ANNUAL REVIEW 1 October 2007–30 September 2008

ANNUAL REVIEW 2008

The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. www.wellcome.ac.uk

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 This Annual Review covers the Chairman Wellcome Trust’s financial year, from Achieving our objectives 1 October 2007 to 30 September 2008. 4 Advancing knowledge Deputy Chairman 16 Using knowledge 24 Engaging society Christopher Fairburn 30 Developing people 36 Facilitating research Roderick Kent 40 Developing our organisation Eliza Manningham-Buller Peter Rigby The year in review Peter Smith 41 Corporate activities Edward Walker-Arnott 42 Financial summary 2007/08 44 Funding developments 2007/08 As at January 2009 46 Streams funding 2007/08 48 Technology Transfer 49 Wellcome Trust Genome Campus 50 Public Engagement 51 52 Advisory committees

Cover image Salbutamol crystals.

Images 1 Practical at the launch of Project Enthuse. 4 Equipment from the lab of Dr Thomas Down. 2 Electron micrograph of a mitochondrion. 5 Community engagement in Malawi. 3 Principal Research Anke Ehlers. 6 Lung cells. CoNtENtS | 1

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EXECUTIVE BOARD MAKING A DIFFERENCE The Wellcome Trust’s mission is to Director of the Wellcome Trust foster and promote research with the aim of improving human and animal Ted Bianco health. During 2005–2010, our aims are: Director of Technology Transfer Advancing knowledge: To support John Cooper research to increase understanding of Director of Resources health and , and its societal David Lynn context Head of Strategic Planning and Policy Using knowledge: To support the Clare Matterson development and use of knowledge to Director of , create health benefit Society and History Engaging society: To engage with David Phillipps society to foster an informed climate Director of Finance within which biomedical research can flourish Alan Schafer Head of Molecular and Developing people: To foster a Physiological research community and individual researchers who can contribute to the John Stewart advancement and use of knowledge Head of Legal and Company Secretary Facilitating research: To promote the Danny Truell best conditions for research and the use Chief Investment Officer of knowledge As at January 2009 Developing our organisation: To use our resources efficiently and effectively.

Strategic Plan updates, summarising progress in achieving specific objectives during 2007/08, can be found at www.wellcome.ac.uk/strategicplan. 2 | DIRECTOR’S STATEMENT

The power of partnership

Much can be achieved by working together in effective collaborations.

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Collaboration has always been central postdoctoral research in a range of capacity to undertake research. The to research, with much to be gained from specialities. We hope that the scheme will African Institutions Initiative, for example, pooling expertise, experience and create a cadre of clinicians with the is funding the establishment of consortia materials. Effective working partnerships expertise to design and conduct studies of universities and research institutions; are a key foundation for the Wellcome on novel human therapies. the Initiative will include institutions both Trust’s work and this year we can pride in Africa and in developed countries but, Industrial partners have also joined us in ourselves on a diverse range of initiatives crucially, will be African-led. It will support the new Project Enthuse, which offers with a wide variety of partners. both well-established institutions and bursaries to help to train the UK’s science promising ones, and aims to develop One of the most exciting developments teachers in the latest scientific discoveries. research leaders who can act as role of the year was the announcement in We are delighted to fund this much- models to enthuse young scientists. December 2007 of a partnership between needed initiative, run by the National the Trust, the Medical Research Council, Science Learning Centre, alongside the Meanwhile, several of our Strategic Cancer Research UK and University UK Government and business partners Awards were given to projects providing College London to establish a world- including AstraZeneca, BAE Systems, training fellowship opportunities for the leading medical research institute in BP, General Electric, GlaxoSmithKline brightest young African scientists. We are London. The UK Centre for Medical and Rolls-Royce. working with African universities and Research and Innovation will provide research institutions to build sustainable Many of our projects are undertaken with superb facilities for scientists working in research programmes initiated and led by partners from outside of the UK and we partnership with UK universities, industry Africans, and provide the infrastructure continue to support scientific capacity and other scientists from around the world. essential for a thriving research building around the world. One highlight environment. It is vital that discoveries about the causes from this year is the Wellcome Trust–DBT of disease are effectively translated into India Alliance, launched together with In Asia, we are proud to have helped to new ; this will require increased India’s Department of Biotechnology. The establish the first ever centre for the numbers of clinical scientists who Alliance will run fellowships, providing diagnosis and treatment of infectious understand the complex interplay support and training for Indian research in Laos, together with the between drugs and human physiology in scientists – from newly qualified postdocs and Mahosot health and disease. Working together through to senior researchers – enabling Hospital, Vientiane. This centre will not with academic and industrial partners, them to pursue excellent career paths and only improve diagnosis and treatment but including GlaxoSmithKline and Wyeth, continue working in their home country. also raise the capacity for medical we have launched Interdisciplinary research and training in the country. In Africa, our Major Overseas Programmes Training Programmes for Clinicians in in Kenya, Malawi and South Africa continue But while efforts against infectious disease Translational Medicine and Therapeutics, to go from strength to strength, and we continue, chronic disease is increasingly which provide support for clinicians from have made a number of other major recognised as a problem for the whole across the UK to pursue MSc, PhD and investments to enhance the continent’s world. The UK project will follow

Images 1 Breast cancer cells. 3 Researcher at the Trust’s Major Overseas Programme in Malawi. 2 Staff and pupils at Simon Langton Grammar School, Canterbury. 4 MRI scan of the head, showing the brain. DIRECTOR’S STATEMENT | 3

Highlights of the year

the health of a cohort of 500 000 people, exhibition that launched in Bristol and is aged between 40 and 69 at entry to the moving to Newcastle, Glasgow and study. In 2008, this project recruited its Liverpool. The partnership between 100 000th participant, and is on track to Ecsite-uk, the UK Network of Science complete recruitment by the end of 2010. Centres and Museums, the At-Bristol Cancer is one of the most important of the science centre and the Sanger Institute chronic diseases; to help to combat this, will enable the public to engage with the the Trust and the Wellcome Trust Sanger science and scientists involved in Institute committed support to the genomics research, and challenge their International Cancer Genome Consortium, perceptions of the subject. a global collaboration of researchers that Such public engagement initiatives seek will fully sequence thousands of cancer 4 5 64 to form a common understanding and genomes to identify the key mutations bring together people from different involved in up to 50 types of cancer. Acting Self-renewal is found to be the ‘default backgrounds. Another of our successful •  in the spirit of open collaboration, the setting’ for embryonic stem cells. projects this year was Science in Film, Consortium will facilitate and encourage which brought eight film makers and Genome-wide association studies the rapid and free exchange of •  eight scientists together to plan, shoot shed light on conditions such as information to ensure that the global and edit short films inspired by science. Crohn’s disease and schizophrenia. research community avoids any The resulting films can be seen on our duplication of effort while building this Brain imaging reveals distinctive website at www.wellcome.ac.uk/ •  body of knowledge. brain activity in people with mental broadcast. disorders. The Sanger Institute is playing a leading Meanwhile, Wellcome Collection role in another international collaboration, Dementia is found to be much more continues to go from strength to strength, •  the , an effort to common than thought in low- and producing a programme of fascinating sequence the genomes of more than middle-income countries. and often challenging exhibitions and 1000 people from all over the world. This events. The exhibition that, to my mind, researchers help INTERPOL will create a more detailed and medically •  brought home the changing of to track down drug counterfeiters in useful catalogue of human genetic human disease was Skeletons: South-east Asia. variation than is currently available, which London’s buried bones (see www. will be of critical importance for future A new TB vaccine generates wellcomecollection.org/skeletons), •  studies of the genetic basis of variation in powerful immune responses in produced in collaboration with the health and disease. African clinical trials. Museum of London’s Centre for Human Genetic variations are also the subject of Bioarchaeology. Seeing 26 skeletons • Survivors of the 7/7 London bombings another large international project. In a from Roman, early medieval and late benefit from psychological treatments follow-up to the Wellcome Trust Case medieval London gave a glimpse at the for post-traumatic stress disorder. Control Consortium – one of the highlights wide array of illnesses people have Wellcome Collection attracts of the 2006/07 Annual Review – we suffered and died from over the last •  300 000 visits in its first year of launched the largest ever study of the 2000 years. Some of these diseases opening. of common diseases. These – notably smallpox – have been genome-wide association studies will consigned to history, while others are • Project Enthuse is launched to involve researchers from at least 60 now rare or readily treated with modern provide UK science teachers with international institutions, analysing DNA antibiotics. But tuberculosis was one of even more continuing professional samples from 120 000 people – a larger the great dangers of the past, just as it is development opportunities. sample than any previously studied. This today in many countries. We hope that Trust promotes informed debate will provide greater sensitivity to uncover through medical research, this and many •  during updating of the Human subtle yet medically important genetic other diseases can join smallpox as Fertilisation and Embryology Act. variations involved in 25 diseases. historical footnotes. Genomics continues to capture the Mark Walport public’s imagination. Inside DNA: A Director genomic revolution is a five-year travelling January 2009

ADVANCING KNOWLEDGE

Supporting research to increase understanding of health and disease, and its societal context. 6 | advancing Knowledge

Brain waves Shaking the Haystack

Brain imaging is revealing distinctive brain activity It’s bonanza time for in people with psychological disorders. genome-wide analyses.

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Abnormal behaviour is seen in many Responses were recorded to faces Last year saw a significant advance in mental conditions and presumably manipulated digitally to show varying the genetic analysis of common reflects disruptions to normal brain degrees of sadness. By analysing activity diseases, with a flood of papers from function. Insight into these across the whole brain, Dr Fu was able to the Wellcome Trust Case Control abnormalities is being gathered by identify patterns consistently seen in Consortium. A further outpouring of brain imaging – increasing people with depression but not controls. findings has followed this year, as understanding and raising hopes of other groups and consortia have Finally, Senior Research Fellow Paul better diagnosis and treatment. applied whole-genome approaches Fletcher and colleagues in Cambridge to a range of conditions. The basis of conditions such as have used brain imaging to explore obsessive–compulsive disorder (OCD) susceptibility to schizophrenia, using Genome-wide association studies are has been difficult to trace, in part ketamine to induce a state of psychosis taking advantage of high-throughput because human behaviours are tricky to in healthy volunteers. genotyping techniques to screen the categorise in a way that makes them entire genome of large numbers of Brain activity was monitored in volunteers amenable to study. A productive way individuals, to identify sites in the genome before and after a dose of ketamine. forward, being taken by Sam Chamberlain that may be contributing to a disease. Some distinctive brain activations seen and colleagues in Cambridge, is to identify This year saw a whole host of studies before ketamine was administered were patterns of brain activity that can act as published dissecting conditions as significantly more common in those robust proxies of behavioural traits. varied as osteoporosis, ankylosing reporting psychotic symptoms. Moreover, spondylitis, psoriasis, Crohn’s disease To this end, they looked at brain activity activation at certain sites seemed to and type 2 . in people with OCD and their unaffected predict which types of symptom an relatives, who might be expected to individual experienced. The latest Crohn’s research identified 21 show similar but less marked new risk , bringing the total to more It may therefore be possible to use brain abnormalities. Indeed, compared with than 30 – though collectively they explain imaging to identify vulnerabilities to controls, activity in areas within the only about a fifth of the total genetic risk. particular psychotic symptoms, before frontal lobes – known to be involved in This suggests that many additional they become clinically apparent. decision-making – were lower in both genes contribute to Crohn’s, and also people with OCD and their relatives. Chamberlain SR et al. Orbitofrontal dysfunction in illustrates how complex the condition is. patients with obsessive-compulsive disorder and their The studies also picked up unexpected Neural correlates of another mental unaffected relatives. Science 2008;321(5887):421–2. connections between diseases – one disorder, depression, have been Fu CH et al. Pattern classification of sad facial processing: toward the development of neurobiological markers in increases susceptibility to both uncovered by Cynthia Fu and colleagues depression. Biol Psychiatry 2008;63(7):656–62. Crohn’s and psoriasis, another from the Institute of Psychiatry, London. Honey GD et al. Individual differences in psychotic contributes to both Crohn’s and asthma. Ultimately, this may lead to more effects of ketamine are predicted by brain function objective diagnosis of depression. measured under placebo. J Neurosci As well as disease, genome-wide studies 2008;28(25):6295–303. have also shed light on other biological

Images 1 Areas of abnormal brain activity (blue) in people with OCD or 3 Large numbers of people can be genotyped in their relatives undertaking a cognitive task. high-throughput facilities. 2 Clinical depression may be associated with specific patterns 4 Embryonic stem cells. of brain activity. advancing Knowledge | 7

Shaking the The ups and downs Haystack of stem fate

It’s bonanza time for Pluripotency may be the default genome-wide analyses. setting for embryonic stem cells.

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characteristics, such as height. A further Embryonic stem (ES) cells have the that occasionally cells have a ‘window of 20 genes affecting height were identified remarkable ability to both self-renew opportunity’ in which they can escape by an Anglo-Swiss consortium, bringing and create all of the other cell types of Nanog control and begin differentiating. the total number to more than 100. the body. A crucial question is how An insight into the possible mechanisms they manage to maintain this Particularly exciting has been the use of of Nanog action has come from Dr pluripotency. Research from Austin genome association studies in Chambers’s work linking pluripotency to Smith at the Wellcome Trust Centre schizophrenia – which has been X inactivation – the epigenetic silencing for Research in Cambridge extremely hard to dissect genetically. A of one X in female (XX) and Ian Chambers in Edinburgh is genome-wide analysis involving nearly cells. In ES cells, unlike most other cells, revealing how a gene called Nanog 500 cases identified a number of potential both X are active. When may play a crucial role. genetic candidates, three of which were they begin to differentiate, X inactivation strongly confirmed in a follow-up in Nanog is known to be important in the is re-established. nearly 17 000 affected individuals. ES cell state, but its exact role has been This timing suggested that Nanog and unclear. Now, Dr Chambers, Professor Wellcome Trust-funded researchers also other pluripotency factors could be Smith and colleagues have found that contributed to a major international involved – and sure enough, when they levels of Nanog protein fluctuate in ES collaboration looking for links between were absent, reversal of X inactivation cells. Cells with low levels – or lacking schizophrenia and copy number was disrupted. Nanog entirely – can still self-renew but variation – deletion or duplication of small are more prone to differentiate. This Significantly, as well as tying together the chunks of DNA. The presence of copy suggests that Nanog is not absolutely processes of X inactivation and number variation was associated with an required for self-renewal, but acts as a pluripotency, these findings link Nanog to increased risk of schizophrenia, as was generic inhibitor of differentiation. epigenetic regulation of gene activity. Thus loss of specific sites on chromosomes 1 Nanog may act at least in part by controlling and 15. In fact, with colleagues in the USA and epigenetic programming of cells. Canada, Professor Smith has found that The picture that is emerging is that self-renewal may be an innate property Silva J, Smith A. Capturing pluripotency. Cell variation at a great number of genes 2008;132(4):532–6. of ES cells. It had been thought that contributes to disease. Most are rare and Chambers I et al. Nanog safeguards pluripotency and external signals were needed to keep ES most are non-deterministic – only a mediates germline development. Nature cells self-renewing, but when all external 2007;450(7173):1230–4. subset of people with a risk gene end up signals were eliminated, ES cells endlessly Ying Q-L et al. The ground state of embryonic stem cell with the condition, possibly because of self-renewed without differentiating. self-renewal. Nature 2008;453(7194):519–23. interactions with other risk genes or with Navarro P et al. Molecular coupling of Xist regulation environmental factors. The emerging picture suggests that and pluripotency. Science 2008;321(5896):1693–5. References for this article can be found at Nanog contributes to ES cells’ intrinsic www.wellcome.ac.uk/annualreview. self-renewal capacity, by blocking This research was supported by a range of differentiation. But fluctuating levels mean funders, including the Wellcome Trust. 8 | advancing Knowledge

Opening up Attention seeking

Structural studies have provided new insights Attention is in short supply – but can into bacterial ion channel opening. be used more flexibly than once thought.

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Ion channels allow cells to transport Ben Luisi in Cambridge. His group’s focus Faced with a barrage of visual material across their membranes has been a drug efflux pump, which ejects information, our brains concentrate on selectively. How opening and closing drugs from the cell. The pump consists of – or attend to – limited aspects of a is achieved, however, is poorly an inner membrane channel (AcrB), an scene. According to conventional understood. Two recent studies have outer membrane channel (TolC) and a thinking, only four or five objects can shed light on the dynamics of two protein linking the two (AcrA). be attended to at a time. Rather than it important bacterial channels – a being a simple numerical capacity, TolC is present as a trimer, part of which pressure-sensitive channel and a however, Paul Bays and Masud forms a plug that meshes with the linking drug efflux pump. Husain at University College London component, AcrB. When particular (UCL) have found that people have a The MscS channel enables bacteria to residues in this area were altered, the limited supply of attention, which is survive a sudden osmotic shock. Faced pump remained partially open, and its parcelled out among different parts of with low osmotic pressure outside, a cell structure suggested a mechanism for a scene. Meanwhile, Alex Thiele and would explode were it not for the opening docking with AcrB. colleagues in Newcastle have found of pressure-sensitive channels, which Opening and closing seems to depend further evidence that the cellular allow ions and small solutes to escape, on an initial interaction between TolC and mechanisms of attention depend on thus relieving pressure. AcrB, which squeezes open the TolC the neurotransmitter acetylcholine. The ion channel consists of seven MscS channel slightly and exposes grooves for Attending to parts of a scene places molecules arranged in a barrel shape, binding of the third component, AcrA. demands on short-term or ‘working’ but its structure is known only in a closed Once engaged, AcrA docks into TolC, . To test the capacity of working state. Now, in St Andrews, fully opening the channel. memory, the UCL team briefly showed Ian Booth in Aberdeen and colleagues With ion channels playing so many critical subjects a screen featuring coloured have used a combination of structural biological roles, understanding how their shapes before changing the position of modelling and electrophysiological opening and closing is controlled is an one of the shapes. As the number of analysis of engineered channels to work important challenge – not least by shapes increased, subjects were less out the structure of the open state and suggesting routes toward the able to spot changes. But no sudden the mechanism of channel opening. development of targeted therapeutics. change occurred at four or five objects. According to their model, the seven MscS Wang W et al. The structure of an open form of an So working memory seems to have a monomers tilt and slide to open and close E. coli mechanosensitive channel at 3.45 Å resolution. small capacity, but instead of being limited the channel – much as the diaphragm Science 2008;321(5893):1179–83. to a fixed number of items, it can be spread mechanism controls the iris aperture in a Bavro VN et al. Assembly and channel opening in a out over a small but variable number. bacterial drug efflux machine. Mol Cell 2008;30(1): camera. 114 –21. Remarkably, when subjects’ eye A similar approach has been adopted by movements were tracked while they Wellcome Trust Senior Research Fellow This research was supported by the Wellcome were looking at shapes in a specified Trust and other funders.

Images 1 Open and closed states of the MscS ion channel. 2 Attention depends on the action of acetylcholine-containing neurons in the brain. 3 Lung cancer cells. advancing Knowledge | 9

Attention The evolution seeking of cancer

Thanks to new DNA-sequencing technologies, the evolution of individual can now be pieced together.

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order, subjects could recall the next The , based This cell divides, creating progeny that, shape in the sequence better than ones at the Wellcome Trust Sanger Institute, on occasion, differ from the parent cell. just focused on. This suggests that the has shown that human cancers are, These changes are passed on to future brain has already allocated attention to genetically speaking, highly complex: generations, where new changes get the forthcoming shape before the eye any one cancer contains many introduced. At any particular time, has actually moved to focus on it. mutations, some directly involved in therefore, a cancer will consist of multiple cancerous growth (‘drivers’), others subclones of cells, all descendants of the In separate studies, Alex Thiele in mere bystanders (‘passengers’). Using original founder. Newcastle and colleagues have shed ‘next-generation’ DNA-sequencing light on the cellular mechanisms Crucially, some of these subclones will technologies, Mike Stratton, Andy underpinning attention. By recording have a selective advantage and will Futreal and colleagues have now been brain activity in individual neurons in the proliferate while others are outcompeted. able to look at DNA rearrangements in visual area of the brain in a primate cancer cells in unprecedented detail By fully characterising the genetic changes model, they showed that attention is and even piece together the seen in cells from 22 people with a linked to levels of acetylcholine. evolutionary history of a cancer. type of leukaemia, the Cancer Genome As well as illuminating a key attribute of Project team was able to piece together the Next-generation sequencing technologies human perception, the two studies have evolutionary history of the subclones seen newly introduced at the Sanger Institute significant clinical relevance. After a stroke, in each individual. Generally, one subclone are radically increasing the generation of for example, some people struggle to dominates in each person – but with cells sequence information – the equivalent of take in information from one side of their turning over rapidly, even rare variants around two human genomes is visual field (hemispatial neglect). have the potential to generate leukaemia. sequenced every day. Abnormal attention is also a feature of These studies highlight how ultra-high- Alzheimer’s disease and attention deficit As a result, genomic rearrangements can throughput sequencing can be applied hyperactivity disorder. A greater now be analysed faster and in more detail to the analysis of cancers. In the future, understanding of underlying mechanisms than ever before. A study of two individuals one application might be sequencing of could therefore point the way to treatments with lung cancer, for example, identified cells from different parts of the body, or for these and other conditions. 103 acquired structural changes in cancer at different stages of disease, to link cells in a background of 306 inherited Bays PM, Husain M. Dynamic shifts of limited working particular features of a cancer to its memory resources in human vision. Science genomic rearrangments, all at base-pair underlying genetic abnormalities. 2008;321(5890):851–4. resolution – demonstrating the feasibility Herrero JL et al. Acetylcholine contributes through of systematic searches for cancer-causing Campbell PJ et al. Identification of somatically muscarinic receptors to attentional modulation in V1. acquired rearrangements in cancer using genome- Nature 2008;454(7208):1110–4. rearrangements. wide massively parallel paired-end sequencing. Nat Genet 2008;40(6):722–9. Development of a cancer is a type of Campbell PJ et al. Subclonal phylogenetic structures This research was supported by a range of evolutionary process. Each human funders, including the Wellcome Trust. in cancer revealed by ultra-deep sequencing. cancer begins with a single aberrant cell. Proc Natl Acad Sci USA 2008;105(35):13081–6. 10 | advancing Knowledge

Energy gap Cold cures

Mitochondrial DNA mutations are Not all pain is the same. surprisingly common.

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Mitochondria generate the bulk of the children and adults were at risk of Many noxious insults trigger pain, cell’s energy. Derived from once-free- mitochondrial DNA disease. such as heat, cold and tissue damage. living bacteria, they retain the remnants All these insults are detected by The inheritance of mitochondrial DNA of an ancestral genome, now down to pain-sensing neurons, nociceptors, disorders is complex – the severity of its last 37 genes. Mutations in these which rapidly send messages to the symptoms varies widely in the offspring genes cause a variety of conditions, spinal cord and then on to the brain. of affected mothers. Offspring get all their typically affecting tissues with high But there are subtle differences in how mitochondria from their mother, but if energy needs, yet their full impact has they are detected, and John Wood of she has a mix of normal and mutant been obscure. Now, Patrick Chinnery, University College London and mitochondria, what decides whether they Doug Turnbull and colleagues at colleagues are unpicking the cellular receive normal or affected mitochondria Newcastle University have found that mechanisms that distinguish different or a mix of both? they affect significantly more people types of pain. than previously thought. The answer, it appears, is pure luck. When Although cold tends to inhibit our sensory the Newcastle team looked at the The Newcastle group used two and motor systems, pain perception is precursors of egg cells created early in approaches to assess the incidence of not affected – it serves a valuable defence development, they discovered that the mitochondrial DNA mutations. One was function. To explore the mechanisms cells inherited a random selection of to assess how many new mutations underlying this effect, Professor Wood’s mutant and normal mitochondria. What appeared in a series of more than 3000 team examined the function of key an offspring ends up with simply depends live births. One in 200 was found to carry nociceptor sodium channels, the on the fraction of mutant mitochondria in a mutation not seen in their mother. activation of which triggers a nerve the egg that gets fertilised. impulse and ultimately leads to the In a complementary strand of work, the Discovery of this ‘mitochondrial genetic sensation of pain. researchers calculated the prevalence of bottleneck’ may provide an opportunity mutations in the working-age population While the activity of most types of channel to screen out eggs with many mutant around Newcastle, by analysing all dropped when skin was cooled, that of mitochondria, reducing the risk that a suspected cases of mitochondrial one specific channel – known as Na 1.8 mother has a severely affected child. v disease seen at a neurology clinic – was unaffected. Moreover, chilling between 1990 and 2004. Schaefer AM et al. Prevalence of mitochondrial actually lowered the threshold at which DNA disease in adults. Ann Neurol 2008;63(1):35–9. Nav1.8 channels opened. Thus Nav1.8 By tracing family members, they found Elliott HR et al. Pathogenic mitochondrial DNA appears to be the crucial element of cold that 9.2 in 100 000 people had clinically mutations are common in the general population. Am J Hum Genet 2008;83(2):254–60. pain sensing by nociceptors. apparent mitochondrial DNA disease, Cree LM et al. A reduction of mitochondrial DNA making it one of the most common molecules during embryogenesis explains the rapid But are there specific nociceptors for pain inherited neuromuscular disorders. segregation of genotypes. Nat Genet 2008;40(2): or does each sensory neuron detect a In addition, a further 16.5 in 100 000 249–54. range of stimuli? To address this question, Professor Wood used a toxin to eliminate

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1 Mitochondria, the cell’s source of energy. 3, 4 Toxin-induced elimination of Nav1.8 neurons (green). 2 Cardiac muscle stained for mitochondria. 5, 6 Chromosomes (blue) are moved in dividing cells by microtubules (red), which attach to (green) advancing Knowledge | 11

Cold cures Long division

Not all pain is the same. The properties of a protein complex key to cell division are gradually being revealed.

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specifically all sensory neurons carrying Separation of chromosomes during cell DNA to make led to the Nav1.8 sodium channel. division depends on the , a rapid loss of kinetochore function. a protein complex assembled on a As expected, responses to cold stimuli One component of the kinetochore, specific region of DNA, the . were lost. In addition, responses to Kar3, is a molecular motor that helps Molecular cables, microtubules, attach mechanical pressure and inflammation to move the kinetochore along themselves to the kinetochore and were also abolished. On the other hand, microtubules in a sliding mechanism. direct chromosomes to separate ends responses to heat and nerve damage Tomoyuki Tanaka and colleagues in of the cell. Groups at Wellcome Trust were unaffected. Na 1.8 neurons thus Dundee have discovered that a second v Centres in Edinburgh and Dundee are appear to be selective for mechanical, mechanism operates at the anchor picking apart the structure and function cold and inflammatory pain but not for points at the end of the microtubule. of this crucial cellular component. sensing of heat or nerve damage. This pulls microtubules, like a rope being , a Wellcome Trust Principal hauled in. A greater understanding of the molecular Research Fellow at the Wellcome Trust and cellular mechanisms of pain detection Folco HD et al. Heterochromatin and RNAi are required Centre for in Edinburgh, has to establish CENP-A at . Science will help to identify processes that could been studying the mechanisms that 2008;319(5859):94–7. be targeted therapeutically. There ensure that a kinetochore forms at the Nakano M et al. Inactivation of a human kinetochore by remains an urgent need for better specific targeting of chromatin modifiers. Dev Cell right location on a chromosome. pain-relieving medicines, particularly for 2008;14(4):507–22. Centromeres contain an unusual histone chronic pain. Tanaka K et al. Molecular mechanisms of microtubule- protein, CENP-A. Professor Allshire’s dependent kinetochore transport toward spindle poles. Zimmermann K et al. Sensory neuron sodium channel team has now found that, in fission yeast, J Cell Biol 2007;178(2):269–81. Nav1.8 is essential for pain at low temperatures. Nature 2007;447(7146):855–8. incorporation of CENP-A at centromeres This research was funded by the Wellcome Trust Abrahamsen B et al. The cell and molecular basis of is dependent on a distinct form of and others. Tomoyuki Tanaka, formerly a mechanical, cold, and inflammatory pain. Science chromatin (known as heterochromatin) Wellcome Trust Research Career Development 2008;321(5889):702–5. that flanks the region where CENP-A is Fellow, is now a Cancer Research UK Senior normally deposited. Research Fellow. Professor Wood is a member of the London Pain Consortium, which received a £5 million Also in Edinburgh, Principal Research Strategic Award in 2007/08. Fellow Bill Earnshaw has found more evidence of the importance of chromatin structure. With colleagues in the USA, he has helped to create human artificial chromosomes with a synthetic centromere to which different types of protein can be targeted. Many proteins had no effect, but those that altered the compaction of 12 | advancing Knowledge

Missing dementia Care and the community

Is dementia less common in developing countries? The secret to informed consent may New research suggests not. lie in community engagement.

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The reported prevalence of dementia America – more than nine million – is Informed consent – ensuring that in developing countries is surprisingly likely to match that in North America. people who participate in research do low. Now, an international collaboration so voluntarily and with a full awareness Moreover, as healthcare is generally led by Martin Prince at the Institute of of what is involved – is a thorny ethical limited in such regions, patient care Psychiatry has found that its issue in developing countries. Research usually falls to spouses or other family prevalence has been substantially in Kenya and Malawi is revealing how members. Dementia is the single biggest underestimated in low- and middle- informed consent operates in the field, factor contributing to dependency, income countries, and that it is almost and emphasising the importance of creating significant economic and as common as in developed countries. pro-active community engagement. psychological pressures: carers are Moreover, dementia is imposing a often forced to cut working hours and Although often discussed, relatively little considerable psychological and are at high risk of depression or other empirical research into informed consent economic burden on large numbers forms of mental distress. has been carried out – a deficit being of carers. tackled by Joseph Mfutso-Bengo in Previous underestimates may reflect the Professor Prince leads the 10/66 Malawi and Sassy Molyneux and fact that people in lower-income countries Dementia Research Group, an colleagues in Kenya. are less likely to seek help for elderly international collaboration assessing the relatives showing signs of dementia – it is Dr Mfutso-Bengo and Dr Molyneux have impact of dementia and related conditions often seen as a ‘natural’ part of ageing. explored the reasons why people do or in low- and middle-income countries. It do not volunteer to take part in trials. It is derives its name from the fact that less The findings suggest that there is a major often assumed that participants believe than one-tenth of population-based health burden going unaddressed in they will benefit from the intervention dementia research has focused on the many countries. More positively, being tested – the so-called therapeutic two-thirds or more of all people with intervention studies in Russia and India misconception. In fact, a broader dementia who live in developing countries. carried out by the 10/66 Group (funded motivation is a desire to access the better by the World Health Organization) Members of the collaboration assessed general healthcare often provided to suggest that simple home-based almost 15 000 people over the age of 65 participants. By contrast, discussions interventions can provide significant in 11 countries, using culturally sensitive with community members suggested benefits to both carers and patients. tools to factor out different perceptions several reasons why people decline to of ageing and dementia. Llibre Rodriguez JJ et al. Prevalence of dementia in take part in trials, including potential Latin America, India, and China: a population-based volunteers’ lack of awareness of health The results suggested that there is a cross-sectional survey. Lancet 2008;372(9637): 464–74. research and investigators adopting ‘hidden epidemic’ of dementia, its Llibre Rodríguez J et al. The prevalence, correlates and culturally insensitive practices. prevalence in urban settings in Latin impact of dementia in Cuba. A 10/66 Group America comparable to those seen in population-based survey. Neuroepidemiology In Kenya, Dr Molyneux, Vicki Marsh, Europe and the USA. By 2040, the 2008;31(4):243–51. Dorcas Kamuya and others have focused number of people with dementia in Latin on strengthening relations between the

Images 1 In Latin American countries such as Cuba, dementia may be more common than thought. 2, 3 Engaging with the local community in Malawi. 4 A young child in a hospital in Malawi. advancing Knowledge | 13

Care and the The hidden costs community of anaemia

The secret to informed consent may Even when treated successfully, lie in community engagement. severe anaemia increases the risk of .

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KEMRI–Wellcome Trust Research Severe anaemia is a major problem in The biggest single factor associated with Programme at Kilifi and its 240 000- Africa. It is responsible for 12–29 per death after discharge was HIV status. strong local community. A malaria cent of childhood admissions to As anaemia is so common, these figures vaccine trial (see page 38) provided an hospital, and between 4 and 10 per point to an alarmingly large number of opportunity to assess internationally cent of these children are likely to die among young African children recommended ‘best practice’ for in hospital. And as Kamija Phiri, Job who have left hospital. informed consent – such as community Calis, Michaël Boele van Hensbroek as well as individual consent and formal and Malcolm Molyneux in the What might be causing anaemia in the tests of participants’ understanding. Malawi–Liverpool–Wellcome Trust first place?T he investigators found that Qualitative studies confirmed the value of Programme for Research in Tropical admission to hospital with severe such practices. Medicine in Blantyre, Malawi, have anaemia was strongly associated with discovered, an alarming number of bacterial infections, malaria, hookworm However, a quiz designed to test those that survive die after discharge infections, HIV and vitamin deficiencies, understanding appeared to fuel from hospital. but not iron or folate deficiencies. misconceptions, and unearthed concerns about blood sampling and vaccine Nearly 20 years ago, a group in Kenya Severe anaemia in children in sub- side-effects. This encouraged additional reported that children who had been Saharan Africa has generally been discussions between the research team treated for anaemia in hospital continued thought to be mainly a result of malaria, and potential participants. Overall, the to die in unexpectedly high numbers but these findings suggest that other relationships between the two groups after being discharged. As this finding infections or dietary deficiencies may were identified as central to community had never been followed up, Dr Boele also be of importance. Understanding members’ perceptions of trials. van Hensbroek and Professor Molyneux the causes of severe anaemia is an set out to see if it was also true of important step towards designing Informed consent is thus not simply a Malawian children. effective treatment and preventative matter of providing factual information and strategies for it, to ensure that the health testing participants’ understanding, which They compared three groups – children of vulnerable young children is protected may underplay the significance of admitted to hospital with anaemia, both in hospital and back in the pre-existing and evolving relationships children admitted for other reasons and community. and attitudes. a community sample – following them for 18 months after enrolment. Phiri KS et al. Long term outcome of severe anaemia Pro-active community engagement is at in Malawian children. PLoS ONE 2008;3(8):e2903. the heart of the Wellcome Trust’s new They found the same disturbing pattern Calis JC et al. Severe anemia in Malawian children. international public engagement initiative, – children who had had severe anaemia N Engl J Med 2008;358(9):888–99. which made 15 awards in 2007/08, were far more likely to die (all-cause including several in East Africa. mortality of 12.6 per cent, compared with 2.9 per cent of the hospital controls and References for this article can be found at 1.4 per cent of the community controls). www.wellcome.ac.uk/annualreview. 14 | advancing Knowledge

NEW FUNDING

CHANGING CHANNELS THE NEXT 999 A FLOURISHING FIELD

A £6.5 million Strategic Award to the The 1000 Genomes Project will shed Two new awards will help to establish OXION network will support light on rare human genetic variation. centres of excellence in medical interdisciplinary research on ion humanities. While initiatives such as the Wellcome channels and their role in disease. Trust Case Control Consortium have done Health is experienced on a profoundly Ion channels (above), pores that control much to identify common genetic variations personal level. Individual perceptions of the flow of ions through cell membranes, increasing disease risks, it is becoming health are often intimately entwined with play important roles in many physiological clear that rare variants are also important: social and cultural factors, as well as processes. They have also been although not widely distributed, collectively personal experience. implicated in numerous medical they account for a significant fraction of In recognition of the importance of this conditions – there are more than 60 ion disease risk. area, the Wellcome Trust has made two channels in which mutations lead to To understand rare variation better, detailed major awards, through its medical human diseases. Ion channels are also genome comparisons are needed over a humanities programme, to establish the targets of many drugs. much larger number of individuals. This is centres of excellence at King’s College OXION, a research and training network the goal of the 1000 Genomes Project, an London and the University of Durham. encompassing 25 groups mainly but not international collaboration being led by At King’s, which will receive £2 million, exclusively based in Oxford, has developed Richard Durbin at the Wellcome Trust Brian Hurwitz and colleagues will study an interdisciplinary approach to ion Sanger Institute. ‘The Boundaries of Illness’ – personal channels. Led by Professor Frances With partners in the USA, China and and cultural representations of health Ashcroft and Professor Nick Rawlins, its Germany, the US$50 million (£34m) 1000 and illness and the boundaries between work ranges from molecular and cellular Genomes Project will analyse the genomes them. approaches to in vivo physiology and of at least 1000 individuals from different behaviour studies, and aims to generate Martyn Evans and colleagues at the populations around the world, generating a better understanding of ion channel University of Durham, awarded £1.8m, a staggering 6 trillion base pairs of function in health and disease. will examine ‘Medicine and Human sequence information. It will examine Flourishing’ – exploring the human side The £6.5m award will provide funds for variation affecting single nucleotides as of medicine, in particular the relationship core infrastructure and support additional well as larger changes such as deletions of health and medicine to wider notions collaborations among members of the or rearrangements. of wellbeing. network. It also includes a training Currently, the capacity to generate human element, enabling researchers to develop Medical humanities research provides an genome sequence information exceeds a range of multidisciplinary skills. opportunity to reflect upon people’s the ability to understand what the data experience medical practice, illness and Finally, it will also help to strengthen links actually mean. By clarifying the extent and health – insights that may help to shape between basic and clinical research, and nature of rare variation, the 1000 Genomes the future delivery of medical care. promote the translation of knowledge into Project will add significant additional new diagnostics and therapies. meaning to the deluge of sequence data. advancing Knowledge | 15

INDIAN INITIATIVES A SELECTION OF NOTABLE GRANTS AWARDED IN 2007/08.

STRATEGIC AWARDS CELL BIOLOGY Professor Mike Tyers (University of Edinburgh) PAIN Cellular networks that control cell size in budding Professor Stephen McMahon (King’s College yeast. London) Core support for the London Pain Consortium. PROJECT GRANTS CENTRE FUNDING DERMATOLOGY Professor Jonathan Rees (University of PARASITOLOGY Edinburgh) Development of a digital tool to aid Professor David Barry (University of Glasgow) diagnosis of skin lesions. Renewal of core support for the Wellcome Trust Centre for Molecular Parasitology. MENTAL HEALTH Professor Glyn Lewis (University of Bristol) PROGRAMME GRANTS Exploring the origins of depression at age 17 in NERVE GROWTH the Avon Longitudinal Study of Parents and Professor Christine Holt (University of Children cohort. Cambridge) Protein dynamics in the growth cone INFLUENZA and long-distance navigation of nerve fibres. Strategic Awards totalling £15 million Professor Ten Feizi (), Dr Alan Hay (National Institute for Medical have been made to support health DEVELOPMENTAL BIOLOGY Professor (University of Research) and Professor Menno de Jong research in India. Oxford) Control of transcriptional networks by (Vietnam Major Overseas Programme) Development of a platform for monitoring A £5m partnership with the Public Health growth factor signalling pathways in the mammalian embryo (Principal Research Fellow changes in the receptor-binding characteristics Foundation of India, supported by a programme grant renewal). of H5N1 flu virus isolated from human infections. grant to Srinath Reddy, will help to OPHTHALMOLOGY establish new Indian Institutes of Public MALARIA Dr Peter Bull (University of Oxford) Malaria Dr Jugnoo Rahi (University College London) A Health and enhance the capacity of the variant surface antigens and development of genome-wide association study of refractive public health system in India. immunity. error (myopia and hypermetropia). In common with other emerging HIV/AIDS PSYCHIATRY economies, India is facing an increasing Dr Simon Gregson (Imperial College School of Professor Ian Goodyer () Brain imaging of adolescents with burden from chronic diseases. With Medicine) Evaluating the impact of HIV prevention and treatment programmes in disruptive behaviour disorders. £4.5m Wellcome Trust funding to Shah Zimbabwe. Ebrahim of the London School of DIABETES CIRCULATION Dr Timothy Frayling (University of Exeter) Hygiene and Tropical Medicine, a South Variation in type 2 diabetes susceptibility genes Asia Centre is being set up in India to Professor David Beech (University of Leeds) TRP ion channel function in vascular smooth expressed in pancreatic beta cells. expand research into the prevention muscle cells. HISTORY OF MEDICINE ENHANCEMENT and control of chronic diseases such AWARD as diabetes and mental illness. VACCINATION Professor Vincenzo Cerundolo (University of SOCIAL MEDICINE Maternal and child mortality and Oxford) and Professor Gurdyal Besra Professor John Stewart (Glasgow Caledonian morbidity in high-mortality populations (University of Birmingham) Synthetic small- and Strathclyde Universities) The relationship chemical agonists of natural killer T cells as in South Asia and sub-Saharan Africa between health and the provision of healthcare in potential vaccine adjuvants. society. are the focus of a £5.5m award to Anthony Costello of University College SEXUAL BEHAVIOUR STRATEGIC AWARD IN BIOMEDICAL Professor Anne Johnson (University College ETHICS London, which will establish a network London) Support for the third British National of researchers and field sites in Survey of Sexual Attitudes and Lifestyles, NEUROETHICS Bangladesh, India, Nepal and Malawi. planned for 2010. Professor Julian Savulescu (University of Oxford) Core support for an interdisciplinary The Trust has also launched a new POPULATION STUDIES neuroethics research centre. partnership with the Government of Professor Stephen Tollman (University of the Witwatersrand, South Africa) Core support for India’s Department of Biotechnology the Agincourt health and socio-demographic Details of all grants made can be found in to fund biomedical research in India. surveillance system in rural South Africa. Grants Awarded 2007/08, available on the Both partners have committed £40m Wellcome Trust website. to the venture.

USING KNOWLEDGE

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

Better by design Future sight

A better understanding of drug–receptor interactions Gene therapy may provide a new may lead to improved beta-blockers. option for young people with a rare form of blindness.

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Beta-blockers, drugs used to treat β2-adrenoceptor was worked out in Although rare, blindness due to various heart conditions, act on 2007 and that of a turkey β1- Leber’s congenital amaurosis (LCA) β-adrenoceptors – cellular receptors adrenoceptor was mapped out in 2008, strikes early and no effective treatment for adrenaline and noradrenaline. by a team at the Laboratory of Molecular is available. Pioneering gene therapy These receptors come in several Biology in Cambridge. at Moorfields Eye Hospital – involving forms with different biological roles. James Bainbridge, an eye surgeon Structural comparisons are beginning to Thanks to a growing understanding of and Advanced Training Fellow at the reveal the basis for specificity in ligand the key factors underpinning ligand Institute of Ophthalmology, and binding. The situation may be even more binding specificity, Jillian Baker, a Adrian Thrasher, a Wellcome Trust complicated, however, as the β1- Wellcome Trust Clinician Scientist Senior Clinical Fellow at the Institute adrenoceptor appears to have two Fellow in Nottingham, is developing of Child Health – has shown that the distinct but overlapping ligand-binding more precisely targeted beta-blockers. technique is safe and in at least one sites. case restored some level of vision. Although in use for decades, beta-blockers Dr Baker’s team has identified a compound have a range of side-effects. In particular, First described around 150 years ago by selective for the β1-adrenoceptor. With a they tend to exacerbate the symptoms of Theodor Leber, LCA appears at birth or £2.9 million Seeding Drug Discovery asthma or other respiratory conditions – in the first few months of life and causes award from Technology Transfer, the so some 300 000 people are denied their progressive deterioration of the Nottingham team aims to improve benefits. In part this is because the drugs and loss of vision. In the 1990s several selectivity further, to develop compounds that act on β1-adrenoceptors, found in genes were identified that caused the suitable even for those with respiratory heart tissue, also interact with β2- condition, including RPE65. complaints. adrenoceptors, which predominate in the Significantly, the structure of the retina respiratory system. Baker JG. The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 seems relatively unaffected in young The nature of the interaction between adrenoceptors. Br J Pharmacol 2005;144(3):317–22. people with RPE65 mutations, which drug and receptor is incompletely Baker JG et al. Role of key transmembrane residues in raised hope that gene therapy could agonist and antagonist actions at the two understood, limiting the scope to devise conformations of the human beta1-adrenoceptor. Mol restore some level of vision. Support strategies to improve drug selection. Pharmacol 2008;74(5):1246–60. for this idea came from studies in mice For example, the amino acid residues Warne T et al. Structure of a beta1-adrenergic and on Briard dogs, which also suffer in the ligand-binding region of 1 and G-protein-coupled receptor. Nature from LCA. β 2008;454(7203):486–91. β2 receptors are very similar, even though Launched in February 2007, a trial led several compounds differ markedly in The β1-adrenoceptor structure research was by Robin Ali involved three young adults how well they bind to each protein. supported principally by a joint grant from Pfizer and Medical Research Council Technology; with LCA. Intact copies of the RPE65 Structural and mutagenesis studies ligand-binding studies were supported by the gene were inserted into the cells of the of β-adrenoceptors might resolve Biotechnology and Biological Sciences retina, using a virus vector. None of the Research Council. these issues. The structure of a three suffered any adverse effects. The

Images 1 Jillian Baker, a Clinician Scientist Fellow at the University 3 A young child with Williams syndrome. of Nottingham. 4 Nigel Carter of the Wellcome Trust Sanger Institute. 2 Gene therapy may be an option for people with some inherited eye conditions. USING Knowledge | 19

Deciphering genetic disease

The DECIPHER database is benefiting patients, clinicians and researchers.

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vision of two remained stable while that Chromosomal rearrangements are a Connecting cases this way can reassure of the third improved significantly – common cause of developmental clinicians that the genetic change detected possibly because the disease was at an conditions in young infants. The is directly linked to the condition – earlier stage of progression. DECIPHER database, set up by Nigel everyone has some shuffled DNA, most Carter at the Wellcome Trust Sanger of it harmless. Information can also be Though preliminary, these findings – Institute and Helen Firth in shared on the progression of disease. along with those from a similar trial Cambridge, enables clinicians and Researchers can use the information to carried out in the USA – justify trials in researchers worldwide to pool investigate genes in the affected regions children with less advanced knowledge about the causes and and how their loss or duplication might degeneration and greater potential for consequences of these conditions. cause the condition. benefit. Bainbridge JW et al. Effect of gene therapy on visual Dr Carter has pioneered the development Parents also benefit from a diagnosis. As function in Leber’s congenital amaurosis. N Engl J Med of tools that can search the entire human well as being able to guide clinical care, a 2008;358(21):2231–9. genome for copy number variation – diagnosis can be comforting – parents at regions that have been duplicated or last have an explanation for their child’s The gene therapy trial was funded by the lost. These alterations are a common condition and can be reassured that they Department of Health, the National Institute of Health Research Biomedical Research Centre cause of developmental conditions. were not in any way to blame. It may also for Ophthalmology and the British Retinitis Traditional methods of diagnosis rely on reveal whether they are at risk of having Pigmentosa Society. microscopic analysis of chromosomes, another affected child. but cannot spot subtle changes. Since it was set up in 2004, more than Dr Carter teamed up with Dr Firth, a 100 centres have registered with clinical geneticist at Addenbrooke’s DECIPHER. More generally, genomic Hospital in Cambridge, to develop the analysis has been taken up by many DECIPHER database so new findings medical genetic centres as an adjunct to emerging from the use of genomic tools conventional methods. And at least one could be shared globally. As conditions centre has already abandoned the may be extremely rare, the global reach microscope in favour of DNA-based tools. can be particularly valuable. For example, Zahir F et al. Novel deletions of 14q11.2 associated with the database enabled researchers to developmental delay, cognitive impairment and similar identify a syndrome caused by a small minor anomalies in three children. J Med Genet 2007;44;556–61. deletion on chromosome 17. A similar Shaw-Smith C et al. Microdeletion encompassing cluster of cases – two from Vancouver, MAPT at chromosome 17q21.3 is associated with Canada, and one from Cambridge – developmental delay and learning disability. Nat Genet revealed a new syndrome linked to loss 2006;38;1032–7. of part of chromosome 14. 20 | USING Knowledge

Boosting the pipeline By Jupiter

High-throughput screens are identifying new Malaria researchers have helped to compounds with antimalarial activity. track down drug counterfeiters.

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As part of an international programme were used. This matching – or ‘guilt by The trade in fake antimalarial drugs of work on Plasmodium falciparum and association’ – gives clues to the possible harms many patients and increases P. vivax malaria parasites, Elizabeth mechanisms of action of test compounds. the risk that drug resistance will Winzeler and colleagues at the develop. Working with INTERPOL, the As the P. falciparum genome has been Genomics Institute of the Novartis WHO and a team of forensic scientists sequenced, high-throughput approaches Research Foundation in San Diego in ‘Operation Jupiter’, Paul Newton can be used to identify possible drug have been using high-throughput from the Wellcome Trust’s South-east targets. The function of many P. screening techniques to identify Asia Programme has helped to locate falciparum genes is not known, which compounds that could form the basis of and shut down a distribution network hampers their use as possible targets. a new generation of antimalarial drugs. of fake antimalarials in China. To work round this problem, the San Conventional screening approaches Diego team measured gene activity at Artesunate, used in many artemisinin- identify compounds that interfere with various developmental stages and in based combination therapies, is a vital target proteins. Often, though, these two malaria parasite species, to identify weapon in the battle against malaria. But compounds have little impact on living distinctive patterns of activity. The role of in countries with a large burden of malaria, systems – possibly because they cannot nearly 1000 genes of unknown function such as Myanmar, Laos, Cambodia, gain access to their targets in the cell. could then be predicted on the basis of Vietnam and Thailand (on the Thai– Cell-based assays overcome this problem shared activity patterns. Myanmar border), as many as half of all but replace it with another: it is hard to artesunate tablets are fake. Although at an early stage, this work is tell what the compound is targeting and identifying possible lead compounds for Dr Newton has done much to publicise hence the mechanism of action. antimalarial drug development. The the scale and impact of the trade in The San Diego team has used most promising candidates will be counterfeit drugs. Recently, he teamed computational methods to tackle this passed onto the Medicines for Malaria up with investigators from INTERPOL, problem. A high-throughput cell-based Venture public–private partnership for representatives of the WHO and Chinese screen of 1.7 million compounds identified further development. law enforcement agencies to analyse and 6000 able to inhibit growth of P. falciparum Plouffe D et al. In silico activity profiling reveals the trace the origins of fake artesunate. in red blood cells. Reassuringly, the 6000 mechanism of action of antimalarials discovered in a In a unique ‘forensic pharmacological’ included most known antimalarials. high-throughput screen. Proc Natl Acad Sci USA 2008;105(26):9059–64. collaboration, six laboratories undertook To work out what these compounds Zhou Y et al. Evidence-based annotation of the a barrage of tests to analyse the might be doing, the team turned to malaria parasite’s genome using comparative composition of the fake drugs – and expression profiling. PLoS ONE 2008;3(2):e1570. ‘activity profiling’ – assessing their identify their possible origins – by effects on a barrage of cell-based This work was supported through a Strategic assessing their chemical composition, assays. The effects of each compound Award to the Novartis Institute of Tropical gases around the tablets in blister packs Diseases, with additional funding from the were then compared with those seen Medicines for Malaria Venture and the and even the pollen embedded in the when chemicals with known targets Singapore Economic Development Board. tablets during manufacture.

Images 1 Malaria-infected red blood cell. 3, 4 Holograms on the packaging of fake antimalarials. 2 Small chemical inhibitors bound to a parasite target enzyme. 5, 6 Helen McShane at the University of Oxford. USING Knowledge | 21

By Jupiter A boost for BCG

A vaccine designed to boost BCG’s anti-TB immunity has generated powerful immune responses in clinical trials.

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Many counterfeits were hard to Some 2 billion people are infected with Moreover, a trial in the UK has shown that differentiate from the genuine product, Mycobacterium tuberculosis, the cause the immune boost provided by MVA85A while others were poor copies (one of tuberculosis, and 2 million die of it does not depend on the length of time managed to misspell ‘tablet’ on its every year. For more than 80 years, the since BCG was given – responses were packaging). Most of the fakes contained BCG vaccine has provided some the same whether it was given weeks or no artesunate, and some contained protection, but it has many drawbacks, years later. potentially toxic ingredients. Even more including its inability to protect adults These highly promising findings support worryingly, some included sub-therapeutic from infection. A new vaccine being rapid progress towards phase IIb clinical amounts of artesunate or artemisinin – developed by Helen McShane, a efficacy trials, which would test the ability which, if consumed, could promote the Senior Research Fellow in Clinical of MVA85A to protect against infection spread of drug-resistant parasites. Science at the University of Oxford, with TB. has been shown to boost immune The presence of a particular type of calcite responses dramatically in clinical trials With a £4m award from Technology and pollen flora in the tablets suggested in South Africa and The Gambia. Transfer and £4m from the Aeras Global that at least some of the counterfeits were TB Vaccine Foundation, Dr McShane has made in southern China. Armed by The vaccine, MVA85A, is based on a begun a phase IIb clinical trial of the INTERPOL with these findings, Chinese modified form of vaccinia virus displaying vaccine in South African children. In authorities made arrests in China’s a TB antigen on its surface. It has been addition, Isis Innovation Ltd, the Yunnan Province in 2006. The suspects designed as a booster vaccine – technology transfer arm of the University are alleged to have traded 240 000 blister stimulating a heightened response by of Oxford, has announced a new joint packs of counterfeit artesunate. re-stimulating the immune response venture with biopharmaceutical company initially generated by a ‘priming’ vaccine Operation Jupiter depended on effective Emergent BioSolutions Inc. to develop such as BCG. Following successful trials international collaboration and analytical the vaccine. in the UK, the vaccine has undergone techniques rarely available in South-east clinical trials in Africa to assess its safety Brookes RH et al. Safety and immunogenicity of the Asia. Without considerable extra candidate tuberculosis vaccine MVA85A in West and ability to stimulate immune responses. resourcing it will be difficult to tackle the Africa. PLoS ONE 2008;3(8):e2921. trade in counterfeit drugs, which are now In both South Africa and The Gambia, Hawkridge T et al. Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy adults in also spreading across Africa. A partial MVA85A had no significant side-effects. South Africa. J Infect Dis 2008;198(4):544–52. solution may lie with portable detectors Most encouragingly, in both settings it Pathan AA et al. Boosting BCG with recombinant that can reliably determine whether generated powerful T-cell immune modified vaccinia ankara expressing antigen 85A: medicines in shops and pharmacies do responses – those thought most likely to different boosting intervals and implications for efficacy trials. PLoS ONE 2007;2(10):e1052. contain their stated active ingredient. protect against M. tuberculosis. Detailed Beveridge NE et al. Immunisation with BCG and Newton PN et al. A collaborative epidemiological analysis suggests that a wide range of recombinant MVA85A induces long-lasting, investigation into the criminal fake artesunate trade in responses is being stimulated. polyfunctional Mycobacterium tuberculosis-specific South East Asia. PLoS Med 2008;5(2):e32. CD4+ memory T lymphocyte populations. Eur J Immunol 2007;37(11):3089–100. 22 | USING Knowledge

What doctors do Gut feeling

Ensuring that doctors follow good medical practice Adding starch to oral rehydration could make a big difference to healthcare delivery. solutions significantly reduces diarrhoea in adults with cholera.

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The past few decades have seen an seen: appropriate prophylactic antibiotic Oral rehydration solutions are effective emphasis on evidence-based use during caesarean sections, for treatments for diarrhoea, a common medicine and ensuring that doctors example, was observed in fewer than 5 and potentially fatal consequence of use treatments known to work. per cent of cases in most hospitals. many infections. Nevertheless, while Research suggests that this approach Rates of episiotomy, which should be used they stabilise a person’s health, these could provide healthcare benefits if it sparingly, ranged from 31 per cent to 95 solutions do not actually stop the were adopted more widely in low- and per cent. diarrhoea, so individuals are still in middle-income countries. discomfort and may be discouraged On the basis of these findings, the SEA- from using them. A study in Vellore, Doctors can draw upon a huge body of ORCHID team has developed interventions India, based on a partnership knowledge, generally in ‘quality-assured’ to help build capacity in the skills needed between researchers from India, the forms such as clinical guidelines and to carry out and assimilate research UK and the USA, has now shown that WHO recommendations. Ensuring that findings. addition of a complex carbohydrate the medical profession follows ‘good Independently, Tazeen Jafar at the Aga can markedly reduce diarrhoea. practice’ is particularly important in low- Khan University, Karachi, Pakistan, and and middle-income countries, which face More than 4.5 million cases of diarrhoea colleagues looked at the role of the strong pressures to use scarce health occur every year, most of them in doctor–patient relationship – and of funds effectively. resource-poor countries. Patients are patients themselves – in the management typically given oral rehydration solutions, SEA-ORCHID (South-East Asia Optimising of chronic conditions. which help to replace lost fluids. Reproductive and Child Health in They discovered that one-third of heart Developing Countries), an international Although effective, early formulations did attack patients were slow to go to hospital, collaboration funded by the Wellcome not halt diarrhoea, leading the people mostly because they were unaware of the Trust and the Australian Health and taking them to wonder whether they need to respond rapidly to the symptoms Medical Research Council, has been were actually working. More recent of heart attacks. They also found that systematically evaluating whether the products have included additives to training for physicians, emphasising the health of mothers and babies in four lower the osmolarity of solutions, to value of doctor–patient communication, South-east Asian countries – Indonesia, reduce the osmotically driven flow of significantly increased patients’ adherence Malaysia, The Philippines and Thailand – water from body tissues into the gut to medication for high . could be improved by better assimilation lumen. Although these solutions reduce With heart conditions a growing problem of emerging medical knowledge. diarrhoea by about 20 per cent, B S in countries such as Pakistan, it is vital Ramakrishna at the Christian Medical An audit of current practice suggested that people get the right treatment when College, Vellore, and colleagues in the that some aspects of maternal and child they need it. UK and USA, were convinced that this care, such as treatment of pre- figure could be lowered still further. eclampsia, follow recommended References for this article can be found at practice. But significant deviations were www.wellcome.ac.uk/annualreview. In laboratory studies they had shown that

Images 1 Men in Pakistan are at increasing risk of heart disease. 3 Contaminated water supplies can lead to the spread of cholera. 2 Adherence to guidelines could improve maternal health 4 Stimulating water uptake in the gut reduces the symptoms in South-east Asia. of diarrhoea. USING Knowledge | 23

Gut feeling NEW FUNDING

A SELECTION OF NOTABLE PUBLIC PROBES GRANTS AWARDED IN 2007/08.

STRATEGIC TRANSLATION AWARD ANTIBIOTICS Mike Dawson (Novacta Biosystems) Optimising lantibiotic compounds specific forC. difficile. TRANSLATION AWARDS BIOMEDICAL ENGINEERING Chris Toumazou (Imperial College London) Development of a wireless implantable sensor to monitor pressure changes in heart chambers continuously after surgery for heart failure. INFLUENZA 4 5 Daniel Henderson (PaxVax, Inc.) An oral adenovirus-based vaccine against influenza for pandemic protection. BIOMATERIALS some complex carbohydrates can be A Strategic Award will fund the Dr Morgan Alexander (University of Nottingham) metabolised in the gut into short-chain development, and release into the Using high-throughput microarrays to identify fatty acids, which stimulate sodium and public domain, of a set of chemical polymers resistant to bacterial colonisation. water uptake from the gut lumen. In probes targeting key enzymes ADJUVANT IDENTIFICATION AND particular, a type of high-amylose maize controlling gene activity. DEVELOPMENT starch is partly broken down in the small The Structural Genomics Consortium Professor Willem van Eden (University of intestine, releasing glucose, but an (SGC) has determined the structures of Utrecht) and Professor Paul Lehner (University undigested ‘core’ survives to the large of Cambridge) Heat shock proteins as adjuvants. many proteins of medical interest intestine, where it is metabolised to (above). As well as benefiting basic Professor Allan Mowat (University of Glasgow) short-chain fatty acids. research, such information can be used The mode of action of immunostimulating complexes. To test its potential, a clinical trial of an in drug development, aiding the design oral rehydration solution fortified with of small molecules that interfere with James Brewer (University of Strathclyde) this high-amylose maize starch was run protein function. Structures are Antigen-presenting-cell and T-cell responses to in Vellore. In people with severe considered pre-competitive and two classes of adjuvant. diarrhoea, mainly due to cholera, the structural data are freely released into the Professor Paul Kaye (University of York) Impact enhanced solution more than halved the public domain. of glycosylation of small-molecule immune duration of diarrhoea and significantly enhancers. This new award, to Chas Bountra and reduced faecal weight after the first 12 Professor Mark Baird (University College of colleagues at the SGC’s Oxford site, hours of therapy. Bangor) Synthetic mycolic acids as potential takes data release one step further. adjuvants. As well as providing physical benefits to Chemical probes against three important SEEDING DRUG DISCOVERY individual patients, shortening the length classes of protein will be developed by of diarrhoea episodes would help to an academia–industry partnership and ANTIBIOTICS prevent the spread of disease and made available for use without restriction. Kevin Judice (Achaogen, Inc.) Aminoglycosides for multidrug-resistant Gram-negative pathogens reduce hospitalisation time and costs. Academic researchers will benefit from and MRSA. With climate change predicted to new tools that can be used to investigate increase the burden of diarrhoeal METABOLIC DISORDERS biological function; industry will have disease still further, such benefits could Professor Brian Walker (University of Edinburgh) access to a set of materials and data that Optimising lead compounds targeting have a huge impact worldwide. could form the basis of new therapeutics. 11β-hydroxysteroid dehydrogenase for use in Ramakrishna BS et al. A randomized controlled trial of metabolic syndrome and cognitive decline in glucose versus amylase resistant starch hypo-osmolar The proteins targeted are all involved in ageing. oral rehydration solution for adult acute dehydrating epigenetic processes – modifications of diarrhea. PLoS ONE 2008;3(2):e1587. DNA or associated proteins that affect Details of all grants made can be found in gene activity. Epigenetic modification has Grants Awarded 2007/08, available on the been implicated in a wide range of Wellcome Trust website. biological processes and diseases.

ENGAGING SCIENCE

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

Happy anniversary Cut and thrust

Wellcome Collection attracted more than Neurosurgery and the sinking of the 300 000 visits in its first year of opening. Mary Rose have been the focus of two acclaimed documentaries.

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Wellcome Collection, opened in June Festival of Britain, all inspired by X-ray They are two compelling stories. The 2007, offers visitors a unique chance . The final exhibition of the English Surgeon documents the to explore different cultural fields year, Skeletons: London’s buried bones, attempts of a leading brain surgeon inspired by science, and to debate featured 26 skeletons from the Museum struggling to save lives in Ukraine. In and discuss wider social issues. An of London’s Centre for Human complete contrast, The Ghosts of the eventful year saw innovative Bioarchaeology, collectively uncovering Mary Rose: Revealed describes how exhibitions on sleeping and 2000 years of London’s history. forensic analysis of sailors’ remains crystallography-inspired design, as may explain the dramatic sinking of The temporary exhibitions were well as a deeply moving photographic the Mary Rose in 1545. complemented by a lively events exhibition of terminally ill people. The programme, which included debates Henry Marsh first visited Kiev in 1992, visitor numbers far exceeded about organ donation, obesity and and was horrified by the conditions expectations and, combined with a genetic tests, performances of a play endured by both patients and doctors. string of plaudits from critics, exploring chronic fatigue syndrome and Since then he has made at least two trips amounted to a highly successful first a festival to launch The Big Draw 2008. a year – taking time off as a consultant at year of operations. St George’s Hospital – to work with The exhibitions and events met with The first new temporary exhibition of the Ukrainian neurosurgeon Igor Petrovich. wide-reaching critical attention from year, Sleeping & Dreaming, a partnership national and international media. As a The English Surgeon, funded by a with the Deutsches Hygiene-Museum, contributor to the Rough Guide website Wellcome Trust People Award, was Dresden, brought together works from put it: “Wellcome Collection is a small, produced by Geoffrey Smith and artists, scientists, film makers and eclectic, imaginative, humane, humorous screened on BBC2 in April 2008 to historians, illuminating a ubiquitous but exhibition of objects related, sometimes critical acclaim. Time Out called it “a mysterious aspect of human behaviour. in the loosest sense, to medicine. It is life-affirming, unforgettable portrait of a Life Before Death, a series of 24 sets of WONDERFUL.” true humanitarian”, and photographs taken of terminally ill people described it as “a lovely, lovely film”. It Wellcome Collection was also one of before and after their deaths, resulted won Best International Feature only four venues shortlisted for this year’s from a collaboration between journalist Documentary at HotDocs 2008. prestigious Art Fund Prize, a national Beate Lakotta and photographer Walter award given to a public venue whose Shot over two chaotic weeks in the 2007 Schels. Featured on the Guardian project demonstrates the most Ukrainian winter, the film shows Marsh website, it broke the newspaper’s record originality, imagination and excellence. agonising over whom he can and cannot for the highest number of hits in a save – and struggling with local logistical 24-hour period. and political constraints. At one point he By complete contrast, From Atoms to has to use a £30 cordless drill to bore Patterns included ‘insulin wallpaper’ and into a patient’s skull. Remarkably, the other intriguing designs from the 1951 operation is a success.

Images 1 T h e Life Before Death exhibition. 4 Professor John Holman, Director of the 2 T h e From Atoms to Patterns exhibition. National Science Learning Centre. 3 Hugh Montgomery, examining the remains of a Mary Rose sailor. 5 A practical demonstration at the launch of Project Enthuse. ENGAGING SCIENCE | 27

Cut and thrust Enthusing teachers

A £30m initiative will ensure that UK science teachers enjoy even more continuing professional development opportunities.

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Not every story has a happy ending. In 2008 the Wellcome Trust joined The initiative will provide generous At the emotional climax of the film, he forces with the UK Government and bursaries covering not only fees and visits the cemetery where Tanya, a leading UK businesses to establish travel for individual teachers but also the patient he was unable to save, is buried, Project Enthuse, a £30 million cost to schools of providing teaching and confronts what it means to fail. initiative to enable science teaching cover and extra funds to help teachers staff to benefit from continuing share what they learn with colleagues. The Ghosts of the Mary Rose – part- professional development courses at As a result, every school in the country funded by the Trust and shown on Five the National Science Learning Centre will be able to send their science in August 2008 – may have solved one in York. teachers on cutting-edge courses. of the biggest mysteries in British naval history. With science and technology widely The Centre has been involved in two seen as crucial to the UK’s economic further important developments this In 1545, the Mary Rose, flagship of the future, science education is of enormous year. It successfully bid for an £18m English navy, sank off Portsmouth during importance. High-quality education is government contract to operate the the Battle of the Solent. While the French fundamentally dependent on teachers, network of regional Science Learning claimed that their cannons took down and it is essential that teaching staff have Centres, on behalf of the DCSF, and also the vessel, when the ship was raised in access to new scientific knowledge and received a £4.4m award from the Gatsby 1982 no cannon damage was found. teaching approaches. Launched in Charitable Foundation to establish a In the film, Hugh Montgomery – scientist, November 2005, the National Science National STEM (science, technology, consultant and one of the volunteer Learning Centre aims to provide engineering and maths) Centre. divers who collected remains in 1982 innovative professional development for Since October 2006, John Holman, – enlists the aid of forensic scientists to science teachers and technicians – Director of the National Science Learning unlock the secrets of the ship’s demise. inspiring teachers to deliver inspiring Centre, has also been the National STEM lessons. Their findings are surprising: some 60 Director, charged with developing a per cent of the men appeared to be of To promote the uptake of courses at the coordinated strategy to support STEM southern European origin – most likely Centre, the Wellcome Trust teamed up teaching. The Gatsby award will further mercenaries or Spanish prisoners of war. with the UK Government’s Department strengthen links between the two areas. The warship probably sank when it for Children, Schools and Families The National STEM Centre will contain attempted a sharp turn, causing water to (DCSF) and a range of UK businesses the most extensive collection of STEM flood through open gun ports. – BP, BAE Systems, GlaxoSmithKline, resources ever housed together – an Conceivably, foreign crew members did Rolls-Royce, AstraZeneca, AstraZeneca ideal complement to the extensive range not understand an order to close the gun Science Teaching Trust, General Electric of courses on offer at the adjacent ports – so the loss of the Mary Rose may Foundation, Vodafone and Vodafone National Science Learning Centre. have been the result of a simple Group Foundation – to establish Project communication error. Enthuse. 28 | ENGAGING SCIENCE

Unmasking Bare to be mental health different

Several projects are helping to foster a more informed ‘Naked Scientist’ nabs Royal Society and compassionate view of mental health issues. award for science communication.

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Mental health conditions are common weeks at the Southwark Playhouse in Chris Smith, Clinical Lecturer and but plagued by stereotyping and London, reaching an audience of more Specialist Registrar in virology at the stigmatisation. Raising awareness of than 1500 people over 18 performances. University of Cambridge, is better the realities of such conditions lies at known for his radio show Naked The theatre company, with Adrian the heart of a series of projects using Scientists (part-funded by a Wellcome Jackson as Artistic Director, worked with film, drama and the web to Trust Society Award in 2005), and a team of mental health specialists to communicate the life experiences of accompanying podcasts and books. ensure that mental health issues were people and families affected by Dr Smith’s pioneering show makes portrayed accurately. More than 100 autism, schizophrenia and epilepsy. complex scientific material audience members got on the stage and accessible to non-scientific Sue Ziebland at the University of Oxford experimented with strategies for audiences worldwide. In August 2008, and colleagues have launched two new confronting and helping someone with he was awarded the Royal Society’s sections of the award-winning website schizophrenia throughout the run. prestigious Kohn Award for his work. www.healthtalkonline.org. ‘Life on the At the Institute of Psychiatry, Elizabeth Autism Spectrum’ features video and The Naked Scientists show is a light- Kuipers and colleagues at the South audio clips of interviews recounting the hearted look at what is happening each London and Maudsley NHS Trust and experiences of 20 adults with autism, week in the world of science, technology Rethink are expanding their website while ‘Parents of Children with Autism’ and medicine, interspersed with popular dedicated to supporting people with features 45 such parents. chart music. Guest interviewees have mental illness. The aim is to involve carers included Sir , astronomer The interviews are supplemented with more in the research process, and and President of the Royal Society, evidence-based information about the disseminate research findings to patients, Sir , inventor of DNA conditions, their management and carers and the wider public. fingerprinting, and , available treatments. The aim is to give Finally, Media Trust Productions have co-discoverer of the DNA double helix. people with mental health conditions and produced five 30-minute films exploring their families an understanding of the Dr Smith’s informal approach, stripping the impact of living with chronic experiences, difficulties – and joys – they science down to its bare essentials, has conditions such as cystic fibrosis, autism, are likely to encounter, and to help them captured the imagination of the listening Crohn’s disease, rheumatoid arthritis and to make informed choices about treatment. public. To encourage debate and add a multiple sclerosis. The series, What Can practical, visual aspect to the medium of Cardboard Citizens – the UK’s only Science Do For Me?, was broadcast on radio, he has tested out new ideas such homeless people’s professional theatre the Community Channel early in 2008, as the weekly ‘kitchen science’ company – received funding to develop attracting 325 000 viewers, while another experiments. Listeners can take part in the famous Georg Büchner play Woyzeck 40 000 users accessed the films on the simple home experiments alongside the as an interactive forum theatre production. Community Channel’s website. The films broadcast and compete to be the first The play – a vehicle for exploring can be viewed on the Community schizophrenia – was performed for three Channel’s broadband player.

Images 1 A scene from the Cardboard Citizens version of Woyzeck. 3 Chris Smith, the Naked Scientist. 2 A scene from the What Can Science Do For Me? programme 4 Soundtrack to a Naked Scientists radio show. on cystic fibrosis. ENGAGING SCIENCE | 29

Bare to be NEW FUNDING different

A SELECTION OF NOTABLE SCIENCE CENTRE REVAMPS GRANTS AWARDED IN 2007/08.

SOCIETY AWARDS DEBATING SCIENCE Tom Shakespeare (Café Scientifique) Rollout of Junior Café Scientifique and launch of a community website. SCIENCE AND RISK Professor David Pratt (Institute of Education) Use of new technological tools to support teaching of risk in socio-scientific issues. LARGE ARTS AWARD IDENTITY 4 5 Anna Ledgard (Artsadmin) A participatory arts project exploring identity, working with young people at the Evelina Children’s Hospital Renal Unit. through on the phones with their findings Two existing galleries – and one brand PEOPLE AWARDS and interpretations. new venture – have received YEAST BIOLOGY substantial awards to develop According to figures for BBC radio, David Colthurst (Simon Langton Grammar innovative visitor experiences. Naked Scientists is the most ‘listened to School for Boys) A yeast molecular biology research project being carried out by sixth- again’ on every station on which it is The Who Am I? gallery in the Science formers. broadcast. It is also top of the US Museum’s Wellcome Wing and Your science charts for downloads and in the Amazing Brain at the At-Bristol science YOUNG DEBATERS Danielle Nicholson (National University of top 20 science podcasts in the iTunes centre will benefit from a major overhaul Ireland) A debating competition for 15-to-18- Music Stores of most countries. This and the chance to reflect the significant year-olds, focusing on biomedical science and provides good evidence that there is a developments in science that have taken its social implications. significant appetite for science – if it is place over recent years. SMALL ARTS AWARDS presented in ways that appeal to The Science Museum has been awarded consumers. DARWIN FILMS £2.5 million to redevelop Who Judith Knight (Artsadmin) Darwin Originals: Dr Smith received a silver gilt medal, a Am I?, and an associated website and four short films providing an unorthodox and gift of £2500 and a grant of £7500 for programme of events at the nearby humorous perspective on Charles Darwin and science communication activities. The Dana Centre. It will focus on genetics his legacy. Kohn Award was established by the and neuroscience, celebrating recent MEMORY Royal Society, with financial support advances and fostering debate about Shona Illingworth ‘Balnakiel’: an installation from the Kohn Foundation. their social, economic and other exploring individual and collective memory, based on work with remote Scottish communities. implications. E-HEALTH PUBLIC ENGAGEMENT Your Amazing Brain, a flagship gallery at At-Bristol, has received a £1.4m award. Perry Walker (New Economics Foundation) Discussions with the public and young people on The gallery will be renamed All About Us, the use of patient records in healthcare research. expanding its scope to other parts of the body and their links with the brain. HISTORY OF MEDICINE PUBLIC ENGAGEMENT A new centre, the Science Gallery at MEDICINE AND LITERATURE Trinity College Dublin (above), which Clair Greenaway (Cheltenham Festival) ‘Writers received a £1m award, aims to be “the and Remedies’: Bringing writers and historians coolest science club on the planet”. together at the Cheltenham Literature Festival Housed in a landmark building, the £10m to discuss medicine in the lives of 18th- and 19th-century authors. centre is adopting a cross-disciplinary thematic approach and aims to build an active community of visitors who help to Details of all grants made can be found in Grants Awarded 2007/08, available on the shape the exhibits and events programme. 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

Overcoming trauma Maternal gain

Survivors of the 7/7 London terrorist bombings have benefited from François Nosten’s groundbreaking psychological treatments for post-traumatic stress disorder. malaria research is recognised by the Institut de France.

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Distressing sensations such as and achieves better outcomes than drug In June 2008 François Nosten, flashbacks, sleep problems and treatments. Director of the Wellcome Trust- strong emotions including anxiety, funded Shoklo Malaria Research Unit One group to benefit significantly has shame, guilt or anger are common in Thailand, received the Christophe & been survivors of terrorist attacks, after any traumatic event. Most Rodolphe Merieux Foundation Prize, including survivors of the Omagh people recover within a few weeks but a €400 000 (£366 000) honour bombing. This led to the creation of the a significant proportion – around a bestowed by the Institut de France on Northern Ireland Centre for Trauma and quarter – continue to experience a researcher or team studying Transformation, which has achieved disturbing and disabling symptoms infectious diseases in developing positive results even in patients with collectively known as post-traumatic countries. severe terrorism-related PTSD. stress disorder (PTSD). Anke Ehlers’s Although malaria therapies exist, until team at the Institute of Psychiatry and Tragically, the London bombings of 7 July recently little was known about how to the University of Oxford has 2005 provided another opportunity to treat pregnant women. Ironically, developed a highly effective form of apply trauma-focused cognitive pregnant women are routinely excluded cognitive therapy that has helped therapies. Professor Ehlers has been part from clinical trials because of the fear of survivors of terrorist attacks and of a collaborative effort to identify and harming an unborn baby. In a deadly other traumatic experiences. treat people directly exposed to the ‘catch-22’ scenario, pregnant women bombings. About 150 people have been With David Clark, Professor Ehlers has may then not be given the best available treated to date and, encouragingly, the proposed a model of PTSD based on the treatment because little is known about treatment effects have been as great as notion that PTSD develops when trauma how they or their child might be affected. those seen after Omagh. survivors continue to perceive the past Working with Nick White, Chairman of trauma as a current threat. This leads to a Ehring T et al. Do cognitive models help in predicting the severity of posttraumatic stress disorder, phobia and the Wellcome Trust’s South-east Asia variety of ways thinking (and behaving) depression after motor vehicle accidents? A prospective Programme, Professor Nosten’s work on that, although intended as coping longitudinal study. J Consult Clin Psychol maternal malaria on the Thai–Myanmar strategies, actually serve to maintain the 2008:76(2);219–30. border cut the number of pregnant condition. Bisson JI et al. Psychological treatments for chronic post-traumatic stress disorder. Systematic review and women dying from malaria from one per In several studies, cognitive factors meta-analysis. Br J Psychiatry 2007;190:97–104. hundred live births to zero. specified in this model have been found to Brewin CR et al. Promoting mental health following the London bombings: a screen and treat approach. Clinical trials showed that pregnancy be the strongest predictors of chronic J Trauma Stress 2008;21(1):3–8. alters the efficacy of antimalarials and PTSD symptoms. The validity of this that the doses of medicines given to model has underpinned a PTSD-specific Professor Ehlers’s Principal Research pregnant women were too low – findings form of cognitive therapy shown to be Fellowship was renewed in 2008. that led to a revision of WHO guidelines. highly effective in several clinical trials. It is superior to alternative psychotherapies

Images Left Participant in a study of brain activity relating 1 The aftermath of the 2005 London terrorist bombings. to sign language use. See page 33. 2 Professor Anke Ehlers of the Institute of Psychiatry. 3 Professor François Nosten. 32 | DEVELOPING PEOPLE

Brain power Inner secrets

What links tadpoles, flies’ wings, seahorses and the Computer analysis can reveal key human brain? A remarkable protein called Lhx2. regulatory features in the genome.

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How do cells form integrated became hem cells even though they With ever more genome sequence structures during development? were in the middle of the cortex. And being generated, a major challenge is Since Hans Spemann’s classic work next to each extra hem, a new to identify biologically important on tadpoles in the 1920s it has been hippocampus was formed from cells that regions. These include the regulatory known that certain cells can direct the would have otherwise become part of other sequences that control the activity of fate of those around them, organising cortical regions. This implies that the hem genes. Thomas Down, a new them into a specific structure. Now, is an organiser that directs adjacent Research Career Development Fellow former International Senior Research cortical cells to form the hippocampus. at the in Cambridge, Fellow Shubha Tole and colleagues is developing software tools that trawl This role of Lhx2 is not the only trick in its have identified a key gene,Lhx2 , that genomic data and identify possible book. Dr Tole’s group has found that it is controls development of the cerebral control regions. also involved in the early growth of cortex and the hippocampus – a nerves carrying sensory information to A major surprise emerging from the seahorse-shaped structure crucial to the cortex. In fact, it is also needed for was the memory formation. development of the olfactory bulb, a key relatively small number of genes encoded Lhx2 is a relative of a protein involved in structure in rodents’ sense of smell. within the genome. The biological fruit-fly wing development. Rather than complexity of humans is thus down to not It is also active in a stream of cells that wings, in mammals Lhx2 has been just the number of components from helps to build the amygdala, a structure thought to be a key specifier of cerebral which we are made but also how those central to the processing of emotional cortex. During development, it is found in components are used. While 1.5 per cent information. This stream of cells cells that become the cerebral cortex but of the genome codes for genes, around 5 originates from the same region that also not in an adjacent strip, known as the per cent appears to be under strong gives rise to the cerebral cortex, hem, present at the edge of the cortex. selective pressure, and many of these revealing an unsuspected link between conserved sequences are likely to be By clever genetic engineering of mice, Dr development of the amygdala and the regulatory elements that control where Tole and colleagues were able to turn cortex. and when genes are active. Lhx2 gene activity on and off in particular Mangale VS et al. Lhx2 selector activity specifies regions of the brain and at particular cortical identity and suppresses hippocampal As a PhD student at the Wellcome Trust times of development. They discovered organizer fate. Science 2008;319(5861):304–9. Sanger Institute at Hinxton, Dr Down that Lhx2 is essential for specification of Saha B et al. Dual role for LIM-homeodomain gene combined his interests in biology and Lhx2 in the formation of the lateral olfactory tract. J the cerebral cortex. It also prevents Neurosci 2007;27(9):2290–7. computing to develop software tools to these cells from turning into hem cells – Remedios R et al. A stream of cells migrating from the aid the analysis of genome sequence thereby ensuring that the hem is formed caudal telencephalon reveals a link between the data. These have included tools to only at the very edge of the cortex. amygdala and neocortex. Nat Neurosci identify distinctive sequence motifs 2007;10(9):1141–50. associated with promoters – the primary When Lhx2 was turned off in patches of regions driving gene activity. Testing one cortical cells, however, these cells

Images 1 Tracking gene activity in populations of cells in the brains of Lhx2 4 Drops of water on the pins of a liquid-handling device. mutant mice. 5 Mairead MacSweeney of University College London. 2 T h e Lhx2 gene plays a key role in building the mammalian cortex. 6 Identifying areas of the brain responding to sign language. 3 Thomas Down of the Gurdon Institute. DEVELOPING PEOPLE | 33

Inner secrets Signs of communication

Studies of sign language are shedding light on communication in people with full hearing as well as in deaf people.

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of these tools in the fruit-fly genome An understanding of the brain’s Interestingly, this even appears to be the identified 120 motifs, 87 of them novel. processing of language has come case for the brain’s response to rhyming For the vast majority, biological evidence mainly from studies of spoken – the equivalent in sign language being suggests that they do indeed function as languages. But as Research Career gestures with similar structural components of promoters. Development Fellow Mairead properties such as hand location. MacSweeney of University College At the Gurdon Institute, Dr Down will There are subtle differences. Areas London has discovered, sign language continue to develop tools to produce a active in lip reading, for example, depend use in deaf people shows similarities comprehensive directory of regulatory on both hearing status and lip reading with but also differences to spoken elements in a range of genomes. In skill, while sign language activates parts language that provide a unique addition, he aims to extend this work to of the brain involved in processing perspective on language processing work out how these elements function motion more than silent speech. In in the brain. collectively, creating regulatory circuits addition, there appears to be growing that control the development of complex British Sign Language uses a set of evidence for a special role for one organisms. hand/arm gestures and facial particular region, the left parietal lobe, in articulations to convey meaning. As well sign language processing. However, its An ambitious long-term aim is to develop as conveying basic linguistic information, precise role is unclear. a full enough understanding of these intonation, emotion and so on can all be systems that new complex regulatory Additional factors can also affect this communicated non-verbally. Sign elements and circuits could be designed basic pattern – for example whether the language thus has many of the same from scratch. individual is deaf or hearing and at what characteristics of spoken language but age they learned sign language. Dogruel M et al. NestedMICA as an ab initio protein obviously involves a different sense – motif discovery tool. BMC Bioinformatics 2008;9:19. Research with these groups can inform vision rather than hearing. How does this Down TA. Large-scale discovery of promoter motifs in our understanding of how the brain is affect language processing in the brain? Drosophila melanogaster. PLoS Comput Biol shaped by experience. 2007;3(1):e7. To address this question, Dr MacSweeney MacSweeney M et al. The signing brain: the and colleagues have been using brain neurobiology of sign language. Trends Cogn Sci scanning and other techniques to explore 2008;12(11):432– 40. brain activity in people perceiving Capek CM et al. Hand and mouth: cortical correlates of lexical processing in British Sign Language and audiovisual speech, silent speech (lip speechreading English. J Cogn Neurosci reading) or British Sign Language. 2008;20(7):1220–34. MacSweeney M et al. Phonological processing in deaf It appears that comprehension of silent signers and the impact of age of first language speech and sign language share many acquisition. Neuroimage 2008;40(3):1369–79. features with that of audiovisual speech. Capek CM et al. Cortical circuits for silent speechreading in deaf and hearing people. All activate particular brain regions Neuropsychologia 2008;46(5):1233–41. predominantly in the left hemisphere. 34 | DEVELOPING PEOPLE

A neglected Go with malaria the flow

Once considered benign, vivax malaria is actually Blood flow to the brain is carefully far from innocuous. controlled – but in a surprising way.

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As well as P. falciparum, other can expect to experience falciparum The brain is a major consumer of Plasmodium species can cause malaria each year and nearly a third vivax energy, and the harder it works the malaria, including P. vivax. Vivax malaria. Again, the prevalence of vivax more energy it needs. As a result, malaria has been considered relatively malaria was higher in young children. brain activity is tightly coupled to harmless, but as Career Development blood flow, which delivers the glucose Moreover, vivax can also be harmful Fellow Ric Price has discovered, it is and oxygen needed to generate during pregnancy. In a separate study, Dr common, serious and, with drug- energy. But as new Sir Henry Price found that the fever and anaemia resistant forms appearing, a growing Wellcome Postdoctoral Fellow Clare associated with vivax as well as threat to health in South-east Asia. Howarth has discovered, this well- falciparum malaria raised the risk of known phenomenon is controlled in Malaria remains a serious problem in premature labour and stillbirth in an unexpected way. South-east Asia, accounting for 40 per pregnant women. cent of the world’s cases. Unlike Africa, After a course on magnetic resonance In part, P. vivax has been neglected where falciparum malaria predominates, imaging (MRI) fired her interest during a because drug resistance has been less of South-east Asia faces infections from physics degree at Imperial College a problem – it first appeared as recently both P. falciparum and P. vivax. London, Dr Howarth was accepted onto as 1989. Now, though, drug-resistant University College London’s highly To test whether P. vivax really is ‘benign’, forms of P. vivax are spreading across competitive Wellcome Trust-funded Dr Price at the Menzies School of Health much of South-east Asia and more Four-year PhD Programme. There her Research in Australia, working with the recently in South America. Cure rates for focus turned to energy consumption by Wellcome Trust’s South-east Asia standard treatments have fallen below the brain. Programme, set out to assess the impact half for both P. falciparum and P. vivax. of the two in Papua, Indonesia. Standard brain imaging techniques, On the brighter side, effective treatments such as functional MRI, make use of the An analysis of hospital admissions over a are available for multidrug-resistant fact that regions of brain activity are four-year period revealed that 64 per cent malaria. Indeed, a clinical trial of two marked by increased blood flow.T his of patients with malaria had P. falciparum, artemisinin combination therapies (ACT) blood flow was thought to be regulated 24 per cent P. vivax and 10.5 per cent confirmed that they were clinically by smooth muscle surrounding arterioles mixed infections. In children under one, effective for treating multidrug-resistant carrying blood to areas of the brain, but however, P. vivax accounted for nearly falciparum and vivax malaria in Papua. Dr Howarth discovered that although half of all malaria admissions. Across all A study of the impact of widespread smaller vessels, capillaries, lack smooth ages, the death rate for P. vivax, 1.6 per deployment of ACT on P. vivax is now muscle, they are sheathed in contractile cent, was comparable to the overall underway. cells known as pericytes. And it is death rate from malaria (2 per cent). contraction of these cells that controls A community study revealed similar References for this article can be found at capillary diameter and regulates regional www.wellcome.ac.uk/annualreview. patterns. More than half of the population blood flow in the brain.

Images 1 In South-east Asia, Plasmodium vivax as well as P. falciparum causes serious malaria. 2 Colour-coded image of blood flow in the brain. DEVELOPING PEOPLE | 35

Go with NEW FUNDING the flow

A SELECTION OF NOTABLE TRANSLATIONAL PARTNERSHIPS GRANTS AWARDED IN 2007/08.

PRINCIPAL RESEARCH FELLOWSHIPS LANGUAGE DEVELOPMENT Professor Dorothy Bishop (University of Oxford)1 The causes and impact of specific language impairment and links to other neurodevelopmental conditions. STRUCTURAL BIOLOGY Professor Randy Read (University of Cambridge)1 Development of new methods for protein crystallography. MALARIA 2 Professor Andy Waters (moving from Leiden to the Wellcome Trust Centre for Molecular Parasitology in Glasgow) Gene expression in the malaria parasite.

As well as making this notable discovery, Four academia–industry partnerships SENIOR RESEARCH FELLOW IN CLINCIAL SCIENCE Dr Howarth has also developed have been awarded £22 million to theoretical models for energy support training of clinicians in consumption by the cerebellar cortex. translational research. Rodrigo Floto (University of Cambridge) Control of antigen processing by Fc receptors. The actual pattern of blood vessels in the Despite the remarkable pace of change in cerebellum is a good match for that SENIOR RESEARCH FELLOW IN BASIC biomedical research, translation into predicted on the basis of regional energy BIOMEDICAL SCIENCE patient benefits has been less rapid.T o needs. NEUROSCIENCE tackle this bottleneck, the Wellcome Trust Professor Dmitri Rusakov (University College She has also helped to estimate the has teamed up with industry to support London)1 Cellular mechanisms of fast signalling amount of energy used by conscious new Interdisciplinary Training at single synapses in the hippocampus. perception of stimuli – rather surprisingly, Programmes for Clinicians in Translational CELL BIOLOGY there is a less than 10 per cent increase Medicine and Therapeutics. Dr Ewald Hettema () in energy use associated with conscious Endoplasmic reticulum and peroxisome The aim of the initiative is to create a pool perception. multiplication. of researchers, fluent in human Looking ahead, Dr Howarth will spend physiology, medicine and clinical INFECTIOUS DISEASE her fellowship partly in the lab of Brian pharmacology, who have the knowledge Dr Cameron Simmons (University of Oxford) Dengue pathogenesis and vaccine design. MacVicar in Vancouver, an expert on glial and skills to develop and evaluate new cells, and partly in Nicola Sibson’s team therapies. The Trust has provided £11m, SIR POSTDOCTORAL in Oxford. Her main focus will be on with matching funding from industry. RESEARCH FELLOWSHIP trying to understand the cellular NEUROSCIENCE Funding has been awarded to: mechanisms that link neuronal activity to Misha Ahrens (University of Cambridge) Newcastle University in partnership control of blood flow. •  Theoretical frameworks for representation of time with Roche, AstraZeneca, Sanofi- in the brain. Peppiatt CM et al. Bidirectional control of CNS Aventis, Sirtris Pharmaceuticals, PTC capillary diameter by pericytes. Nature INTERMEDIATE CLINICAL RESEARCH 2006;443(7112):700–4. Therapeutics and GlaxoSmithKline FELLOWSHIP Schölvinck ML. The cortical energy needed for the University of Cambridge and NEUROSCIENCE conscious perception. Neuroimage 2008; •  (University College London) 40(4):1460–8. GlaxoSmithKline Dr Dharshan Kumaran The neural mechanisms underlying knowledge • the Universities of Edinburgh, acquisition in the human brain. Aberdeen, Dundee and Glasgow, and RESEARCH TRAINING FELLOWSHIP Wyeth Research NEUROENDOCRINOLOGY • Imperial College London and Seyed Sam (Imperial College London) The action GlaxoSmithKline. of kisspeptin, a neuropeptide linked to puberty, in the hypothalamus.

1 Fellowship renewals. Details of all grants made can be found in Grants Awarded 2007/08, available on the Wellcome Trust website. FACILITATING RESEARCH

Promoting the best conditions for research and the use of knowledge. FACILITATING RESEARCH | 37

Dealing with data Stop and start

The Wellcome Trust has been working to enhance Clinical Research Facilities are researchers’ access to patient data. helping to improve clinical practice.

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Personal information, such as that researchers and patient groups, aiming Studies at Wellcome Trust Clinical held in patient records and large- to develop guidance for best practice in Research Facilities (CRFs) have scale databases, offers huge the use of patient records for research. revealed the benefits of smoking bans potential for health research. The As well as agreeing on the importance of and led to fewer complications after Wellcome Trust has been working to patient confidentiality, delegates abdominal surgery. ensure that these resources can be supported a number of principles, The Edinburgh CRF provided support for used more widely in research, with including the need for transparency, the STOPIT (Study of Public Place due safeguards to maintain data clearly defined processes for the use of Intervention on Tobacco Exposure) study, confidentiality and security. data, and improved public awareness of funded by NHS Health , which patient record use in research. A Sir Mark Walport, the Trust’s Director, provided dramatic evidence of the health consensus document, endorsed by the and the Information Commissioner, impact of passive smoking. Smoking in Royal College of General Practitioners, Richard Thomas, conducted a Data public places was banned in Scotland a will be published in 2009. Sharing Review, publishing a report in year before the English ban. During this July 2008, which looked at the use and The Trust also responded to several time, admissions for acute coronary sharing of personal data in the public and consultations, including the General syndrome dropped by 17 per cent in private sectors. One of their conclusions Medical Council’s consultation on Scotland but only 4 per cent in England. was that greater use could be made of consent and confidentiality and the NHS The Cambridge CRF has been used in a personal data in research, with principles Connecting for Health consultation on large, Trust-funded pilot study evaluating of data confidentiality extending to the wider use of patient information. a stepwise primary-care-based screening researchers as well as health Finally, a new e-health funding programme for type 2 diabetes, professionals. partnership with three Research generating valuable information for The Trust emphasised the potential Councils has sought to stimulate and healthcare planners. public benefits of greater data access in support the use of electronic databases Studies at the Manchester CRF have its input to the draft NHS Constitution, in health research. A total of £10.6 million dramatically reduced complications published in June 2008. The Trust was was awarded to 17 projects, with the arising from surgery on abdominal aortic also involved in discussions with the UK Trust contributing £9.3m. The awards, aneurysms. Jane Eddleston’s studies Department of Health on the 2008 announced in July 2008, included three showed that exercise testing of patients revision to the Health and Social Care public engagement projects exploring – who often have other cardiovascular Act. The updated Act allows for patient the issues surrounding use of personal conditions – could be used to identify information to be shared for medical information in health research. those most at risk. research when there are significant potential public benefits. Spotlight on personal information: www.wellcome.ac.uk/About-us/Policy/ References for this article can be found at In May 2008, the Trust hosted a national Spotlight-issues/Personal-information/ www.wellcome.ac.uk/annualreview. consensus meeting involving GPs,

Images 1 Health records contain a wealth of information that could be used in research. 2 Tobacco smoke has serious harmful effects. 38 | FACILITATING RESEARCH

Clinical approach Hybrid vigour

A clinical trial facility in Kenya has hosted Accurate information helped to groundbreaking work on a malaria vaccine. ensure a mature debate about mixed-species embryos.

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One of the factors holding back The Kilifi facility occupies a building In 2007, the Government introduced medical research in Africa is a dearth funded by the Trust and the Malaria draft legislation to update the 1990 of centres and staff able to carry out Clinical Trials Alliance, and complements Human Fertilisation and Embryology clinical trials. A facility established at the main laboratory and administrative Act. Perhaps the most contentious the KEMRI–Wellcome Trust Research block funded by the Trust. Kilifi now has change was a provision to allow the Programme at Kilifi, Kenya, has not all the facilities needed to run major creation of human–animal hybrid only hosted a highly successful international trials, and has trained local embryos – seen by scientists as vital clinical trial of the world’s leading staff to design and run their own studies in embryonic stem cell research but malaria vaccine but is also providing to equally high standards. Moreover, by of ethical concern to some groups. To a base to test locally important concentrating the physical infrastructure encourage informed discussion about interventions and develop a skilled and specialist support staff, the facility a potentially highly emotive subject, local workforce. can offer a high-quality environment for the Wellcome Trust organised a range all kinds of intervention – vaccine, drug of briefings and other activities to Malaria kills around a million people a trials or other clinical studies. communicate the scientific, medical year, most of them young children in and ethical context of the new Act. sub-Saharan Africa. Progress towards Thus, as well as globally important trials, an effective vaccine has been painfully the facility also hosts studies addressing The UK has a well-established regulatory slow, but there are encouraging signs local public health questions. For framework for research on human that some have a significant (albeit not example, Jay Berkley has begun a embryos, rooted in the 1990 Human complete) protective effect. Trust-funded trial of prophylactic Fertilisation and Embryology Act. The antibiotic use in malnourished children. new legislation was designed to take Of these, the RTS,S vaccine developed After being discharged from hospital, account of the rapid pace of change by GlaxoSmithKline is the most such children often die when they return since 1990, including the use of human– promising, typically achieving protection home. Dr Berkley is testing whether a animal hybrid embryos, a potential rates of about 30 per cent. Even more year’s use of antibiotics after discharge source of human embryonic stem cells. positively, a phase II trial, organised by can protect vulnerable children during the Malaria Vaccine Initiative and run in Although of great medical potential, this critical period. Kilifi and a second site inT anzania, research on such cells is held back by a upped this figure to 53 per cent, thanks Bejon P et al. Efficacy of RTS,S/AS01E: clinical malaria lack of human material. To overcome this in 5 to 17 month old children. N Engl J Med to a new immune-boosting adjuvant. 2008;359:2512–32. difficulty, human DNA can be inserted into non-human eggs and early-stage These exciting findings have justified a Abdulla S et al. Safety and immunogenicity of RTS, S/AS02D malaria vaccine in infants. N Engl J Med embryos grown to the point at which much larger phase III trial involving 2008;359:2533–44. embryonic stem cells can be isolated. 15 000 children across several sites in Africa, including Kilifi and theT rust- The Malaria Vaccine Initiative is funded by the To promote a reasoned debate, the Trust funded facilities in Malawi. Bill and Melinda Gates Foundation and operated developed briefing material on the key by the not-for-profit organisation PATH. issues for members of the House of

Images 1 Staff at the Clinical Trial Facility in Kilifi. 2 An early human embryo. FACILITATING RESEARCH | 39

Hybrid vigour NEW FUNDING

A SELECTION OF NOTABLE INTO AFRICA GRANTS AWARDED IN 2007/08.

CAPITAL AWARDS MOLECULAR MEDICINE Professor Irene Leigh (University of Dundee) A Centre for Molecular Medicine bringing together basic and clinical research groups. TROPICAL MEDICINE Professor (Liverpool School of Tropical Medicine) A facility for multidisciplinary and translational tropical medicine research. DENTAL RESEARCH Professor Jennifer Kirkham (University of Leeds) 2 5 A Dental Clinical and Translational Research Unit. MICROBIOLOGY Professor Jeff Errington (Newcastle University) A Centre for Bacterial Cell Biology. Lords and the House of Commons. The Medical research and training in STRATEGIC AWARDS Trust also helped to arrange meetings Africa have received a £20 million BIOINFORMATICS between scientists and MPs, to explain boost. Professor Janet Thornton (European the science contained in the legislation A sustainable research base requires Bioinformatics Institute) Bringing a commercially and the potential medical benefits of developed high-quality chemogenomic high-quality research facilities but also research. database into the public domain. training and career opportunities for Thanks to these efforts, and those of home-grown researchers. Four Strategic HIV Professor Jonathan Weber (Imperial College scientists, other organisations and Awards announced in 2008 are intended London) Core support for an HIV vaccine testing patient groups, the UK Government was to provide training and infrastructure facility. persuaded that the creation of human– support for the brightest young African E-HEALTH animal hybrid embryos in medical researchers – the potential scientific research was justified. leaders of tomorrow. Professor Andrew Morris (University of Dundee) Developing a Scotland-wide interdisciplinary In addition to its work with politicians, the The KEMRI–Wellcome Trust Research centre for work linked to electronic patient Trust also organised public engagement Programme, Kenya, received an award of records. activities to encourage broader informed almost £9m. Funding will be used to Professor John Danesh (University of debate. These included a leaflet about develop capacity in translational Cambridge) A pilot study linking blood donations human–animal hybrid embryos and their research, social science and clinical trials. to electronic patient records. value in research, a supplement in The Brian Greenwood from the London BIOMEDICAL RESOURCES Times on stem cells, a web spotlight School of Hygiene and Tropical Medicine including interviews with stem cell VIROLOGY has been awarded over £7m to support Dr David Lewis (Health Protection Agency) scientists, and a Radio 4 debate chaired training of African scientists to undertake Securing the future of the National Collection by Ed Stourton from the Today high-quality malaria research in African of Pathogenic Viruses. programme. universities. HUMAN GENETICS The work has helped to ensure that Dr Willem Ouwehand (University of Cambridge) Also receiving funding are two Wellcome research in the UK can continue within a Storing material from controls used in Wellcome Trust Senior Research . Robert Trust Case Control Consortium genome-wide transparent and ethically robust Wilkinson at the University of Cape Town, analyses. regulatory framework. The Human South Africa, has received £3m to Fertilisation and Embryology Authority RESEARCH RESOURCES IN MEDICAL establish a Clinical Infectious Disease HISTORY has recently granted licences to three Centre focusing on HIV and TB. research groups to create human–animal ARCHIVES hybrid embryos for research in areas Alison Elliott from the London School of Peter Harper (University of Bath) Cataloguing including muscular dystrophy and heart Hygiene and Tropical Medicine has of the papers of Nobel laureate Sir Bernard Katz. disease. received £1m to develop infection and immunity research and training within Details of all grants made can be found in Grants Awarded 2007/08, available on the Uganda. Wellcome Trust website. DEVELOPING OUR ORGANISATION

Using our resources efficiently and effectively.

TAKING STOCK A HIGHER PROFILE ACTIVE ENGAGEMENT More efforts are being made to A rapid response minimised the The Wellcome Trust has been engage with the scientific community. impact of the global financial crisis a keen participant in global on the Wellcome Trust’s asset base. health discussions. While response-mode funding remains core to the Trust’s work, more proactive With financial markets looking vulnerable, Although UK-based, the Wellcome Trust strategies are also being developed. in 2008 the Trust moved swiftly to protect has an international agenda. It funds the value of its investment portfolio. It considerable research in developing Central to this approach has been expanded its equity sale programme countries and has played a pivotal role the recruitment of senior scientific from £3 billion to a total of over £4.5bn in numerous international consortia. figures. Recent years have seen the and disposed of certain other assets, Human health is an international issue. arrival of Professor Richard Morris, generating record levels of cash holdings. a leading neuroscientist from the This year, the Trust has been involved University of Edinburgh, and Dr Alan While this provided considerable in multilateral discussions to develop a Schafer, a geneticist and former head protection from the year’s turmoil, the road map for avian influenza research, of GlaxoSmithKline’s Technology depth of the financial crisis led to a net spanning vaccine and drug development, Development Department. fall in the Trust’s investment asset base surveillance and epidemiology. Fred to £13.1bn at 30 September 2008, a Hayden, seconded from the University With other senior scientific staff, Pat drop of 10.8 per cent over the year. of Virginia, has been appointed to Goodwin and Jimmy Whitworth, they This compares favourably with the falls coordinate this work and is spending one have set out to build stronger links with in global and UK equities of 16 per week a month at the Trust’s offices. the research community and other key cent and 21 per cent, respectively. groups. The aim has been to gather input The Trust is also in discussion with the on the possible ways in which the Trust Ten-year returns for equities have WHO about a coordinated distribution can act catalytically to drive forward reached their lowest levels since the policy for vaccines and drugs, should an fields of research and application of new US War of Independence in the 1770s. avian influenza pandemic break out. knowledge into practical benefits. With equities now offering relatively good value, the Trust has begun to The Trust has been active in organising reinvest, while maintaining sufficient Frontiers Meetings, bringing together reserves of cash to support charitable key individuals to discuss emerging and activities without having to dispose important areas, including, in 2007/08, of assets at distressed prices. autism research and the ethics of genome-wide analyses. Overall, the Trust’s financial position remains strong. Since the flotation of With a diverse portfolio of funding Wellcome plc in October 1985, returns schemes, including response-mode have averaged 14.9 per cent a year, grants, Strategic Awards and special considerably exceeding both the global initiative funding, the Trust is well placed equity index and the Trust’s targeted to take these new ideas forward. return (6 per cent real returns). OVERVIEW | 41

Corporate Activities 2007/08

A brief overview of the Wellcome Trust’s corporate activities over the year.

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Governors were freely available through PubMed undertaking numerous activities to In January 2008, Professor Dame Kay Central and UK PubMed Central. promote clinical research in the UK. It is Davies and Professor Christopher also a founder member of the Association The Director of the Wellcome Trust, Fairburn from the University of Oxford and of Medical Research Charities, which Sir Mark Walport, coauthored a report on Professor Peter Rigby, Chief Executive of celebrated its 21st anniversary by sharing of personal data with Information the Institute of Cancer Research, London, publishing a booklet and website, A Very Commissioner Richard Thomas (see joined the Board of Governors. Public Benefit, outlining medical benefits page 37). derived from charitable funding of research. Two lay Governors also joined the Board Peers and partners in 2008: Rod Kent and Baroness Sir Mark Walport is a non-executive As well as its work with the World Health Manningham-Buller, former Director- board member of the Office of Strategic Organization (see left), the Trust has been General of the Security Service. Coordination of Health Research, a in discussion with the Bill and Melinda government body set up to develop and Policy Gates Foundation about joint initiatives in implement a national strategy for In 2008 the Trust has played an active role international settings. A particular focus translational medicine research. A key in parliamentary and public discussions has been food companies’ activities in focus this year has been on translational about the possible use of human–animal developing countries and emerging medicine, e-health and public health. embryos in research (see pages 38–39). economies, faced with both widespread malnutrition and a growing epidemic of Several high-level meetings have been With the Medical Research Council (MRC) obesity. held during the year to discuss climate and the Academy of Medical Sciences, the change and its impact on health. Human Trust commissioned a study to quantify the In the UK, the Trust has launched a number health and wellbeing are under serious economic benefits of medical research of initiatives with UK Research Councils, threat from climate change, particularly in (report available at www.wellcome.ac.uk/ including the MRC (neurodegenerative developing countries. economicbenefits). The work is an disease), the Engineering and Physical experimental approach to the assessment Sciences Research Council (EPSRC; Wellcome Collection of economic returns, using cardiovascular medical engineering) and the Economic The Trust’s innovative public venue, disease and mental health as case studies. and Social Research Council (‘e-health’, Wellcome Collection, celebrated its first with the MRC and EPSRC). It has also birthday in July 2008. It has been hugely The Trust has continued to promote open been engaged in extensive discussions successful, attracting 300 000 visitors access. In 2007, the UK PubMed Central with the UK Government, the MRC and and many positive reviews. Publishers Panel – comprising research Cancer Research UK about the funders and publisher trade associations Wellcome Collection was also shortlisted £500 million UK Centre for Medical – agreed a set of principles for the re-use for the prestigious Art Fund Prize – a Research and Innovation (see page 44). of documents for which open access fees national award recognising originality, have been paid. By February 2008, more The Trust is also a partner in the UK Clinical imagination and excellence in public than a quarter of Trust-funded papers Research Collaboration, which has been venues.

Images 1 Professor Dame Kay Davies. 2 Jugglers at Wellcome Collection’s first birthday celebrations. 3 Clinical research, a priority area in the UK. 42 | financial summary 2007/08 financial summary 2007/08

In the year ending 30 September 2008, the Wellcome Trust’s total charitable expenditure was £701.6m.

Total charitable expenditure for BREAKDOWN OF WELLCOME TRUST the year increased significantly to CHARITABLE EXPENDITURE 2007/08 £702 million (2006/07: £520m). This rise principally reflected a number of large Strategic Awards and new Total: £701.6m initiatives launched during the year. These were made possible by a GRANTS OTHER EXPENDITURE one-off budget supplement of BIOMEDICAL SCIENCE DIRECT ACTIVITIES £500m, likely to be committed over £456.8m £42.6m the next five years. TECHNOLOGY TRANSFER SUPPORT COSTS Careers £30.2m £43.8m Expenditure on careers support totalled £147.3m (2006/07: £125.5m). MEDICINE, SOCIETY Six Principal Research Fellowships were AND HISTORY1 awarded or renewed during the year. £38.3m International WELLCOME TRUST Some £52.3m was awarded to SANGER INSTITUTE researchers at institutions outside the £89.9m2

UK and Republic of Ireland, including 1 History of medicine, biomedical ethics those at the Wellcome Trust’s Major and public engagement with science. Overseas Programmes. This represents 2 Including £14.3m from other funders. a 26 per cent increase over 2006/07 (£41.4m). A further £18.4m was awarded to researchers at UK institutions for research to be carried out overseas. Total international expenditure was DIRECT ACTIVITIES: £42.6M £70.7m. Direct activities are those managed by Biomedical science Infrastructure the Wellcome Trust itself or in £8.1m Support specifically for buildings, partnership with others. These include: Technology Transfer £11.0m refurbishment, equipment and resources Wellcome Trust Genome Campus, Medicine, Society amounted to £121.8m, a substantial •  excluding the Sanger Institute and History increase over 2006/07 (£13.4m). This £16.4m  increase mainly reflects several large • Wellcome Trust directly managed public engagement capital awards in the UK and overseas. •  Genome Campus activities £7.1m This figure does not include the scientific conferences. significant expenditure on equipment or •  infrastructure provided as part of other Trust grants.

NB: These categories are not exclusive: some CHARITABLE EXPENDITURE 2004–08 (£M) grants (e.g. international fellowships and capital awards) fall into more than one category. In 700 658 these cases, sums awarded have been included in all relevant categories, to give a more realistic 600 Direct expenditure indication of expenditure in each area. 500 473 Wellcome Trust Sanger Institute 446 444 Grants awarded 400 344 300

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100 Further information is available from the Wellcome Trust’s Annual Report and Financial 0 Statements 2008. The Annual Report is 2004 2005 2006 2007 2008 available at www.wellcome.ac.uk. financial summary 2007/08 | 43

FUNDING HIGHLIGHTS INVESTMENTS 2007/08

£30.5m1 £4.9m A challenging year saw the value Wellcome Trust Case Control Transferring chemogenomic of the Wellcome Trust’s investment Consortium phase 2 funding databases to the European portfolio fall by 10.8 per cent to Bioinformatics Institute £13.1 billion. £29.3m The global financial crisis has presented Capital Awards in the UK £4.9m significant challenges to the management Capital Awards to science centres £26m of the Trust’s investment portfolio. Active restructuring of investments across Principal Research Fellowship £4.5m classes, however, helped to mitigate support South-east Asia Major some of the more extreme fluctuations. Overseas Programme: clinical trial Between March 2006 and May 2008, the £20m of artesunate in children with Trust sold more than £4.5bn of equities, Research and training support severe malaria reducing its equity holdings from 69 per in Africa £4.1m cent of its portfolio in September 2005 to 38 per cent in September 2008. More £16m Achaogen: new aminoglycosides than 80 per cent of UK equities have Support for Kenya Major for drug-resistant bacteria been sold, reducing their contribution Overseas Programme £4m from 32 per cent to 6 per cent of the total portfolio. £15m Clinical trial of TB vaccine Strategic Awards to India The Trust also reduced its holdings of £4m commercial property and sold a £10m Structural Genomics Consortium: US$250m portfolio of mature private Project Enthuse chemical probes for epigenetic equity buyout fund interests in early 2008. control proteins £8.8m Holdings of short-term cash and bonds were increased from 5 per cent to 9 per Renewal of core funding, Malawi £3.9m cent of the portfolio, reaching record levels Major Overseas Programme Strategic Awards in Medical of £1.3bn by the end of the year. These Humanities £8.7m holdings should provide sufficient liquidity to support the Trust’s activities during the HIV vaccine testing facility, £3.5m undoubtedly turbulent times ahead. Imperial College London Novacta Biosystems Ltd: development of lantibiotics The value of the Trust’s hedge fund £8.6m2 for C. difficile portfolio remained steady at £3.2bn. As Cancer Genome Project: these are largely US dollar-denominated identifying drug-sensitising £2.8m assets, the dollar’s 13 per cent increase genotypes Renewal of core funding, in value against sterling proved beneficial. Wellcome Trust Centre for The strength of the dollar also contributed £6.5m Molecular Parasitology, Glasgow to a 2 per cent appreciation in the value of OXION ion channel research the buyout portfolio. network £2.5m The Trust’s portfolio of venture funds Strategic Awards in delivered a creditable 11 per cent return £5.8m Biomedical Ethics in 2007/08, despite limited opportunities 1000 Genomes Project £2m for companies to be floated in public markets. £5m Adjuvant identification and London Pain Consortium development initiative With equities now looking more attractive for long-term investors, the Trust is £5m 1 Includes £7.7m awarded to the looking to expand its holdings, PaxVax: pandemic flu vaccine Wellcome Trust Sanger Institute. particularly in large global companies. development 2 Includes £4.6m awarded to the Wellcome Trust Sanger Institute. 44 | funding developments 2007/08

Funding developments 2007/08

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

The Wellcome Trust reserves a NEW FUNDING INITIATIVES significant part of its funding for major initiatives and projects of ADVANCING KNOWLEDGE USING KNOWLEDGE international significance. These UK Centre for Medical Research and Medical Engineering initiative are generally supported through •  •  Innovation Using health research evidence Strategic Awards, which, along •  Research centre in neural circuits in policy making with some other large or unusual •  and behaviour, UCL awards, are considered by a The Trust and the Engineering and Neurodegenerative diseases Strategic Awards Committee. •  Physical Sciences Research Council initiative (EPSRC) have launched a joint £45m Ongoing funding programmes are Genome-wide analyses •  initiative to boost innovation in medical based around funding streams, The Wellcome Trust, with the UK engineering within the UK. covering core areas of biomedical Government, the Medical Research science and the medical humanities. With the Alliance for Health Policy and Council (MRC), Cancer Research UK and Cutting across these streams are Systems Research, the Trust has University College London (UCL), is funding programmes in Technology launched an initiative to strengthen the creating a £500 million UK Centre for Transfer and Public Engagement. capacity of policy makers to use health Medical Research and Innovation research evidence in policy making. Each funding stream has associated (UKCMRI). The Centre, due to open by with it one or more Funding the end of 2013, will be located next to Committees, responsible for most the British Library and the Eurostar ENGAGING SOCIETY funding decisions. Strategy terminal at St Pancras. The Trust has International Public Engagement Committees advise the Trust on needs committed £100m to the project. •  Genetic variation and health and opportunities within specific areas: •  The UKCMRI will bring together groups (1) Neuroscience and Mental Health; An International Public Engagement from the MRC’s National Institute for (2) Molecular and Physiological initiative has been launched to support Medical Research, the Cancer Research Sciences; (3) Pathogens, Immunology projects strengthening links between UK Research Institute and UCL, and will and Public Health; (4) Medical research and the public in developing forge links with researchers in nearby Humanities; (5) Technology Transfer; countries. universities and hospitals. Sir , and (6) Public Engagement. President of Rockefeller University in New A focused call for Society Award The funding streams offer a variety York, will head an independent science proposals related to genetic variation and of forms of support, such as project planning committee to determine the health was launched in spring 2008. and programme grants, and career new Centre’s scientific mission and the Public engagement activities were also development awards. Technology facilities needed to achieve it. supported through the electronic patient Transfer funding comprises Translation In partnership with the Gatsby Charitable record initiative (see right). Awards and Strategic Translation Foundation, the Trust is developing a new Awards, as well as Strategic Translation research centre. It will be known as the Awards in Seeding Drug Discovery. Sainsbury–Wellcome Centre for Neural Public Engagement support is primarily Circuits and Behaviour and will be hosted through the Engaging Science by UCL. programme, which includes Society Awards, People Awards and Small The Trust and the MRC have launched a and Large Arts Awards. £30m initiative to support interdisciplinary consortia studying the mechanisms Occasional large capital awards are underlying neurodegenerative diseases made to support nationally or such as Alzheimer’s disease, multiple internationally important developments. sclerosis and Parkinson’s disease. Building on the success of the Wellcome Trust Case Control Consortium, a scheme has been launched to support further genome-wide analyses. funding developments 2007/08 | 45

FUNDING ANALYSIS

DEVELOPING PEOPLE RESEARCH POLICY AND PRACTICE Total no. of grant applications: 2999 Total no. of grants awarded: 1131 Indian Biomedical Research Careers Concordat to Support the Career • • Value of applications considered: £1.291bn Programme Development of Researchers Value of grants awarded: £525m Expanding the International Senior Guidelines for application of the •  •  No. of Strategic Awards awarded: 38 Research Fellowship scheme 3Rs in research No. of programme grants awarded: 44 An Integrated Research Application The Trust and the Indian Government are • No. of PRFs awarded/renewed:1 6 System jointly funding a Biomedical Research No. of SRFs awarded/renewed: 22 Careers Programme, to be delivered by The Trust has signed up to the Concordat No. of intermediate fellowships awarded: 34 the Wellcome Trust–DBT India Alliance, a to Support the Career Development of No. of training (junior) fellowships awarded: 69 new independent, public charitable trust. Researchers, which provides guidelines No. of PhD training studentships supported: 184 Each year, the Alliance is expected to on the employment of contract research award around 40 Early Career staff in the UK higher education sector. FUNDING RATES Fellowships, 20 Intermediate Fellowships By no. By amount The Trust, the MRC, the Biotechnology and 15 Senior Research Fellowships. Project grants 27% 26% and Biological Sciences Research Programme grants 53% 50% The Trust’s International Senior Research Council, the Natural Environment New PRFs (full app.) 100% 100% Fellowship scheme has expanded to Research Council and the National SRFs (full app. Basic) 26% 30% include Croatia, Slovenia and the Slovak Centre for the Replacement, Refinement SRFs (full app. Clinical) 13% 14% Republic. The scheme is intended to and Reduction of Animals in Research SRFs (full app. Tropical) – – build countries’ capacity to carry out (NC3Rs) have collaborated to produce a SRFs (full app. International) 12% 13% high-quality science, providing future common set of principles covering the Intermediate fellowships 21% 23% generations of scientists with use of animals in research and Training (junior) fellowships 24% 24% opportunities to develop careers in their application of the 3Rs. Compliance with History of Medicine home countries. the guidelines will be a condition of Strategic & Enhancement 50% 58% funding for new grants involving the use History of Medicine ad hoc 24% 20% of animals. The guidelines also cover History of Medicine outreach 50% 12% FACILITATING RESEARCH research in laboratories outside the UK. Research Resources in African institutions initiative Medical History 48% 41% •  The Trust has also fed into the • Electronic patient record initiative Biomedical Ethics 33% 30% development of an Integrated Research People Awards 23% 23% The Trust has launched a new initiative to Application System (IRAS), which was Society Awards: Activities 21% 14% strengthen institutional research capacity introduced in 2008. IRAS captures Large Arts Awards 21% 16% in Africa. Funding will be provided to information required for applications to a Small Arts Awards 16% 16% support the creation of consortia among number of review bodies and ethics institutions in Africa as well as between committees across the health and social Total no. of institutions receiving African institutions and those in the UK or care sector. It should streamline funding in 2007/08 (UK): 71 other developed countries. The centre of administration and save time for Total no. of institutions receiving funding in 2007/08 (non-UK): 34 gravity for funding will be in the host researchers seeking permission to African institutions. conduct research within the UK National OUTSTANDING LIABILITIES2 Health Service. Total grants liabilities: £1.26bn In partnership with the Economic and No. of countries receiving funding: 35 Social Research Council, the EPSRC and Fellows currently supported: 758 the MRC, the Trust ran a one-off Researchers currently supported: 4324 competition to support programmes Total no. of institutions (UK): 102 based on the use of electronic patient Total no. of institutions (non-UK): 112 records in health research.

1 Includes PRF programme grant renewals. 2 As at 30 September 2008. PRF: Principal Research Fellowship SRF: Senior Research Fellowship 46 | streams funding 2007/08

STREAMS FUNDING 2007/08

1 October 2007 to 30 September 2008.

Total number of grants awarded 211 Value of grants awarded £93.6m New and renewed Principal and Senior Research Fellowships 14 MOLECULES, GENES AND CELLS Number of programme grants awarded 13 Value of programme grants awarded £16.1m The Molecules, Genes and Cells stream supports high-quality research that will OTHER MAJOR AWARDS: further our understanding of the fundamental biology and specialist • £30.5m Wellcome Trust Case Control Consortium phase 2 • £5.8m Strategic Award for 1000 Genomes Project functions of molecular, cellular and • £4.9m Strategic Award for chemogenomic databases genetic processes, and their role in • £4m Strategic Award for public domain epigenetic probes health and disease.

Total number of grants awarded 191 Value of grants awarded £65.3m New and renewed Principal and Senior Research Fellowships 5 IMMUNOLOGY AND INFECTIOUS DISEASE Number of programme grants awarded 13 Value of programme grants awarded £18.5m The Immunology and Infectious Disease stream aims to increase our knowledge OTHER MAJOR AWARDS: and understanding of the infectious organisms that cause disease in humans • £20.4m African training and infrastructure awards • £8.8m renewal of core funding for Malawi Major Overseas Programme and animals, and of the immune systems • £8.7m Strategic Award for HIV testing facility that fight these organisms. • £3.4m Strategic Award for respiratory medicine centre, Imperial College London • £3.4m Strategic Award to Jenner Institute • £2.8m renewal of core funding for Wellcome Trust Centre for Molecular Parasitology • £2m Adjuvant Identification and Development initiative

Total number of grants awarded 226 (inc. 68 electives) Value of grants awarded £51.8m New and renewed Principal and Senior Research Fellowships 5 NEUROSCIENCE AND MENTAL HEALTH Number of programme grants awarded 6 Value of programme grants awarded £8.2m The Neuroscience and Mental Health funding stream aims to support high- OTHER MAJOR AWARDS: quality research into the function of the • £6.5m Strategic Award for OXION network nervous system in health and disease. • £5m Strategic Award for London Pain Consortium

OTHER ACTIVITIES DURING YEAR: • £5.5m ‘pump priming’ initiative for young clinicians with Academy of Medical Sciences streams funding 2007/08| 47

Total number of grants awarded 89 Value of grants awarded £31.9m New and renewed Principal and Senior Research Fellowships 3 PHYSIOLOGICAL SCIENCES Number of programme grants awarded 6 The Physiological Sciences funding Value of programme grants awarded £7.1m stream aims to support high-quality basic and clinical research relevant to the understanding of biological processes at the cell, organ, system and whole-animal levels in health and disease.

Total number of grants awarded 62 Value of grants awarded £26.8m New and renewed Principal and Senior Research Fellowships 1 POPULATIONS AND PUBLIC HEALTH Number of programme grants awarded 5 Value of programme grants awarded £10.6m The Populations and Public Health stream supports research to improve OTHER MAJOR AWARDS: understanding of the determinants of disease and quality of life in populations, • £15m Strategic Awards in India • £9.3m e-health initiative and to provide a sound evidence base to inform decisions in public health and OTHER ACTIVITIES DURING YEAR: healthcare delivery. • £4.7m UK Centres for Excellence in Public Health under the UKCRC

Total number of grants awarded 145 Value of grants awarded £9.3m Number of programme grants awarded 0 MEDICAL HUMANITIES Value of programme grants awarded £0

The Medical Humanities stream aims to OTHER MAJOR AWARDS: enhance understanding of the historical • £3.9m Strategic Awards in medical humanities and social context of medicine and • £2.5m Strategic Awards in biomedical ethics biomedical science. It supports research in history of medicine and biomedical ethics, and encourages use of findings, for example to inform public policy making. 48 | TECHNOLOGY TRANSFER

TECHNOLOGY TRANSFER

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

Development work on vaccines for pandemic flu, tuberculosis and leishmaniasis was supported this year, alongside innovative research on biocompatible materials for cartilage repair and production of blood substitutes from human stem cells. In addition, a £45 million initiative in medical engineering was launched to drive forward the development of new products.

Translation Awards support a diverse Several awards reflected the needs of cells to generate red blood cell array of technologies, covering the developing countries. Paul Kaye and concentrates for blood transfusion and physical sciences and mathematics as colleagues at the University of York, for an innovative bacteriophage-based well as biology; they are available to both example, are developing a therapeutic approach to treat Staphylococcus academic institutions and early-stage T-cell-based vaccine for human visceral aureus and MRSA. companies. Of 43 full applications leishmaniasis, while Cambridge The £91m Seeding Drug Discovery received during 2007/08, 37 per cent Optronics Ltd is working on a low-cost initiative, launched in 2005, has so far were successful. The mean value of compact microscope for routine made 17 awards over four rounds of awards was £608 000 (range £25 000– diagnostic use in resource-poor settings. funding (mean value £3m; range 1.6m) and the average duration was 30 Strategic Translation Awards are £1.3m–5.0m). In 2007/08, seven awards months (range 9–42 months). Funding designed to support translational were made for drug discovery programmes decisions are generally made within three research in areas of key importance to in therapeutic areas spanning sepsis, to four months. the Wellcome Trust. Twenty-two malaria, bacterial infections, cardiovascular Projects funded address a wide range of applications have been considered to disease and degenerative central potential applications, including date (mean value £3.3m, range nervous system disorders. therapeutics, vaccines, diagnostics, £1m–8.6m), in diagnostics, vaccines, During the year, a new £45m initiative in medical devices and enabling regenerative medicine, genotyping medical engineering was launched in technologies. technology, medical engineering and partnership with the Engineering and drug discovery. CellMedica Ltd received funding to Physical Sciences Research Council. It develop a virus-specificT -cell therapy for Seven new projects in academic aims to support the development of immunosuppressed patients. In surgery, institutions and companies were taken centres of excellence integrating an award to Orthox Ltd is supporting forward this year. These included medicine with the physical sciences, work on a novel approach for repair of research on vaccines against mathematics and engineering to foster a cartilage tears within knee joints using a tuberculosis (Helen McShane, University culture of innovation and product bioresorbable, load-bearing cartilage of Oxford) and pandemic influenza (Dan development in areas of unmet medical implant, while Morgan Alexander and Henderson, PaxVax, Inc.), as well as need. Final funding decisions will be colleagues at the University of antiviral drugs for dengue fever (Alex made in 2008/09. Nottingham are using high-throughput Matter, Novartis Institute for Tropical Several companies that received support microarrays to identify polymers resistant Diseases). Mike Stratton and Andy through Translation Awards for validation to bacterial colonisation, to prevent Futreal, leaders of the Cancer Genome of their technologies have had success in biofilm formation. Project at the Wellcome Trust Sanger raising further funds, including the start-up Institute, are working with colleagues in In veterinary medicine, Andrew Waller companies Population Genetics the USA on high-throughput screening and colleagues at the Animal Health Trust Technologies Ltd, Aircraft Medical Ltd, and genotyping techniques to identify were awarded funding to develop a Achaogen, Inc. and CardioDigital Ltd. drug-sensitising genotypes in human point-of-care test for horses infected with Overall, companies and projects funded cancer cells. Streptococcus equi (the cause of through Technology Transfer have raised ‘strangles’). Other notable awards covered the over £273m in third-party support to date. possible use of human embryonic stem 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’s investment in new DNA-sequencing technology has radically increased its output of genome sequence data. It continues to be a major player in numerous international consortia and collaborations. Meanwhile, the Wellcome Trust Advanced Courses programme and Meetings Programme are continuing to expand their portfolio of courses, conferences and workshops.

Wellcome Trust Sanger Institute in the second phase of the Wellcome rooms were set up at Wellcome Trust This year marked the 15th anniversary of Trust Case Control Consortium (see Major Overseas Programmes in Vietnam the Sanger Institute, which has grown into pages 6–7). DNA samples from 120 000 and Malawi, and both drew participants one of the world’s outstanding biomedical people are being analysed – the largest from a range of countries within their institutions. The Institute’s remit is to ever genetic study of common diseases. regions. understand gene function in health and Sanger Institute researchers are part of In 2008/09 the programme will expand to disease; its projects range from cancer to several consortia unpicking the genetic 22 courses – 14 Advanced Courses and cognition, diabetes to development, underpinning of common human eight workshops. These include workshops embryology to evolution. It also provides disease, and recent findings include in India and Thailand, and an advanced valuable free scientific resources to the genes implicated in obesity and microbiology laboratory course in Malawi, scientific community. susceptibility to infection. The Institute as well as a Genomic Epidemiology of also provides specialist resources to Reflecting the huge influence of its work, Malaria course at Hinxton. clinicians, such as the DECIPHER an analysis by ScienceWatch ranked the database (see page 19). Sanger Institute the number one UK Wellcome Trust Conference Centre institution for citation impact during This year the Institute has been instrumental and Meetings Programme 2003–07. Richard Durbin headed the list in establishing two international consortia: In 2007/08, 2040 delegates participated of UK-based individuals. the 1000 Genomes Project (see page 14); in 23 events held at Hinxton as part of the and the International Cancer Genome Wellcome Trust Meetings Programme. This year the Sanger Institute invested in Project, led by Mike Stratton, which will External sponsorship deals were used to ‘next-generation’ technologies to build on identify the key mutations in 50 cancer fund bursaries and additional invited its world-leading position in genome types – creating a valuable resource and speakers. Highlights included pilots of sequencing. The output is staggering: ultimately promising better ways of new events, such as the Wellcome Trust whereas the first human genome took 13 diagnosing, treating and preventing cancer. School of Human Genomics and years to complete, the Institute generated Fundamentals of Clinical Genetics, which the equivalent of 300 human genomes in Wellcome Trust Advanced Courses were both well received and will be just six months. The Advanced Courses programme ran repeated. The success in sequencing and 18 courses including four new courses Conference facilities at Hinxton enjoyed associated bioinformatics platforms has at Hinxton: Genome-wide Approaches another busy year, generating more than been recognised by a grant from the with Fission Yeast, the Joint Wellcome £2 million of business (80 per cent to Medical Research Council to sequence Trust–European Bioinformatics Institute like-minded organisations charged at 17 strains of laboratory mouse. This work Proteomics Bioinformatics Workshop, subsidised rates). The remaining complements the Sanger Institute’s Genomics and Molecular Virology, and business filled gaps in the conference international mouse gene knockout Practical Aspects of Small Molecule Drug diary and generated income to subsidise projects (KOMP and EUCOMM), which Discovery. scientific events. reached a major milestone this year by Its overseas programme has also been producing 1000 knockout alleles in A feasibility study is currently underway to progressing. In addition to the pathogen mouse embryonic stem cells. determine the options for expanding the and human bioinformatics workshops conference facilities. The Sanger Institute will play a major role held in Uruguay and Kenya, additional IT 50 | PUBLIC ENGAGEMENT

PUBLIC ENGAGEMENT

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

As well as grants for UK activities, this year the Wellcome Trust made its first awards for projects in developing countries. Education and film making remained priorities, while a major new initiative was launched to document and track public attitudes to science in the UK.

Grants A notable award was made to Marie- Darwin200 Society Awards: Ten large awards Louise Newell and the Africa Centre, To commemorate the 200th anniversary (over £30 000) were made. Two aiming to place youth at the forefront of of the birth of Charles Darwin, a wide significant projects, building on previous community engagement in research in range of projects are being developed successful funding, involve young South Africa. under the ‘Darwin200’ banner. The most people. Tom Shakespeare in Newcastle ambitious is to provide new Darwin- Capital funding: Three major capital is expanding the Junior Café Scientifique inspired experiments for every state awards were made to the Science Museum, programme, while Tony Gilland and the school in the UK. Teachers will be the science centre At-Bristol and the Institute of Ideas are continuing the supported by continuing professional Science Gallery Dublin (see page 29). nationwide Debating Matters schools development resources, programmes on debating competition. Teachers TV and access to an online Education library of evolution-related clips from the People Awards: There were 34 awards In September 2008 Primary Science, the BBC archives. (up to £30 000) made to support a first in a new series ofPerspectives on diverse range of activities, including Education, was published. The series will The Trust is als developing multimedia performances, exhibitions, talks, provide commentaries from researchers projects, including an animated version conferences, debates and documentaries. and policy makers on key issues in science of the Tree of Life, a website showcasing education. The first volume was well the best Darwin resources and an online Arts Awards: Three large (over £30 000) received and, alongside other work in game for teenagers. and 36 small grants were awarded. education research, reinforces the Trust’s Broadcast Development Awards: commitment to science education policy. Supporting researchers and broadcast Some 18 awards (up to £10 000) were Training workshops on narrative A review of the first five years of the made to support the development of techniques were run for Trust-funded National Science Learning Centre early-stage ideas for TV, radio or new researchers. Among those benefiting conducted in April 2008 confirmed that media into compelling proposals that can was Hugo Spiers from University College the Centre has made a significant impact. be pitched to the broadcast industry. One London, who delivered the BA Award Its core funding was renewed, while large grant was made to Dan Chambers Lecture at the Annual Festival of Science £27 million additional funding has been at Blink Productions to co-produce with in Liverpool. secured through Project Enthuse (see a feature-length programme, page 27). Through the Science on Film scheme, The Great Sperm Race, on the journey scientists were able to partner with from testicle to conception. In addition, In May 2008 the Trust brought together documentary makers to create films for Jonathan Hall and Hannah Robinson educational researchers and users of the Soho Short Film Festival. won the Grand Prize at the American research to consider how ‘experimental Screenwriters Association International approaches’, including randomised Public attitudes Screenplay Competition for Fireworks. controlled trials, might be applied in The National Centre for Social Research educational research. International Engagement Awards: was commissioned to conduct the first There were 15 awards (up to £30 000) Two issues of Big Picture were published phase of Wellcome Monitor – a survey of made under the new International this year, on drug development and ‘how people’s knowledge about and attitudes Engagement Awards programme. we look’. towards biomedical science. 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 space, a bookshop and a café.

Wellcome Collection was officially opened in June 2007. During its first full year of operation, it attracted more than 300 000 visits (almost twice as many as originally forecast). The exhibitions and live events programmes recorded almost 170 000 visits. A further quarter of a million people visited the Wellcome Collection website.

During its first year, Wellcome Collection On the weekend of 26–28 September Notable additions to the collections proved popular with public and critics 2008, ‘Drawing on Life’, the national included casenotes by celebrated alike. An external evaluation found that launch of The Big Draw, attracted more forensic pathologist Sir Bernard 98 per cent of those surveyed rated their than 5000 visits – Wellcome Collection’s Spilsbury, whose career encompassed visit as excellent or good. Nearly 67 per busiest weekend since opening. The the Crippen case and the ‘Brighton cent felt that they had learned more event was a collaboration between Trunk Murders’, a portrait of Lili Elbe, one about health, medicine and science as a Wellcome Collection, the Campaign for of the first to undergo gender result of their visit. Drawing, University College London and reassignment surgery (in 1929–30), and the Bow Arts Trust. the notebooks of Temporary exhibitions Robert Storrs (1801–1847), an early Exhibitions spanned a range of topics, Wellcome Collection Club adopter of the stethoscope. from sleep to archaeology (see page 26). Currently, the Wellcome Collection Club Almost 6500 visitors attended a gallery has around 400 members. As well as the Wellcome Images tour over the year. A family activity pack comfortable facilities of the Club, there With nearly 3500 images published was introduced a few months after are opportunities to meet and relax at during the year and more than 100 000 opening to enable younger visitors to Club socials, and specially organised images freely available on its new navigate the galleries. events run on a monthly basis. website, Wellcome Images continues to grow and to disseminate the Library’s Events Wellcome Library collections. The Wellcome Image An ongoing programme of live public With over 33 000 visits, the Library had Awards, a celebration of the best images events supports the exhibitions. At its busiest year yet. In the first user added during the year, attracted ‘Flesh’, for example, held in November satisfaction survey since its return to 183 widespread publicity. An exhibition of the 2007, visitors could take a suturing Euston Road, responses to the newly award-winning images toured Japan. session with a plastic surgeon and find refurbished spaces were overwhelmingly out about mummification and positive: “it is a total joy and pleasure to Conference Centre plastination. have access to the Wellcome Library”; Over 27 000 delegates attended 495 “your amazing collection refreshes my events throughout the year. User In May 2008, Nobody Lives Forever, a scholarly enthusiasm”. feedback was highly positive. play written by Judith Johnson and performed by Y Touring Theatre Library hours were extended to include Business Company, explored the questions raised all-day Saturday opening, while the Blackwell bookshop has proved to be a by stem cell research. Performances successful public ‘Insights’ programme popular destination for book launches. were held while the Human Fertilisation of visits included a variety of themes Wellcome Collection’s café, run by and Embryology Bill was going through such as The Body in History and Healing Peyton and Byrne, won the Theme Bar Parliament. Herbs. These one-hour sessions enable and Restaurant Awards prize for Best visitors to see collections first hand and Café Bar 2008. meet the staff who curate them. 52 | ADVISORY COMMITTEES advisory commitTEes

Advisory Committee for the Basic Science Interview Clinical Interview Committee Professor J Fox Wellcome Trust–National Committee University College London Professor B P Morgan Institutes of Health Four-year Professor M J Humphries (Chair) Cardiff University Professor E Lynge PhD Studentship Programme (Chair) University of Manchester University of Copenhagen, Professor C Boshoff Dr G Felsenfeld Denmark Professor R C Allshire University College London (Chair) National Institutes of Health, University of Edinburgh Dr J McMillan Bethesda, USA Professor R J M Franklin University of Hull Professor N J Buckley University of Cambridge Dr J Clarke King’s College London Professor M Petticrew University of Cambridge Professor F Karet London School of Hygiene and Professor P R Burton University of Cambridge Dr D C Douek Tropical Medicine University of Leicester National Institutes of Health, Dr P Klenerman Professor I J Perry Bethesda, USA Professor A Galione University of Oxford University College Cork, Ireland University of Oxford Dr M M S Heck Professor F Y Liew Dr S Webster University of Edinburgh Professor C Kleanthous University of Glasgow Imperial College London University of York Professor A J King Professor P H Maxwell University of Oxford Professor R C Miall Imperial College London History of Medicine Funding University of Birmingham Dr M J Lenardo Professor E Simpson Committee National Institutes of Health, Professor G R Screaton Imperial College London Professor M A Jackson Bethesda, USA Imperial College London Professor A Thrasher (Chair) University of Exeter Professor C J McBain Professor C M R Turner University College London Professor P Biller National Institutes of Health, Institute of Biomedical and Life Professor B Walker University of York Bethesda, USA Sciences, University of Glasgow University of Edinburgh Dr J M T Ford Dr S Muller Professor F M Watt Retired general practitioner University of Glasgow Wellcome Trust Centre for Stem Cognitive and Higher Systems Cell Research, University of Dr L T Kassell Dr P Schwartzberg Funding Committee Cambridge University of Cambridge National Institutes of Health, Professor J P Aggleton Bethesda, USA Professor S W Wilson Professor S King (Chair) Cardiff University Department of Anatomy and Oxford Brookes University Dr J R Sellers Developmental Biology, University Professor D V M Bishop National Institutes of Health, Professor H Marland College London University of Oxford Bethesda, USA University of Warwick Professor T Griffiths Dr J-P Vincent Dr T Rütten Biomedical Ethics Funding Newcastle University National Institute for Medical Newcastle University Committee Research, Medical Research Professor G E Lewis Dr S Shamdasani Council, London Professor A Webster University of Bristol University College London (Chair) University of York Professor M J Morgan Dr J Welshman Arts Award Funding Committee Professor M Dixon-Woods City University, London Lancaster University University of Leicester Professor H Nicholson Professor J O’Keefe Professor M Worboys (Chair) University of London Professor E H Matthews University College London University of Manchester Emeritus Professor, University K Khan Dr A Owen of Aberdeen London Organising Committee University of Cambridge Immunology and Infectious of the Olympic and Paralympic Dr J McMillan Professor I Robertson Disease Funding Committee Games University of Hull Trinity College Dublin, Ireland Professor D Goldblatt L Le Feuvre Professor N Pfeffer Professor R Salmelin (Joint Chair) Institute of Child Curator and writer London Metropolitan University Helsinki University of Technology, Health, London Dr R Levinson Dr R Simpson Finland Professor F C Odds University of London Durham University (Joint Chair) University of Aberdeen G Lewis Professor D Wassenaar E-Health Funding Committee Professor J Allen Poet University of KwaZulu-Natal, South Professor D E Detmer University of Edinburgh Africa Dr F McKee (Chair) American Medical Professor A Craig Writer and curator H Whittall Informatics Association Liverpool School of Tropical Nuffield Council on Bioethics R Mortimer Dr R Apweiler Medicine Film maker Dr Michael Wilks European Bioinformatics Institute Professor P Craig British Medical Association Dr S Ochugboju Professor D Bell University of Salford Biomedical scientist/international Queen’s University Belfast Professor P R Crocker science communicator Professor C Brayne University of Dundee Dr R J T Wingate University of Cambridge Professor P Garside King’s College London Professor D P B Elias University of Strathclyde Professor S Yearley University of Warwick Dr F Geissmann University of Edinburgh Dr R Fitton Hôpital Necker – Enfants Malades, Care Record Development Board, Paris, France Connecting for Health ADVISORY COMMITTEES | 53

The Wellcome Trust is committed to the principles of . 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 2007/08.

Professor G Griffiths Professor H M Evans Molecular and Physiological Professor G Murphy University of Cambridge (to 1 June 2008) University of Sciences Strategy Committee University of Cambridge Durham Professor P Griffiths Professor P M Stewart Professor B V L Potter University College London Professor K W M Fulford (Chair) University of Birmingham University of Bath (to 1 June 2008) University of Professor H Jenkinson Professor D M Altshuler Professor L M Roberts Warwick University of Bristol Massachusetts General Hospital, University of Warwick Professor M A Jackson Boston, USA Professor S Kaufmann Professor E J Robertson University of Exeter (to 1 April 2008) Max Planck Dr C D Austin University of Oxford Institute for Infection Biology, Professor H King National Human Genome Professor C E Sunkel Berlin, Germany University of Reading Research Institute, Bethesda, USA University of Porto, Portugal Professor M Keeling Professor G Richardson Professor A Bradley Professor A B Tobin University of Warwick (to 1 June 2008) King’s College Wellcome Trust Sanger Institute, University of Leicester London Cambridge Professor C D O’Connor University of Southampton Professor T Treasure Professor G Fitzgerald Neuroscience and Mental (to 1 June 2008) Honorary University of Pennsylvania, Professor P Openshaw Health Strategy Committee Professor, Clinical Operational Philadelphia, USA National Heart and Lung Institute, Research Unit, University Professor M C Raff London Professor M J Humphries College London (Chair) University College London University of Manchester Professor M Palmarini Professor J P Aggleton University of Glasgow Professor A J Hunter Molecular and Cellular Cardiff University GlaxoSmithKline Professor D Pfeiffer Neuroscience Funding Professor K H Ashe Royal Veterinary College, Hatfield Committee Dr S E Lewis University of Minnesota, University of California, Berkeley, Professor R Randall Professor D M Turnbull Minneapolis, USA USA University of St Andrews (Chair) Newcastle University Professor D J Kupfer Professor S G Oliver Dr G Rudenko Professor C H Davies University of Pittsburgh, University of Cambridge University of Oxford GlaxoSmithKline Pennsylvania, USA Professor I Robinson Professor E Schurr Professor C Holt Professor M H Sheng National Institute for Medical Montreal General Hospital, Canada University of Cambridge Massachusetts Institute of Research, London Technology, Cambridge, USA Professor R Shattock Professor C F Inglehearn Professor J Smith St George’s Hospital Medical St James’s University Hospital, Professor W Singer University of Cambridge School, University of London Leeds Max Planck Institute for Brain Research, Frankfurt am Main, Professor E Sockett Professor D M Kullman Molecules, Genes and Cells Germany University of Nottingham University College London Funding Committee Professor A Toga Professor K Martin Professor S G Oliver UCLA School of Medicine, Los Library Advisory Committee Institute of Neuroinformatics, (Chair) University of Manchester Angeles, USA Zürich, Switzerland J Wilkinson Professor K R Ayscough Professor S Tonegawa (Chair) University of Manchester Professor R Miles University of Sheffield Massachusetts Institute of INSERM, University of Paris, Dr T Boon Technology, Cambridge, USA France Professor P Beales Science Museum University College London Professor D M Turnbull Professor D Rubinsztein A S Byatt Newcastle University University of Cambridge Professor N Brockdorff Arts Council England University of Oxford Professor G Schiavo A Fleming Pathogens, Immunology and Cancer Research UK, London Professor S Brunak Freelance working in film and video Population Health Strategy Technical University of Denmark Professor A Stephenson Committee A Green University of London Dr R M Cooke National Library of Wales, Dr R M Atlas GlaxoSmithKline Aberystwyth Professor D G Wilkinson (Chair) University of Louisville, National Institute for Medical Professor J Errington Kentucky, USA Dr N D Hopwood Research, London Newcastle University University of Cambridge Professor Z A Bhutta Professor L Wilkinson Dr A P Gould Aga Khan University Hospital, Cardiff University National Institute for Medical Karachi, Pakistan Medical Humanities Strategy Research, London Committee Professor H J Willison Dr F Binka University of Glasgow Professor T Hyman University of Ghana, Legon Professor R A Hope Max Planck Institute for Molecular (Chair to 1 June 2008) Professor B R Bloom Biology and Genetics, Dresden, University of Oxford Harvard School of Public Health, Germany Boston, USA Professor N Britten Professor J Iredale Peninsula Medical School, Exeter Professor N Chaturvedi University of Edinburgh Imperial College London Professor N L G Eastman Professor M Jobling St George’s Hospital Medical Professor P J Donnelly University of Leicester School, London University of Oxford Professor J Ladbury University College London 54 | ADVISORY COMMITTEES advisory commitTEes

Professor G Dougan Populations and Public Health Professor T Hunter R&D for Affordable Healthcare Wellcome Trust Sanger Institute, Funding Committee The Salk Institute for Biological in India Committee Cambridge Studies, San Diego, USA Professor N Chaturvedi Dr R Parekh Professor S B J Ebrahim (Chair) Imperial College London Professor T E Wellems (Chair) Advent Venture Partners London School of Hygiene and National Institute of Allergy and Professor M L Barreto Dr A Allsop Tropical Medicine Infectious Diseases, Bethesda, Federal University of Bahia, Brazil AstraZeneca USA Professor D Goldblatt Professor C Brayne S Bayman Institute of Child Health, London University of Cambridge Stonebridge International, USA Public Engagement Strategy Professor P T LoVerde Professor U D’Alessandro Committee Professor G Dougan University of Texas, San Antonio, Prince Leopold Institute of Tropical Wellcome Trust Sanger Institute, USA Professor N J Rothwell Medicine, Belgium Cambridge (Chair) University of Manchester Professor S Macintyre Professor M Egger Dr R Kumar University of Glasgow Professor F Balkwill University of Bern, Switzerland Dr Reddy’s Laboratories, University of London Professor B P Morgan Hyderabad, India Professor G P Garnett Cardiff University Q Cooper Imperial College London Professor Sir R N Maini Writer and broadcaster Professor F C Odds Imperial College London Professor A O House University of Aberdeen Professor M A Jackson University of Leeds Dr C Newton University of Exeter Professor M E J Woolhouse BioFocus DPI Professor T H Jafar University of Edinburgh Dr H Nicholson Aga Khan University, Karachi, Professor S Reddy Royal Holloway College Pakistan Public Health Foundation of India, Physiological Sciences Professor N S Rose New Delhi, India Professor A M Johnson Funding Committee London School of Economics University College London Professor K Vijayraghavan Professor I C A F Robinson J Sjøvoll National Centre for Biological Professor C King (Chair) National Institute for Medical Framwellgate School Durham Sciences, Bangalore, India Case Western Reserve University, Research, London Cleveland, USA T Smit Dr A Wood Professor K M Channon Eden Project Lilly Research Centre Professor A Lopez University of Oxford University of Queensland, Herston, Dr S Webster Professor H T Cook Australia Imperial College London Research Resources in Imperial College London Medical History Funding Dr Z Matthews Professor Lord Winston Committee Professor A F Dominiczak University of Southampton Imperial College London University of Glasgow Professor H King Professor M McKee (Chair) University of Reading Professor M Gautel London School of Hygiene and Public Health and Tropical King’s College London Tropical Medicine Medicine Interview Committee J Andrews Newcastle University Professor C Godson Professor A D Morris Professor P T LoVerde University College Dublin, Ireland University of Dundee (Chair) University of Texas, San N Bell Antonio, USA The National Archives Professor A J Knox Professor B S Ramakrishna University of Nottingham Christian Medical College and Professor M J Cardosa Y Dahnsjö Hospital, Vellore, India Universiti Malaysia Sarawak, The National Trust Professor L Lanyon Malaysia University of London Professor T Smith J Etherton Swiss Tropical Institute, Basel, Professor M Caulfield London Borough of Barking and Professor N W Morrell Switzerland Barts and The London, Queen Dagenham University of Cambridge Mary’s School of Medicine and Dr C Stoltenberg Professor M A Jackson Professor S O’Rahilly Dentistry Norwegian Institute of Public University of Exeter University of Cambridge Health, Norway Professor K K Cheng H Lindsay Professor M Perretti University of Birmingham Professor J Volmink Freelance collections care Barts and The London, Queen Stellenbosch University, Cape Professor A Lalvani consultant Mary School of Medicine and Town, South Africa (from 1 June 2008) Imperial Dentistry I Milne College London Royal College of Physicians of Dr A M Prentice Principal Research Fellowship Professor L Richter Edinburgh London School of Hygiene and Interview Committee Human Sciences Research Tropical Medicine Council, South Africa Professor P W J Rigby Professor G A Rutter (Chair to 1 January 2008) Institute Professor G Tomson Imperial College London of Cancer Research, London Karolinska Institute, Stockholm, Professor I Sargent Sweden Dr D Ish-Horowicz University of Oxford (Chair from 1 April 2008) Institute of Dr F Wabwire-Mangen Professor J Seckl Cancer Research, London Makerere University, Kampala, University of Edinburgh Uganda Professor C Frith Professor D G Thompson University College London Professor M Wahlgren Hope Hospital, Manchester Karolinska Institute, Stockholm, Sweden Professor A Tinker University College London ADVISORY COMMITTEES | 55

Seeding Drug Discovery Standing Advisory Group Technology Transfer Challenge THEMED COMMITTEE Funding Committee on Ethics Committee MEETINGS HELD IN 2007/08 Professor W N Charman Professor S Holm Professor J Allen (Chair) Monash University, (Chair) Cardiff University University College Dublin, Ireland Biomedical Sciences Melbourne, Australia Professor B Greenwood Professor W N Charman Professor G B Warren Professor J Allen London School of Hygiene and Monash University, Melbourne, (Chair) Max F Perutz Laboratories, (to 18 September 2008) University Tropical Medicine Australia Vienna, Austria College Dublin, Ireland Professor G Laurie Dr L Fass Professor J Carlstedt-Duke Professor K-H Altman University of Edinburgh GE Healthcare Karolinska Institute, Stockholm, (to 8 May 2008) Swiss Federal Sweden Professor T W Meade Dr G C Forrest Institute of Technology, Zürich, London School of Hygiene and Genosis Ltd Professor R G Hill Switzerland Tropical Medicine Imperial College Lodnon Professor P Ghazal Dr P England K Whitehorn (to 1 May 2008) University of Professor A C Minson ProXara Biotechnology Limited Freelance journalist Edinburgh University of Cambridge Professor J Griffin Dr A Hudson Professor J P Waltho Numerate Inc. Study Design Expert Group Pharma research consultant University of Sheffield Dr F D King Professor P Donnelly Dr K Johnson Professor K R Willison University College London (Chair) University of Oxford Index Ventures Cancer Research UK, London Dr T J Rink Professor R Collins Dr F D King Professor P Wong Board member, Adnexus University of Oxford University College London Johns Hopkins University, Therapeutics Inc., Sepracor Inc. Maryland, USA and Santhera Pharmaceuticals Professor N Craddock Dr G Lawton Cardiff University Lectus Therapeutics Ltd Medical Humanities Sir Henry Wellcome Professor J Danesh Dr W Luyten Postdoctoral Fellowship University of Cambridge PharmaDM Professor M A Jackson Interview Committee (Chair) University of Exeter Professor J H Darbyshire Professor E Mathiowitz Professor J C Smith MRC Clinical Trials Unit, London Brown University, Providence, USA Professor S Gilman (Chair) University of Cambridge Emory University, Atlanta, USA Dr P Deloukas Dr G Michel Professor J C Buckingham Wellcome Trust Sanger Institute, Foundation of New Innovative Professor R A Hope Imperial College London Cambridge Diagnostics University of Oxford Professor D A Cantrell Professor C P Farrington Dr R Parekh Professor G Jones University of Dundee Open University Advent Venture Partners University of Ulster Professor A C Dolphin Professor R J Hayes Dr J Rasmussen University College London London School of Hygiene and CNS consultant Medicine, Society and History Tropical Medicine Capital Awards Professor W C Earnshaw Dr F Sams-Dodd University of Edinburgh Professor J L Hutton Bionomics Ltd J Vitmayer University of Warwick (Chair) Horniman Museum, London Professor K Gull Dr M Skingle University of Oxford Professor M Khoury GlaxoSmithKline Professor F Balkwill Centers for Disease Control and Queen Mary’s School of Medicine Professor S C R Williams Professor C Toumazou Prevention, Atlanta, USA and Dentistry, London (from 1 April 2008) King’s College Imperial College London London Professor A Morris P Jennings University of Dundee Sensation & Stratosphere, Dundee Technology Transfer Strategy Society Awards Funding Professor D J Porteous Panel S MacDonald Committee (established University of Edinburgh University College London Dr T J Rink 1 April 2008) Professor M J Prince (Chair) Board member, Dr S Webster Dr S Webster King’s College London Adnexus Therapeutics Inc., Imperial College London (Chair) Imperial College London Sepracor Inc. and Santhera Professor J N Weber Pharmaceuticals R Gould Imperial College School of Translational Medicine and Theatre director and producer Medicine, London Dr J Hills Therapeutics Bristol-Myers Squibb Dr A McFarlane B Zaba Professor G Fitzgerald The Royal Botanic Gardens, Kew London School of Hygiene and Dr R Parekh (Chair) University of Pennsylvania, Tropical Medicine (to 20 July 2008) Advent Venture USA Professor M Parker Partners University of Oxford Professor W G Haynes Dr Andrew Wood University of Iowa, USA N Partridge Lilly Research Centre Terrence Higgins Trust Professor P M Stewart Professor Lionel Tarassenko University of Birmingham Professor D J Porteous (from 1 April 2008) University of University of Edinburgh Oxford Dr S Preston University of Durham M Whitby Red, Green & Blue Co. Ltd 56 | acknowledgements

Acknowledgements The Wellcome Trust Annual Review is All images are courtesy of Wellcome Images We are grateful to everyone who agreed distributed via a mailing list held by the (http://images.wellcome.ac.uk) except as follows: to be reviewed in this issue, everyone Wellcome Trust. If you would like to be Contents and p. 1: 2 (D Furness), 6 (A Weston); pp. 2–3: 1 (A Cavanagh); pp. 6–7: 1 (adapted from who supplied images or gave us added to the list, or if you have a Chamberlain et al., reproduced with permission from permission for their images to be used, colleague who would like to receive the AAAS), 2 (I van Bussel), 3 (A Weston), 4 (A Cavanagh); and the many members of Wellcome Wellcome Trust Annual Review, please pp. 8–9: 1 (from Wang et al., reproduced with permission from AAAS), 2 (Medical Microscopy Trust staff who helped to produce this contact: Sciences, Cardiff University); pp. 10–11: 1 (D Furness), volume. 2 (MRC NIMR), 3, 4 (from Abrahamsen et al., Publishing Department reproduced with permission from AAAS), 5, 6 Editor Wellcome Trust (L Trinkle-Mulcahy); pp. 12–13: 1 (E Martino/Panos); pp. 14–15: ion channel (P Stansfeld, M Sansom, Ian Jones, Isinglass Consultancy FREEPOST F Ashcroft/OXION); pp. 18–19: 2 (K Whitley); RLYJ-UJHU-EKHJ Project Manager pp. 20–21: 1 (D Scharf/SPL), 2 (from Plouffe et al., Slough SL3 0EN reproduced with permission from PNAS), 3, 4 (from Lucy Moore Newton et al., reproduced with permission from T +44 (0)20 7611 8651 PLoS Medicine); pp. 22–23: 1 (W Page/Panos), Writers 2 (N Durrell McKenna), 3 (A Vardhan/iStockphoto), F +44 (0)20 7611 8242 Penny Bailey 4 (S Schuller), protein structure (B Marsden/Structural E [email protected] Genomics Consortium); pp. 26–27: 3 (Windfall Films); Ian Jones pp. 28–29: 1 (Cardboard Citizens/Robert Day), Mun-Keat Looi www.wellcome.ac.uk/publications 2 (Media Trust Productions), Science Gallery (Science Gallery Dublin); p. 31: 1 (Rex Features), 3 (S Nosten); Editorial staff ISBN 978 1 84129 081 2 pp. 32–33: 1 (from Mangale et al., reproduced with Tom Freeman permission from AAAS), 2 (O Burston); pp. 34–35: 1 The Wellcome Trust is a charity (M Terao/iStockphoto), 2 (I Macrae); p. 37: 1 (S Klein/ Design registered in England, no. 210183. Its iStockphoto), 2 (iStockphoto); pp. 38–39: 1 (T Lang), 2 (Y Nikas); p. 46: top left (A Tanczos), top right Anja Fouad sole trustee is The Wellcome Trust (Y Nikas), centre left (A Cavanagh), centre right Limited, a company registered in (University of Edinburgh), bottom left (MI Walker), Photography England, no. 2711000, whose registered bottom right (D Furness); p. 47: top left (A Boyde), top David Sayer right (D Furness), centre right (A Sieveking), bottom left office is at 215 Euston Road, London Mark Jones (Malawi images) (C Riley); p. 48 (A Cavanagh). NW1 2BE, UK. Cover image: Publisher Salbutamol crystals. Salbutamol is used in inhalers First published by the Wellcome Trust, Hugh Blackbourn for conditions where there is a narrowing of the 2009. airways, such as bronchitis, asthma and emphysema. Comments on the Wellcome Trust The cluster of crystals is about 600 μm in diameter. © The trustee of the Wellcome Trust, Annie Cavanagh Annual Review are welcomed and London. should be sent to: This is an open access publication and, Hugh Blackbourn with the exception of images and Publishing Department illustrations, the content may, unless Wellcome Trust otherwise stated, be reproduced free of Gibbs Building charge in any format or medium, subject 215 Euston Road to the following conditions: content must London NW1 2BE, UK be reproduced accurately; content must F +44 (0)20 7611 8270 not be used in a misleading context; the E [email protected] Wellcome Trust must be attributed as the original author and the title of the document specified in the attribution. Wellcome Trust Gibbs Building 215 Euston Road London NW1 2BE, UK Cert no. SGS-COC-2524 T +44 (0)20 7611 8888 F +44 (0)20 7611 8545 E [email protected]

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WELLCOME TRUST ANNUAL REVIEW 1 October 2007–30 September 2008

ANNUAL REVIEW 2008

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