ANNUAL REVIEW 2005 THE WELLCOME TRUST The Wellcome Trust is the most diverse biomedical research charity in the world, supporting a spectrum of activity from basic science to history of medicine.

CONTENTS BOARD OF GOVERNORS 2 Director’s statement Dominic Cadbury Chairman 4 Advancing knowledge Martin Bobrow 16 Using knowledge Deputy Chairman 22 Engaging society Leszek Borysiewicz* 28 Developing people Adrian Bird 32 Facilitating research William Castell* 36 Developing our organisation Patricia Hodgson Ronald Plasterk 37 Wellcome Trust 2004/05 Alastair Ross Goobey 38 Funding 2004/05 Peter Smith 52 Advisory committees Jean Thomas Edward Walker-Arnott

*From 1 January 2006

L–R Human cells in culture. ‘Ball and stick’ molecular Signage within the modelling. Wellcome Trust’s new ‘Germlights’ by Sue headquarters building Withers, Proof, from a at 215 Euston Road, Wellcome Trust science London. and art exhibition. Professor Andy Tait of Professor Andrew the Wellcome Trust Hattersley of the This Annual Review covers the Wellcome Centre for Molecular University of Exeter Parasitology in Glasgow. examining a patient Trust’s financial year, from 1 October with diabetes. 2004 to 30 September 2005. CONTENTS 01

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

As at January 2006 DIRECTOR’S STATEMENT 02

A YEAR OF DISCOVERY It has been a year that demonstrates that investing in the best people to work on the best ideas in the best environments produces landmark discoveries.

One of the greatest satisfactions Last year Dr Georgy Koentges and 1991–92 and their parents, which we of directing the Wellcome Trust colleagues made ground-breaking fund jointly with the Medical Research is seeing the many discoveries steps forward in the understanding of Council, continue to produce emerging from the research we how our skeletons and muscles develop, important findings. fund. The most effective way to and why certain genetic disorders affect Research resources fund the research that leads to particular parts of our bodies. This has The year also saw the fruit of several new discoveries is to support the significantly altered our view of a key large international collaborative projects, best researchers, the best teams biological process, as has the work of in which the Trust is a major partner. and the best ideas. To help guide Professor Adrian Hayday and colleagues These build on the Human Genome our research communities and at King’s College London. They have Project, aiming to translate genome provide them with the opportunities discovered that immature T cells have sequence data to give a better to make real progress, this year a crucial role in generating special understanding of health and disease. we launched our Strategic Plan defence cells that patrol the vulnerable 2005–2010: Making a Difference. sites exposed to the outside world, such The International HapMap Consortium as skin and the gut. This has created a published a detailed catalogue of The new Plan is about creating a new view of the thymus function. human genetic variation, which is framework (see page 36), a set of already accelerating the search for high-level principles to guide – but not In the clinical arena, this year saw genes involved in common diseases. constrain – research communities that the results of the largest-ever clinical trial The Wellcome Trust Sanger Institute look to us for funding. The Strategic Plan on the treatment of severe malaria. This played a key role in generating this map. will be a living document, allowing us to work in South-east Asia, led by Professor In another outstanding year, the Sanger adjust our direction as new opportunities Nick White, brought calls for immediate Institute took a key role in international arise. Key to this will be flexibility in our change to medication practices. partnerships that sequenced the mechanisms for awarding grants. This In Vietnam, Dr Jeremy Farrar and genomes of parasites causing three year we launched a Strategic Awards colleagues have advanced our major diseases in developing countries – scheme, with grants that will enable us understanding of avian influenza in sleeping sickness, Chagas’ disease to fund strategic initiatives of many kinds humans. Their research suggests that and leishmaniasis – and the human in a timely manner. We also broadened the virus can affect many parts of the X chromosome. our UK eligibility criteria, so that we can body – not just the lungs, as previously Knowing the shape of a protein is fund the best scientists throughout the thought. The core funding of the Vietnam crucial for understanding its biological UK and enable them to collaborate with Programme and our other Major function, and the Structural Genomics scientists worldwide. Overseas Programmes in Kenya and Consortium (SGC), a public–private Thailand was renewed this year. Funding Discoveries partnership between the Wellcome Trust, of £26 million was agreed in recognition Support of curiosity-driven research GlaxoSmithKline, and funding agencies of the internationally important work remains the biggest single element of our in Canada and Sweden, is determining these Programmes are carrying out. funding portfolio. Such support has led the three-dimensional structures of to some outstanding research outputs – In the UK, researchers working with proteins relevant to human disease. discoveries that give us a better ALSPAC, a cohort study of 14 000 The SGC has, to date, solved the understanding of health and disease. children born in the Avon area in structures of over 100 complex proteins, DIRECTOR’S STATEMENT 03

HIGHLIGHTS OF THE YEAR

including important drug development A supportive environment • Artesunate is more effective than targets for malaria and diabetes. To achieve our mission, we need quinine for treatment of severe These are tremendous research a climate within which biomedical malaria, a large clinical trial in resources, all freely available to research can flourish. The Trust Asia reveals. has again been active in this area. researchers around the globe. • Genome sequences of Last year we also agreed to fund The completion of the National Science two important parasites, another such community resource. Learning Centre is an important step Trypanosoma brucei and The Wellcome Trust Case Control forward. It will provide teachers and Leishmania, are published. Consortium will be one of the biggest other educators with access to the • Building work is completed on projects ever undertaken to identify resources and expertise to get to grips the National Science Learning the genetic variations that may with the complexities of contemporary Centre at York. predispose people to, or protect science. In turn, teachers will go on them from, 11 major diseases, to inspire today’s young people to • Community MRSA is identified including type 1 diabetes, Crohn’s become the scientists of tomorrow, as a re-emergent strain from disease and rheumatoid arthritis. and give them the confidence to the 1950s. Practical application understand, debate and question • Work on early T-cell development Key to our mission is ensuring that issues surrounding science. sheds new light on the thymus. research knowledge results in health This year we have again been actively • Structural Genomics Consortium benefit. CardioDigital Limited, a spin- engaging with Government, policy places structures of 100 out company from Napier University, makers and opinion formers on issues medically important proteins Edinburgh, has developed and is affecting the research base. These in the public domain. piloting software that can significantly include stem cell research, use of enhance the information extracted human tissues, career structures for • Source of calories, not just from existing medical hardware, clinical and basic scientists, and number, influences lifespan in such as pulse oximeters. continuing professional development fruit flies fed low-calorie diets. for science teachers. We have also Professor Steve Howdle, Professor • Bacterial illness is found to actively promoted the ‘open access’ Vladimir Popov and colleagues have account for an unexpectedly high model of science publishing, to help developed ‘PolyHap’ implants, which proportion of deaths of African ensure that research findings are have been used by surgeons to help children admitted to hospital. shared as widely and as rapidly rebuild the faces of children injured in as possible. • An influential report on neglected accidents or born with serious defects. diseases highlights the important As this Annual Review illustrates, our This has already benefited a baby with role of public–private funding portfolio is a treasure trove a jaw tumour and a 12-year-old girl partnerships. who had been barely able to open of stories of discovery. Capturing these her mouth from birth. stories systematically is not easy, and • New estimates suggest that the understanding the longer-term impacts global prevalence of malaria is far Dr Mary Moran at the London School of research is particularly difficult. The higher than previously thought, of Economics and Political Science research process is incremental, and particularly in Asia. published an excellent analysis showing the road from discovery to application that public–private partnerships (PPPs) • More than 120 000 visitors attend can be long and complex. We plan have performed better than either the Future Face exhibition at the to develop new ways to capture the sector working alone when it comes Science Museum. diverse outputs and outcomes of our to delivering safe, effective, affordable many awards. Through this approach drugs for neglected diseases. we hope to gain a better picture of We awarded one such non-profit how, through the work of our many PPP, the Medicines for Malaria dedicated grantholders, we are truly L–R Venture (MMV), £10 million in funding – Structure of nuclear in Hackney, east making a difference. transport factor 2 from London, using new matched by the UK Department for Cryptosporidium technologies to explore International Development. MMV parvum, determined by ethical issues in science. Mark Walport the Structural Genomics Influenza virus attached runs the world’s largest dedicated Consortium. Director to cells in the upper programme of antimalarial drug Students at Highwire, respiratory tract. January 2006 research and development. a city learning centre

ADVANCING KNOWLEDGE Supporting research to increase understanding of health and disease, and its societal context. ADVANCING KNOWLEDGE 06

FRUIT-FLY DIETS GERM OF AND LONGEVITY AN IDEA Experiments on fruit flies suggest that what is eaten, rather than just A mouse gene has been found how much, influences lifespan. to promote the development of cells vital for reproduction.

Cut down a fruit fly’s diet to half per gram. The researchers could The Blimp1 gene has been of its normal calories, and the therefore feed the flies on a yeast- identified as a key factor in average lifespan almost doubles. restricted diet or a sugar-restricted the development of mouse germ Similar effects are seen in a wide diet with the same number of calories, cells (eggs and sperm). It appears range of organisms, from yeast and compare the effects on lifespan. to act by preventing primordial to mice, but it has been thought They found that reducing either dietary germ cells from following a that it was calorie reduction in yeast or sugar could reduce mortality developmental path that turns general, rather than the specific and extend lifespan, but by an amount them into body cells. source of calories, that that was unrelated to the calorie Germ cells are special. While other increases longevity. content of the food – and yeast had cells of the body last no longer than a much greater effect per calorie than Professor Linda Partridge and the lifetime of an organism, germ cells, did sugar. colleagues at University College uniquely, have the potential to seed the London have now found that, per For fruit flies at least, the research next generation. In mice, the cells that calorie, different constituents of suggests that it is not simply calorie will generate germ cells are specified the diet have very different effects intake that influences longevity, but in early development, in response to a on lifespan, implying that the links also the specific nutritional make-up signal that about 40 cells receive from between calorie restriction and of the food. In which case, Professor their neighbours. Two research groups longevity may be more complex Partridge and colleagues suggest, have identified the Blimp1 gene as an than once thought. the full effect of dietary restriction on important part of this key cellular lifespan could be obtained by reducing In the lab, Drosophila are fed on a decision-making mechanism. critical nutrients in the food without diet of yeast (contributing a mixture of A critical step in this process is reducing overall calorie intake. nutrients including protein and fat) and the repression of a developmental sugar (carbohydrates), which provide Mair W et al. Calories do not explain extension programme followed by all other body of life span by dietary restriction in Drosophila. roughly the same number of calories PLoS Biol 2005;3(7):e223. cells (somatic cells). Dr Azim Surani and colleagues in Cambridge, and Dr Elizabeth Robertson and colleagues in Oxford, independently discovered that

L–R Professor Linda Attachment of the Partridge, University trapezius muscle to College London. the skull. Neural crest- A section through an derived cells (blue) give early mouse embryo. rise to both muscle The Blimp1 gene is and connective tissue active in a single layer attachments. of cells (stained green) Neural crest cells form on the outside edge muscle cells (stained of the embryo. red and green) and Dr Azim Surani, non-muscle tissue University of Cambridge. (just green). ADVANCING KNOWLEDGE 07

HEAD AND SHOULDERS Skeletal and muscle components of the shoulder and neck are formed together, and are derived from one type of stem cell.

the Blimp1 gene is central to this In vertebrates, the skeleton For example, cells derived from repression. In the absence of Blimp1, and muscles of the shoulder and mesenchymal stem cells in the neural cells that resemble germ cells develop neck are formed as a composite crest (a structure formed very early in but do not follow the usual germ cell rather than as separate systems, embryonic development) anchor the development pathway, and eventually researchers at University College head to the front of the shoulder. A turn into somatic cells. London and elsewhere have separate population, originating from Dr Robertson’s team studied the role discovered. mesodermal stem cells, links trunk muscles to the posterior neck and of Blimp1 in knockout mice, which, In the past, the skeleton has been shoulder skeleton. as well as having other defects, are thought to be the basis of organisation entirely lacking germ cell precursors. in vertebrates, with distinct types of These new findings explain why Dr Surani’s team also noted disruption stem cell giving rise to the skeleton some genetic disorders affect particular to germ cell development in mutant and muscles in separate processes. parts of the neck and shoulders: the mice. In addition, they used cell- mutations affect specific populations Using a new genetic labelling technique labelling techniques to confirm that of cells. They also shed light on the able to track individual stem cells from cells making Blimp1 in normal embryos evolution of skeletons – for example, the embryo to the adult animal, are those that turn into germ cells. suggesting that a bone called the Dr Georgy Koentges from UCL, and cleithrum, seen in extinct land animals, The research thus provides important colleagues in Sweden and the USA, has become integrated into the insight into a fundamental biological found that mesenchymal stem cells shoulder blade in modern vertebrates. puzzle: development of the cells that were responsible for forming muscle perpetuate a species’ existence. scaffolds, the place where muscles Matsuoka T et al. Neural crest origins of the neck and shoulder. Nature 2005;436(7049):347–55. anchor to bones, as well as the Ohinata Y et al. Blimp1 is a critical determinant This research was supported by the Wellcome of the germ cell lineage in mice. Nature muscles themselves. Trust, the Biotechnology and Biological Sciences 2005;436(7048):207–13. Research Council, the Medical Research Council, Vincent SD et al. The zinc finger transcriptional The work paints a completely new the US National Institutes of Health and the repressor Blimp1/Prdm1 is dispensable for early picture of vertebrate development. international Human Frontier Science Program. axis formation but is required for specification of primordial germ cells in the mouse. Development 2005;132(6):1315–25. ADVANCING KNOWLEDGE 08

NICE WHEN THINK POSITIVE YOU STOP Relief and reward are all the same to the human brain. New research is changing our understanding of T-cell development in the thymus.

According to the popular saying, then, after a visual cue, gave them Professor Adrian Hayday and difficult tasks are like banging your either pain relief, extra pain or nothing. colleagues at King’s College head against a brick wall: it’s nice Half the time, though, the cue was London have found that when you stop. A team led by Ray false, so subjects constantly had to development of different kinds Dolan at the Wellcome Department update their expectations of what was of T cell in the thymus is more of Imaging Neuroscience at coming next. Using brain imaging, the closely linked than previously University College London have researchers could then see what effect thought. The findings shed new now found, using brain imaging, expectation of pain relief had, even light on key aspects of immune- why this is so. when it didn’t actually occur. cell development. The new research suggests that the The expectation of relief activated The thymus, a gland found overlying brain treats relief from pain and natural reward-like pathways in the amygdala the heart, is where the immune reward in a similar way. In addition, and midbrain, while ‘aversive’ signals system’s T cells develop. Two main people suffering prolonged pain can were activated elsewhere in the brain types of T cell exist, αβ and γδ; broadly ‘learn’ to predict relief, something that when the relief failed to materialise. speaking, αβ cells circulate in the could affect how they deal with pain in bloodstream tackling a diverse range Unravelling how psychological the future. of microbes, while γδ cells patrol the phenomena affect brain activity could body’s boundaries with the outside The group tested the effect of Pavlovian be useful in creating more effective world, such as the skin and gut. conditioning – where an arbitrary cue pain relief or techniques to manage becomes associated with a painful chronic pain. One of the most striking features stimulus, so eventually the cue triggers of the thymus is the large number of Seymour B et al. Opponent appetitive–aversive a response even without the stimulus. neural processes underlie predictive learning of T cells it generates, most of which are They exposed people to prolonged pain relief. Nat Neurosci 2005;8(9):1234–40. eliminated. Immature T cells – known pain (tolerable to the subjects) and as DP or ‘double-positive’ cells as they

L–R The experience of A section through the pain can be influenced thymus, a gland crucial by other forms of brain to the development of activity. our immune defences. Functional magnetic A cell in culture resonance imaging engineered to make gives insight into areas melanopsin, which of brain activity. makes it light-sensitive. Cells in the retina stained to show the presence of melanopsin. ADVANCING KNOWLEDGE 09

SEEING THE LIGHT

A chemical found in the human eye can render mammalian cells sensitive to light.

produce two key T-cell surface Professor Mark Hankins and responsive to light, Professor Hankins molecules – proliferate, but only those colleagues at Imperial College and colleagues inserted the gene for deemed to be of potential value in the London and the University of melanopsin into cultured mouse cells. fight against infection go on to later Manchester have shown that The modified cells expressed the developmental stages. melanopsin, a protein present in protein and generated electric In their latest research, Professor ganglion cells in the eye, is able currents when illuminated, confirming Hayday and colleagues discovered to make mouse cells sensitive that melanopsin is a genuine that this multitude of DP cells are not to light. Melanopsin works in photoreceptor protein. simply passively waiting to be chosen a similar way to invertebrate The induced currents were dependent or culled: they also have a specific role photoreceptors, prompting on the presence of particular forms of of their own. The DP cells release questions about how ganglion retinaldehyde, a chemical needed for factors (such as lymphotoxin) that act cells evolved. light detection in the rods and cones. on neighbouring immature T cells, For a while it has been clear that a As with these photoreceptors, pushing them towards a γδ T-cell fate. light-sensing system exists in the eye, melanopsin requires cis-isomers Thus, as well as generating the αβ T separate from the rod and cone cells of retinaldehyde to function. However, cells, these DP precursors also ensure needed for vision. A small number of there was also some light-sensitivity that γδ T cells are produced – so the non-vision ganglion cells at the back when all-trans-retinaldehyde was body has a balance between these of the eye respond to light and are added, suggesting that melanopsin two types of defence cell. required for setting the body’s internal is able to convert it into the 11-cis clock (its circadian rhythms). form – something seen only in Silva-Santos B et al. Lymphotoxin-mediated invertebrates before. regulation of gammadelta cell differentiation The retinal ganglion cells contain by alphabeta T cell progenitors. Science melanopsin, which has the hallmarks Melyan Z et al. Addition of human melanopsin 2005;307(5711):925–8. renders mammalian cells photoresponsive. of a light-sensitive protein. To see if Nature 2005;433(7027):741–5. melanopsin could make cells ADVANCING KNOWLEDGE 10

FLU ON THE BRAIN BEATING MALARIA Symptoms of avian flu could be more diverse than Severe malaria is better treated previously suspected. with artesunate than quinine, a large multicentre trial has shown.

A study in Vietnam suggests that and colleagues, at the Paediatric Funded by the Wellcome Trust the H5N1 strain of avian influenza Hospital Number One, the Hospital and led by Professor Nick White – virus can affect the brain and for Tropical Disease and the Oxford Director of the Wellcome Trust central nervous system before University Clinical Research Unit in South-east Asia Major Overseas respiratory problems appear. As Ho Chi Minh City, isolated avian Programme – the trial compared antiviral agents are likely to work influenza virus strain H5N1 from all treatments for severe malaria only early in disease, this could of these specimens. Given the similarity in 1500 adult patients in centres have important implications for of symptoms, it is likely that his sister across Bangladesh, India, avian flu treatment. was also infected. Indonesia and Myanmar. In February 2004, in Dong Thap In humans, nervous system infection The trial compared the effectiveness Province in southern Vietnam, a sister is an extremely rare complication of flu, of two plant-derived drugs: quinine and brother aged nine and four died but it is common in birds. Worryingly, (currently the accepted treatment for within two weeks of each other. H5N1 virus may be progressively severe malaria in most affected regions) adapting to mammals – and becoming Both children arrived in hospital against artesunate – a drug derived more neurologically virulent. In addition, having had fever, diarrhoea and from the sweet wormwood plant. It is the presence of virus in faeces increasing drowsiness for several days. the first trial to show that the mortality highlights a potential route of human- In hospital, they went into coma and of severe malaria can be reduced by to-human transmission. died. Respiratory symptoms appeared changing from quinine to another drug: only during the last day of their lives. If the symptoms of H5N1 are more the results showed that artesunate In both cases, acute encephalitis diverse than previously thought, clinical reduced the death rate by 35 per cent. (brain inflammation) was reported surveillance might need to focus not as the cause of death. only on respiratory illnesses, but also on clusters of unexplained deaths or However, because the boy was severe illnesses. included in an ongoing research study, tissue specimens were taken. de Jong MD et al. Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by In November 2004, Menno de Jong coma. N Engl J Med 2005;352(7):686–91.

L–R Avian flu virus H5N1 has A group of red blood infected several people cells infected with the in South-east Asia and malaria paraiste. eastern Europe. The paediatric ward of Flu virus particles. Kilifi General Hospital in A patient with severe Kenya. malaria. ADVANCING KNOWLEDGE 11

AVOIDABLE DEATHS

Bacterial infections are a major – and avoidable – cause of death in African children.

Artesunate is already widely used as Invasive bacterial infections have 26 per cent were of children admitted part of a combination therapy, to treat been found to be the leading with invasive bacterial infections. This people with uncomplicated malaria. cause of death among children suggests that bacterial disease may These results indicate that it is also at a rural sub-Saharan district be causing more deaths in children effective against severe malaria. hospital. A new study, the largest than malaria, even in an area where As well as saving lives, artesunate is of its type ever undertaken in malaria is endemic. easier and safer to use than quinine – Africa, highlights the need for Extrapolation of these findings across and cheaper. Although the results for prevention and for overcoming sub-Saharan Africa would imply that adults are clear, more information is the political and financial barriers disease due to just two bacterial needed on its possible benefits for to widespread use of existing species, Haemophilus influenzae and children. Another multicentre clinical vaccines for bacterial diseases. Streptococcus pneumoniae, would trial, also funded by the Wellcome Trust, With little epidemiological data available account for nearly half a million deaths is underway to test whether it is equally on bacterial infections among children in children under five every year. Most effective in children in Africa – where in sub-Saharan Africa, James Berkley, of these deaths could be prevented severe malaria has its biggest impact. Anthony Scott and colleagues studied with the use of existing vaccines. Dondorp A et al. Artesunate versus quinine for every acute paediatric admission to Kilifi The study suggests that bacterial treatment of severe falciparum malaria: a District Hospital in Kenya. The team randomised trial. Lancet 2005;366(9487):717–25. diseases are more important to documented nearly 20 000 admissions, public health than has been thought – to assess the prevalence of bacterial a misperception that could explain infections and to identify the most the failure to prioritise the introduction common infectious organisms. of vaccines.

Of all childhood deaths, 22 per cent Berkley JA et al. Bacteremia among children were associated with malaria, but admitted to a rural hospital in Kenya. N Engl J Med 2005;352(1):39–47. ADVANCING KNOWLEDGE 12

HEARING AID OVERCOMING NEGLECT Thanks to universal screening of all newborn babies for hearing Drug treatment may help people problems, infants are being referred to specialist services earlier. whose vision and attention have been affected following a stroke.

A relatively new technique, to a delay before infants were referred When people suffer a stroke, they otoacoustic emission, can be to specialists. may have problems viewing things used to test hearing in all babies Following the successful trials of on one side of space – the side at birth (universal newborn universal newborn screening, it is being opposite that affected by the screening). A controlled trial of this introduced across the UK. Dr Kennedy stroke. Dr Masud Husain and approach, undertaken by Dr Colin and colleagues have now carried out colleagues have discovered that Kennedy and colleagues at the an eight-year follow-up on the babies this ‘hemispatial neglect’ can University of Southampton in the enrolled in the original trial. They found be improved by treatment 1990s, provided evidence of its that the proportion of all babies with with guanfacine. benefits, and an eight-year follow- permanent childhood hearing Guanfacine has previously been used up has confirmed that it ensures impairment referred before the age to treat high blood pressure. It also babies and families receive of six months increased from 11 of 35 acts on the brain, boosting the activity support as rapidly as possible. (31 per cent) without universal of neurons that use noradrenaline as Hearing difficulties in children are rare screening to 23 of 31 (74 per cent). a neurotransmitter. but can have a significant impact on The study re-emphasises the value of their social and intellectual development. universal screening in rapidly identifying There are advantages to early diagnosis, hearing impairments, so early help can so parents and health specialists can be given to the baby and parents. begin helping a child as soon as Kennedy C et al. Universal newborn screening possible. Babies used to have their for permanent childhood hearing impairment: an hearing tested early in life, but this led 8-year follow-up of a controlled trial. Lancet 2005;366(9486):660–2.

L–R A newborn baby: A representation of the screening soon after brain highlighting areas birth identifies children of the visual cortex. with impaired hearing. Colonies of Damage to one side of Staphylococcus aureus. the brain following a stroke visualised through two forms of brain imaging. ADVANCING KNOWLEDGE 13

FIFTIES SUPERBUG RETURNS A 1950s penicillin-resistant strain of Staphylococcus aureus is re-emerging in the community, now resistant to methicillin.

Dr Husain, a Wellcome Trust Senior Infections with methicillin- typing, or MLST), Dr Enright found Research Fellow in Clinical Science resistant S. aureus (MRSA) occur that community-acquired strains are at the Institute of Neurology, University most often in hospitals, but some, not ‘feral’ hospital strains, and have College London, tested the drug in with increasing frequency, are a different evolutionary history. Some people who had damage to the visual found in public places. These of the community strains are areas on the right side of their brains, community-acquired MRSA descended from the ‘type 80/81’ and suffered left hemispatial neglect. strains differ from hospital strains, strain, notable for being unusually The drug helped them find stimuli Dr Mark Enright (University of transmissible and virulent, and to their left, suggesting that this Bath and now Imperial College probably the most frequent cause kind of drug could be beneficial London) and colleagues have of severe staphylococcal disease in to individuals with impaired vision found, and some are descended the mid-to-late 1950s. At the time, and attention after stroke. from a penicillin-resistant strain the strain was sensitive to methicillin,

Malhotra PA et al. Noradrenergic modulation of that appeared in the 1950s and and so was suppressed when this space exploration in visual neglect. Ann Neurol was supposedly vanquished antibiotic was deployed in the 1960s. 2005 (Epub ahead of print). by methicillin in the 1960s. Now, however, the strain is re- emerging in the community, having Rather than affecting elderly gained resistance to methicillin. hospitalised patients, community- acquired MRSA seems to cause Although only about 100 cases of disease in children and young adults. community-acquired MRSA infection The strains involved are resistant to have been identified in the UK in the fewer antibiotics than hospital MRSA, last three years, such cases are more but produce a dangerous toxin that common in the USA, mainland Europe can cause large boils, septic shock and Australia, and the researchers or, in rare cases, a devastating point out that these strains could pneumonia that kills more than pose a serious public health challenge 40 per cent of those affected. in coming years. By comparing the ‘DNA fingerprints’ Robinson DA et al. Re-emergence of early pandemic Staphylococcus aureus as a of various MRSA strains (using a community-acquired methicillin-resistant clone. technique called multilocus sequence Lancet 2005;365:1256–8. ADVANCING KNOWLEDGE 14

WAR MEDAL PREVENTING DIABETES An account of British military medicine in World War II won British children of south Asian the 2004 Templer Medal Book Prize. origins show early signs of susceptibility to type 2 diabetes.

In Medicine and Victory: British Published by Oxford University Certain populations are known military medicine in World War Press, Medicine and Victory is the to be at particular risk of Two, Mark Harrison argues that first comprehensive account of British developing common diseases the medical services had a major military medicine in World War II since such as heart disease or diabetes. impact on the outcome of the the official history published in the early South Asians, for example, are war, and contributed to the Allied 1950s. It examines medical work in all particularly prone to type 2 victory, by enabling the British the main theatres of the war, from the diabetes. New research from Army to keep its troops in action. front line to the base hospital, and Dr Peter Whincup and colleagues covers all aspects of medical work, has revealed that signs of this Director of the Wellcome Unit for the including the prevention of disease susceptibility can be found in History of Medicine at the University and the treatment of casualties. schoolchildren. of Oxford, Dr Harrison was awarded the 2004 Templer Medal Book Prize Since it assumes no previous Dr Whincup’s team at St George’s for Medicine and Victory. The award knowledge of either medical or military Hospital Medical School, London, is made each year by the Society for history, Medicine and Victory provides compared various metabolic measures Army Historical Research to the book an accessible introduction to this often – such as blood glucose levels, that makes the most significant neglected aspect of warfare. response to insulin and amounts of contribution to advancing knowledge Medicine and Victory: British military medicine fat tissue – in British schoolchildren and understanding of the history of in World War Two. Oxford University Press 2004 of European and south Asian origin. ISBN 0199268592. the British Army.

L–R Evacuation of patients by Young boys in Kenya. jeep in World War II. Audience participation at Testing for diabetes in the 2005 Global Forum Tower Hamlets. on Bioethics in Research Monitoring blood meeting in Malawi. glucose levels. ADVANCING KNOWLEDGE 15

GLOBAL ETHICS

Researchers and sponsors do have obligations to their study populations after trials end, but the exact nature of these is open to debate.

The Asian children had significantly The Sixth Global Forum on in underdeveloped countries will have higher insulin and blood glucose levels. Bioethics in Research, organised gained benefits during a trial – such They also had slightly higher measures by the Wellcome Trust and held as access to medicines or better of fat tissue, but even when this was in Malawi in March 2005, saw healthcare. Afterwards, should the factored out, their insulin and blood constructive debate on the body funding the research continue glucose measures remained obligations of researchers and to provide these benefits? If so, for how abnormally high. sponsors working in developing long? Indefinitely? The results suggest that the south countries. While some issues were easy to agree Asian children are showing early signs The Global Forum on Bioethics on, for others consensus was hard to of insulin resistance and raised blood in Research is an informal partnership find. Nevertheless, informed debate glucose levels – classic signatures of established by a number of involving such a range of parties, type 2 diabetes. Whether the causes organisations with a shared interest in from such different cultures and are genetic or environmental (or a the ethics of research involving people backgrounds, was fruitful in identifying combination) is unclear, but the findings in developing countries. key issues and moving the field along. suggest that diabetes prevention Representatives from some 40 The meeting also coincided with the measures should be targeted countries attended the meeting, launch of the Wellcome Trust’s position particularly early in these populations. from as far afield as South America, statement on international research Whincup PH et al. British South Asians aged Australasia, Mongolia and China, as ethics and the publication of a report 13–16 years have higher fasting glucose and insulin levels than Europeans. Diabet Med well as Africa and Europe. Delegates from the Nuffield Council on Bioethics 2005;22(9):1275–7. represented almost every discipline (which is part-funded by the Wellcome and group with an interest in this area: Trust) on good ethical practice in the biomedical researchers, clinicians, developing world. ethicists, lawyers, community Position statement: representatives and others. www.wellcome.ac.uk/node3305.html Nuffield Council on Bioethics – The Ethics of Under discussion was the Research Related to Healthcare in Developing responsibility different groups might Countries: www.nuffieldbioethics.org/go/ourwork/ developingcountries/introduction have after a research project has Short report on sixth meeting: ended. Usually, study populations www.wellcome.ac.uk/doc_wtx027728.html

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

BREATHTAKING NEW FACES

A person’s breathing rate can be measured from his or her fingertip. A revolutionary new implant is helping surgeons to rebuild damaged faces.

It is often vital to measure an the researchers realised that some of A pioneering polymer and mineral individual’s respiration rate but the the regular patterns in the signal were implant, which readily bonds with equipment involved, such as face caused by the person’s breathing. bone without causing adverse masks or an electrocardiogram, is By refining their software, they were reactions, has helped surgeons cumbersome and expensive. Now, able to measure both respiratory rate to rebuild the faces of children thanks to new software, accurate and respiratory effort automatically, injured in accidents or born measurements can be obtained continuously and non-invasively. with serious disfigurements. from a monitoring device already Recent clinical trials on premature Developed by UK and Russian widely used in hospitals. babies have confirmed the effectiveness scientists, ‘PolyHap’ implants have been used on around 50 Professor Paul Addison and of the technique. The next step is to children, including a baby with a colleagues at Napier University in design a pulse oximeter in which this jaw tumour and a 12-year-old girl Edinburgh hit upon their innovation extra measuring facility is already an who had been barely able to open while analysing the signals from a integral part. her mouth from birth. pulse oximeter – a medical device This technology was developed by used to measure oxygen saturation researchers at CardioDigital Ltd – a The PolyHap implants combine a and heart rate. A light probe is clipped company set up in 2001 by Professor polymer commonly used in dentistry to the person’s finger, and transmitted Addison, Dr Brendan McGuckin and and a mineral-like substance called light is detected and analysed. Dr Jamie Watson. In the longer term, hydroxyapatite, which can integrate Using a relatively new technique, they aim to develop other tools to into bone structures and support wavelet transform, to analyse the extract extra useful information from bone growth without breaking down pulse oximeter signal (called the medical signals. or dissolving. The collaborating scientists also found a way to increase photoplethysmogram or pleth), www.cardiodigital.com porosity – important for new bone growth – and to clean out toxins from the polymer implants using high-pressure carbon dioxide.

L–R Patterns in data collected A cross-section through by pulse oximeters can a new tooth grown in shed light on other a mouse, showing physiological activity. differentiation of dentine PolyHap implants (D), pulp (P) and the have been successfully root (R). used to rebuild children’s faces. USING KNOWLEDGE 19

THE BIOTOOTH

Advances in tissue engineering could enable people who lose a tooth to grow a replacement, made of their own cells, in their own mouths.

The implants were developed by After the age of 50, people in incisors and so on), and even attach teams led by Dr Vladimir Popov from Western countries lose an average themselves to the jawbone by soft the Institute of Laser and Information of 12 teeth. At present the options connective tissue. If left long enough, Technology in Troitsk, near Moscow, are to replace them with dentures the teeth form roots and erupt. and Professor Steve Howdle of or an artificial implant. Researchers Having demonstrated the feasibility Nottingham University. are investigating the possibility of of this technology in the mouse, the When a child is assessed for an replacing a lost or damaged tooth researchers now aim to move the operation at the St Vladimir Children’s with a living, natural tooth created science established in the mouse into Hospital, Moscow, scientists use from the patient’s own tissue, and commercial product development – advanced imaging and laser-based grown in its intended location in and test the ‘BioTooth’ in humans. the patient’s mouth. techniques (laser stereolithography) Crucial to the success of the BioTooth to create a three-dimensional plastic To achieve this, in 2002, Professor is the need to identify an effective cast of the damaged area. Having Paul Sharpe at the Dental Institute, and easily accessible source of the assessed, with the surgeon, how King’s College London, founded individual’s own cells to use as raw much bone needs to be removed, a regenerative dentistry company, material. This avoids rejection by the the scientists then mould the Odontis Ltd, with a Wellcome Trust immune system, and because tooth individual PolyHap implants. technology transfer grant. The size, shape and colour are genetically Current Wellcome Trust-funded company is dedicated to growing determined, it also means the research is targeted at the use of a human teeth by studying the complex engineered teeth will more closely new laser-based process (sintering) formative processes that produce match the person’s natural teeth. teeth in a developing embryo – and to create implants from biodegradable Having tested the potential of various combining this understanding with polymers and incorporating very cell types, the researchers found that advances in stem cell biology and delicate growth hormones to improve adult stem cells derived from bone tissue engineering. the performance of the implants. marrow can replace embryonic Popov VK et al. Laser stereolithography and Experiments in mice have shown that mesenchyme in the tooth formation supercritical fluid processing for custom-designed if the two different types of cell that implant fabrication. J Mater Sci Mater Med process. Other research suggests 2004;15(2):123–8. produce a tooth bud in an embryo – that progenitor stem cells capable of epithelial and mesenchymal cells – are generating a variety of tooth tissues, combined in culture, then implanted including enamel, could be present in an adult mouth, new teeth start to within teeth themselves. form. Moreover, the teeth form in the Modina S, Sharpe PT. Tissue engineering of correct orientation, are the right size teeth using adult stem cells. Arch Oral Biol and shape for their location (molars 2005;50(2):255–8. are shaped like molars, incisors like USING KNOWLEDGE 20

TACKLING NEGLECT VIRAL DETECTION Innovative new approaches are fundamentally changing the way A new visual dipstick test can neglected diseases are tackled, a new report suggests. detect HIV, hepatitis B and hepatitis C simultaneously.

A team from the London School The Moran report identifies PPPs as a A team from the Department of of Economics and Political critical driver of this increase in activity, Haematology at the University of Science, led by Dr Mary Moran, and suggests that they deserve the Cambridge has created a dipstick has documented dramatic change active support of policy makers system for detecting multiple viral in research into ten ‘neglected and politicians. Dr Moran’s team infections. The system is sensitive, diseases’, including malaria, recommends the creation of a public simple and does not require the tuberculosis, leprosy and sleeping fund to pay for research and specialised equipment currently sickness. These changes could development of drugs for neglected needed to test blood samples result in at least eight new drugs diseases within PPPs, which they for HIV and hepatitis. being developed by 2010. estimate would cost up to £1.1 billion Dr Helen Lee and colleagues have (US$1.9 billion) over ten years. After a barren period when very few previously developed a cheap and therapies were introduced for these The report also argues that a package easy-to-use diagnostic dipstick test for diseases, which kill around three million of incentives should be established chlamydia, an important and difficult-to- people a year and cause the loss of to encourage research by small or diagnose sexually transmitted infection. the equivalent of 92 million years of medium-sized companies, which are Now, the group has adapted the healthy life, there are now more than increasingly important players in the technology to detect viruses and 60 drug research projects underway. neglected disease field. multiple infections. Around three-quarters of these projects PDFs of an executive summary and the full Current testing for HIV and hepatitis are conducted under the umbrella of report (The New Landscape of Neglected Disease Drug Development) can be found involves fluorescent probes designed public–private partnerships (PPPs) for at www.wellcome.ac.uk/doc_wtx026606.html. drug development.

L–R Drug development Professor Bob Snow, for neglected diseases with Dr Sam Ochola, has been boosted Head of the Division of significantly by public– Malaria Control in Kenya. private partnerships. The malaria parasite Hepatitis B virus within red blood cells. particles. USING KNOWLEDGE 21

MAPPING MALARIA

More than half a billion cases of deadly Plasmodium falciparum malaria occurred in 2002 – suggesting that malaria is an even bigger problem than previously thought.

to bind to viral nucleic acids (DNA Professor Bob Snow and his use of new methods in geographic and RNA). Not only is this procedure team, at the University of Oxford information systems and data from expensive and time-consuming, it and the Kenya Medical Research Earth-orbiting satellites. also requires special instruments. Institute–Wellcome Trust According to the new analysis, more Dr Lee’s team developed a new Laboratories in Nairobi, have than two-thirds of cases occurred in dipstick for HIV-1, hepatitis B and used a variety of methods to Africa, where P. falciparum malaria hepatitis C, all major global public calculate the likely number of mostly affects children under five. health problems. The dipstick was cases of malaria in a single year, But far more cases than previously tested on clinical samples, after 2002. Their estimate of 515 million thought take place outside Africa, amplification of viral nucleic acid. clinical episodes of P. falciparum with nearly 25 per cent of worldwide It detected many different strains of suggests that tackling malaria will cases occurring in South-east Asia the viruses, and produced sensitive, require even greater attention than and the Western Pacific. reproducible and specific results. governments and health agencies might have anticipated. Although the numbers remain As it does away with the need for estimates, they provide a more complex instrumentation, the dipstick The latest estimates used accurate picture of the likely global could potentially be of great benefit, contemporary and historical burden of malaria – important if the particularly in resource-poor settings. epidemiological, geographical and disease is to receive the public health Dineva MA et al. Simultaneous visual detection of demographic information to model priority it deserves. multiple viral amplicons by dipstick assay. J Clin where people live, the likelihood Microbiol 2005;43(8):4015–21. Snow RW et al. The global distribution of clinical that they become infected, and episodes of Plasmodium falciparum malaria. their susceptibility to developing Nature 2005;434(7030):214–7. the disease. The models also made

ENGAGING SOCIETY Engaging with society to foster an informed climate within which biomedical research can flourish. ENGAGING SOCIETY 24

LITTLE AND LARGE TEACHING PROFESSIONALS Contrasting topics – nanoscience and obesity – were covered in the The completion of the National Science first issues in the Big Picture series for teachers and post-16 students. Learning Centre heralds a new era for teachers’ professional development.

The Big Picture series was influences on weight control, as well as If UK science is to flourish, it launched in January 2005, the personal and social consequences needs trained and motivated successor to LabNotes. The of rising levels of obesity. It also science teachers armed with publication provides teachers encouraged readers to consider who up-to-date knowledge and skills. and post-16 students with should take responsibility for tackling The new National Science up-to-date information on key this mounting problem. Learning Centre funded by the areas of biomedical research, Issues and supplementary materials Wellcome Trust, and a key report while exploring their social and are freely available on the Wellcome commissioned by the Trust, ethical implications. Trust website. The obesity issue also represent important contributions to achieving this essential aim. The nanoscience issue focused features an interactive online game on the science and application of for students, who have to raise an Science teachers face considerable nanotechnologies, engineering at ‘Ob’, an alien life form with a tendency challenges. They have to train the next scales smaller than 100 nanometres to become obese. The nanoscience generation of scientists and engineers, (for comparison, a human hair is issue also included an online activity – but also equip non-specialists with the 80 000 nm wide). Many exciting a version of a ‘Democs’ game, which knowledge and skills they need to thrive opportunities exist, but the strange enables classes to debate the in a technologically advanced society. properties of material at such scales regulation of an emerging area such They need to keep abreast of the take us into areas of unknown risk. as nanotechnology. potential offered by new technologies. The obesity issue looked at www.wellcome.ac.uk/bigpicture And, above all, they need to stay up to physiological, psychological and social speed with a rapidly changing subject. Little wonder that teachers’ professional development has become a key issue. It received a major boost with the decision of the Wellcome Trust and the Department for Education and Skills in 2002 to co-fund a £51 million initiative to develop a national network of Science Learning Centres, intended to provide high-quality continuing

L–R Nanometre-sized crystals Elia Alba’s Doll Heads created at the University (Multiplicities), 2001, of Cambridge. from the Future Face The newly opened exhibition. National Science Learning Centre at York. ENGAGING SOCIETY 25

FACE-TO-FACE WITH THE FACE More than 125 000 visitors attended a major exhibition at the Science Museum exploring the human face.

professional development (CPD) Future Face, a Wellcome Trust Curated by Sandra Kemp, Director of opportunities for science teachers exhibition at the Science Museum Research at the Royal College of Art, and technicians. in London, was a thought- the exhibition was named one of the In 2004/05, the building housing provoking and occasionally Times Higher Education Supplement’s the National Science Learning Centre challenging look at faces and the Research Projects of the Year. It was was completed. Based in York and impact they have on others. Its accompanied by a book and CD- managed by the White Rose imaginative juxtaposition of ROM, and was complemented by Consortium, comprising the Universities medical objects and imagery, debates and discussions, a ‘Face on of Leeds, Sheffield, York and Sheffield artworks old and new, and Film’ weekend held in November 2004 Hallam, the Centre is set to provide an scientific discovery provided many at the Curzon Mayfair, and other unrivalled facility for teachers from both novel insights into the everyday yet special events in venues throughout primary and secondary schools. still mysterious phenomenon of London (including the Science faces and face recognition. Museum’s Dana Centre). What of its intended clientele? In 2005, the Wellcome Trust commissioned a Running from October 2004 to A ‘Facing Death’ symposium, held major survey of primary and secondary February 2005, Future Face was the at the National Portrait Gallery in school teachers in England’s state final exhibition in a series mounted January 2005, brought together schools, to establish their experience by the Wellcome Trust at the Science dynamic voices from the worlds of art of CPD, what they wanted from Museum. It explored several history, media, medicine and science CPD, and what obstacles prevented fundamental questions about the to discuss the past, present and future greater participation. human face. What makes a face? of the facial representations of death. Why are faces so important to our Future Face: Image, identity, innovation is While most respondents were strongly sense of identity? And how do people published by Profile Books in association with supportive of CPD in principle – and the Wellcome Trust and can be ordered via Profile react to damaged and different faces? Books at www.profilebooks.co.uk or +44 (0)20 particularly wanted more subject- 7421 6172. Price £12.99. ISBN 1 86197 768 9. The exhibition also explored the specific courses – they were not The Future Face CD-ROM can be ordered satisfied with current opportunities. modification and reconstruction of the by emailing [email protected]. Price: face for medical or cosmetic reasons, £10.00 for a pack of five, including postage and Science teachers were least confident packing. ISBN 1 84129 050 5. in their current expertise and most and considered what faces might look keen to enhance their skills. like in the future.

The CPD report can be found at www.wellcome.ac.uk/believers. ENGAGING SOCIETY 26

THE PAST DISSECTED INNOVATIVE DEBATES The Hunterian Museum offers a ghoulish but instructive vision Informed public debate lay at of medicine past. the heart of three projects run in 2004/05.

The Hunterian Museum at the an extensive museum, which he used A Pop Idol-style debating Royal College of Surgeons, for teaching and for research on topics competition for sixth-form and which reopened in February as diverse as the transplantation of further education college students, 2005, provides visitors with a teeth and the breeding of bees. After provocative online debates chance to see the equipment his death, the collection was given to organised by Spiked Online, and used for the first ‘keyhole’ gall the Royal College of Surgeons. a series of public debates at the bladder removal in England, The museum is open to the public, Institute of Contemporary Arts preserved crocodile embryos, free of charge, Tuesday to Saturday – (ICA) in London all helped a variety and a prototype ‘bionic’ heart, or virtual tours can be undertaken on of public groups to consider the among more than 3500 the Royal College of Surgeons website. future of biomedical science. fascinating exhibits. The refurbishment of the Hunterian Winstanley College from Wigan At the heart of the Hunterian Museum Museum was funded by the Wellcome won the 2005 ‘Debating Matters’ is an astonishing 18th-century medical Trust, the Heritage Lottery Fund, the competition, run by the Institute of collection – the legacy of the ground- Royal College of Surgeons, the Ideas with support from a Wellcome breaking anatomist and surgeon John Hunterian Trustees and others. Trust Engaging Science Society Award. Hunter FRS (1728–1793). He built up The competition brings together www.rcseng.ac.uk/museums/ students from all backgrounds to debate topical scientific issues. Before announcing their decision, the judges give each student and team Pop Idol- style feedback on their performances and arguments. The competition is being run again in 2005/06, with heats being held across the UK.

L–R A selection of exhibits at Public participation is the newly reopened helping researchers to Hunterian Museum. understand the genetic Encouraging contribution to sleep schoolchildren to find out patterns. about and debate issues surrounding science. ENGAGING SOCIETY 27

HANDS ON SCIENCE

Members of the public have gained first-hand experience of biomedical research, thanks to People Awards.

With Wellcome Trust support, online Research developments in body Webb, Vivienne Gaskin and Professor publisher Spiked ran a series of web- clocks, genes affecting language Amanda Fisher of Imperial College. based debates and public events on and keyhole surgery have been A working DNA sequence lab was topics such as global outbreaks of among the exciting scientific installed at the ICA, enabling visitors infectious disease, drugs and health, areas featured in Engaging to see researchers in action, talk to and complementary medicine. These Science People Awards. With scientists and help in the analysis experiments highlighted the these small but flexible awards, of results. possibilities offered by the web to researchers have been able to School students are a crucial audience engage large numbers of people in engage members of the public for public engagement. A project constructive debate. directly with science. organised by Professor O James The ICA public debates included From September to November 2004, Garden, Stephen Wigmore and ‘Open Access Science’ (January Dr Simon Archer and colleagues at Andrew de Beaux at the University of 2005), ‘Science and Democracy’ the University of Surrey gave visitors Edinburgh has given children a chance (March 2005), which explored how to the Science Museum a chance to to try their hand at surgical procedures the public can feed into scientific policy participate directly in a research project. such as keyhole surgery and suturing. making, and ‘The Trouble with Boys’ The Surrey team has been exploring There is a competitive element to the (September 2005), examining what can the genetic links to body clocks – project, with students being assessed be done about the current educational circadian rhythms – particularly whether for speed and accuracy. and emotional underdevelopment of people are at their best in the morning People Awards provide sums boys. Featuring leading scientists, (‘larks’) or at night (‘owls’). Visitors of up to £30 000 for innovative authors, commentators and politicians, completed questionnaires on their daily public engagement projects. They the debates enabled public audiences habits and provided mouth swabs for are designed to be a fast and flexible to get to the heart of some of today’s DNA analysis. way of providing support to scientists, key socioscientific issues. Participation was also central to a science communicators or other project run at the Institute of mediators keen to work with Contemporary Arts (ICA) by Dr Julie public groups. DEVELOPING PEOPLE Fostering a research community and individual researchers who can contribute to the advancement and use of knowledge. DEVELOPING PEOPLE 29

THE TAIL OF A SPACE TO DEGRADING ACTIVITY THINK A protein complex that accelerates an important nuclear RNA- In the brain, the hippocampus processing machine has been identified. deals with memories of spatial but not social relationships.

The exosome is one of the were found: a cytoplasmic form The hippocampus is vital cell’s fundamental machines. that is involved in the turnover of for memory, but researchers It processes and trims precursor messenger RNA (mRNA), and the disagree on its exact role. Now, RNAs, making them ready for version in the nucleus that processes Dr Dharshan Kumaran and Senior use by the cell. At the University nuclear pre-mRNAs, ribosomal RNAs, Research Fellow Dr Eleanor of Edinburgh, Professor David small nuclear RNAs and small Maguire have shown that it is Tollervey, a Wellcome Trust nucleolar RNAs. active when people visualise Principal Research Fellow, and On its own, in a test-tube, the navigating to different locations colleagues have now identified a exosome works rather slowly, so but not when they imagine complex of proteins that speeds it was thought that its activity in networks of friends. up the exosome’s work. cells might be boosted by additional Dr Maguire has previously shown Eukaryotic cells produce a huge factors. Professor Tollervey’s team that taxi drivers have notably large amount of RNA, but this is seldom has now found such an accelerating hippocampi, presumably because used ‘as is’. In most cases, long factor: the TRAMP complex (short for of their need to carry about ‘the precursor RNAs need to be trimmed the Trf4p/Air2p/Mtr4p polyadenylation knowledge’ of London landmarks. and cut up into mature forms that complex) adds a poly(A) tail to But does the hippocampus store a can be used as templates for protein defective ribosomal RNAs and small ‘virtual map’ of the physical world or is synthesis or as components of the nucleolar RNAs, which promotes their it recalling relationships between objects protein factories themselves, the degradation in the nucleus by the in a more generic way? exosome. This system shows notable ribosomes. To compare these theories, Dr Kumaran similarities to RNA degradation in In 1997, Professor Tollervey and and Dr Maguire used functional bacteria, suggesting that it is of colleagues identified the complex magnetic resonance imaging to reveal ancient evolutionary origin. of ten exonuclease proteins – the which parts of participants’ brains were exosome – that plays a key role in this LaCava J et al. RNA degradation by the active as they visualised the route exosome is promoted by a nuclear processing, as well as in degrading polyadenylation complex. Cell between their friends’ houses and then defective RNAs that fail quality control 2005;121(5):713–24. the social connections between the checks. Two forms of the exosome friends themselves. The tasks activated separate brain networks, with the hippocampus involved only in spatial, not social, processing.

Kumaran D, Maguire EA. The human L–R hippocampus: cognitive maps or relational Professor David memory? J Neurosci 2005;25(31):7254–9. Tollervey, University of Edinburgh. Dr Eleanor Maguire, Institute of Neurology, University College London. DEVELOPING PEOPLE 30

AS SIMPLE AS APC LEFT–RIGHT HEART A protein complex instrumental in regulating the cell cycle Genes that control the asymmetry has a previously unsuspected role in the nervous system. of the heart may underlie common congenital heart defects.

By controlling protein degradation, Not much is known about this process About one child in 125 is born the anaphase-promoting in neurons, but it has been studied for with a congenital heart defect – complex/cyclosome (APC/C) is many years in dividing cells. A key a problem with the development crucial to the normal functioning component is the APC/C complex of the heart itself or of the major of the cell cycle in many different of proteins. Dr Brand and colleagues blood vessels that connect to organisms. Dr Andrea Brand and looked to see if this complex might the heart. Professor Shoumo colleagues at the Gurdon Institute also be active in neurons at the Bhattacharya’s studies of the of Cancer and Developmental neuromuscular synapses, where nerve mouse gene Cited2 suggest that Biology in Cambridge have meets muscle, in the fruit fly Drosophila. many such defects may be due shown, unexpectedly, that the They found that the APC/C has to problems with the development APC/C also plays an important two highly significant effects – on the of the heart’s asymmetry. role at synapses, the junctions size of synapses and the transmission During embryonic development, the between neurons, and hence in of signals across them. The APC/C heart begins as a single tube that then nervous system function. acts on muscle cells, regulating the ‘loops’ and contorts, eventually forming The activity of neurons is very finely number of receptors for glutamate, a the four chambers of the adult heart. controlled. An important aspect of this neurotransmitter released by neurons This is necessary for two parallel control, it has recently become clear, innervating the muscle. circulations to develop: the right side comes from tight regulation of protein The discovery of APC/C activity at the of the heart delivering blood to the levels within cells. One way this can synapse opens up a new area of study lungs, the left side delivering blood to be achieved is through the ubiquitin of this key aspect of animal biology. the body. Common congenital heart system, which tags proteins for defects arise when this development van Roessel P et al. Independent regulation of degradation within the cell. synaptic size and activity by the anaphase- goes awry, leading to, among other promoting complex. Cell 2004;119(5):707–18. things, holes in the heart, closed valves, or misalignment of the great vessels.

L–R A neuromuscular Computer-generated synapse (yellow) formed images of the mouse between a neuron (red) heart. and its target muscle Manipulating four-cell (green). The muscle embryos. nuclei and tracheal tubes are labelled in blue. Labelling of individual cells in a four-cell Professor Shoumo mouse embryo. Bhattacharya, University of Oxford. DEVELOPING PEOPLE 31

EARLY DEVELOPERS

The fate of cells in the mouse embryo is influenced by their first divisions.

Professor Bhattacharya, a Wellcome Somehow, a single cell – the the first cell cleavage predicts the Trust Senior Research Fellow at the fertilised egg – has to generate ‘embryonic–abembryonic’ axis – Wellcome Trust Centre for Human an entire adult body, with all its one daughter cell tends to give rise Genetics in Oxford, has found that body parts in the right place. In to tissues of the animal, plus some the Cited2 gene plays a key role in many organisms, the asymmetric surrounding tissues, while the other the left–right patterning of the mouse distribution of key factors in the tends to generate cells that will form heart. Highly inbred (genetically very egg establishes polarities such supporting tissues and others that similar) mice lacking Cited2 had severe as the front-to-back axis. In will signal how the body should heart defects – the left side of the mammals, though, this process develop. But whether or not this heart developed as a right side, a is more flexible and poorly happens depends on the pattern condition called right isomerism that understood. Dr Magdalena of cleavage divisions. also occurs, rarely, in humans. Non- Zernicka-Goetz and colleagues Dr Zernicka-Goetz also discovered pedigree mice lacking Cited2 had a have now shown that despite this that it was possible to predict the range of less severe heart defects, flexibility, early patterns of cell future development of cells in four-cell such as holes in the heart and division in mice can influence embryos that had divided following a misalignment of the great vessels. the course of development. certain pattern. Moreover, the progeny As the defects seen in the latter mice Dr Zernicka-Goetz, a Senior Research of each of the four cells had different are similar to the diverse range of Fellow at the Gurdon Institute of developmental properties – congenital heart defects seen in Cancer and Developmental Biology contradicting received wisdom that all humans – who are also ‘non-pedigree’ in Cambridge, carefully manipulated four cells are equivalent at this stage. – the research suggests problems with one-cell mouse embryos before they Remarkably, however, all cells in the heart’s left–right patterning may be divided. Her aim was to alter the plane embryos retain developmental flexibility at fault in both cases. of cell division, or how the contents and so these properties are not fixed Bamforth SD et al. Cited2 controls left–right of the cell are partitioned between until later. patterning and heart development through a daughter cells, and to use cell labelling Plusa B et al. The first cleavage of the mouse Nodal–Pitx2c pathway. Nat Genet zygote predicts the blastocyst axis. Nature 2004;36(11):1189–96. techniques to see what happened 2005;434(7031):391–5. to the progeny of each cell. Piotrowska-Nitsche K et al. Four-cell stage mouse Using such techniques she was blastomeres have different developmental properties. Development 2005;132(3):479–90. able to show that, in most embryos, FACILITATING RESEARCH Promoting the best conditions for research and the use of knowledge. FACILITATING RESEARCH 33

BENCH TO BEDSIDE PROTEIN POWER Wellcome Trust Clinical Research Facilities have hosted a wide range The Structural Genomics of clinically important research. Consortium has published the structures of over 100 proteins.

Based at Birmingham, Cambridge, Cambridge has hosted a number of Proteins are responsible for most Edinburgh, Manchester and important studies on body metabolism cellular functions that underlie life, Southampton, Wellcome Trust and obesity, including work that and are the targets of most drugs. Clinical Research Facilities (CRFs) identified an unsuspected role for They are therefore crucial to our were set up to provide much- the TrkB protein in human obesity.5 health. To advance basic and needed space in a hospital setting Southampton’s Clinical Research applied research on proteins, the for research involving people. Facility has hosted research in a wide Structural Genomics Consortium Studies carried out in the facilities range of areas, from the genetic basis (SGC), a not-for-profit company, is are helping to clarify mechanisms of resistance to hepatitis C virus6 and determining the three-dimensional of disease, and providing results susceptibility to osteoarthritis,7 to the structures of proteins of medical of direct clinical relevance. effect of food additives on hyperactivity relevance, and placing them in the 8 public domain without restriction. In Edinburgh, for example, the CRF in children. has hosted numerous studies on Research carried out in Manchester The SGC applies a high-throughput a large cohort of elderly Scottish has identified genetic variations that approach to structure determination, people, who underwent a series predispose to early-onset arthritis and concentrating on human proteins likely of mental examinations in the 1930s. psoriasis.9,10 The facility was also used to be of medical importance and These studies are providing a wealth for studies of brain function in people proteins from pathogenic organisms, of information on early and mid-life with antisocial personality disorder such as the malarial parasite. factors linked to cognitive decline (psychopathy) and borderline The structures are freely released, 1,2 in the elderly. Of more immediate personality disorder.11 creating a valuable resource for clinical relevance was a trial of statin 1 Gow AJ et al. BMJ 2005;331:141–2. academic research and drug discovery. therapy for calcific aortic stenosis, the 2 Shenkin SD et al. Psychol Bull During 2004/05, the SGC has been 3 build-up of deposits on heart valves. 2004;130(6):989–1013. highly successful, achieving its first- 3 Cowell SJ et al. N Eng J Med One of the Birmingham CRF’s 2005;352(23)2389–97. year milestone of 50 human and specialisms is gene therapy. It has, 4 Searle PF et al. Clin Exp Pharmacol Physiol malaria protein structures on budget for example, tested an approach to 2004;31:811–6. and two months ahead of schedule. cancer gene therapy in which cancer 5 Yeo GSH et al. Nat Neurosci 2004;7:1187–9. By year-end it had completed well cells are engineered to make a pro- 6 Khakoo SI et al. Science 2004;305:872–4. over 100 structures. 4 7 Jordan KM et al. J Rheumatol drug-metabolising enzyme. 2005;32:678–83. The SGC has been funded by the 8 Bateman B. Arch Dis Child 2004;89:506–11. Wellcome Trust, GlaxoSmithKline and 9 Donn R et al. Arthritis Rheum a group of Canadian funding agencies. 2004;50:1604–10. 10 Donn RP. J Invest Dermatol (in press). Earlier this year Swedish funders joined L–R 11 Vollm B et al. Crim Behav Ment Health the SGC and a Swedish node was A whole-body scanner 2004;14:39–55. launched at the Karolinska Institute. at the Cambridge Clinical Research Facility. www.thesgc.com Structure of the human enzyme GDP-D-mannose 4,6-dehydratase. FACILITATING RESEARCH 34

TALKING ABOUT TRITRYP DIABETES GENOMES A new website captures the life stories of people with diabetes, The genomes of parasites causing in freely available audio recordings. three major diseases in developing countries have been sequenced.

A new website, An Oral History of they had benefited from past research The Wellcome Trust Sanger Diabetes, features the recollections and so were glad to contribute to Institute played a major role in of 50 people diagnosed with future research. Their audio recordings the sequencing of the genomes diabetes between 1927 and 1997. provide a resource for historians, of Trypanosoma brucei and They talk with passion and humour healthcare professionals, people Leishmania major, two of the about their daily lives, providing with diabetes, and anyone interested three ‘tritryp’ genome sequences a unique oral history of diabetes in exploring the human aspect of living published in 2005. during the 20th century. with diabetes. Together, they provide Known as ‘neglected diseases’ a unique historical overview of The website provides full, unedited because relatively little effort has been treatments and medical developments recordings, short audio samples, applied to finding cures, diseases during the 20th century. written summaries, full transcripts, caused by T. brucei, its South American and ways of locating sections of the An Oral History of Diabetes is based at the relative T. cruzi and Leishmania together Oxford Centre for Diabetes, Endocrinology and interviews that cover particular topics. Metabolism; it is funded by the Wellcome Trust kill more than 150 000 people every and run by Professor David Matthews, University year, and debilitate millions more. Most participants agreed to talk about of Oxford. their experiences because they felt www.diabetes-stories.com One of the most surprising findings revealed by the genome sequencing was the extent of antigenic diversity coded within the T. brucei genome. To evade host immune responses, the parasite periodically switches its surface protein coat. Its genome has turned out to contain far more coat protein genes than was previously thought, enhancing its ability to escape the attention of the immune system. The T. brucei and Leishmania genomes were sequenced at the Wellcome Trust Sanger Institute, in partnership with the Karolinska Institute, Stockholm, the Seattle Biomedical Research Institute, and The Institute for Genome Research in the USA. L–R Photographs from the Single-celled Oral History of Diabetes trypanosome parasites. website. A get-together for Dr Al Ivens, one of the children from the team at the Sanger ALSPAC cohort. Institute that sequenced the ‘tritryp’ genomes. FACILITATING RESEARCH 35

CHILDREN’S GIFTS

Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) continue to provide insight into many areas of medicine.

In partnership with sequencing centres The ALSPAC study team has protective immunity. In ALSPAC and the World Health Organization’s followed around 14 000 children children, salivary IgA levels against Special Programme for Research and and their parents from before a range of meningococcal antigens Training in Tropical Diseases (TDR), birth. The children are now increased with age, suggesting that the Wellcome Trust produced a CD- around 13–14 years old. IgA is important in host defence ROM package including the three Throughout this time, detailed against meningococci.3 genome sequences, genome-browsing information has been gathered Bone mass in later life is related software, PDFs of the Science articles, about their health and lifestyle. to birth weight, suggesting that the background material, and introductory The cohort’s size, and the range environment in the womb influences tutorials on parasite biology and their of information gathered, means later bone development. In ALSPAC diseases. The CD-ROMs are available that many health-related families, several aspects of maternal from TDR free to researchers in associations can be explored. diet in pregnancy were linked to developing countries. Exposure to mercury is known children’s bone mass and other The Sanger Institute also published to affect childhood cognitive measures at age nine, suggesting the sequence of Theileria annulata, development and early motor skills. that maternal diet is programming a parasite of cattle that has a There have been fears that thimerosal bone development in childhood devastating impact on farming, – a mercury-containing preservative (although the effect sizes are small).4 particularly in sub-Saharan Africa. used in some children’s vaccines – Paracetamol use in late pregnancy has Clues to the organism’s biology might harm young children. Use of been linked to an increased risk of early revealed by the genome sequence ALSPAC data, however, revealed no wheezing in offspring. Further work on are suggesting new approaches link between exposure to thimerosal the ALSPAC cohort confirmed that use to drug and vaccine development. and poor cognitive performance.1 of paracetamol, but not aspirin, in late Ivens AC et al. The genome of the kinetoplastid In another ALSPAC analysis, pregnancy was associated with parasite, Leishmania major. Science 2005;309(5733):436–42. depression in fathers was associated asthma. If the association is causal, Berriman M et al. The genome of the African with adverse emotional and as much as 7 per cent of childhood trypanosome Trypanosoma brucei. Science behavioural outcomes in children asthma could be put down to 2005;309(5733):416–22. paracetamol exposure.5 Pain A et al. Genome of the host-cell transforming aged 3.5 years, and an increased parasite Theileria annulata compared with T. risk of conduct problems in boys. 1 Heron J et al. Pediatrics 2004;114(3):577–83. parva. Science 2005;309(5731):131–3. Paternal depression thus seems 2 Ramchandani P et al. Lancet to have a specific and lasting effect 2005;365(9478):2201–5. 2 3 Horton RE et al. Epidemiol Infect on children’s early development. 2005;133(5):883–9. Up to a third of people carry Neisseria 4 Tobias JH et al. Osteoporos Int 2005 (in press). meningitidis, but rates of invasive 5 Shaheen SO et al. Clin Exp Allergy 2005;35(1):18–25. meningococcal disease are fairly low – ALSPAC is jointly funded by the Wellcome Trust possibly because of naturally acquired and the Medical Research Council. DEVELOPING OUR ORGANISATION Using our resources efficiently and effectively.

STRATEGIC PLAN INVESTMENTS ONLINE APPLICATION The Wellcome Trust has published Active management of our A new online grant application its second Strategic Plan, Making portfolio of investments has seen system, eGrants, was launched a Difference, covering the period its value rise to £12.3 billion. in 2005. 2005–2010. Our funding is made possible by the Launched in February 2005, the Our Strategic Plan sets out our aims, income derived from our asset base – eGrants system has proved a popular objectives and priorities for the next a mixed portfolio of property, equities option with grant applicants. It has five years. Its title, Making a Difference, and other forms of investment. The been developed in close partnership reflects our desire to continue making a asset base is managed both to secure with institutional administrative offices significant impact in our areas of our long-term future and to generate and is integrated with their systems. operation. income to support ongoing funding The eGrants system will be in Six strategic aims have been identified commitments. place for the next couple of years. in the Plan – advancing knowledge, The investment portfolio has benefited Meanwhile, a project has begun to using knowledge, engaging society, this year from an upturn in global create a radically new system that developing people, facilitating research markets. Expenditure also increased will encompass grant application and developing our organisation. These significantly this year (see page 38). and management, refereeing, and form the basis of the front section of Overall, we currently plan to spend committee review. this Annual Review. some £2.25 billion over the next This new system is currently These strategic aims provide a flexible five years. scheduled for rollout in 2007. framework, guiding but not More information about investments, constraining the work we support in and full details of expenditure, can order to achieve our mission. be found in our Annual Report. OVERVIEW 37

WELLCOME TRUST 2004/05 A brief overview of corporate activities over the year.

Clinical research publication. From 1 October 2006, The statement sets out the ethical This year the Wellcome Trust has been outputs from grants awarded before framework that underlies the Trust’s an active contributor to the UK Clinical 1 October 2005 must also be made funding decisions in these areas, and Research Collaboration (UKCRC), a available. To facilitate this, a special provides guiding principles and practical partnership of the key agencies involved submission system for Trust papers advice. The Trust also worked with the in clinical research and practice in the has been set up on PubMed Central. Biotechnology and Biological Sciences UK. By working together to set a future Research Council and the Medical Strategy Committees agenda for clinical research, the UKCRC Research Council to develop a funders’ The Wellcome Trust’s new ‘streams’ is helping to ensure that the UK can policy statement on managing risks of structure was formally introduced on maintain and enhance its position as research misuse. 1 October 2004. During the year, the a world leader in this area, building on first meetings were held of new Strategy Among its submissions to external such strengths as the NHS and Committees for each stream. These will consultations, the Trust provided input biomedical research expertise. consider needs and opportunities within into a Department for Culture, Media Progress this year included their areas, and provide strategic input and Sport consultation on human publication of the report Medically to the Board of Governors. remains, emphasising the value of and Dentally Qualified Academic Staff: such material in research and education. Strategic Awards Recommendations for training the The Trust provided input into several A new funding scheme was launched researchers and educators of the future, areas of legislation that could impact in 2005 to provide a highly flexible produced by the Academic Affairs on biomedical research, including the route of support for internationally Subcommittee of the UKCRC and the Mental Capacity Bill, the Serious renowned groups seeking to develop Department of Health’s Modernising Organised Crime and Police Bill, the research programmes in innovative Medical Careers initiative, chaired by Charities Bill, and the Human Tissue Act. directions. Strategic Awards will Mark Walport. The Trust also launched allow groups considerable freedom Governors and senior staff a major clinical research infrastructure to develop and enhance their research This year, Chris Edwards completed his initiative under the UKCRC umbrella. and training programmes. term as a Governor. William Castell was Open access appointed Chairman-designate. He will Other important grants changes The Trust has continued to press for join the Board of Governors in January during the year included moves to enhanced access to scientific research, 2006 and will succeed Dominic Cadbury open up grants eligibility, for example through open access to the scientific as Chairman in May 2006. In September to researchers in institutions funded by literature. For grants awarded after 2005, Danny Truell joined the Trust as Research Councils or cancer charities. 1 October 2005, research papers partly Chief Investment Officer. or wholly funded by the Wellcome Trust Policy developments must be made freely accessible via A new policy statement on research PubMed Central as soon as possible, involving people in developing countries and no later than six months after was released in 2005 (see page 15). FUNDING 2004/05 38

FUNDING 2004/05 1 October 2004 to 30 September 2005.

In the year ending 30 September Breakdown of Wellcome Trust expenditure 2004/05 2005, the Wellcome Trust’s total charitable expenditure was £483m Total: £482.8m (see right), a considerable increase from last year’s figure of £382m. £343.8m Grants As in previous years, the largest single element of Trust expenditure (more than £300m) was for investigator-led £102.1m proposals in biomedical science Direct* (summarised in the following pages). £14.6m Biomedical science £305.6m Biomedical science £3.1m Technology Transfer £12.9m Technology Transfer Major awards £12.5m Medicine, Society £25.3m Medicine, Society and History and History The Trust is providing £14.6m support £71.9m Genome Campus £36.9m for three Grand Challenges in Global Support† Health projects. This new partnership, * initiatives managed by the £18.1m Biomedical science supported by the Gates Foundation Wellcome Trust or with partners £2.2m Technology Transfer £9.2m Medicine, Society and History (US$450m), the Wellcome Trust and the † costs to support the running £7.4m Genome Campus Canadian Institutes of Health Research of each activity (US$4.5m), is focusing on 14 major scientific problems. engagement amounted to £25.3m Investments (2003/04: £26.1m). This encompasses The value of the Trust’s investment The Trust-funded projects centre response-mode funding schemes, portfolio ended the year at £12.3bn, on HIV vaccine development (Robin ReDiscover awards and £4.3m for the up £1.8bn from the start of the year. Shattock, St George’s Hospital Medical newly opened National Science Learning This represents an annual return (after School, London), protective immunity Centre (pages 24–25). allowing for inflation) of 19.5 per cent. against malaria (Professor Dominic Returns have averaged 14.1 per cent Kwiatkowski, Oxford) and TB latency Projects run directly by the Wellcome over the past three years and 7.7 per (Professor Douglas Young, Imperial Trust (or in partnership with others) cent over the past ten years. The College London). accounted for a further £12.5m of expenditure in this area. This Wellcome Trust’s long-term financial International health was also the focus includes support for the Wellcome position therefore remains strong, of a £10m award to the Medicines Library and the Trust’s own public despite the large drop in global markets for Malaria Venture, a not-for-profit engagement activities. earlier this decade. public–private partnership developing new drugs for malaria. New and renewed fellowships Wellcome Trust Genome Campus BASIC CLINICAL and Sanger Institute Principal and senior: 04/05 03/04 04/05 03/04 Total expenditure at the Wellcome Trust Principal Research Fellowships New 1 1 0 0 Genome Campus amounted to £79.3m Renewal 2 3 1 0 (2003/04: £75.6m). Most of this went Senior Research Fellowships New 7 6 4 2 Renewal 5 7 3 1 on support of research and development International 7 12 – – of facilities at the Wellcome Trust Sanger Intermediate: Institute (page 49). Research Career Development 24 18 – – Fellowships (and other Medical humanities and public intermediate fellowships) engagement Intermediate clinical fellowships –– 13 9 Grants funding in the medical Training: humanities (history of medicine Research training Four-year PhD Studentships 89 76 – – and biomedical ethics) and public Research Training Fellowships – – 27 29 FUNDING 2004/05 39

Funding highlights £10m Careers support Medicines for Malaria Venture. Total expenditure on careers support £25.7m Plus £10m from Department for International across all funding streams amounted Renewal of Major Overseas Development. to some £92 million. There were small Programmes in South-east Asia increases in the numbers of most UK and Kenya. £8.8m senior and intermediate-level page 41 Renewal of core funding fellowships awarded during the year for Wellcome Trust Centre for (see below left). Following a relaunch £14.6m the History of Medicine at UCL. of the Careers Re-entry Fellowship Three Grand Challenges page 47 scheme, which provides a route back in Global Health projects. into science after a career break, £8.6m three fellowships were awarded. £14m Wellcome Trust Case Control Seven International Senior Research Diamond synchrotron project. Consortium. Fellowships (available in central and In conjunction with Sanger Institute. £13.1m page 42 eastern Europe, India and South Africa) Renewal of Wellcome were also awarded in 2004/05. Trust centres. £8.4m International support Cambridge, Glasgow, Oxford Renewal of core funding for The main focus of the Wellcome and Manchester. JDRF/Wellcome Trust Diabetes Trust’s international funding are its and Inflammation Laboratory, Major Overseas Programmes. Core £13m Cambridge. funding of the South-east Asia and Animal Health in the Developing Jointly with Juvenile Diabetes Research Kenya Programmes was renewed. World awards. Foundation (JDRF) The Africa Centre for Health and page 42 Population Studies in South Africa £11.8m received two years’ additional core One new Principal Research £8.1m support, worth £3.1m. Fellowship and three renewals. Technology transfer funding Andrew King (Oxford) page 44 for early-stage drug discovery, Funding for four UK Centres for Clinical Adrian HIll (Oxford) page 40 University of Dundee. Tropical Medicine was renewed (£1.1m). Martin Humphries (Manchester) page 43 Two Senior Fellowships in Clinical Tony Monaco (Oxford) page 43 page 48 Tropical Medicine were awarded, along £4.5m with two intermediate-level fellowships Grants awarded (£m) ALSPAC renewal. in tropical medicine. Plus £4m from MRC. Infrastructure page 46 Some £7m was awarded for biomedical resources and large equipment grants. £4.3m Infrastructure costs also form part of National Science Learning Centre many other types of Trust support. (out of a total commitment New grant initiatives of £25m). • Strategic awards pages 24–25 • Clinical research infrastructure initiative £2.3m • Engaging Science research awards ReDiscover funding for new • Livestock for Life public science centre and museum engagement awards. funding. page 50 IMMUNOLOGY AND INFECTIOUS DISEASE 40

IMMUNOLOGY AND INFECTIOUS DISEASE The Immunology and Infectious Disease stream aims to increase our knowledge and understanding of the infectious organisms that cause disease in humans and animals, and of the immune systems that fight these organisms.

• No. of grants awarded: 229 Among 16 programme grant awards, Also in Oxford, Dr Paul Klenerman Professor Gillian Griffiths (University of (University of Oxford) had his Senior • Value of all grants awarded: Oxford), a Senior Research Fellow in Research Fellowship in Clinical Science £105.1m Basic Biomedical Science, was funded renewed for five years. Dr Klenerman • New and renewed programme for studies on secretion at the studies hepatitis C virus (HCV); he grants (no./value): 16/£19.9m immunological synapse. Professor has identified differences in the immune • Animal Health in the Developing Griffiths will study human genetic response in acute resolving and chronic World awards (no./value): 12/£13m diseases in which cytotoxic T-lymphocyte infections, and begun to study the role function is impaired, to identify proteins of T-cell immune escape variants. He Principal Research Fellow Professor involved in the release of compounds now plans to study the role of T cells Adrian Hill (University of Oxford) was from secretory granules. in HCV disease in greater detail and awarded five years’ further support. Professor Massimo Palmarini (University to assess the impact of viral variation The first section of Professor Hill’s of Glasgow) was awarded a programme on disease progression. programme will be to improve vectors, grant to investigate the mechanism by Viruses are also the focus of and the antigenic composition of malaria which the Jaagsiekte sheep retrovirus Dr Gregory Towers (University College and tuberculosis vaccines, in order to assembles and releases its viral particles. London), currently a Research Career enhance their T-cell immunogenicity and He will study a mutant virus that has a Development Fellow, who was awarded their effectiveness. A second part will dominant negative interference effect a Senior Research Fellowship in Basic look at the genetic basis for susceptibility on wild-type virus. Biomedical Science. During this to these two diseases. α A new programme grant will also enable fellowship Dr Towers identified TRIM5 Professor Chris Rudd (Imperial College Professor Rick Maizels (University of as a key mediator of innate immunity London) and Professor Steve Fuller Edinburgh) to investigate cellular and to retroviruses. In his senior fellowship, (University of Oxford) had the programme molecular mechanisms of immune Dr Towers will study the mechanism grants associated with their Principal α regulation in helminth infections. of action of TRIM5 , and how viruses Research Fellowships renewed. The programme will attempt to establish such as HIV overcome this component Professor Rudd studies immune cell whether the T regulatory cell population of innate immunity. signalling, particularly the signals that expansion in helminth infection inhibits An International Senior Research link the T-cell receptor and co-receptors immunity and whether they come from Fellowship was awarded to with immunity. Professor Fuller’s work an already committed cell line or are Dr Caroline Tiemessen (Johannesburg), focuses on cryo-electron microscopy induced on infection. to investigate the innate and acquired of pathogens and receptor complexes. cellular immunity in HIV-seropositive One of his main aims will be to study the A Senior Research Fellowship in mothers and their infants. By looking structures of two viruses, Semliki Forest Clinical Science was awarded to at the mother’s and the baby’s immune virus and tick-borne encephalitis virus, Dr Helen McShane (University of responses, Dr Tiemessen hopes to and their intermediates during fusion, Oxford) to support her work on novel uncover factors involved in vertical to reveal the organisation that leads tuberculosis vaccines. Dr McShane transmission of the virus and to aid to their very rapid membrane fusion. will study the immune response to the new TB vaccine MVA85A and will the battle against in utero or develop a challenge model to study intrapartum infection. protective responses in TB. IMMUNOLOGY AND INFECTIOUS DISEASE 41

Further international support went to Major Overseas Programmes Dr Amit Sharma and Dr Chetan Chitnis, The focus of the Major Overseas Wellcome Trust Centre for Molecular Parasitology both Wellcome Trust International Programmes in Kenya and South-east The Wellcome Trust Centre for Senior Fellows at the International Asia is to research scientific areas of Molecular Parasitology at the University Centre for Genetic Engineering and local significance, to promote science of Glasgow, led by Professor Dave Biotechnology, New Delhi, India, who in the regional community (including Barry, carries out research on basic were funded to establish an X-ray training programmes) and to inform features of parasites, using genetic crystallographic facility. Dr Gonzalo national policy making. Both and molecular technology allied with de Prat Gay (Fundación Instituto Leloir, Programmes underwent their five-yearly organismal biology. The research Argentina) and Dr Kevin Gaston reviews in 2005 and were highly includes work on: African trypanosomes, (University of Bristol) were awarded a praised for their work in all three areas, the causative agent of human sleeping collaborative project grant to study the receiving the commitment of a further sickness and the wasting disease molecular basis for transcription control three years of funding. nagana in cattle; malaria; and Theileria, and genomic DNA replication initiation The Programme in Kenya focuses a protozoan parasite of cattle. The in human papillomavirus. on malaria and infectious diseases INSERM unit established at the Centre Among other notable grants, Dr Isobel of children (pages 11 and 21). The in 2004 held its official opening during Smith (University of Cambridge) was Programme is now fully integrated with September 2005. The Centre was awarded a Research Career Re-entry the Kenya Medical Research Institute; also involved in the sequencing Fellowship to look at the function of new laboratories have been completed of Trypanosoma brucei and the mouse butyrophilin receptors. and will become fully operational during annotation of the ‘Tritryp’ genomes Dr Smith is returning to science the early part of 2006. (see pages 34–35). after a career break of nine years. The South-east Asia Programme Dr David Beighton (King’s College comprises units in Thailand and London) was awarded a project grant Vietnam. Professor Nick White, who to investigate the fate of bacteria when leads the Programme, was awarded they are sealed underneath a dental the Royal Society GlaxoSmithKline restoration. Professor John Britton Prize in 2005. The work in Thailand (University of Nottingham) was awarded aims to develop and evaluate effective a project grant to undertake a trial of and practical means of diagnosing, the effect of therapeutic hookworm treating and preventing significant infection in allergic rhinoconjunctivitis tropical diseases, including malaria and asthma. (pages 10–11), melioidosis, Some 12 awards totaling £13m leptospirosis and rickettsial infections. were made through the Animal Health Work in Vietnam centres on malaria, in the Developing World initiative, which dengue, typhoid, central nervous supports research on livestock diseases system infections and avian flu (page that impact significantly on human 10), and places significant emphasis health and wellbeing in developing on encouraging clinical science countries. Capacity building was an in the country. important feature of these awards and support was provided for training of local researchers. MOLECULES, GENES AND CELLS 42

MOLECULES, GENES AND CELLS The Molecules, Genes and Cells stream supports high-quality research that will further our understanding of the fundamental biology and specialist functions of molecular, cellular and genetic processes, and their role in health and disease.

• No. of grants awarded: 163 chromosome painting. The second in breast cancer, multiple sclerosis, award, of almost £1.6m, was made autoimmune thyroid disease and • Value of all grants awarded: £73m to Principal Research Fellow Professor ankylosing spondylitis. • New and renewed programme Daniel St Johnston of the Gurdon The collaboration of 24 leading human grants (no./value): 14/£15m Institute, to establish a Drosophila geneticists will analyse 20 000 DNA proteomics resource. A notable trend among awards made samples from people with these was the use of new methods and The stream made a significant disorders to identify variations in DNA technologies. For example, an award contribution to the Trust’s international that may contribute to (or protect to Professor Ian Eperon (University of funding portfolio over the year. This against) disease. The variations – single Leicester) and Professor Francesco included five new International Senior nucleotide polymorphisms, or SNPs – Muntoni (Imperial College) makes Research Fellows: two in the Czech will then be compared with DNA taken use of new methods to rescue the Republic, two in Poland and one in from 3000 healthy controls to uncover incorporation of silent or defective exons India. In addition, four collaborative the differences between the two groups. during RNA splicing. If successful, this research grants were awarded to The Wellcome Trust Sanger Institute will research could be used to treat many facilitate research between UK and generate the genotyping data and the diseases resulting from splicing defects. overseas investigators. results will be analysed by statistical The use of new technologies was also A Career Re-entry Fellowship was experts at the Wellcome Trust Centre pivotal to the programme grant awarded awarded to Dr Shona Lang (University for Human Genetics and the Department to Senior Research Fellow Dr Andrew of York) for her study of adult prostatic of Statistics in Oxford, and the University Jarman (University of Edinburgh). Dr stem cells. This award will enable of Cambridge. Dr Lang to recommence her scientific Jarman aims to integrate experimental, JDRF/Wellcome Trust Diabetes functional genomic, and computational research career after a three-year break. and Inflammation Laboratory techniques to characterise early Three new Senior Research Fellowships The JDRF/Wellcome Trust Diabetes neurogenesis in Drosophila, and were awarded this year. As well as one and Inflammation Laboratory (DIL) to identify the factors that influence held in the Wellcome Trust Centre for at the University of Cambridge is a joint neural stem cell development and Cell Biology, University of Edinburgh initiative between the Juvenile Diabetes differentiation. (see box), awards were made to Research Foundation (JDRF) and the Dr John Strouboulis (Institute of Child The stream also funded a significant Wellcome Trust. It aims to identify the Health, London) and Dr Hisao Kondo amount of research infrastructure key genes and pathways involved in (University of Cambridge). throughout the year. This included type 1 diabetes, and hence to identify awards for multi-user equipment Dr Ben Luisi (University of Cambridge) and develop targeted treatments (plasmon surface resonance and HPLC was awarded the Trust’s first ‘50–50’ and interventions. systems) to Professor Paul Thornalley Senior Research Fellowship, in which the In late 2004, the DIL was awarded an (University of Essex) and an award Wellcome Trust and the host institution £8.4m renewal of funding until 2011 to Senior Research Fellow Dr Alfred jointly fund the Fellow’s enhanced salary from the Trust and the JDRF, including Antson (University of York) to set up during the renewal period. renewals of the programme grants of a facility for X-ray data collection at Wellcome Trust Case Control Professor David Clayton and Professor the York Structural Biology Laboratory. Consortium Linda Wicker. biomedical The Wellcome Trust Case Two awards supported Structural Genomics Consortium resources at the University of Control Consortium is a large and By the end of its first year of operations Cambridge. The first, to Professor comprehensive £8.6m study that in July 2005, the Structural Genomics Malcolm Ferguson-Smith, renewed aims to uncover the genetic variations Consortium, a £46m partnership aimed support for the Cambridge Resource associated with 12 common diseases, at determining the 3D structures of Centre for Comparative Genomics. This including tuberculosis, coronary heart proteins of medical importance and resource provides chromosome-specific disease, type 1 and type 2 diabetes, placing them in the public domain, had DNA from a wide range of species. rheumatoid arthritis, Crohn’s disease, determined the structures of 78 novel Funding was also provided to develop bipolar disorder and hypertension. proteins, significantly exceeding its a database to record the comparative A supplementary study will look at a target of 50 structures (see page 33). maps generated by cross-species smaller number of genetic variations MOLECULES, GENES AND CELLS 43

Wellcome Trust/Cancer Research In 2005, the Centre underwent its groups around the world through UK Gurdon Institute second five-yearly review. Following the formation of the Malaria Genomic The Gurdon Institute of Cancer and a successful review, its Wellcome Trust Epidemiology Network. Principal Developmental Biology at the University Centre status was confirmed and core Research Fellow Professor Lon Cardon of Cambridge, directed by Professor support was renewed. was awarded funds as part of another Jim Smith, focuses on two interrelated Also during the year, the Principal large-scale collaborative project, the aspects of cell biology: how cells acquire Research Fellowship and associated Wellcome Trust Case Control and maintain their normal function during programme grant of Professor Martin Consortium (see main text). development, and how they escape from Humphries were renewed, and a www.well.ox.ac.uk normal controls and become cancerous. programme grant was awarded to Following its five-yearly review in January Professor Karl Kadler for research on Wellcome Trust Centre for 2005, the Gurdon Institute retained the spatial organisation of collagen fibrils. Cell Biology Wellcome Trust Centre status and its The Wellcome Trust Centre for Cell www.ls.manchester.ac.uk/wtccmr/ core support was renewed. In June, Biology at the University of Edinburgh, led by Professor Adrian Bird, seeks the Institute hosted an international Wellcome Trust Centre for symposium to mark the opening of its Human Genetics to understand the fundamental new building and to honour the founding The Wellcome Trust Centre for Human characteristics of living things at the Chairman, Professor Sir John Gurdon. Genetics at the University of Oxford, cellular level, such as growth, movement, Also during the year, Professor Jim Smith directed by Professor Tony Monaco, self-replication and development. was awarded a programme grant for undertakes research into the genetic It has particular strengths in: the study research on vertebrate mesoderm basis of common diseases. Many of RNA, including its transcription, formation, and Dr Nancy Papalopulu, common diseases, such as psychiatric processing, transport and destruction; who works on Xenopus neurogenesis, disorders, infectious diseases, heart the cell division cycle, focusing on had her Senior Research Fellowship disease and diabetes, have both genetic the structure and segregation of renewed. See also page 31. and environmental causes. The goal chromosomes; and gene expression www.gurdon.cam.ac.uk of the Centre is to identify the genetic in developing systems, particularly factors that influence our susceptibility epigenetic processes such as Wellcome Trust Centre for to diseases, and thus to understand DNA methylation. Cell–Matrix Research better the underlying biological process During the year, two new Trust-funded The Wellcome Trust Centre for and how these genetic factors interact group leaders have been appointed: Cell–Matrix Research, led by Professor with the environment to cause disease. Dr Eric Schirmer was awarded a Senior Martin Humphries, is an interdisciplinary During the past year, core support Research Fellowship (role of the nuclear research centre embedded within the for the Centre was renewed, as were envelope in genome architecture and Faculty of Life Sciences at the University the Principal Research Fellowships of cellular differentiation), and Dr Adele of Manchester. The Centre has the Professor Monaco and Professor Adrian Marston was awarded a Research long-term aims of elucidating the Hill. The programme grant of another Career Development Fellowship (control structure and function of extracellular Principal Research Fellow, Professor of chromosome segregation during matrices and cell–matrix adhesions, Stephen Fuller, was also renewed. meiosis). Professor Adrian Bird’s defining the contribution of cell–matrix programme grant, for studies on interactions to human diseases, and Professor Dominic Kwiatkowski received methyl-CpG binding proteins and their developing approaches for preventing an award from the Grand Challenges role in DNA methylation, was renewed. and treating these diseases. in Global Health initiative (of which the Wellcome Trust is part) to integrate and www.wcb.ed.ac.uk build on the work of malaria research NEUROSCIENCE AND MENTAL HEALTH 44

NEUROSCIENCE AND MENTAL HEALTH The Neuroscience and Mental Health funding stream aims to support high-quality research into the function of the nervous system in health and disease.

• No. of grants awarded: 133 of the mature brain to recover functions The award will provide infrastructure compromised following hearing loss. support to facilitate the translation of • Value of all grants awarded: This research will contribute to our basic research into clinical application. £37.3m understanding of cochlear transplantation The scientific focus of the research is • New and renewed programme and will help to establish whether the function of key brain structures grants (no./value): 7/£6.1m behavioural training can be used to and circuits that are implicated in the promote the rehabilitation of hearing pathophysiological changes The Principal Research Fellowship in deaf individuals. underpinning major neuropsychiatric of Professor Tony Monaco (University and neurological disorders, such as of Oxford) was renewed, enabling him In this field, Professor Tim Griffiths depression, schizophrenia, Parkinson’s to continue his attempts to identify (University of Newcastle upon Tyne) disease and Alzheimer’s disease. susceptibility genes for specific reading had his Senior Research Fellowship and language disorders. Children with in Clinical Science renewed. His In the field of basic biomedical language development problems are research addresses the question sciences, Professor Hugh Willison likely also to have difficulties in reading, of how complex sound information (University of Glasgow) was awarded and Professor Monaco will study is processed by brain systems a programme grant to take further his a cohort of individuals affected by a implicated in language, memory and studies of the pathogenetic mechanisms spectrum of relevant disorders, with emotion. He will analyse critical brain of Guillain–Barré syndrome. This the ultimate aim of elucidating the components using functional imaging inflammatory nervous system disease neurodevelopmental pathways experiments with individuals affected is a leading cause of neuromuscular implicated and giving insight into by brain disorders that influence sound paralysis. This multidisciplinary potential therapies. perception, such as schizophrenia. programme aims to elucidate in parallel the mechanisms of tissue damage in Dr Mairead MacSweeney (Institute The Senior Research Fellowship in animal models and in humans, in order of Child Health, London) was awarded Clinical Science of Dr Masud Husain to develop therapeutic approaches. a Research Career Development (University College London) was also Fellowship in Basic Biomedical Science. renewed. Dr Husain studies spatial An International Senior Research She will examine the impact of late sign neglect, a common disabling disorder Fellowship was awarded to Dr Norbert language acquisition on language found in the majority of stroke cases Hajós, who will be working at the processing and reading ability in deaf (see pages 12–13). It is characterised University of Budapest in Hungary on people. Similarly, Professor Gerald by a lack of awareness (‘neglect’) of the molecular basis of endocannabinoid Altmann (University of York) and Dr Kate objects or people on the side of the signalling in neuronal communication. Nation (University of Oxford) were body opposite the damaged area of the Endocannabinoids are endogenous awarded a project grant for studies into brain. Neglect can hamper rehabilitation metabolites that have been implicated in the neurobiological bases of language. in some individuals. Dr Husain aims analgesia and mood-changing behaviour. They will investigate language processing to identify the functional components The experiments will be specifically in a group of children with poor language underlying neglect, to discover whether performed in those brain regions where comprehension. This research aims to particular brain regions are selectively cannabinoids may influence memory develop procedures that will help such damaged, and to identify functional formation and anxiety-like symptoms. children to improve their reading abilities. or anatomical factors associated with In another area, Dr Alexandra Chittka poor recovery. Professor Andrew King (University (King’s College London) was awarded of Oxford) was awarded a Principal A major joint award with the Medical a Career Re-entry Fellowship. Her work Research Fellowship to study the basis Research Council was also made in is aimed at understanding the role in of perceptual learning in the auditory the area of behavioural and clinical pathological pain conditions of cortex. He aims to identify those brain neuroscience to Professor Trevor PRDM4, a molecule expressed during regions involved in sound localisation Robbins and Professor Edward Bullmore development in nociceptive neurons. and to determine the capacity at the University of Cambridge. PHYSIOLOGICAL SCIENCES 45

PHYSIOLOGICAL SCIENCES The Physiological Sciences funding stream aims to support high-quality basic and clinical research relevant to the understanding of biological processes at the cell, organ, system and whole-animal levels in health and disease.

• No. of grants awarded: 104 pulmonary disease (COPD). This tissues and the role of matrix proteins programme will examine the underlying in the maintenance of human health • Value of all grants awarded: cause of steroid resistance in COPD and skeleto-pathogenesis. £27.6m with the hope of leading to a better Professor Lance Lanyon (Royal • New and renewed programme understanding of the inflammatory Veterinary College) was also awarded grants (no./value): 16/£8.7m mechanisms of the disease and a programme grant to continue his to more effective treatments. Awards made through the Physiological research on the adaptive control of bone Sciences funding stream have Another award in a related area strength. In particular, his proposal will continued to illustrate the broad range was made to Professor John Dark explore the mechanisms involved in the of applications received. Awards were (University of Newcastle upon Tyne), strain-adaptive process, such as how made in such diverse areas as sleep who is investigating the mechanisms the effects of oestrogen and strain apnoea (Dr Mary Morrell, Imperial and time-course of donor lung injury regulate the number or activity of College London, who is studying the development following brain death, and oestrogen receptors, and how these influence of the ageing process on amelioration of lung reperfusion injury by responses are related to the responses cardiovascular activation in obstructive donor treatment. The aim is to uncover of bone cells to a range of other sleep apnoea) and dermatology the causes of organ injury in brain-dead influences affecting bone mass. (Professor Jonathan Rees, University of donors, with the hope of improving the In a related field, Dr Keith Baar Edinburgh, who is investigating scratch availability of organs for transplantation. (University of Dundee) was awarded and itch in individuals with skin disease). Also in this area, Research Training a ‘new investigator’ project grant for A major joint award with ICICI Ltd Fellowships were awarded to his study into the role of mTOR/PDK1- and the Parthenon Trust was made Dr Rachel Davies (University of activated protein kinases in the to Dr Caroline Fall (University of Cambridge) to establish the connection development of skeletal muscle Southampton). She aims to develop between a mutation in BMPR-II and hypertrophy. This proposal focuses an evidence-based nutritional the narrowing and occlusion of blood on a family of proteins that may play a intervention to reduce low birth vessels in the lung, as seen in role in the ability of muscle to respond weight in a poor urban setting in India. pulmonary arterial hypertension, and to resistance exercise. By elucidating The plan is to enhance the micronutrient to Dr Christopher Johnson (University the molecular events required for the quality of women’s diets, before of Cambridge) to look for variants development of skeletal muscle conception and throughout pregnancy, of a specific subset of major hypertrophy, he hopes to identify using locally available foods (samosas), histocompatibility complex genes and molecular targets for pharmacological with a view to increasing fetal survival assess whether they are associated treatments of loss of muscle mass due and growth, and reducing infant with sarcoidosis (inflammation of the to ageing and chronic illness. mortality. The longer-term aim of this lymph nodes, spleen and other organs). In addition, Dr Kuda Ranatunga study is to improve the wellbeing of A second general theme of (University of Bristol) was awarded women and children living in poverty musculoskeletal research also a project grant to investigate the and overcrowded conditions in an emerged during the year. Professor correlation between the molecular basis urban environment. Jennifer Kirkham (University of Leeds) of muscle contraction and muscle There were several awards made during was awarded a programme grant for behaviour at physiological temperatures. the year in related areas of respiratory her study of odontogenesis (tooth The proposal aims to shed light on how disease. Notable among these was formation), a paradigm of mammalian muscles change their behaviour at low the award of a programme grant to biomineralisation and the role of temperatures, important in conditions Professor Peter Barnes (Imperial College extracellular matrix in the control such as hypothermia, and at high London) for his studies on the role of of crystal deposition and growth. temperatures, including during histone deacetylase-2 in the regulation This proposal aims to provide new strenuous exercise. of inflammation and corticosteroid information to elucidate mechanisms of sensitivity in chronic obstructive biomineralisation in mammalian skeletal POPULATIONS AND PUBLIC HEALTH 46

POPULATIONS AND PUBLIC HEALTH The Populations and Public Health stream supports research to improve understanding of the determinants of disease and quality of life in populations, and to provide a sound evidence base to inform decisions in public health and healthcare delivery.

• No. of grants awarded: 61 Dr Vikram Patel (Institute of Psychiatry) Professor Marie-Louise Newell has and Dr Michael English (University of been appointed the Africa Centre’s • Value of all grants awarded: Oxford), who both previously held new Director. £12.3m Wellcome Trust intermediate fellowships, ALSPAC • New and renewed programme were awarded Senior Clinical Fellowships The Avon Longitudinal Study of Parents grants (no./value): 2/£1.1m in Tropical Medicine for their work on and Children (ALSPAC) is a cohort study mental healthcare in India and on (Figures include grants awarded of 14 000 children (and their parents) healthcare delivery for severely ill children through the Health Consequences born in the Avon area between 1 April in Kenya respectively. At the intermediate of population Change Programme, 1991 and 31 December 1992. It was level, Dr Anna Hansell (Imperial College a five-year initiative begun in 2001.) established by Professor Jean Golding School of Medicine) was awarded a (University of Bristol) and Professor This year, awards were made for Clinical Fellowship to study air pollution Marcus Pembrey. research into a range of major public in the UK, while Dr Shakoor Hajat health issues in developing countries (London School of Hygiene and Tropical ALSPAC is a unique resource with a and in Europe. For example, Professor Medicine) will be studying the impacts of major strength in intensive phenotyping, Linda Richter received an award for heatwaves on mortality in Europe under allowing the study of continuous traits continuing studies of a longitudinal his Research Career Development (such as cognitive functions), psychosis- cohort of urban South African youth Fellowship. One Training Fellowship, like symptoms, and common childhood (‘Birth to Twenty Cohort’), which has one PhD Studentship and six Master’s diseases including asthma and obesity. already been followed for 14 years. awards were also supported. Since the retirement of Professor Golding The new studies will look at the Africa Centre in July 2005, the project has been led by crucial time of adolescence and A major review of the Africa Centre for Professor George Davey-Smith under the determinants of adverse health Health and Population Studies in South the auspices of the University of Bristol’s outcomes related to sexuality, Africa, which the Wellcome Trust has Centre for Lifecourse and Genetic reproduction and chronic diseases. funded since 1998, took place in 2005. Epidemiology. A renewal of a five-year A collaborative network for analysis of grant for core support of over £8.5m The Africa Centre has successfully data across community-based studies was jointly agreed by the Medical established one of the most detailed of HIV in Africa will add value to several Research Council and the Wellcome demographic information systems longitudinal Trust-funded projects Trust in July 2005. in Africa, gathering data on births, (including the ‘Africa Centre’ – see deaths, migration and socioeconomic UK Biobank below). This four-year project will be led status in a population of 90 000 people UK Biobank is the long-term prospective by Ms Basia Zaba of the London School in a rural area of KwaZulu-Natal severely longitudinal study of 500 000 healthy of Hygiene and Tropical Medicine, who affected by HIV. volunteers aged 40–69. UK Biobank will be relocating to Tanzania. has been developing the infrastructure The Africa Centre now intends to build A project led by Professor Bruce Neal to support the project and further refining on this platform with further studies of of the George Institute, Sydney, Australia, experimental protocols; the full-scale HIV, covering the determinants of will test new ways of collecting and launch is scheduled for 2006. disease, delivery of anti-retroviral drugs reporting information about trends in in rural areas, the effects of the epidemic Professor Rory Collins, of the Clinical causes of death in countries with limited on households and social structures, Trials Surveillance Unit, University of resources. The study will take place in and prevention of HIV infection. Core Oxford, was appointed Chief Executive India and could help developing-country funding has been agreed for two years and Principal Investigator in governments to plan health services until 2007, with funding for an additional September 2005. more effectively. three years being dependent on further development of the Centre’s scientific plans. MEDICAL HUMANITIES 47

MEDICAL HUMANITIES The Medical Humanities stream aims to enhance understanding of the historical and social context of medicine and biomedical science. It supports research in history of medicine and biomedical ethics, and encourages use of findings, for example to inform public policy making.

• No. of grants awarded: 154 information from the hospital’s admissions registers up to 1914. Wellcome Trust Centre for • Value of all grants awarded: the History of Medicine The preservation of clinical case notes £15.8m After a successful review in April 2005, in the Lothian Health Services Archive the Centre was awarded five years’ core History of medicine has ensured the long-term stability of a funding of £8.8m. The breadth of the history of medicine vast collection of the folder-based case programme is well illustrated by the notes of clinical professors, which were Notable outputs from 2004/05 included: diversity of topics featuring in awards in increasingly poor condition. Sanjoy Bhattacharya’s Fractured States: made during the year. These included Smallpox, Public Health and Vaccination Biomedical ethics ‘Medicine and Society in Tenth-Century Policy in British India, 1800–1947 (with The biomedical ethics programme Baghdad’ (Dr Peter Pormann, University Mark Harrison and Michael Worboys; consists of two strands: UK-based of Warwick), ‘Health Care in the British Orient Longman, India, and Sangam funding supporting research on the West Indies’ (Dr Margaret Jones, Books, UK); Jordan Goodman’s The ethical, legal, social or public policy University of Oxford) and ‘Road Traffic Rattlesnake: A Voyage of Discovery aspects of advances in biomedical Accidents’ (Dr W Luckin, University to the Coral Sea (Faber and Faber); science, and a research ethics scheme of Bolton). Christopher Lawrence’s Rockefeller aimed at developing countries. Dr Mark Harrison, Director of the Money, the Laboratory and Medicine in Wellcome Unit for the History of The Trust also organised the 6th Edinburgh 1919–1930: New Science in Medicine at the University of Oxford, Global Forum on Bioethics in Research an Old Country (University of Rochester was awarded the 2004 Templer (see page 15), as well as a biomedical Press); and Medieval Chinese Medicine Medal (see page 14). ethics summer school, ‘Neuroscience, (RoutledgeCurzon), edited by Vivienne Ethics and Society’, held in Oxford in Lo and Christopher Cullen. More unusual outputs included a film, September 2005. This four-day event The Centre also published the record Trafalgar Battle Surgeon, made by enabled junior researchers to explore of four Wellcome Witness Seminars: Justin Hardy of Asylum Films, with ethical issues in neuroscience and ‘Innovation in Pain Management’, ‘The help from Professor Laurence Brockliss mental health, and develop ideas for Rhesus Factor and Disease Prevention’, (University of Oxford). This public research proposals. It attracted high- ‘The Recent History of Platelets in engagement award resulted in a one- profile speakers from neuroscience and Thrombosis and Other Disorders’, hour film shown on Channel 4, as well neuroethics, and went some way to and ‘Short-course Chemotherapy for as a scholarly work entitled Nelson’s developing a research and training Tuberculosis’. Staff at the Centre also Surgeon (Laurence Brockliss, John agenda in neuroethics for the UK. Cardwell, and Michael Moss; Oxford made numerous appearances on University Press). In addition, the Oral Grants awarded during the year television and radio during the year. History of Diabetes in the 20th Century covered many of the key issues in project launched an informative web biomedical research and its application, resource (see page 34). including mental capacity in individuals with psychiatric disorders (Dr Matthew Research Resources Hotopf, Institute of Psychiatry), genetic in Medical History databases (Professor Michael Parker, This scheme funds projects cataloguing, University of Oxford), ‘trial communities’ preserving, conserving or digitising in developing countries (Dr P Wenzel important archival collections. Highlights Geissler, London School of Hygiene and of this year’s funding included the Great Tropical Medicine), and philosophical Ormond Street Hospital Database perspectives on responsibility and Project, which involved the creation of personality disorders (Dr Luca Malatesti, a database to hold all the transcribed University of Hull). TECHNOLOGY TRANSFER 48

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

Technology Transfer at the The projects address a wide range Strategic Translation Award to date) Wellcome Trust aims to fund of potential applications, including to advance their work developing new projects that are too early to attract therapeutics, vaccines, diagnostics and therapies for neglected diseases, such venture capital or to be seen by medical devices. Others were in support as African sleeping sickness, Chagas’ industry as credible in-licensing of new platform technologies. One award disease and leishmaniasis, which attract opportunities. Over a period of was made to investigate the effectiveness little or no interest from pharmaceutical seven years, around 70 translational of policy tools for promoting translation companies. The Dundee team’s goal is research projects from 46 in the neglected diseases, while another to translate the insights arising from basic institutions have been funded under was to run workshops in intellectual research into candidate drugs, taking Development Fund and Translation property for scientists working in them to a point at which public–private Award schemes. Many of these developing countries. partnerships or the commercial sector have raised additional investment Strategic Translation Awards are can develop them further. and a number have already designed to support translational There has been encouraging progress developed products, although research in areas of key importance in a number of the projects supported it is still too early to appreciate the to the Wellcome Trust. These may be through Technology Transfer funding. full impact of the funding provided. technologies that have a particular role Examples include: the launch of a The Wellcome Trust has two forms in support of the Trust’s mission and miniaturised adenosine triphosphate of translational research support address an unmet need in healthcare, sensor (by Sarissa Biomedical Ltd, a administered through Technology and where it is felt that Technology spin-out of the University of Warwick); Transfer. Translation Awards are Transfer can add value by providing the development of a compact video a response-mode form of support. project management support or by laryngoscope (by Aircraft Medical Ltd, They are used to support a diverse array securing follow-on funding. based in Edinburgh); and the creation of technologies, not only from biology Six Strategic Translation Award of powerful new software for medical but also from the physical sciences and applications have been considered devices (by CardioDigital Ltd, based in mathematics. The common requirements to date, in diagnostics, vaccination, Edinburgh) and for biomarker research are that the research is aimed at the tools for genome analysis and drug (by BlueGnome Ltd, based at the improvement of health and that the discovery – the last of these in both University of Cambridge). project can be advanced to a point conventional commercial markets In addition, several small companies that at which it represents an attractive (central nervous system and metabolic have received Wellcome Trust support proposition for follow-on support by disease) and tropical diseases during early validation of their a third party. Academic institutions and (parasitic protozoan infections). technologies have had success raising early-stage companies can apply for The mean value of awards has been further funds. These include CellTran Ltd, these awards, and projects are directly £2.5 million (ranging from £519 000 DanioLabs Ltd, Diagnostics for the Real managed by the institution or company. to £8.1 million). World, Novacta Biosystems Ltd, ProXara Of 48 applications received from 33 A new initiative, Seeding Drug Biotechnology Ltd and Senexis. institutions, 29 per cent were funded, Discovery, designed to advance Finally, a report titled ‘The New covering applicants in both university translational research in small molecules Landscape of Neglected Disease Drug departments and small businesses. across a broad range of therapeutic Development’, produced by a group at The mean value of these awards has areas, has been recently announced as the London School of Economics, was been £336 356 (ranging from £20 000 a focus for further Strategic Translation published in the second half of the year to £896 366) and the average duration Award support. and is already proving highly influential 24 months (ranging from six to 36 Professor Mike Ferguson and (see page 20). months); the average time from colleagues at the University of Dundee application to decision has been were awarded £8.1 million (the largest around three to four months. 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.

Buildings providing additional Pathogen genome research has ‘Prion Biology’, ‘Pharmacogenomics’, laboratory space and research and focused on diseases that affect huge ‘Functional Genomics in the Mammalian support facilities for the Genome numbers of humans and animals, Nervous System’ and ‘Population Campus were completed in summer such as the ‘tritryps’ (see pages 34–35). Genomics’. The first four events were 2005, the culmination of a project Other projects target organisms that held jointly with Cold Spring Harbor begun in 2002. The buildings have have a significant economic impact in Laboratory in the USA, the last one been carefully landscaped to developing countries, exacerbating the jointly with the European Commission. minimise their environmental problems caused by human disease. A smaller meeting to discuss technology impact. Among other ‘green’ The Sanger Institute sequenced the roadmapping for malaria was also held initiatives, a Wetlands Nature genome of Theileria annulata, one of a jointly with the Gates Foundation and Reserve has been established genus that threatens 250 million cattle the Malaria Vaccine Initiative. around the river Cam, providing from Africa to Asia. The sequence is The Wellcome Trust Conference Centre habitats for many rare species being used by other Wellcome Trust- continues to increase in popularity, with and a peaceful environment for funded researchers to search for over £1.3m of meetings held this year. local residents. new treatments. Meetings whose primary purpose is Wellcome Trust Sanger Institute Well-established Sanger Institute scientific are run at discounted rates. resources showed remarkable growth. A world-leading provider of genomic Wellcome Trust Advanced Courses The data downloaded from the Ensembl data, information and biological Wellcome Trust Advanced Courses genome browser increased by 20 per resources, the Wellcome Trust Sanger provide hands-on training in the latest cent year-on-year, and visits to all Sanger Institute is continuing to increase its laboratory techniques and related IT Institute sites also increased by 20 per focus on high-throughput biological applications for PhD students, cent. Of new resources, more than 1800 studies. Sequence generation continues postdoctoral scientists and clinicians. MICER clones, which can be used to to be a major activity, however: by year- The Courses are held in laboratories delete or duplicate regions of the mouse end, the Sanger Institute had produced in the Sanger Institute. nearly 3 billion bases of finished DNA genome, have been dispatched, and Five Advanced Courses were held in sequence, the largest of any public nearly 400 gene-trap cell lines, which 2004/05: ‘High-resolution Molecular body. The Sanger Institute is increasingly enable investigators to create mutant Cytogenetics’; ‘Microarrays and the focusing sequencing activities on mice, are distributed each year. Transcriptome’; ‘Functional Genomics’; biological and medical questions, The Sanger Institute’s publications ‘Human Genome Analysis: Genetic and strategic plans for 2006–11 will in 2005, which include eight in Nature Analysis of Multifactorial Diseases’; and accelerate programmes in these areas. and 12 in Science, increasingly reflect ‘Genomics and Clinical Microbiology’, post-genomic research such as In human genomic biology, the Sanger a course on molecular genetics studies on DNA replication, hearing, Institute was a principal participant in the techniques for clinicians. In addition, cognition, evolution, embryology and International HapMap Consortium, which four IT-based courses were run – the epigenetics. Of 221 papers in 2005 developed a resource to speed gene Open Door Workshops, ‘Working with to date, 12 covered studies on cancer. discovery in biomedicine. The Institute the Human Genome Sequence’ and The Sanger Institute’s strategic plan for also led the international team that ‘Working with Pathogen Genomes’ – 2006–11 is designed to build on these published the sequence of the human which gave scientists training in strong foundations in genome-based X chromosome, which contains clues genome analysis software. to human evolution, the origins of biological research. The programme is being expanded for chromosomal sex determination, Wellcome Trust Conference Centre 2005/06, with seven Advanced Courses, and many genes implicated in disease. Partnerships and international four Open Door Workshops in Hinxton, Other research included studies on collaboration continued to be a key one Open Door Workshop in Uruguay, copy-number variation – how some component of the Wellcome Trust and, in conjunction with Cold Spring humans may have more DNA than Conference Programme. Five Harbor, two Open Door Workshops others – and the origins of the peoples international conferences were held in Brazil and Mexico. of Madagascar. this year: ‘Interactome Networks’, PUBLIC ENGAGEMENT 50

PUBLIC ENGAGEMENT The Wellcome Trust’s Public Engagement activities aim to raise awareness and understanding of biomedical science, its social and ethical implications, and its historical context.

As well as 42 small People Awards, Commission, the Wellcome Trust and Education eight Society Awards (of £50 000 the Wolfson Foundation, set up to Construction of the National Science and above) were made under enable museums and science centres Learning Centre in York was completed the £3 million public engagement to refresh their exhibitions. in 2005 (see pages 24–25). grants scheme, Engaging Science. Twelve awards were made in May A major piece of research on UK primary Society Awards for research were 2005 under the second round of Pulse – science education was published on launched in September 2005, to support a funding initiative supporting young 12 September 2005. The Wellcome academic research designed to advance people’s arts projects inspired by Trust commissioned Queen’s University knowledge about public engagement biomedical science. Pulse 2 continued Belfast and St Mary’s University College with biomedical science. to fund performing arts projects, but Belfast to explore teachers’ views and extended the challenge to other art experiences of primary science, and Animal Health in the Developing World: forms, including visual arts, film, creative to recommend ways in which it could Livestock For Life, a £3 million grant writing and new media. be improved. scheme to strengthen links between livestock keepers, practitioners, The Wellcome Trust and the BBC The Wellcome Trust part-funded the researchers, policy makers and other ran a second ‘Imagine’ photographic creation of three programmes for stakeholders working in the field of competition in 2004/05, based on the Teachers’ TV, the new digital TV channel international animal health, was theme: ‘How biomedical science is for teachers launched in February 2005. launched in June 2005. changing us’. Winning entries were The programmes, which explored stem displayed at the Royal Albert Hall, cells, HIV/AIDS and the Cancer Genome Some 140 applications were received London, and at science centres Project, were made by the production under the Sciart scheme, which offers around the UK in 2005. company Glasshead, to support the up to £500 000 per year to support new Wellcome-funded science GCSE, innovative arts projects investigating Future Face – the final exhibition in a ‘Twenty First Century Science’. biomedical science and its social series mounted by the Wellcome Trust contexts. Three Production Awards at the Science Museum – ran from Consultations and debate (of £50 000 upwards) and ten 1 October 2004 to 13 February 2005 Two public consultation reports were Research and Development awards (see page 25). Touch Me, a Wellcome published in August 2005. ‘Information (of up to £15 000) were made. Trust-funded exhibition at the Victoria and Attitudes: Consulting the public and Albert Museum (16 June to 29 about biomedical science’ and ‘What In October 2004, the Wellcome Trust August 2005), explored the pleasures do People Think about Gene Therapy?’, contributed to six of the 17 awards and sensations of touch. The refurbished a survey of public knowledge of and made to science centres and other Hunterian Museum of the Royal College attitudes to gene therapy and its social institutions throughout the UK in round of Surgeons was re-opened by Her and ethical implications. three of ReDiscover, and in March 2005 Royal Highness The Princess Royal contributed to eight of 20 awards made Three innovative methods of debate on 9 February 2005 (see page 26). in the fourth and final round. ReDiscover were funded by the Trust in 2004/05 is a joint venture between the Millennium (see pages 26–27). LIBRARY AND INFORMATION RESOURCES 51

LIBRARY AND INFORMATION RESOURCES The Wellcome Library provides free public access to more than a million items related to the history of health, disease and medicine. The Wellcome Trust also works to enhance access to key information resources and publishes material in a range of formats for a variety of audiences.

The Library Awards 2005 ceremony, which took Developed by the UK Web Archiving ‘Turning the Pages’, an award-winning place in the Wellcome Library in Consortium (UKWAC) – the British interactive technology developed by July 2005. Library, JISC, the National Archives, the the British Library, was installed at the Many of the treasures from the Library’s National Library of Wales, the National Wellcome Library at 210 Euston Road Asian Collections were featured in the Library of Scotland and the Wellcome in May 2005. The technology enables Wellcome Trust-funded exhibition Asia: Trust – the project has archived 299 readers to ‘turn’ the pages of three rare Body Mind Spirit, which focused on titles and 1090 individual web sites, and beautiful works from the Library’s health and wellbeing in Asia, and ran collecting 84 GB of data. rare book, Asian and manuscript from 13 October to 12 December 2004. Publishing holdings, to examine them in detail, and The exhibition was held at the Brunei The Trust launched two new publications to read or listen to commentaries. The Gallery at London University’s School of in 2005. Wellcome Science, to be manuscripts can also be viewed online. Oriental and African Studies (SOAS) and published three times a year, provides A previously unknown recording of a was a collaboration between Asia in-depth reviews of the most exciting speech made by Florence Nightingale House, the Wellcome Library and SOAS. research funded by the Wellcome Trust, in support of the Light Brigade Relief in Biomedical information plus guides and insight into the latest July 1890 has been restored and made Significant progress was made during scientific discoveries. available in collaboration with the British the year on the Medical Digitisation Wellcome Focus, published once a year, Library, which is preserving the original Project, a partnership with the Joint provides an overview to a particular area fragile wax cylinder. A digitally enhanced Information Systems Committee (JISC) of medicine and key areas of research version of the recording is available and the National Library of Medicine within it. The first issue, Antibiotic on its Voices of History CD. (NLM) to digitise material from medical Resistance: An unwinnable war?, The Wellcome Library and the US journals. Funding from the Wellcome explored the science and medical impact National Library of Medicine worked Trust and JISC will allow the project of microbial resistance and how research together to digitise materials from to digitise at least 1.7 million pages, is tackling it. Francis Crick’s personal archive and which will be freely available via Two issues in the Big Picture series were make them available to view over the PubMed Central. published – on obesity and nanoscience internet. Digitised materials include a Web-based content presents new (see page 24). pencil sketch showing first impressions archiving challenges, due to its of the famous DNA double helix, the Dengue, the latest CD-ROM ephemeral nature. The Wellcome telegram informing Crick that he had in the Trust’s award-winning Topics Library has been a leading member won the Nobel Prize in 1962 and letters in International Health series, was of a project assessing the feasibility from schoolchildren asking for advice published in 2005. It was developed of systematic archiving of important on how to “be a good scientist”. in collaboration with the UNICEF– websites. A searchable archive of UNDP–World Bank–WHO Special The most outstanding images recently websites selected for their scholarly, Programme for Research and Training acquired for the Wellcome Library’s cultural and scientific value is now in Tropical Diseases (TDR). Medical Photographic Library were available at www.webarchive.org.uk. highlighted at the Biomedical Image ADVISORY COMMITTEES 52

ADVISORY COMMITTEES

Animal Health in the Professor J H Naismith Professor S McLean Professor P B Jones Developing World Funding (to February 2005) University University of Glasgow University of Cambridge of St Andrews Committee Professor S Mendus Professor E M Joyce Professor H R P Miller Professor F C Odds University of York University College London (Chair) University of Edinburgh University of Aberdeen Professor N Nevin Professor M J Morgan Professor P A Conrad Professor C E Rudd Queen’s University Belfast City University, London University of California, Davis, USA Imperial College of Science, Professor M Reiss Professor J C Rothwell Technology and Medicine, London Professor M C M De Jong Institute of Education, London Institute of Neurology, University Wageningen University, Dr R E Sockett College London Professor M Richards The Netherlands University of Nottingham University of Cambridge Professor W Schultz Professor R H Gilman Professor D Soldati University of Cambridge Professor S Yearley Johns Hopkins University, University of Geneva, Switzerland Baltimore, USA University of Edinburgh Professor A Thapar Professor J A Vazquez-Boland Cardiff University Dr C Heffernan University of Bristol Clinical Interview Committee University of Reading Professor J M Wardlaw Professor R E Phillips Western General Hospital, Basic Science Interview (Chair) University of Oxford Dr M Jeggo Committee University of Edinburgh CSIRO Livestock Industries, Professor M R Bennett Australia Professor G Banting University of Cambridge History of Medicine Funding (Chair) University of Bristol Committee Dr R Kock Professor T J Elliott Organisation of African Professor N J Buckley Southampton General Hospital Professor M A Jackson Unity/InterAfrican Bureau for Animal University of Leeds (Chair) University of Exeter Resources, Nairobi, Kenya Professor C G Fairburn Professor T J Elliott University of Oxford Dr J Andrews Professor G H Palmer Southampton General Hospital Oxford Brookes University Washington State University, USA Professor J A Franklyn Professor D B Goldstein University of Birmingham Professor V Berridge Dr C Peacock University College London London School of Hygiene FARM Africa, London Professor I R Griffiths and Tropical Medicine Professor P W Ingham University of Glasgow Professor D U Pfeiffer University of Sheffield Professor M A Crowther Royal Veterinary College, Hatfield Professor D P Kelleher University of Glasgow Professor A R Mayes Trinity College Dublin, Ireland Dr M J Witty University of Liverpool Dr J M T Ford Professor M Maze Pfizer Animal Health, Sandwich Professor L H Pearl Dr M Harrison The Institute of Cancer Research, Imperial College School University of Oxford Basic Immunology London of Medicine, London and Infectious Disease Mr J N P B Horden Funding Committee Dr H Skaer Professor S H Sacks Royal Holloway, University University of Cambridge Guy’s, King’s and St Thomas’ of London Professor A C Hayday School of Medicine, King’s (Chair) Guy’s, King’s and St Professor D F Smith College London Dr T Tansey Thomas’ School of Medicine, University of York University College London King’s College London Professor A J Silman Professor C M R Turner University of Manchester Professor P J Van Der Eijk Dr B Arnold University of Glasgow University of Newcastle upon Tyne German Cancer Research Centre, Professor D M Turnbull Professor M J Whitaker Heidelberg, Germany University of Oxford Immunology and Infectious University of Newcastle upon Tyne Disease Strategy Committee Professor G S Besra Professor M Yaniv Cognitive and Higher University of Birmingham Dr R M Atlas Pasteur Institute, Paris, France Systems Funding (Chair) University of Louisville, Professor M Duszenko Committee Kentucky, USA University of Tübingen, Germany Biomedical Ethics Funding Professor J N P Rawlins Committee (Chair) University of Oxford Professor P Smith Professor R M Elliott Governor, Wellcome Trust University of St Andrews Mr A Tomei Professor J P Aggleton (Chair) The Nuffield Foundation, Cardiff University Professor J O Thomas Professor B Gicquel London Governor, Wellcome Trust Pasteur Institute, Paris, France Professor D V M Bishop Dr C Barton University of Oxford Professor V S Chauhan Professor P D Griffiths International Centre for Genetic Professor A V Campbell Royal Free and University College Professor A Brice Engineering and Biotechnology, Centre for Ethics in Medicine Medical School, London Pitié-Salpêtrière Hospital, Paris, New Delhi, India France Dr M J Keeling Dr D Coles Professor D G Colley European Commission, University of Warwick Professor R J Dolan University of Georgia, USA Brussels, Belgium Institute of Neurology, University Professor R M Maizels Professor C C Goodnow Professor N L G Eastman College London University of Edinburgh Australian National University, St George’s Hospital Medical Professor K H G Mills Professor P A Garety Canberra, Australia School, University of London Institute of Psychiatry, King’s Trinity College Dublin, Ireland Professor A C Hayday Professor P Kaufert College London King’s College London Professor B P Morgan University of Manitoba, Canada Cardiff University ADVISORY COMMITTEES 53

The Wellcome Trust is committed to the principles of peer review. We are indebted to the many researchers who gave up their time to sit on our advisory committees, and to the thousands of scientific referees, in the UK and overseas, who provide comments on grant applications. The following pages list the membership of our advisory committees during 2004/05.

Professor K P Klugman Medical Humanities Strategy Dr D G Wilkinson Molecules, Genes and Cells Emory University, Atlanta, USA Committee National Institute for Medical Strategy Committee Research, London Professor H R P Miller Professor R A Hope Professor B Alberts University of Edinburgh (Chair) University of Oxford Professor H J Willison (from July 2005) (Chair) University University of Glasgow of California, San Francisco, USA Professor R E Phillips Professor P Smith University of Oxford Governor, Wellcome Trust Molecules, Genes and Cells Professor A P Bird Governor, Wellcome Trust Professor A B Rickinson Mr E Walker-Arnott Funding Committee University of Birmingham Governor, Wellcome Trust Professor S G Oliver Professor R Plasterk Governor, Wellcome Trust Professor M E J Woolhouse Professor H M Evans (Chair) University of Manchester University of Edinburgh University of Durham Dr V Allan Professor J O Thomas University of Manchester Governor, Wellcome Trust Library Advisory Committee Professor K W M Fulford University of Warwick Professor J A Armour Professor D M Altshuler Mr P K Fox Massachusetts General Professor M A Jackson University of Nottingham (Chair) University of Cambridge Hospital, USA University of Exeter Professor P R Avner Mr E Walker-Arnott Professor G Banting Professor H King Pasteur Institute, Paris, France Governor, Wellcome Trust University of Bristol University of Reading Professor L R Cardon Dr P Ayris Professor A Berns Professor G Richardson University of Oxford University College London Library The Netherlands Cancer Institute, King’s College London Professor H Cook Professor R A Dixon The Netherlands John Innes Centre, Norwich University College London Mr A Tomei Dr R Brent The Nuffield Foundation Mr N Kingsley Professor P S Freemont University of California, The National Archives, Kew Professor T Treasure Imperial College of Science, Berkeley, USA Technology and Medicine, London Guy’s and St Thomas’ Dr P N Goodfellow Ms J Wilkinson NHS Foundation Trust The British Library, London Dr A J Greenfield GlaxoSmithKline Molecular and Cellular Medical Research Council Mammalian Genetics Unit Professor S G Oliver Livestock for Life Awards Neuroscience Funding University of Manchester Funding Committee (from Committee Professor D Heinegard July 2005) Lund University, Sweden Professor P W J Rigby Professor V H Perry The Institute of Cancer Research, Professor H R P Miller (Chair) University of Southampton Professor A I Lamond London (Chair) University of Edinburgh University of Dundee Dr C D Benham Professor J M Thornton Dr J Claxton GlaxoSmithKline Professor C L Mummery European Bioinformatics Institute, European Commission, Professor P J Brophy Netherlands Institute for Cambridge Brussels, Belgium Developmental Biology, University of Edinburgh Professor J R Gillespie The Netherlands Neuroscience and Mental Professor G L Collingridge University of California, Davis, USA Professor S Neidle Health Strategy Committe University of Bristol Dr C Heffernan University of London Professor D Purves Professor V Crunelli (Chair) Duke University, University of Reading Professor A J Rees Cardiff University Durham, USA Professor K Homewood University of Aberdeen Professor M Götz Professor A P Bird University College London Professor L M Roberts Institute of Stem Cell Research, Governor, Wellcome Trust Dr B Ilsoe University of Warwick Munich, Germany Professor R Plasterk Danish Ministry of Foreign Affairs, Dr D L Stemple Professor C F Inglehearn Governor, Wellcome Trust Copenhagen, Denmark Wellcome Trust Sanger Institute, University of Leeds Dr R Kock Cambridge Professor D M Clark Professor D M Kullmann Institute of Psychiatry, King’s Organisation of African Unity/ Professor A B Tobin University College London College London InterAfrican Bureau for Animal University of Leicester Resources, Nairobi, Kenya Professor S H Lovestone Professor D A S Compston Professor M F Tuite Institute of Psychiatry, King’s University of Cambridge Dr A McLeod University of Kent, Canterbury AGAL, Food and Agriculture College London Professor V H Perry Dr J P Vincent Organization, Rome, Italy Professor B Robertson University of Southampton National Institute for Medical University of Leeds Dr C Peacock Research, London Professor M C Raff FARM Africa, London Dr G Schiavo University College London Professor J P Waltho Cancer Research UK, London Dr S Ramdas University of Sheffield Professor J N P Rawlins ANTHRA, Andhra Pradesh, India Research Institute University of Oxford Professor R J White Professor K P Steel Mr C D Spencer University of Glasgow Professor A Toga Agriculture and Rural Development Wellcome Trust Sanger Institute, Reed Neurological Research Department, Tunis, Tunisia Cambridge Professor D I Wilson Center, Los Angeles, USA University of Southampton ADVISORY COMMITTEES 54

ADVISORY COMMITTEES

Physiological Sciences Populations and Public Principal Research Mr D Bromfield Funding Committee Health Funding Committee Fellowship Interview BBC, London Professor P J T Vallance Professor S B J Ebrahim Committee Mr C Cable (Chair) Royal Free and University (Chair) London School of Hygiene Professor P W J Rigby The Imaginarium, Anchorage, USA College Medical School, London and Tropical Medicine (Chair) The Institute of Cancer Research, London Dr G Delacote Professor D J Beech Professor N Chaturvedi The Exploratorium, University of Leeds Imperial College School Professor M Bobrow San Francisco, USA of Medicine, London Governor, Wellcome Trust Professor T B Bolton Mr T R Devitt St George’s Hospital Medical Professor J H Darbyshire Professor R O Hynes University of Wisconsin–Madison, School, University of London Medical Research Council Clinical Massachusetts Institute USA Trials Unit of Technology, USA Professor E R Chilvers Dr S Duensing University of Cambridge Professor C A Dezateux Professor T E Wellems University of California, USA Institute of Child Health, London National Institute of Allergy Professor R Dimaline Professor G Durant and Infectious Diseases, USA University of Liverpool Dr A C Ezeh Australian National Science African Population and Health Professor D J Fitzgerald Public Engagement Strategy and Technology Centre, Research Centre, Nairobi, Kenya University College Dublin, Committee Questacon, Australia Republic of Ireland Professor J C Falkingham Professor N J Rothwell Professor R Duschl Southampton University Professor A T Hattersley (Chair) University of Manchester Rutgers University, USA Peninsula Medical School, Exeter Professor A Fontanet Ms P Hodgson Ms R Edwards Pasteur Institute, Paris, France Professor S G Hillier Governor, Wellcome Trust Qualifications and Curriculum Authority, London University of Edinburgh Professor A F Glasier Mr A Ross Goobey Edinburgh Healthcare NHS Trust Professor M S Marber Governor, Wellcome Trust Dr A Friedman New York Hall of Science, USA King’s College London Professor K Hill Dr D Bell Harvard Initiative for Global Professor P Maxwell Association of Science Education Mr D Schatz Health, USA Imperial College of Science, Pacific Science Centre, Mr P Dodd Seattle, USA Technology and Medicine, London Professor S J Jejeebhoy Made in China UK Ltd The Population Council, Professor S H Ralston Ms G Thomas New Delhi, India Ms C Fox Miami Museum of Science University of Edinburgh Institute of Ideas, London Professor K T Khaw and Planetarium, USA Professor I C A F Robinson University of Cambridge Professor A Irwin National Institute for Medical University of Liverpool ReDiscover Joint Funders’ Research, London Professor R Martorell Committee (finished in 2005) Emory University, Atlanta, USA Professor M A Jackson Professor M Bobrow Professor G A Rutter University of Exeter University of Bristol Professor M Tanner (Chair) Governor, Wellcome Trust Swiss Tropical Institute, Switzerland Professor R Millar Mr E Walker-Arnott Professor A M Tomkins University of York Institute of Child Health, London Populations and Public Governor, Wellcome Trust Dr R Persaud Dr H Couper Professor M K B Whyte Health Strategy Committee The Maudsley Hospital University of Sheffield Professor L Peltonen-Palotie The Millennium Commission (Chair) Biomedicum Helsinki, Professor K Sykes Mr M D’Ancona University of Bristol Physiological Sciences Finland The Millennium Commission Strategy Committee Professor P Smith Mr A Tomei Ms J Donovan Professor P M Stewart Governor, Wellcome Trust The Nuffield Foundation (Chair) University of Birmingham The Millennium Commission Professor F Binka Dr G Watts Mr M O’Connor Professor A P Bird INDEPTH Network, Ghana BBC Radio 4 Governor, Wellcome Trust The Millennium Commission Professor N Day Mr S Webster Sir Eric Ash Professor F M Ashcroft Imperial College London Strangeways Research Laboratory, Trustee, The Wolfson Foundation University of Oxford Cambridge Professor Lord Robert Winston Dr V Harrison Professor K R Chien Imperial College School of Professor P J Donnelly The Wolfson Foundation Massachussetts General University of Oxford Medicine, London Hospital, USA Lord Randolph Quirk Professor S B J Ebrahim ReDiscover Advisory Board Professor G Fitzgerald Trustee, The Wolfson Foundation University of Bristol (finished in 2005) University of Pennsylvania School Sir Derek Roberts of Medicine, Philadelphia, USA Professor P Elliott Dr P-E Persson Trustee, The Wolfson Foundation Imperial College School (Chair) Heureka Science Centre, Professor J Hunter of Medicine, London Finland Research Resources in GlaxoSmithKline Professor W Graham Dr B Aprison Medical History Funding Professor J J Mullins University of Aberdeen Museum of Science and Industry, Committee University of Edinburgh Chicago, USA Professor H King Professor H Jaffe (Chair) University of Reading Professor P J T Vallance University of Oxford Dr A Bandelli Royal Free and University College International consultant Ms N Bell Medical School, London The National Archives, Richmond ADVISORY COMMITTEES 55

Mrs J Etherton Dr D Glaser Professor P Ghazal Tropical Interview Valence House Museum, University College London University of Edinburgh Committee Dagenham Medical School Mr S Hawkes Professor K P Klugman Professor M A Jackson HQ Arts Ltd, Pontefract Professor D Horwell (Chair) Emory University, University of Exeter University of East Anglia Atlanta, USA Ms S Hill Ms H Lindsay Eden Project, Cornwall Dr W Luyten Professor C E Clayton London Metropolitan Archives IriDM, Leuven, Belgium University of Heidelberg, Germany Mr R Levinson Ms Y M T Player-Dahnsjö University of London Dr R Parekh Professor R H Gilman University of Dundee Abingworth Management Johns Hopkins University, Ms V Reiss Limited, London Baltimore, USA Sciart Funding Committee Arts Council England Dr M Skingle Professor P T LoVerde Production Awards 2005 Mrs L Thomas GlaxoSmithKline Southwest Foundation Professor A Payne for Biomedical Research, Study Design Expert Group (Chair) Dartington College of Arts Technology Transfer San Antonio, USA Professor P J Donnelly Strategy Panel Ms M Ellis (Chair) University of Oxford Dr F Wabwire-Mangen Film London Dr T J Rink (from March 2005) Makerere Professor P R Burton (from November 2004) (Chair) University, Kampala, Uganda Dr L Goodman University of Leicester The London Institute Professor R Plasterk Professor R Collins Governor, Wellcome Trust Ms K Huffman Radcliffe Infirmary, Oxford Cornerhouse, Manchester Dr S Foden Dr P Deloukas Professor B Hurwitz Wellcome Trust Sanger Institute, Dr R G Hill King’s College London Cambridge Merck Sharp & Dohme UK Ms L Le Feuvre Professor R J Hayes Dr R Parekh Goldsmiths College London London School of Hygiene Abingworth Management Limited, London Dr J Turney and Tropical Medicine Science writer Professor M Khoury Tropical and Clinical Dr R J T Wingate Centers for Disease Control Immunology and Infectious King’s College London and Prevention, Atlanta, USA Disease Funding Committee Professor M E J Woolhouse Society Activity Awards Professor A D Morris University of Dundee (Chair) University of Edinburgh Funding Committee (from February 2005) Professor D J Porteous Professor Z A Bhutta The Aga Khan University Hospital, Professor R Millar University of Edinburgh Karachi, Pakistan (Chair) University of York Professor M J Prince Professor U d’Alessandro Dr D Bentley Institute of Psychiatry, (from May 2005) Prince Leopold (to August 2005) Wellcome Trust King’s College London Institute of Tropical Medicine, Sanger Institute, Cambridge Professor R W Snow Antwerp, Belgium Wellcome–KEMRI Research Dr S Joss Professor D Goldblatt University of Westminster Programme, Nairobi, Kenya Institute of Child Health, London Professor D P Strachan Dr G Mulgan Professor P Hagan Young Foundation, London St George’s Hospital Medical School, University of London University of Glasgow Professor M Parker Professor S Krishna University of Oxford Professor J N Weber Imperial College School St George’s Hospital Medical Mr N Partridge of Medicine, London School, University of London Terrence Higgins Trust Professor S Wyke Dr D G Lalloo Dr S Preston University of Stirling University of Liverpool University of Durham Dr B Zaba Dr M M Lederman Mr M Whitby London School of Hygiene (from May 2005) Case Western The Red Green and Blue and Tropical Medicine Reserve University, Cleveland, USA Company Ltd Professor D U Pfeiffer Technology Transfer Society Awards Funding (from May 2005) Royal Veterinary Challenge Committee College, Hatfield Committee; Pulse Dr T Bianco Dr H Nicholson (Chair) Wellcome Trust Professor N G Saravia (Chair) Royal Holloway, University Centro Internacional de of London Dr G Forrest Entrenamiento e Investigaciones Independent consultant Médicas, Colombia Ms H Durman Resource Base, Southampton Professor B Furr Professor E Schurr AstraZeneca plc (from May 2005) Montreal General Hospital, Canada ACKNOWLEDGEMENTS 56

Acknowledgements The Wellcome Trust Annual All images are courtesy of images (M Zernicka-Goetz); p. We are grateful to everyone Review is distributed via the Wellcome Library, except 33 protein structure (Structural who agreed to be reviewed a mailing list held by the as follows: Genomics Consortium); pp. in this issue, everyone who Wellcome Trust. If you would 34–35 (L–R) images from An Contents and p. 1 human cells supplied images or gave us like to be added to this list, Oral History of Diabetes (N R (M Daniels); p. 2 (L–R) protein permission for their images or if you have a colleague Hill, Oxford Centre for structure (Structural Genomics to be used, and the many who would like to receive Diabetes, Endocrinology and Consortium), flu virus (R members of Wellcome Trust the Wellcome Trust Annual Metabolism), ALSPAC party Dourmashkin); pp. 4–5 a staff who helped produce Review, please contact: (ALSPAC); p. 37 (L–R) cross-section of the retina this volume. computer-generated image Publishing Department showing rods (small cells) and of the heart (D Patterson), the Editor Wellcome Trust cones (large cells) (C Guerin); Clinical Research Facility at Ian Jones FREEPOST pp. 6–7 (L–R) early mouse Cambridge, the development ANG 6754 embryo (A Surani), labelled Project Manager of polarity in a Drosophila Ely CB7 4YE, UK cells in embryos (G Koentges); Lucy Moore embryo (I Palacios and D pp. 8–9 (L–R) headache (Getty T +44 (0)20 7611 8651 St Johnston). Writers Images), light-senstive cell and F +44 (0)20 7611 8242 Penny Bailey stained retinal cell (M Hankins); Cover image: E [email protected] Lisa Melton pp. 10–11 (L–R) man selling Scanning electron micrograph Giles Newton www.wellcome.ac.uk/publications poultry meat (Rex Features), of red blood cells entangled avian flu virus (CDC/C in the fibrin mesh of a clot, Editorial staff ISBN 1 84129 058 0 Goldsmith/J Katz/S Zaki/SPL), computer-coloured red/yellow Tom Freeman The Wellcome Trust is a man with malaria (D A Warrell/ (D Gregory and D Marshall). Design registered charity, no. 210183. International Health Image Joanna Pollard Its sole Trustee is The Collection), malaria-infected Wellcome Trust Limited, blood cells (D Ferguson, Design Manager a company registered in ISM/SPL), paediatric ward in Amanda Allen England, no. 2711000, whose Kilifi (C Penn); pp. 12–13 (L–R) Picture research registered office is 215 Euston newborn baby (A Sieveking), Anne-Marie Margetson Road, London NW1 2BE. brain showing visual cortex (M Lythgoe and C Hutton); p. 15 Photography First published by the Kenyan youths (C Penn); pp. David Sayer Wellcome Trust, 2006. 18–19 (L–R) pulse oximeter Comments on the Wellcome © The Trustee of the data (CardioDigital Ltd), Trust Annual Review are Wellcome Trust, London. Polyhap implant faces (V welcomed and should be Popov), regenerated tooth All rights reserved. No part sent to: (P Sharpe); p. 21 (L–R) Bob of this publication may be Snow and Sam Ochola Ian Jones, Publisher reproduced, stored in a (C Penn); malaria parasite Publishing Group retrieval system, or transmitted (Moredun Animal Health Wellcome Trust by any means electronic, Ltd/SPL); pp. 24–25 (L–R) Gibbs Building mechanical, photocopying, nano-crystals (G W Ho and M 215 Euston Road recording or otherwise without Welland), Doll Heads (Henrique London NW1 2BE, UK the prior permission of the Faria Fine Art/Elia Alba); pp. Wellcome Trust. F +44 (0)20 7611 8270 26–27 (L–R) Hunterian E [email protected] Wellcome Trust Museum exhibits (Hunterian Gibbs Building Museum), wake-up call (Rex 215 Euston Road Features); p. 28 Dr Paul London NW1 2BE, UK Barlow, University of Edinburgh, next to the nuclear T +44 (0)20 7611 8888 magnetic resonance machine; F +44 (0)20 7611 8545 pp. 30–31 (L–R) synapse (A E [email protected] Brand), CGI mouse heart (S www.wellcome.ac.uk Bhattacharya), mouse embryo

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