wellcome Trust Research Immunology and Infectious Professor B Wynne Programme, Nairobi, Kenya Disease Funding Committee (Chair) Lancaster University Professor D P Strachan Professor M E J Woolhouse J Cummins St George’s Hospital Medical (Chair) University of Edinburgh Office for Public Management, School, University of London Professor U d’Alessandro London Professor J N Weber Prince Leopold Institute of Tropical Professor S Cunningham-Burley Imperial College of Science, Medicine, Antwerp, Belgium University of Edinburgh Technology and Medicine, London Professor P Hagan Professor G Gaskell Professor S Wyke University of Glasgow London School of Economics University of Stirling Professor S Kaufmann and Political Science Professor B Zaba Max Planck Institute for Infection Dr L Henderson London School of Hygiene and Biology, Germany Brunel University Tropical Medicine Professor S Krishna St George’s Hospital Medical Professor J Leach Technology Transfer School, London University of Leeds Challenge Committee Dr D G Lalloo J Lewis Dr A Boyd University of Liverpool National Centre for Social AB Discovery Research, London Professor M M Lederman Professor W Charman Case Western Reserve University, Professor J Osborne Monash University, Victoria, Cleveland, USA King’s College London Australia Professor P Mwaba Dr A Stockl Professor K Davies University of Lusaka, Zambia University of East Anglia, Norwich University of Oxford Professor P Openshaw Dr L Fass Standing Advisory Group Imperial College of Science, (from March 2007) on Ethics Technology and Medicine, London GE Healthcare Professor S Holm Professor D U Pfeiffer Dr G Forrest (Chair) Cardiff University Royal Veterinary College, Hatfield Independent Consultant Professor B Greenwood Professor B S Ramakrishna Professor P Ghazal London School of Hygiene and Christian Medical College, University of Edinburgh Medical Tropical Medicine Vellore, India School Professor G Laurie Professor E Schurr Dr A Hudson University of Edinburgh Montreal General Hospital Independent Consultant Professor T Meade Research Institute, Quebec, Dr K Johnson Canada K Whitehorn Index Ventures Study Design Expert Group Dr F King Professor P J Donnelly Dr G Lawton (Chair) University of Oxford Lectus Therapeutics Ltd Professor P R Burton Dr W Luyten (to December 2006) University IriDM, Leuven, Belgium of Leicester Dr R Parekh Professor R Collins Advent Venture Partners Radcliffe Infirmary, Oxford Dr J Rasmussen Professor P R Deloukas Independent Consultant Wellcome Trust Sanger Institute, Dr F Sams-Dodd Cambridge Neurofit SAS, France Professor R J Hayes Dr M Skingle London School of Hygiene and GlaxoSmithKline Tropical Medicine Professor M Khoury Technology Transfer Centers for Disease Control and Strategy Panel Prevention, Atlanta, USA Dr T Rink Professor A D Morris (Chair) University of Dundee Dr J Hills Professor D J Porteous Bristol-Myers Squibb University of Edinburgh Dr R Parekh Professor M J Prince Advent Venture Partners Institute of Psychiatry, King’s Dr A Wood College London Eli Lilly Research Centre ACKNOWLEDGEMENTS 56

Acknowledgements The Wellcome Trust Annual Review is All images are courtesy of Wellcome Images We are grateful to everyone who distributed via a mailing list held by the (http://images.wellcome.ac.uk) except as follows: agreed to be reviewed in this issue, Wellcome Trust. If you would like to be Contents and p. 1: 1 (Dr Laurence Tetley, IBLS, University of Glasgow), 4 (CDC: Jim Gathany/Steven everyone who supplied images or added to the list, or if you have a Glenn, Laboratory & Consultation Division), 5 (Beagle gave us permission for their images colleague who would like to receive the 2), 6 (Africa Centre for Health and Population Studies); to be used, and the many members Wellcome Trust Annual Review, please pp. 2–3: 2 (Brian Marsden, Structural Genomics Consortium), 4 (Anne Weston); pp. 6–7: 1 (Rafael of Wellcome Trust staff who helped contact: Ramirez Lee/iStockphoto), 2 (Dr T J McMaster), produce this volume. 3 (Matthew Daniels), 4 (Annie Cavanagh); pp. 8–9: Publishing Department 2 (Dr Jonathan Clarke), 3 (Deborah Padfield), 4 (Simon Editor Wellcome Trust Beggs); pp. 10–11: 1 (Annie Cavanagh), 2 (CDC: Ian Jones, Jim Gathany/Steven Glenn, Laboratory & Consultation FREEPOST Division), 3 (Dr Laurence Tetley, IBLS, University of Isinglass Consultancy Ltd RLYJ-UJHU-EKHJ Glasgow); pp. 12–13: 1 (adapted from Dalley et al., Slough SL3 0EN reprinted with permission from AAAS), 2 (Jon Schulte/ Project Manager iStockphoto), 3 (Masud Husain); p. 14: left (Africa Lucy Moore T +44 (0)20 7611 8651 Centre), right (Sovereign, ISM/SPL); p. 15: (Laura F +44 (0)20 7611 8242 Trinkle-Mulcahy and Angus Lamond); pp. 18–19: Writers 1 (University of Edinburgh), 2 (A Stich), 3 (Hugh Sturrock), Penny Bailey E [email protected] 4 (Mdu Mahlinza); pp. 20–21: 1 (R Dourmashkin), Ian Jones 2 (Chau Doan), 3 (J Whiting), 4 (Anne-Katrin Purkiss), www.wellcome.ac.uk/publications 5 (N Durrell McKenna); pp. 22–23: 1 (Beagle 2), Henry Nicholls 2 (Beagle 2), 3 (Medical Microscopy Sciences, Cardiff ISBN 978 1 84129 077 5 University), 4 (Professor Guang-Zhong Yang, Imperial Editorial staff College London); pp. 26–27: 3 (The Royal Museums Tom Freeman The Wellcome Trust is a charity of Art and History, Brussels); pp. 28–29: 4 (Hardy and registered in England, no. 210183. Its Sons), 5 (Centre of the Cell); pp. 30–31: 1 (Stefan Bones/ Design sole trustee is The Wellcome Trust Panos), 3 (Catherine Millar); pp. 32–33: 2 (University of Anja Fouad Edinburgh), 4 (Schistosomiasis Control Initiative), 5 Limited, a company registered in (National Cancer Institute/SPL); pp. 34–35: 4 (Medical Design Manager England, no. 2711000, whose registered Microscopy Sciences, Cardiff University); pp. 36–37: Steve Russell office is at 215 Euston Road, London 1 (Brian Marsden, Structural Genomics Consortium), 2 (Diamond Light Source); pp. 38–39: 2 (Professor P Picture research NW1 2BE, UK. Motta/Department of Anatomy, University La Sapienza, Rome/SPL), 3 (Hshen Lim/iStockphoto), 4 (EMBL– Manika Power First published by the Wellcome Trust, European Bioinformatics Institute); p. 46: top left (Oliver Photography 2008. Burston), top right (Dr Andrea H Brand), centre left (David Gregory and Debbie Marshall), bottom left David Sayer © The trustee of the Wellcome Trust, (Dr Steve Wilson), bottom right (Rachel Ashworth and London. William Hinkes); p. 47: top left (Professor Alan Boyde), Comments on the Wellcome Trust top right (David Gregory and Debbie Marshall), centre Annual Review are welcomed and This is an open access publication and, right (C Penn); p. 50: (Manuel Harlan). should be sent to: with the exception of images and Cover image: illustrations, the content may, unless Colour-enhanced image of Clostridium difficile Lucy Moore (Annie Cavanagh). Publishing Department otherwise stated be reproduced free of Wellcome Trust charge in any format or medium, subject Gibbs Building to the following conditions: content must 215 Euston Road be reproduced accurately; content must London NW1 2BE, UK not be used in a misleading context; the Wellcome Trust must be attributed as F +44 (0)20 7611 8270 the original author and the title of the E [email protected] document specified in the attribution. Wellcome Trust Gibbs Building 215 Euston Road London NW1 2BE, UK T +44 (0)20 7611 8888

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CONTENTS BOARD OF GOVERNORS 2 Director’s statement William Castell Chairman Achieving our objectives Adrian Bird 4 Advancing knowledge Deputy Chairman 16 Using knowledge Kay Davies 24 Engaging society Christopher Fairburn 30 Developing people Patricia Hodgson 36 Facilitating research Richard Hynes 40 Developing our organisation Peter Rigby The year in review Alastair Ross Goobey 41 Corporate activities Peter Smith 42 Financial summary 2006/07 Edward Walker-Arnott 44 Funding developments 2006/07 As at January 2008 46 Streams funding 2006/07 48 Technology Transfer 49 Wellcome Trust Genome Campus 50 Public Engagement 51 Wellcome Collection 52 Advisory committees

Images This Annual Review covers the 1 A trypanosome parasite. 3 Examining material in 5 The Beagle 2 spacecraft. Wellcome Trust’s financial year, from 2 Stephen Fry in the Wellcome Library. 6 The Africa Centre for 1 October 2006 to 30 September 2007. Wellcome Collection. 4 Malaria parasites inside Health and Population red blood cells. Studies. ELOETUTANA EIW1Otbr20–0Spebr2007 WELLCOME TRUSTANNUALREVIEW1October2006–30September

ANNUAL REVIEW 2007

The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £500 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. www.wellcome.ac.uk WELLCOME TRUST ANNUAL REVIEW 2007

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