Annual Review 2004 - Wellcome Trust

ANNUAL REVIEW2004

THE WELLCOME TRUSTAn independent, privately owned endowed medical research charity.Our mission is to foster and promote research with the aimof improving human and animal health.CONTENTS2 Director’s statement4 Knowledge14 Resources20 Translation28 Public engagement34 A year at the Wellcome Trust36 Financial summary37 The funding year38 Immunology and Infectious Disease40 Molecules, Genes and Cells42 Neuroscience and Mental Health43 Physiological Sciences44 Populations and Public Health45 Medical Humanities46 Technology Transfer47 Wellcome Trust Genome Campus48 Public Engagement50 Funding committeesThis Annual Review covers the WellcomeTrust’s financial year 1 October 2003 to30 September 2004.AIMS AND OBJECTIVESOur four Aims identify the prioritieson which we concentrate. EachAim is underpinned by a seriesof Objectives which establishthe practical measures being takento achieve the Aims and, ultimately,our mission.4 KnowledgeAdvancing knowledge andunderstanding in the biomedicalsciences and their impact onsociety – past, present and future.• Supporting basic, appliedand strategically importantresearch in biomedical sciences.• Researching the societalimpact of biomedical science –past, present and future.14 ResourcesContributing to a long-termand vibrant research environment.• Human resources: meetingtraining and career developmentneeds of researchers.• Physical resources: buildingsuitable conditions for research.

CONTENTS120 TranslationAdvancing the translationof Trust-funded researchinto health benefits.• Promoting patient-orientatedand health services research.• Advancing the disseminationand exploitation of the resultsof Trust-funded research.28 Public engagementEngaging with the publicthrough informed dialogue.• Stimulating an informeddialogue to raise awarenessand understanding of biomedicalscience, its achievements,applications and implications.BOARD OF GOVERNORSSir Dominic CadburyChairmanProfessor Martin BobrowDeputy ChairmanProfessor Adrian BirdProfessor Christopher EdwardsAlastair Ross GoobeyDame Patricia HodgsonProfessor Ronald PlasterkProfessor Peter SmithProfessor Dame Jean ThomasEdward Walker-ArnottEXECUTIVE BOARDDr Mark WalportDirector of the Wellcome TrustLinda ArterDirector of Financeand Information ManagementDr Ted BiancoDirector of Technology TransferJohn CooperDirector of Human Resourcesand ServicesDr David LynnHead of Strategic Planning and PolicyClare MattersonDirector of Medicine, Societyand HistoryDavid PhillippsDirector Designate of FinanceDr Sohaila RastanDirector of Science FundingJohn StewartHead of Legal and Company SecretaryAs at January 2005L to RThe bacterium,Escherichia coli.Kenyan child.Human embryoat the blastocyst stage.A portrait of twinsby David Teplica.Interactive exhibitat the science centre,Thinktank, in Birmingham.

DIRECTOR’S STATEMENT2WORKING WITH OTHERSIt’s been a year when working in partnership has deliveredreal benefits.Highlights of the year• The highly accurate and complete‘gold standard’ human genomesequence is released.• Mutations in the ERBB2 geneare discovered in a subset of lungcancers, opening up the prospectof targeted therapy.Looking back on a busy year, I amdelighted at the progress we have seen– the discoveries our researchers havemade, the accelerating applicationof research, and the changes we havemade within the Wellcome Trust itself.And I am also pleased that so muchhas been achieved in partnership withothers. I firmly believe that scientificopportunities will be exploited to besteffect, and medical needs met, whenpeople work together to harness theirenergies to common purpose.Our Major Overseas ResearchProgrammes in developing countries,for example, have been based onpartnerships with local Governmentsand academic and health infrastructures.By dealing with local issues, they haveprovided genuine benefits to their hostcountries. Because of these strong links,their activities have quickly fed into localpolicy and practice.This year we report on the continuingsuccess of artemisinin combinationtherapy for malaria, pioneered byProfessor Nick White and colleaguesin South-east Asia, as well as a trialof steroid therapy in tuberculousmeningitis, which has significantlycut death rates, and has led to changesin government health policy.Recently, the Wellcome Trust wasawarded a Merit Award from thePeople’s Committee of Ho Chi MinhCity, which I had the honour of acceptingfor the Trust during a fascinating visitto see the work of our researchersin Thailand, Vietnam and Laos. ProfessorWhite and Dr Jeremy Farrar were alsohonoured by the Committee. Thisrecognition is an endorsement of ourlong-standing collaborative approachin the region.UK scienceIn the UK we have continued to workconstructively with the UK Government,which has consistently recognised theimportance of the country’s researchbase. There is an outstanding communityof imaginative and productive researchersin the UK. We will continue to supportresearch in the UK whilst its excellentscience base is maintained. The additionalfunds for science provided in the 2004Spending Review, including moreresources as an explicit underpinningof charity-funded research, are signalsthat the Government is as committedas we are to the future of UK science.There are other areas in which we areworking closely with the Government.A long-standing partnership, to constructthe UK’s new synchrotron facility, receiveda further financial boost this year (£120million in total, with more than £100million extra from the Government).Although we are pleased to work inpartnership with Government in supportof research, our independence alsoenables us – and, indeed, requires us –to play an important role as a critic ofGovernment when it pursues policiesthat may have an adverse impact onbiomedical research for public good.We have worked very hard during theyear to gain acceptance of amendmentsof proposed legislation that couldhave serious adverse consequencesfor important medical research.Partnership also increases theeffectiveness of our voice in this publicpolicy work; we have worked closely withthe UK research funding and academiccommunity to produce joint responsesto, among other things, the draft HumanTissue Bill and Mental Capacity Bill.A single coherent voice has undoubtedlybenefited all parties and led to moreconsidered legislation.Two of the most important andchallenging areas are clinical andinternational research. The creationof a new partnership, the UK ClinicalResearch Collaboration (UKCRC),is recognition that clinical researchwill only thrive if all the key protagonistswork together – funders, the healthservice and the higher educationcommunity. We look forward toannouncing new initiatives under theUKCRC umbrella in the very near future.We have also developed a jointcommitment to prioritise malariaresearch, and are discussing with other

DIRECTOR’S STATEMENT3• A biochemical defect causingneonatal diabetes is identified,allowing babies to be givenmedication rather than injections.• Beneficial effects of rapamycinanalogues in models ofHuntington’s disease suggesta new therapeutic approach.• Avian flu victims are treatedat Wellcome-funded facilitiesin Vietnam, capturing valuabledata on the impact of the virus.• Analysis of clinical trials datafor artemisinin combinationtherapy confirms its potencyas an antimalarial drug.• A trial with steroids markedlycuts deaths from tuberculousmeningitis in Vietnam.• ‘Myskin’, an innovative dressingincorporating patients’ own cells,is launched in the UK NHS.• Pain exhibition at the ScienceMuseum attracts a recordnumber of visitors.funders, including the Department forInternational Development, how wemight best work together. Moreover,with the UK assuming presidency of theG8 group of nations on 1 January 2005,and a spotlight on Africa as a majorpriority, we have a real opportunityto make a difference to a continent thatsuffers so badly from disease.In our Public Engagement work, wedeveloped ground-breaking exhibitionswith the Science Museum and the BritishMuseum (and in 2005 will be collaboratingwith the Victoria and Albert Museumon a new exhibition on touch). Ourscience centre and museum exhibitrenewal initiative, Rediscover, was also apartnership venture – with the MillenniumCommission and the Wolfson Foundation.Building work began in the year forthe National Science Learning Centre,funded by us as part of a £51 millionpartnership with the Department forEducation and Skills. The ScienceLearning Centre network will providea major boost to science teachingin the UK, benefiting the next generationof scientists and, more generally,helping to create a scientificallyenquiring population.This year has seen many excitingresearch findings published. A smallselection of these are summarisedin the following pages. It is clear weare living in a golden age of biomedicalresearch, as human genome data andhigh-throughput technologies offerexperimental possibilities undreamedof a generation ago; similarly, newapproaches to imaging and the studyof the brain give us unprecedentedinsight into the workings of the brain.An important challenge is not onlyto nurture this age of discovery but alsoto ensure that we capture practicalmedical benefits afforded by the flowof new knowledge.StreamsInternally, our year was markedby a move into a new building, theimplementation of a new corporateidentity, and the introductionof our streams model of funding.Our new building has been designedto encourage greater interaction betweenstaff – fostering ‘internal partnerships’and a greater sense of integration andcommon purpose. Our building is alsoopen and welcoming, a physical symbolof our desire to engage with ourmultitude of stakeholder communities.Our new corporate identity similarlyreflects a desire to be seen asapproachable, as well as distinctiveand independently minded.All these strands will come together inour new strategic plan, which we willdevelop during 2005 and launch towardsthe end of the year. The strategic plan,the follow-up to Planning for the Future:The Wellcome Trust 2000–2005, willoutline our aims for 2005–2010, andidentify more specifically how we willachieve these.Ultimately, it is the unstinting workof our grantholders that enables usto meet our objectives, and we lookforward to continuing to work inpartnership with them to advancetowards our ultimate goal – improvinghuman and animal health.Mark WalportDirectorJanuary 2005Mark Walport (right)visiting a ward atMahosot Hospital, Laos.

KNOWLEDGEKNOWLEDGE5

KNOWLEDGE6VANISHING GENESThe ‘gold standard’ genome has been publishedand is full of surprises.GENEGEOGRAPHYDNA variation shows geographicalclustering, which can distort thefindings from large genetic studies.The International Human GenomeSequencing Consortium has publishedits scientific description of the finishedhuman genome sequence – the ‘goldstandard’ genome.The current genome sequencecontains 2.85 billion nucleotides andencompasses around 99 per cent of theeuchromatic (or gene-containing) portionof the human genome. All but 341 ofthe 150 000 gaps present in the 2001working draft sequence have beenfilled in, and the sequence is 99.99per cent accurate – ten times moreaccurate than the original goal.The most surprising finding – and onethat hit the headlines worldwide – wasthe tiny number of protein-codinggenes in the genome. The new analysispredicts that there are only 20–25 000protein-coding genes in the genome,far fewer than the 100 000 confidentlypredicted a decade ago, and eventhe 30–40 000 estimated in 2001.A further intriguing finding is the numberof pseudogenes – genes that havelost their function and are graduallydecaying away. Indeed, recent studieshave already identified about 20 000pseudogenes, and there may evenbe more ‘dead’ genes in our genomethan ‘live’ ones.The largest single contribution to thehuman genome sequence was madeby the Wellcome Trust Sanger Institute.It is now trying to work out how so fewgenes can build something as complexas a human being.Finding that a particular genetic variantis more common in people with, say,diabetes than in those without is a cluethat the gene may be increasingsusceptibility to the disease. But isthe association real, or are the differentgenetic make-ups of the peopleinvolved in the study – the populationstructure – clouding the results?The extent of the problem washighlighted in a study by ProfessorPeter Donnelly and colleagues in Oxfordand Montreal, which examined 15 000DNA variations across three populationgroups (European American, AfricanAmerican and Asian) and within theAsian group. 1 Using statistical models,they found that the effects of populationstructure increase markedly with samplesize, leading to false positive resultsand missed real effects.This is a real headache for researcherssearching for genetic factors that haveonly small effects on common diseases,who need to examine large numbersof people.L to RSequencing at theWellcome TrustSanger Institute.Professor Lon Cardon,who is studying geneticvariation in theUK population.Professor InderjeetDokal (left) of ImperialCollege London.Faulty chromosomerepair is the cause ofdyskeratosis congenita.

KNOWLEDGE7SHORT NOT SWEETThe length of telomeres can predict when a rare inheriteddisorder will strike.Life would be much easier if weunderstood the genetic structureof the UK – and that is the goalof a new £2.3 million Wellcomefundedproject being led by Sir WalterBodmer, with Professor Donnellyand Professor Lon Cardon in Oxford.DNA will be collected from 3500people, in 30 rural locations, whoseparents and grandparents also livedin the same area.The data and DNA samples will becomea national resource for researchersto use to match their disease samples,thus reducing the chances of spuriousassociations. The resource will beparticularly valuable with a numberof very large population studies,such as the UK Biobank project,now underway.1 Marchini J, Cardon LR, Phillips MS,Donnelly P. The effects of human populationstructure on large genetic association studies.Nat Genet 2004; 36(5): 512–7Dyskeratosis congenita is adevastating disease that leadsto premature ageing, bone marrowfailure and cancer. Over the pastfew years, Professor Inderjeet Dokaland colleagues at Imperial College,London, have identified the geneticbasis of this rare inherited disorder.Most recently, they have clarifiedone of its most perplexing features –why symptoms appear earlierin successive generations. 1Affecting one person per million,the mutations that cause dyskeratosiscongenita disrupt telomeres – the tipsof chromosomes. When chromosomesare copied during cell division, telomerestend to get shorter. To compensatefor this, actively dividing cells makean enzyme, telomerase, which repairstelomeres. Without it, cells tendto go through a certain numberof divisions and then die.In dyskeratosis congenita, mutant genes(such as that coding for telomerase,TERC) mean that chromosome repairis faulty, and telomeres erode at anaccelerated rate. Tissues with activelyproliferating cells – gut, skin and bonemarrow – are the first to be affected.The earliest sign of accelerated wearand tear is usually abnormal skinpigmentation followed, years later,by cancer, premature ageing and bonemarrow failure, which often proves fatal.But why do children’s symptomsappear at an earlier age than in theirparents? This phenomenon is alsoseen in some other genetic disorders,where a three-letter fragment of DNAmultiplies in successive generations.What Professor Dokal and colleaguesdiscovered was that the lengthof a patient’s telomeres predictedwhen symptoms would first emerge –the shorter the telomere, the soonersymptoms appeared. As the telomeresget shorter in successive generations,so the disease strikes earlier.1 Vulliamy T et al. Disease anticipation is associatedwith progressive telomere shortening in familieswith dyskeratosis congenita due to mutationsin TERC. Nat Genet 2004; 36(5): 447–9.

KNOWLEDGE8STUCK IN A RUTLIVING BRAINSSerotonin depletion could explain the inflexible behavioursseen in people with psychiatric disorders.Brain imaging is revealing brainactivity during social interactions.People with obsessive–compulsivedisorder (OCD) or schizophrenia,and those who abuse drugs,typically have something in common:inflexible behaviours. New researchpoints the finger at deficienciesin the neurotransmitter serotonin:as Professor Trevor Robbins,Dr Angela Roberts and colleaguesat the University of Cambridge havediscovered, depletion of serotoninin the prefrontal cortex leadsto very similar abnormalities. 1We need cognitive flexibility to copewith daily life. Both learning and‘unlearning’ – changing tack in lightof further experience – are criticalto human experience. If that flexibilitybreaks down, a whole array ofuncontrollable behaviours can emerge:toe tapping, finger drumming, tics,knocking or pacing. In humans, thereare other signs that the brain has lostits flexibility: a rigid way of looking atthings, a refusal to let go of an idea,or fanatical attitudes.To explore the possible involvementof serotonin pathways, the Cambridgeteam depleted serotonin from theorbito-frontal cortex of marmosets.They then tested the animals’ abilityto solve both a visual learning taskand a ‘reverse learning’ task.Those marmosets whose serotonin hadbeen depleted were stuck in a learningrut: they had no difficulty in acquiringknowledge, but made more mistakesin ‘unlearning’, suggesting that theircognitive flexibility had declined.A similar effect has been seen in humanvolunteers whose serotonin levels werereduced by dietary manipulation.The finding that low serotonin inthe prefrontal cortex inhibits flexiblethinking provides insight into humanpsychiatric disorders. Not only will ithelp clinicians understand the difficultiesexperienced by patients with OCD,schizophrenia or drug-induceddamage, but it also has significantimplications for their treatment.1 Clarke H et al. Cognitive inflexibility followingprefrontal serotonin depletion. Science 2004;304: 878–80.Humans are intensely social creatures.It is vital, then, that our brains canperceive and interpret socially relevantinformation. A team led by ProfessorChris Frith at the Institute of Neurologyin London has been locating the neuralareas we engage during a rangeof social interactions.One valuable skill is our ability toassociate people with particular valuesor characteristics: are they honest,trustworthy and so on. To understandhow the brain responds to people’smoral standing, volunteers werescanned while they judged facesof people known to be fair or unfairplayers in the Prisoner’s Dilemma game.The faces of fair players lit up specificneural circuits, confirming that thereis an area in the brain dedicatedto processing information aboutpeople’s moral status. 1It is also useful to know whether aperson is trying to deceive us. Workingwith collaborators in France, ProfessorFrith studied people who had beenwatching videos of actors liftinga box. The participants were askedto judge whether the actors were liftinga heavy box or just pretending. Again,

KNOWLEDGE9MAKING CHOICESPatients should consent to medical treatment. But an inability to givereasoned consent may be more common than doctors appreciate.specific areas of the brain lit up whenpeople thought they were beingdeceived. 2 These areas are linkedto emotional responses, which fitswith the fact that we find deceptionemotionally distressing.Empathy is a unique human attribute,a ‘social glue’ that allows us tounderstand what others feel. To explorethe neural basis of empathy, ProfessorFrith’s group compared brain activityin volunteers either receiving a painfulstimulus or witnessing their loved onesexperience pain.Painful stimuli triggered both physicaland emotional areas of the brain,but witnessing someone else in paintriggered just the emotional response. 3So we cannot share a loved one’sphysical pain, but we can sharea similar emotional experience.1 Singer T et al. Brain responses to the acquiredmoral status of faces. Neuron 2004; 41(4):653–62.2 Grezes J, Frith C, Passingham RE. Brainmechanisms for inferring deceit in theactions of others. J Neurosci 2004; 24(24):5500–5.3 Singer T et al. Empathy for pain involvesthe affective but not sensory componentsof pain. Science 2004; 303(5661): 1157–62.To consent to medical treatment,patients should be making voluntaryand informed choices, and have themental capacity to make a decision.Patients lack mental capacity whenthey cannot understand theinformation being given to them,or use it to decide on a course ofaction, or are unable to communicatetheir decision. Usually, mentalcapacity is taken as read unless thepatient’s difficulties are very obvious.However, recent research suggeststhat the numbers of mentallyincapacitated patients may bebeing significantly underestimated.Professor Matthew Hotopf andcolleagues at the Institute of Psychiatry,Preston and Yale tested the degreeof cognitive impairment of patientsadmitted to a London hospital.Some 31 per cent of inpatients wereconsidered to lack mental capacity.However, when clinical teamsinterviewed inpatients, they rated just8 per cent as lacking mental capacity. 1Most patients probably rely on doctorsto make the most appropriate decisionfor them. A need to assess mentalcapacity in a medically pressing situationcould present significant difficultiesto the medical profession. On the otherhand, there is clearly also a need toprotect vulnerable patients, particularlywhen major – and irreversible – medicaldecisions are being made.These kinds of issues are beingconsidered in the UK’s draft MentalCapacity Bill. The researchers suggestthat, even if legislation is seen as tooheavy handed, the issue of patients’mental capacity should be given moreattention by doctors.1 Raymont V et al. Prevalence of mentalincapacity in medical inpatients and associatedrisk factors: cross-sectional study. Lancet 2004;364(9443): 1421–7.L to RNeurons in the brain.Brain imaging can revealthe neural areas usedduring social interactions.Professor Chris Frithof the Instituteof Neurology, London.People with Alzheimer’sdisease may lack themental capacity to giveinformed consent.

KNOWLEDGE10HEATEDDISCUSSIONGlobal warming does not appearto have driven the rise in malariaacross Africa.VOMITING SAND FLIESBy creating a sticky ‘hairball’ in the sand fly gut, the Leishmaniaparasite promotes its transmission – and ensures its survivalin its new host.A belief that global warming isresponsible for the recent resurgenceof malaria is misguided, accordingto an analysis of 80 years of climatedata in Africa. The analysis, led byDr Simon Hay and colleagues atthe University of Oxford, found noevidence that climate had changedthe suitability for malaria transmissionacross Africa. 1After decades in decline, malariahas made a comeback in many partsof Africa. Malaria mortality in youngchildren almost doubled from the1980s to the 1990s. The disease nowcauses around 3000 deaths each day.To find out whether this resurgencecould be linked to climate, Dr Hay’steam used a climate-driven biologicalmodel of malaria transmission to showthat changing patterns of temperatureand rainfall between 1911 and 1995had not made for a more hospitableclimate for mosquitoes and malaria.In a couple of regions, shifts in malariatransmission suitability were linkedto changes in rainfall.A bite from an infected sand fly is allit takes to catch the tropical diseaseleishmaniasis. Yet exactly how thesand fly delivers its lethal cargo has,until recently, remained a mystery.Now Wellcome-funded scientistshave discovered a key aspect oftransmission: a sticky gel secretedby the parasite and regurgitated bythe sand fly.Leishmaniasis is a parasitic diseaseaffecting about 12 million peopleworldwide, causing disfiguring ulcersand, in severe cases, death. Majorepidemics have occurred in Indiaand Bangladesh, and it is a scourgeof migrating populations, such as thoseaffected by civil war.Infection starts when a sand fly biteinjects the single-celled parasiteLeishmania, along with sand fly saliva.However, a team led by Dr Paul Batesat the Liverpool School of TropicalMedicine has discovered thatLeishmania is not a passive passengerin this process. It produces a gelatinoussecretion that forms a thick plugin the sand fly’s gut. This ‘hairball’stops the fly from feeding properlyand, as a result, the insect bitesrepeatedly, and for longer, increasingthe likelihood of transmission. 1As well as manipulating the behaviourof its insect vector, the parasitesecretion also affects its new humanhost. It includes a long, sugar-coated,phosphorylated protein (filamentousproteophosphoglycan, fPPG), whichis regurgitated by the sand fly andinjected into the victim. The fPPGappears to promote parasite survivaland exacerbates disease.The research has important implications.It immediately suggests possible newstrategies for tackling transmission,by blocking the action of the gel. But italso highlights how interactions betweenall the key players – parasite, vector andhost – need to be studied to give a clearview of disease transmission.1 Rogers ME et al. Transmission of cutaneousleishmaniasis by sand flies is enhanced byregurgitation of fPPG. Nature 2004; 430: 463–7.Rather than global trends, theresearchers emphasise that localfactors – migration, health serviceprovision and, particularly, the risein drug resistance – are likely to havea bigger impact on malaria transmission.1 Small J, Goetz SJ, Hay SI. Climatic suitabilityfor malaria transmission in Africa, 1911–1995.Proc Natl Acad Sci USA 2003; 100(26): 15341–5.L to RClimate is unlikely to playa part in the malariaresurgence in Africa.Sand flies regurgitatea sticky gel secretedby the Leishmaniaparasite which makesinfection more likely.Boy with an ulcer causedby Leishmania infection.Malaria-infectedred blood cells.Soay sheep populationson a remote Scottishisland are sensitiveto weather conditions.

KNOWLEDGE11UNWANTEDIMPORTScientists have tracked downthe origins of Africa’s drugresistantmalaria parasites.SHEEP DIPIn a study of periodic sheep decimations, seasonal fluctuationsin bad weather may be better at predicting mortality than local climate.Scientists co-funded by the WellcomeTrust and the US National Institutesof Health have uncovered evidencethat drug-resistant malaria in Africawas imported from South-east Asia.The boom in air travel has meant thatmalaria travels the globe too. Every year30 000 malaria cases are imported intoindustrialised countries. The figure forAfrica is unknown, but is likely tobe substantial.Today pyrimethamine (coformulated withsulphadoxine) is a mainstay of malariatreatment. But mutations in a geneknown as dhfr (dihydrofolate reductase)allow the parasite to survive. Parasiteshave up to four mutations in the dhfrgene – the more they have, the hardierthey are; with the full complement offour, they are resistant to all drugstargeting this enzyme.By genotyping the dhfr gene andsurrounding DNA, Dr Cally Roper,London School of Hygiene and TropicalMedicine, and collaborators have shownthat the most resistant parasites in Africadid not arise there, but originated inSouth-east Asia. 1 The parasite with fourmutations has not yet been seenin Africa, but if malaria parasites aretravelling from Asia to Africa, then thereis every chance it could be importedand become established.Our lives and those of other speciesare inextricably entwined – we areall part of a natural system. Climateobviously has an enormous impacton this system, yet the links betweenclimate and population numbersare rarely well understood. Withcurrent fears about climate instability,this is becoming a matter ofgrowing concern.A team of scientists led by Dr BryanGrenfell at the University of Cambridgehas spent 20 years exploring theimpact of climatic factors on a naturalpopulation – Soay sheep living ona remote Scottish island. This sheeppopulation ‘crashes’ every three to fouryears, when 70 per cent of the animalsperish during winter. They typically diefrom starvation, either because theyburn up more energy to keep warmor because there is little grass leftto graze on.Dr Grenfell’s team has been tryingto find out why this population is sounstable. They looked for correlationswith a range of possible causes andfound that foul weather over a threemonthperiod was the strongestpredictor of a population crash.Surprisingly, local weather variablesfailed to predict these deaths. Instead,variation in a large-scale, seasonalclimate index spanning several months –the North Atlantic Oscillation – providedthe most reliable forecast.A harsh spell – heavy rain, strong windsor low temperatures – at any time duringa three-month period was associatedwith high sheep mortality, eitherimmediately or after a few days.This appears to be obscured in the localclimate data, but is captured in crudeform by the North Atlantic Oscillation. 1These counter-intuitive results suggestthat, in order to predict populationchanges in response to ecologicalstresses such as climate change,large-scale, seasonal climate indicesspanning several months – such asthe North Atlantic Oscillation – maybe preferable to local records. In thelonger term, though, the need is toidentify more specifically which localfactors are ecologically most important.1 Hallett TB et al. Why large-scale climate indicesseem to predict ecological processes betterthan local weather. Nature 2004; 430: 71–5.Data collection has been funded by the WellcomeTrust, the Natural Environment Research Counciland the Biotechnology and Biological SciencesResearch Council.1 Roper C et al. Intercontinental spreadof pyrimethamine-resistant malaria. Science2004; 305(5687): 1124.

KNOWLEDGE12CROSS-CHANNELTHERAPYThanks to the discovery of the precise cause of infant diabetes,young children can be given medication rather than insulin injections.DISSECTINGDIABETESThe mechanisms of type2(adult-onset) diabetes arebeginning to be unravelled.Permanent neonatal diabetes isa severe, but fortunately rare formof diabetes. The causes have beenlargely unknown, but researchershave now found that many casesare due to a genetic mutation thatdisrupts control of insulin-releasingbeta cells. 1 The research alsosuggests that sulfonylurea drugstypically used by adults with type2 diabetes may be a useful treatment.In neonatal diabetes, a lack of insulinbecomes apparent in the first threemonths after birth. Insulin treatmentis required for life.Insulin is produced by beta cells inthe pancreas, which sense changesin the blood’s glucose levels, and altertheir secretion of insulin accordingly.Crucial to this process is an ion channel– the ATP-sensitive potassium channel(K ATP channel) – that spans themembrane of beta cells.If glucose levels go up, more ATPis made in the cell; this ATP bindsto the channel and closes it, therebyreducing potassium loss anddepolarising the beta-cell membrane.This causes an influx of calcium,which triggers the release of insulin.Professors Andrew Hattersley(Peninsula Medical School, Exeter)and Frances Ashcroft (Universityof Oxford) and colleagues foundmutations in the gene encodingKir6.2, a key subunit of the potassiumchannel, in ten out of 29 infants withneonatal diabetes. The mutation stopsthe channel responding to ATP, soit never closes totally. The beta cellconstantly leaks potassium, andit cannot secrete insulin.Sulfonylurea drugs are known to acton the K ATP channel, and some patientswith mutant Kir6.2 did secrete insulinwhen given such drugs. Follow-upstudies have confirmed that children withKir6.2 mutations no longer need insulininjections when given sulfonylurea drugs.1 Gloyn AL et al. Activating mutations in the geneencoding the ATP-sensitive potassium-channelsubunit Kir6.2 and permanent neonatal diabetes.N Engl J Med 2004; 350: 1838–49.If the body’s tissues becomeinsensitive to the action of insulin,rising blood sugar levels have avariety of damaging effects – leadingto the symptoms of type 2 diabetes.While most cases are thought to involveinteractions between many genes andenvironmental risk factors, diabetes cansometimes be caused by a mutationin a single gene.Dr Inês Barroso (Wellcome Trust SangerInstitute), Professor Steve O’Rahilly(University of Cambridge) and colleaguesfound just such a mutation in a genecalled AKT2. AKT2 protein is a crucialcomponent of the cell’s systems forregulating cell growth, survival andmetabolism. This study reveals its centralrole in cellular responses to insulin. 1Mutations in AKT2 are unlikely to explainmost cases of diabetes. A more likelyscenario is that other subtle variationsin or around the AKT2 gene contributeto the common form of diabetes.The team is now hunting for variantsin populations with type 2 diabetesto explore this possibility.1 George S et al. A family with severe insulinresistance and diabetes due to a mutationin AKT2. Science 2004; 304: 1325–8.

KNOWLEDGE13TAILORED TREATMENTTwo forms of diabetes respond very differently to drugs – pointingthe way to tailored drug treatments based on genetic make-up.BALANCINGACTSWith fears of an ‘obesity epidemic’growing, it is crucial we learn moreabout the metabolic processesunderlying our energy balance,and how they can trigger disease.The genetic make-up of patientswith type 2 diabetes has been foundto affect their sensitivity to drugtreatments. The findings could leadto more tailored treatments, and isan early example of a pharmacogenomicapproach to medicine.Type 2 diabetes is an adult-onsetform of diabetes that frequentlyrequires treatment with drugs.The most commonly used drugs aresulphonylureas or metformin, whichincrease insulin secretion or reduceinsulin resistance, respectively.Treatment guidelines assume that allpatients respond similarly, even thoughthe underlying causes of the diabetesmay be quite different.Professor Andrew Hattersley, EwanPearson and colleagues at thePeninsula Medical School, Exeter,compared the drug responses of peoplewith a specific form of diabetes causedby mutations in the HNF-1α gene withthose in other patients who haddiabetes of unknown cause.They found that people with HNF-1αdiabetes responded differently to thetwo drugs: patients with HNF-1αdiabetes had around a fivefold greaterresponse to sulphonylureas than tometformin, while patients in the othergroup responded similarly to the twotreatments. 1 The difference arosebecause the response to sulphonylureasin HNF-1α patients was fourfold greaterthan in the second group, even thoughthe former used a lower drug doseto avoid hypoglycaemia.As the genetic basis of type 2 diabetesis untangled, it is likely that furtherdifferent forms of the disease will beidentified, each with a particular patternof responses to diabetes drugs. If so,drugs and the doses used could thenbe refined according to a patient’sgenetic background.1 Pearson ER et al. Genetic causeof hyperglycaemia and response to treatmentin diabetes. Lancet 2003; 362: 1275–81.L to RLaboratory researchinto diabetes is helpingto change treatments.Inês Barroso (right),who is studying the roleof the AKT2 gene in type2 diabetes.Diabetes can causedamage to the retina.Professor AndrewHattersley (left) examinesa patient’s eye.• The ‘metabolic syndrome’ (a combinationof high blood pressure, insulinresistance and impaired lipidmetabolism) is usually associatedwith obesity. An international teamincluding Professors John Mullinsand Jonathan Seckl in Edinburghhas shown that high levels of glucocorticoidhormone regeneration in theliver can give rise to the metabolicsyndrome in the absence of obesity. 1This could occur in people of normalweight who have symptoms ofmetabolic syndrome, such as thosewith ‘fatty liver’ disease.• A mammalian enzyme known asPASK is related to a bacterial oxygensensor, FixL. A team led by ProfessorGuy Rutter in Bristol has discoveredthat PASK is also a sensor: inpancreatic beta cells, it respondsto glucose concentrations, regulatingkey beta-cell genes. 2 PASK thusappears to play a role in the body’sresponse to changing nutrient levels.• CBS domains are tandemly repeated60 amino acid domains found inmost living organisms. Althoughmutations in CBS gene sequencescause a range of inherited diseases,the domain’s role has been unclear.Professor Grahame Hardie andcolleagues at Dundee have nowshown that the domains bindadenosyl compounds (such as AMP,ATP or S-adenosyl methionine). Inmany cases, including AMPK, a keyenergy sensor in the body, thedomains appear to link the protein’sactivity to the cell’s energy status. 31 Paterson JM et al. Proc Natl Acad Sci USA2004; 101: 7088–93.2 da Silva Xavier G et al. Proc Natl Acad Sci USA2004; 101: 8319–24.3 Scott JW et al. J Clin Invest 2004; 113: 274–84.

RESOURCES14RESOURCES

RESOURCES15Human resources: meeting training and careerdevelopment needs of researchers.Physical resources: building suitable conditionsfor research.Wellcome-funded research fellowshave produced many excitingresearch discoveries this year.Articles here summarise twoexamples, both of which couldhave major medical implications:• Page 16: Huntington’s disease iscurrently untreatable but a study inmice has suggested a possible newtherapeutic approach;• Page 17: Small offspring often gothrough ‘catch-up’ growth – whichcould affect their long-term health.Historians have quite different resourceneeds from scientists:• Page 16: One danger is that sourcematerials literally disappear. A specialWellcome scheme is helping toensure that irreplaceable papersare secured for future generations;• Page 18: The Guildford ArchivingProject is ensuring that internaltobacco industry papers remainaccessible on the web, a valuableresource for anyone studyingindustry tactics and behaviour.Through the Joint Infrastructure Fundand Science Research InvestmentFund, two partnerships with theUK Government, the Wellcome Trustprovided £450 million to tackledeficiencies in the UK’s academicresearch infrastructure:• Page 18: Two internationallysignificant facilities opened in Oxfordthis year. They are not just a betterworking environment but are alsochanging the way scientists interactand conduct research.Finally, research itself generatesbiological resources. Sharing theseprovides a fillip for research:• Page 19: Genetic resources areaccelerating research on mousemodels and making the frogan even more useful tool.

RESOURCES16HUNTINGTON’S HOPEWork on fruit flies and mice has identified a potentialtherapeutic strategy for Huntington’s disease.SHELFPRESERVATIONMaterial relating to key figures inEdinburgh’s distinguished medicalhistory has been preserved.A drug normally used to preventorgan rejection could stop a toxicprotein accumulating in the brainsof people with Huntington’s disease.Researchers at the University ofCambridge, led by Wellcome TrustSenior Research Fellow Dr DavidRubinsztein, have discovered thatthe drug rapamycin reduces theeffects of the Huntington’s diseasemutation in cultured cells, fruit fliesand mice, raising hopes that it couldbe used to treat this nervous systemdisorder in humans. 1Huntington’s disease is a rare, inheriteddisease characterised by abnormal bodymovements and impaired cognition;symptoms typically appear inmiddle age.It is caused by a faulty gene thatchanges the huntingtin protein intoa toxic product which accumulates inthe brain and interferes with brain cellfunction. There are genetic tests todetect the faulty Huntington’s gene, butthere is no cure or effective treatment.The Cambridge researchers discoveredthat rapamycin may be able to protectthe brain by cranking up ‘autophagy’ –one of the ways in which the cell candispose of proteins. In their models,when used before too much toxicprotein accumulated, rapamycinfunnelled mutant huntingtin intocompartments of the cell that digest it.The researchers found that a rapamycinanalogue, CCI-779, slowed downneurodegeneration in a fly model of thedisease, while in the mouse, it improvedperformance on four differentbehavioural tasks.CCI-779 has the advantage that it isdesigned for long-term use. The drugis currently in phase 2 and phase 3clinical trials for cancer, though morestudies would be needed before humantrials were begun for Huntington’s.1 Ravikumar B et al. Inhibition of mTOR inducesautophagy and reduces toxicity of polyglutamineexpansions in fly and mouse models ofHuntington disease. Nat Genet 2004; 36(6):585–95.Those who cannot remember the past,said philosopher George Santayana,are condemned to repeat it. Historicalenquiry aims not just to remember thepast but to understand it and, perhaps,to ensure that we learn from it ratherthan repeat it.The Research Resources in MedicalHistory scheme was set up to ensurethat significant collections are preservedand opened up for study, through useof new conservation and preservationtechnologies and cataloguing. Some£2 million has been awarded so far,to support 58 projects.In Edinburgh for example, LothianHealth Services Archive has preservedthe Royal Infirmary of Edinburgh casenotes of two leading mid-20th centurymedics – Derrick Dunlop, ChristisonProfessor of Therapeutics and ClinicalMedicine from 1936 to 1952, andJames Learmonth, University Professorof Surgery from 1939 to 1956, whoincluded George VI among his patients.

RESOURCES17CATCH-UP GROWTHFeeding up lightweight babies may be storingup longer-term problems.The collection includes some 37 000case notes which provide a fascinatingglimpse of day-to-day life on the wardsduring a crucial period of changein medicine. As such they helpilluminate everything from changingmedical education to shifts in attitudestowards experimentation on patients.Edinburgh was central to manyof these developments.In an earlier project, the archiverestored material from two other keycharacters in Edinburgh medicine –Edwin Bramwell, widely regardedas the founder of Edinburghpostgraduate medical education,and Norman Dott, the first medic afterJoseph Lister to receive the Freedomof the City of Edinburgh.Without preservation, these collectionsmight have been lost for ever – victimto the ravages of time and rusty paperclips.Now, historically valuable materialhas been carefully conserved andsecured for future generations.Parents take pride in seeing theirtiny newborns fill out into chubbytoddlers. But for very small babies,rapid ‘catch-up’ growth may notbe as healthy as it seems – a studyof mice suggests it could actuallybe shortening their lifespan. 1The startling results were obtained byDr Susan Ozanne, a Research CareerDevelopment Fellow,* and ProfessorNick Hales at the University ofCambridge. They monitored thelongevity of mice whose mothers werefed a poorly nutritious diet during theirfetal development or just after birth.They also tested the impact of a‘cafeteria-style’ diet after weaning.The pups that lived longest were thosethat were well fed in the womb and thensuckled by mothers on a relatively lowqualitydiet. Their lifespans were furtherenhanced if they were not given acafeteria-style diet, rich in sugar and fat,after weaning.At the other extreme, the pups thatlived the shortest lives were those thatgrew poorly in the womb, but weresubsequently suckled by mice on ahigh-quality diet. Their lifespans werecut further if they ate obesity-inducingfood after weaning.Low birth weight is already knownto predispose to late-onset conditionssuch as high blood pressure anddiabetes. These results suggest thatthe normal reaction to low birth weights– a period of catch-up growth to bringinfants up to a normal size – maycontribute to these detrimental longtermeffects.The results could have implicationsfor babies born underweight, who areusually fed a rich diet to accelerategrowth. In view of the findings, theresearchers argue that more attentionneeds to be paid to the nutrition ofhuman infants in the early years.1 Ozanne SE, Hales CN. Lifespan: catch-up growthand obesity in male mice. Nature 2004;427(6973): 411–2.*Dr Ozanne is now a British Heart FoundationLecturer at the University of Cambridge.L to RRapamycin analoguescould help people withHuntington’s disease.Paper-clips can causesignificant damageto archive collections.An archivist fromthe Lothian HealthServices Archive.A period of ‘catch-up’growth for underweightnewborns could damagetheir long-term health.

RESOURCES18OPENING TIMETOBACCO ARCHIVEThe Wellcome Trust’s recentinfrastructure investmentis now bearing rich fruit.A massive photocopying operation is ensuring a tobaccogiant’s inner workings will remain in the public domain.Seventeen new buildings fundedby two high-profile Wellcome Trustpartnerships with the UK Government– the £750 million Joint InfrastructureFund (JIF) and £1 billion ScienceResearch Investment Fund (SRIF) –were opened or occupied during theyear. Two buildings in Oxford illustratehow new facilities are supportinglarger-scale and more integratedapproaches to biomedical research.In February 2004, HRH The Queen andHRH The Duke of Edinburgh officiallyopened the new £60 million ChemistryResearch Laboratory at the Universityof Oxford. With nearly 17 000 squaremetres of laboratory and office space,it is one of the largest researchdepartments in the world. Facilitiesinclude 11 nuclear magnetic resonancemachines, 11 mass spectrometers andan X-ray crystallography facility.In September 2004, Nobel PrizewinnerJames Watson opened the HenryWellcome Building of Gene Function.The new £19 million building hasbeen designed to encourage greaterinteraction between researchersin genetics, human anatomy andphysiology and experts in importantnew fields such as bioinformaticsand biostatistics.This will allow researchers to mounta united effort to discover how genescause disease – and to focus onground-breaking treatments for manyimportant diseases.A website containing 1 million pagesof formerly secret documents fromthe world’s second-largest tobaccocompany, British American Tobacco(BAT), went online in October 2004.Researchers and the public will nowhave free and unfettered access toinformation relating to BAT’s activities,which reveal disturbing evidenceof the industry’s efforts to thwartanti-smoking initiatives and marketcigarettes to vulnerable populations.The website is a joint project, knownas the Guildford Archiving Project,between the London School of Hygieneand Tropical Medicine, the Universityof California San Francisco and theMayo Clinic. BAT was forced to makethe documents public in 1998 aftera legal settlement by a US court againsta number of tobacco companies.The settlement ruled that all corporatedocuments submitted during the‘discovery’ process for the case mustbe made available via two archives, oneat Guildford, UK (operated by BAT), andthe other at Minnesota, USA (operatedby an independent paralegal firm).L to RAerial view of the newchemistry labs at Oxford.Nuisance smokers,by Henry Heath, 1827.Allan Bradleyof the Wellcome TrustSanger Institute.Research on miceis providing valuableinsight into importantbiological processes.Information currently on the new websiterelates to company practice from theearly 1900s to the mid-1990s. Internalcorrespondence, research and reportsoffer a unique insight into the strategiesused by tobacco companies to promotethemselves and their products, includinginfluencing scientific research and publicpolicy, targeting marketing, advertisingand promotion activities at youngpeople and women, and the strategicexploitation of cigarette smuggling.The documents reveal how BAT hastargeted emerging markets in thedeveloping world, including, forexample, its intention to market to“dirt poor little black farmers” and “lowincome low literacy” people in SouthAsia and the Middle East.Crucially, the site will preserve thecollection beyond 2009, when BATis allowed to close the depository.The Guildford Archiving Project has been fundedby the Wellcome Trust, the Flight AttendantMedical Research Institute, Cancer ResearchUK, Health Canada and the American HeartAssociation. The BAT document archive websitecan be accessed at www.bat.library.ucsf.edu

RESOURCES19SHARING SUCCESSResources created for a laboratory’s own researchare also being shared to benefit the wider community.BEYONDTHE HELIXWe now know that humans have onlyabout 23 000 genes. Our biologicalcomplexity is thus more to do with howthose genes are used – how and wherethey are turned on and off. Manydifferent mechanisms of gene controlare being discovered – and the higherorderarrangement of DNA is turningout to be particularly important.Studies in model organisms areproviding many insights into thebiological roles of genes. Thanks togenome sequencing projects, genebasedapproaches are wildly popular.Now, new techniques are beingdeveloped to enable even greateruse to be made of genomic reources.At the Wellcome Trust Sanger Institute,Dr Allan Bradley’s team has developeda technique to speed up research onmice. To explore the function of a gene,researchers often study the effectsof mutations that disrupt or changethe gene. Producing such mutationscan be time-consuming, however.Dr Bradley’s team has developed a newhigh-throughput method to alter genes– MICER (Mutagenic Insertion andChromosome Engineering Resource).The MICER resource 1 consists ofa large collection (library) of DNAfragments, corresponding to partsof mouse genes, which can be usedto target and disrupt mouse genes(or even insert specific new sequences).Some 100 000 different MICER vectorsare available from the Sanger Institute.Another technical advance from theBradley lab makes these vectors evenmore useful. Mammalian cells carrytwo copies of each gene, and the newmethod ensures that both copiesare disrupted. 2Meanwhile, researchers in Cambridgehave launched a new genomicsresource for the frog Xenopus tropicalis.The African clawed frog Xenopus laevishas long been a favourite of biologists.Unfortunately, having a duplicatedgenome, it is not good for geneticstudies, and it takes more than a yearto reach sexual maturity. Conveniently,Xenopus tropicalis is diploid andmatures in just four months.To speed up research into X. tropicalis– a field that is still in its infancy –Dr Enrique Amaya, Dr NancyPapalopulu and Professor Jim Smithat the Wellcome/Cancer ResearchUK Gurdon Institute in Cambridge, incollaboration with the Sanger Institute,have sifted through more than200 000 fragments of the X. tropicalisgenome and identified 7000 genes. 3Full-length clones are available throughthe MRC Geneservice, while theGurdon Institute has also produceda database describing the sequencesand associated genomic information.Such resources should help kick-starta potentially valuable field of researchand add to the pantheon ofexperimental organisms usedin research around the globe.1 Adams DJ et al. Mutagenic Insertion andChromosome Engineering Resource (MICER).Nat Genet 2004; 36(8): 867–71.2 Guo G, Wang W, Bradley A. Mismatch repairgenes identified using genetic screens in Blmdeficientembryonic stem cells Nature 2004;429(6994): 891–5.3 Gilchrist M et al. Defining a large set of fulllength clones from a Xenopus tropicalis ESTproject. Dev Biol 2004; 271: 498–516.(www.gurdon.cam.ac.uk/informatics/Xenopus.html)• In budding yeast, Professor NickProudfoot and colleagues at theUniversity of Oxford found that theDNA of active genes was not linear,as typically drawn in textbooks, butwas looped, with control proteinsshared between the start and endpoints of the gene. This looping wasessential to the activation of the gene. 1• RNA interference (RNAi) is an excitingarea of study, as these tiny RNAscan silence genes very effectively.Generally, they act by triggeringa massive destruction of the RNAintermediate (messenger RNA) readfrom a gene, but Dr Vera Schramkeand Professor Robin Allshire, aWellcome Principal Research Fellowat the Wellcome Trust Centre for CellBiology, University of Edinburgh, havediscovered that small RNA moleculescan somehow drive the formationof ‘closed’, tightly packed DNAconformation and shut down genes. 2• A collaboration led by Dr Nigel Carterat the Wellcome Trust Sanger Instituteand Dr Wendy Bickmore at the MRCHuman Genetics Unit in Edinburghhas examined DNA conformationacross the entire human genome.As expected, active genes lay inregions of open chromatin, andinactive genes in tightly packedchromatin. But there were exceptions:some genes in open chromatin wereinactive, while some in compactchromatin were active. 31 O’Sullivan JM et al. Nat Genet 2004; 36(9):1014–8.2 Schramke V, Allshire R. Science 2003; 301:1069–74.3 Gilbert N et al. Cell 2004; 118(5): 555–66.

TRANSLATION20Promoting patient-oriented and health services research.Advancing the dissemination and exploitation of theresults of Trust-funded research.‘Translation’ is all about making apractical difference – generating andusing new knowledge to provide healthbenefits to people. There are manyways in which those benefits maybe realised:• Page 22: Genetic analysis of cancersis revealing new drug targets;• Page 22: A ‘dipstick’ diagnostic toolfor Chlamydia is being taken up andused, and adapted for otherinfections;• Page 23: Field tests of malariadiagnostic kits confirm theirpractical value;• Page 23: Studies of deadly avian fluare helping us prepare for furtheroutbreaks.Malaria continues to exact adevastating toll, particularly amongyoung children in Africa. Around 3000children in Africa die every day. Clinicalresearch is tackling several aspectsof the disease:• Page 24: Artemisinin combinationtherapy – drug treatment pioneeredin South-east Asia – could have amajor impact if widely used in Africa;• Page 24: Unravelling the compleximmune response to themalaria parasite;• Page 25: How the parasite becomesresistant to the antimalarialdrug mefloquine;• Page 25: Why cerebral malaria isn’talways what it seems.The most direct benefits, of course,come from studies on patients.Wellcome-funded clinical researchis continuing to suggest and testnew therapies, in the UK and indeveloping countries:• Page 26: In Vietnam, steroids havebeen shown to enhance survival aftertuberculous meningitis infection;• Page 26: In the UK, the WellcomeTrust’s Clinical Research Facilitieshave begun to deliver a streamof important findings and are havinga significant local impact;• Page 27: The ‘Myskin’ smartdressing was launched duringthe year for burns patients.

TRANSLATION21TRANSLATION

TRANSLATION22GENE TARGETSThe identification of genes responsible for particular formsof cancer is opening up the possibility of targeted cancer therapies.TESTINGTIMESThe dipstick diagnostic test forChlamydia is being widely adopted.The Cancer Genome Project at theWellcome Trust Sanger Institute has,for the first time, identified mutationswithin the ERBB2 gene in human lungcancer. 1 The mutations, found in10 per cent of a specific type oflung cancer called adenocarcinoma,cause the ERBB2 protein to bepermanently active. These cancersmay be treatable with an existingdrug, trastuzumab.The Cancer Genome Project teamis cataloguing the changes within thegenomes of cancer cells and identifyingthe mutant genes responsible for thedisease. Lung cancer is a particularlyimportant target, as it is the secondmost common form of cancer in theUK, after breast cancer.The ERBB2 gene (also known as HER2or Neu) is present in multiple copies in20 per cent of breast cancers and lessoften in other cancers. The discoverythat ERBB2 mutations can also causelung cancer is significant as the drugtrastuzumab (marketed as Herceptin)targets ERBB2 and is very effectivefor the treatment of breast cancerswith multiple copies of the ERBB2gene. Previous trials of trastuzumabfor lung cancer were not successful,but the Cancer Genome Project teamproposes that it, or another drug thattargets ERBB2, should be retestedin cases of lung adenocarcinomawith ERBB2 mutations.This finding follows the team’s discoveryin 2002 that the BRAF gene is mutatedin 70 per cent of cases of malignantmelanoma, a potentially lethal formof skin cancer. The mutations appearto produce a permanently activatedBRAF protein. With Wellcome TrustTechnology Transfer funding, the teamhas been searching for molecules thatcan switch off the mutant protein – andseveral promising leads have emerged.1 Stephens P et al. Lung cancer: intragenic ERBB2kinase mutations in tumours. Nature 2004; 431:525–6.The rapid testing technology createdby Dr Helen Lee and colleagues at theUniversity of Cambridge has movedon apace since the team completedthe development of its Chlamydia‘Firstburst’ dipstick a year ago.This rapid test provoked interestfrom organisations around the world,including the American Red Cross,a major pharmacy chain, as well as anumber of diagnostic companies andnon-profit organisations that deal withwomen’s sexual health. The first-voidurine collector the group developedreceived the Best Medical FuturesDiagnostic Innovation award.The Chlamydia rapid test was recentlyadapted to detect trachoma, an eyedisease that affects 150 million peopleworldwide and causes 6 million casesof blindness or visual impairment. Fieldtrials on schoolchildren in Tanzania haveproduced excellent results.Now Dr Lee’s Diagnostics DevelopmentUnit, based at Addenbrooke’s Hospital,is developing a triplex rapid test capableof detecting HIV, hepatitis B andhepatitis C viruses in the same sample.The test, supported by a WellcomeTechnology Transfer Award, will beused to improve blood safety indeveloping countries.

TRANSLATION23FIELD TESTFLU FEARSHandy diagnostic tests for malariacan be used easily in the field, newresearch suggests.South-east Asia needs its own local high-qualityclinical centres to tackle the perils of avian flu.A trial of two malaria diagnostic kitshas shown that error rates are low andthat they can be used with minimaltraining. 1 These kinds of diagnostictests thus seem highly suitable for usein the field.Diagnosing malaria quickly can makea huge difference to the treatmentof the disease. The standard methodof diagnosis, looking at blood smearsunder the microscope to spot parasites,is time-consuming, expensive andrequires extensive training.With help from the Wellcome Trust’sresearch programme in Thailand,Dr Mayfong Mayxay and colleaguesin rural Laos have trialled two tests,ParacheckPf and OptiMAL, which use‘dipsticks’ to test blood samples for thepresence of proteins from the parasite.After one hour of training, 64 villagehealth volunteers, with no previouslaboratory experience, performed twodifferent tests accurately.People infected with the deadly avianinfluenza virus strain H5N1 weretreated and studied at Wellcomesupportedfacilities in Vietnam. Havingexcellent clinical and laboratoryfacilities in a country directly affectedby avian flu is an enormous benefitwith a disease that is so rapidlylethal and of such global publichealth importance.During late 2003 and early 2004,the avian influenza virus H5N1 sweptthrough poultry stocks across Asia.Most worryingly, it also spread to somepeople, causing a severe and often fatalrespiratory illness.There are constant fears that this strainwill spread from birds to humans.An even greater worry is that the virusadapts to human hosts, and beginsto be transmitted from person to person– in a manner similar to the ‘Spanish flu’in 1918. It is vital, therefore, that welearn as much as possible about thevirus and its effects on people.The Hospital for Tropical Diseases andthe Clinical Sciences Research Institutesupported by the Wellcome Trust inHo Chi Minh City was chosen by theVietnamese government as the nationalcentre for admission of all suspectedcases and for the clinical and scientificanalysis of the virus. The detailedexaminations of ten patients infectedwith the virus (eight of whom died)were published by the New EnglandJournal of Medicine, 1 and the speedof publication – only a few weeks afterthe patients were admitted to hospital –highlights the value of combiningclinical and scientific expertise ina single institution.1 Hien TT et al. Avian influenza (H5N1) in 10patients in Vietnam. New Engl J Med 2004;350: 1179–88.The researchers then followed sixvolunteers over ten months to checkthe accuracy of the testing and howoften retraining was required. Errorrates were extremely low comparedto microscopy (less than 2 per cent),and minimal training was required.1 Mayxay M et al. An assessment of the useof malaria rapid tests by village health volunteersin rural Laos. Trop Med Int Health 2004; 9:325–9.L to RMelanoma cells:70 per cent of malignantmelanoma are causedby BRAF mutationsHelen Lee and her teamat Cambridge havedeveloped a rapid testto detect chlamydia.Anopheles gambiae,which transmitsthe malaria parasite.Poultry is the main hostof the avian flu virus.There are fears that anavian flu epidemic couldbegin in South-east Asia.

TRANSLATION24ACT NOWFIGHTING BACKAn analysis of clinical trials withartemisinin combination therapyhas confirmed its enormous value.Models suggest how the malaria parasite evades the human immunesystem so successfully, and new hope for a malaria vaccine.Artemisinin combination therapy(ACT) – the use of artemisinin orrelated compounds along with asecond antimalarial drug – has beenpioneered by Professor Nick Whiteand colleagues at the Wellcome Trust’sSouth-east Asia Major OverseasProgramme. Extensive trials haveshown that ACT is safe and effective.The Thai unit has published nearly10 per cent of all antimalarial drugtrials since 1966, enrolling more than20 per cent of patients.Derived from the plant Artemisia annua,artemisinin and its derivatives are nowwidely used in South-east Asia.To reduce the risk of resistance,combination treatments are preferred.In 2004, the International ArtemisininStudy Group reported a meta-analysisto assess the value of artesunate whenadded to other drugs. Pooling datafrom 16 studies and nearly 6000patients, they found that the additionof artesunate had significant benefits. 1Since 2001 the World HealthOrganisation has increasingly promotedACT, recommending that any countrychanging antimalarial treatment policyshould switch to ACT. Over 20 countrieshave switched, and many others havebegun to change. The latest studyreinforces how valuable the therapycould be in a continent in which malariais threatening to run away unchecked.1 International Artemisinin Study Group. Artesunatecombinations for treatment of malaria: metaanalysis.Lancet 2004; 363: 9–17.The human immune system wageswar against the malaria parasite asit tries to eradicate an infection.Having identified parasite proteins,the system ramps up productionof antibodies that will help kill theparasite; the parasite’s response isto change its proteins. But possiblynot too much, a new mathematicalmodel suggests.The models, produced by acollaboration between researchersin Oxford, Edinburgh and Kenya,examine the parasite’s PfEMP1receptors, proteins that it insertsinto the surface of red blood cellswhile it is reproducing inside. Thisprotein is a prime target for theimmune system, but with more than50 variants the parasite can switchto a new type, allowing it to prolongthe infection.The new model suggests that eachvariant elicits two types of immuneresponse: a long-lived response directedagainst that protein alone; and minor,short-lived responses that target partsof the protein shared by more than oneprotein. 1 The latter responses delaythe appearance of variants with similarshared portions. So the switchingoccurs sequentially, each new variantbeing the most immunologically distinctfrom its preceding types. As a result,the overall duration of infection isincreased; eventually, long-lastingresponses are produced against theentire variant repertoire, and theinfection ends.Meanwhile, in their quest to developa malaria vaccine, Professor Adrian Hill(University of Oxford) and colleagueshave been studying parasite proteinsthat induce an immune response. Oneproblem facing vaccine researchers isthat while proteins have been found thatdo stimulate an immune response, noneso far has led to protection againstnatural malaria infection.In studies in The Gambia, theresearchers have tested a newcandidate that includes part of theparasite’s circumsporozoite protein,which it produces in its sporozoitestage – the stage that is injected intothe bloodstream by a feeding mosquito.They found that while several portionsof the circumsporozoite protein inducedan immune response, one fragment inparticular was associated with a longerlastingimmune protection againstmalaria. 2 This, they suggest, makes it agood option to include in new vaccines.1 Recker M et al.Transient cross-reactive immuneresponses can orchestrate antigenic variationin malaria. Nature 2004; 429: 555–8.2 Reece WH et al. A CD4(+) T-cell immuneresponse to a conserved epitope in thecircumsporozoite protein correlates withprotection from natural Plasmodium falciparuminfection and disease. Nature Med 2004; 10(4):406–10.

TRANSLATION25EJECT ANDSURVIVEThe genetic basis of mefloquineresistance has been revealed.ASSESSING MALARIADeadly cerebral malaria is difficult to diagnose and is poorlyunderstood. Research in Malawi is providing a clearer picture.Resistance to the antimalarial drugmefloquine, introduced in Thailandin 1984, took just six years to develop.Researchers have now discoveredhow the parasite became resistantto the drug – by duplication of a keyparasite gene.Dr Ric Price (a Wellcome CareerDevelopment Fellow in Clinical TropicalMedicine), Professor Sanjeev Krishna(St George’s Hospital Medical School,London), Professor Nick White andDr François Nosten (WellcomeTrust–Mahidol University–OxfordTropical Medicine ResearchProgramme, Thailand) and colleagueshave studied patients in the Karencommunity living in a malarious hillforest on the northwestern borderof Thailand. This harbours the world’smost multidrug-resistant Plasmodiumfalciparum parasites.They found that resistance to mefloquinewas associated with extra copies ofa Plasmodium gene known as pfmdr1. 1The gene codes for a molecular pumpthat ejects the drug from the parasitecell before it has a chance to do anyharm. Presumably, the more copiesof the pfmdr1 gene that a parasite has,the more pump protein the parasitemakes – and the more likely it is tosurvive treatment with mefloquine.1 Price RN et al. Mefloquine resistancein Plasmodium falciparum and increased pfmdr1copy number. Lancet 2004; 364: 438–47.Plasmodium falciparum, the mostdangerous malaria parasite, spendspart of its life multiplying within redblood cells. Later on, infected cellsbecome ‘sticky’ and adhere to thewalls of blood vessels; when thisoccurs in the brain, as it does in about1 per cent of cases, cerebral malariaand coma result. Even with the besttreatments, 15–20 per cent of childrenin such comas will die.In reality, it is not easy to tell whethera child in a coma has cerebral malariaor some other coma-causing illness.In addition, the effects on the brainare not well defined.To investigate, Professor MalcolmMolyneux (Malawi–Liverpool–WellcomeTrust Cinical Research Programme)and colleagues in Malawi, the UK andUSA conducted autopsies on 31children who had been diagnosedwith cerebral malaria. They found,surprisingly, that although all thepatients had parasites in their brains,seven of them (23 per cent) hadactually died from other causes. 1The only clinical way of distinguishingmalarial from non-malarial coma wasto examine the eye – almost all of thosewith malarial coma had damage to thecapillaries in the retina.Another study by Professor Molyneuxand colleagues in Malawi and Franceidentified a second feature peculiarto children with severe malaria – muchhigher levels of tiny particles derivedfrom the lining of blood vessels. 2Parasitised red blood cells attach to thislining, usually in deep, inaccessibletissues. These particles may thereforebe an indicator that infected cells arecollecting in vital organs.1 Taylor TE et al. Differentiating the pathologiesof cerebral malaria by postmortem parasitecounts. Nature Med 2004; 10: 143–5.2 Combes V et al. Circulating endothelialmicroparticles in Malawian children with severefalciparum malaria complicated with coma.J Am Med Assoc 2004; 291: 2542–4.This study was funded by the Wellcome Trust,the French Ministry of Research, the PAL+Programme, and the UNDP/World Bank/WHOSpecial Programme for Research and Trainingin Tropical Diseases.L to RArtemisia annua,a source of agentsused to treat drugresistantmalaria.Kevin Marsh, headof Wellcome’s researchprogramme in Kenya.Kenyan children,for whom malariais an everyday scourge.A malaria-infectedred blood cell.Professors PeterWinstanley (left) andMalcolm Molyneux.

TRANSLATION26STEROIDSUCCESSSteroids help people survivea tuberculous meningitis infection.CLINICAL ADVANCESAs well as hosting valuable patient-oriented research, ClinicalResearch Facilities are having important regional influence.Tuberculosis is usually associatedwith lung disease. But its cause,Mycobacterium tuberculosis, can alsoinvade other parts of the body, suchas cerebrospinal fluid. The resultinginflammation (tuberculous meningitis)causes death or severe neurologicalproblems in more than half of thoseaffected. Research in Vietnam,however, has shown that steroid usesignificantly reduces mortality.Reasoning that corticosteroids mightreduce inflammation, a team led by GuyThwaites at the Pham Ngoc Thach TBand Lung Hospital, the Hospital forTropical Diseases and the OxfordUniversity Clinical Research Unit, HoChi Minh City, ran a trial of the steroiddexamethasone plus antibiotics in 545patients in Vietnam. 1The trial showed that additionaltreatment with dexamethasone reducedmortality (although it did not reducethe risk of severe disability after ninemonths). The steroids not only reduceinflammation, but may also reduce therisk of other severe problems, such aspotentially fatal clinical hepatitis, whichwould have forced doctors to changethe antibiotic therapy.The work has led to changes intreatment guidelines for managingtuberculous meningitis.1 Thwaites, G et al. Dexamethasonefor the treatment of tuberculous meningitisin adolescents and adults. N Engl J Med 2004;351(17): 1741–51.Wellcome Trust Clinical ResearchFacilities (CRFs) were set upto provide a specialist hospitalenvironment dedicated to researchinvolving people. A review of progresshas revealed that all five CRFs haveestablished effective infrastructureand management systems. Highqualityresearch is being carried outwithin them. And they are also playinginfluential roles locally and nationally.The CRFs – at Birmingham,Cambridge, Edinburgh, Manchesterand Southampton – were establishedas partnerships between the WellcomeTrust, the Department for Health,and the Scottish Executive.As well as hosting valuable research,the CRFs are having wider influence,becoming recognised regional centresof clinical research excellence. Theyact as beacons of best practice forgovernance and ethics, have developedstrong collaborative links with localNHS R&D offices, and created localeducational programmes targetedat clinical researchers in their areas.The Edinburgh facility now also hostsa regional centre of the NationalTranslational Cancer Research Network.One notable feature has been thedevelopment of a strong network ofnurse managers around the CRFs, aswell as a growth in nurse-led research.The CRFs have been used as a modelfor other similar facilities set up aroundthe country.Evidence of the success of the venturealso comes from the steady streamof research papers coming out of theCRFs. Among the many importantstudies are the following:Birmingham: Cannabinoid therapy formultiple sclerosis; antibody therapy forvasculitis; gene therapy for liver cancer.Cambridge: Genetic causes of obesity;neurochemical impact of drug abuse;immune response to respiratorysyncytial virus in children.Edinburgh: Impact of air pollutionon cardiovascular disease; geneticsusceptibility to cardiovascular diseasein a rural population of Orkney.Manchester: Using pelvic floorexercises to tackle stressincontinence; molecular geneticsof autoimmune disease.Southampton: Management of hepatitisC virus infection; effects of low birthweight on infant lung function.One future challenge is to identifyways to capitalise on this initial successto strengthen clinical research in the UK.

TRANSLATION27LIVING BANDAGESAn innovative product launched this yearwill provide a new option for burns victims.OF PIGSAND PEOPLESkin grafting is the first-line treatmentfor burns but sometimes, in severecases, there is not enough skin to goround. CellTran, a start-up companybased in Sheffield and a recipientof Wellcome Technology Transferfunding, has come up with a solution:Myskin, ‘living bandages’ containingthe patient’s own skin cells.The skin cells are usually taken fromthe thigh, under local anaesthetic,and then transferred to a small polymerdisc, coated with a chemically controlledplasma polymer film which promotesthe growth of skin cells. After fiveto seven days, the discs are placeddirectly onto the wound and the areais wrapped in bandages. The polymerfilm is engineered to release the cellswhen exposed to the wound, thushelping new layers of skin to grow.There is a strong surgical need forthis kind of device. CellTran’s newtechnology is faster, simpler and moreL to RMycobacteriumtuberculosis, whichcan cause tuberculousmeningitis.Body fat scanningequipment at theCambridge ClinicalResearch Facility.The Edinburgh ClinicalResearch Facility building.CellTran has developed‘living bandages’ to treatsevere burns.robust than other methods, which takeup to two to three weeks to grow thecells and involve a much morecomplicated process. Myskin alsomarks the first time cells have beenplaced directly onto a patient’s woundvia a bandage.Myskin was launched for the treatmentof severe burns in April 2004 at theBritish Burns Association, Manchester.CellTran has partnered with a UKdistribution partner, Vernon Carus,a Top 50 NHS supplier, so the productis easily available within the NHS.CellTran has begun a large clinical trialof Myskin’s effects on diabetic ulcers,and preliminary studies have shown thatit works well on difficult-to-heal wounds.CellTran Ltd has been funded by theWellcome Trust, Sheffield UniversityEnterprises Ltd, and the White RoseTechnology Seedcorn Fund.The Wellcome Trust–BurroughsWellcome Fund Infectious DiseasesInitiative, launched in 1999, broughttogether researchers from the UK,North America and the developingworld. The initiative aimed to providelarge-scale, long-term support fortrilateral partnerships, in which thecentre of gravity would be in thedeveloping country. Some 13 projectswere funded, to the tune of £18 million(US$27 million), based in Asia, Africaand South America.While many projects are at earlystages, they have clearly deliveredmajor benefits to the participantsand host institutions, and in somecases have had a direct impacton public health.• A study in Bangladesh on the causes,prevention and treatment of neonatalinfections in the community hasraised the profile of neonatalhealthcare locally. The research hasfed into national policy making, whilea training manual in newborn careis being adopted at a national level.• In Vellore, India, a project on rotaviralgastroenteritis in children has hadan unexpected benefit – a substantialdecrease in infant mortality in theurban slum in which it was based,as field workers now recogniseillness and refer it to the project’slocal clinic.• The Peruvian cysticercosis projectis studying infection with theintestinal tapeworm Taenia solium,which forms cysts in both humansand its intermediate host, the pig.The team is also testing candidatevaccines, with spectacular success:the vaccines provide more than99 per cent protection. The projectteam has now been awardedUS$15.5 million by the Bill andMelinda Gates Foundation toevaluate a cysticercosis eliminationprogramme in an area of Peru.

PUBLIC ENGAGEMENT28Stimulating an informed dialogue to raise awareness andunderstanding of biomedical science, its achievements,applications and implications.Public engagement aims to buildbridges between scientific and othercommunities. The language, conceptsand accumulated knowledge ofscience can be daunting, and presentobstacles to the wider public sharingin the excitement (and frustrations) ofmodern science, or joining debate intoits possible implications or application.By the same token, separating sciencefrom other aspects of modern life willsurely impoverish the discipline –particularly one with such a humandimension as biomedicine.Bridge building can take many forms:• Page 30: ‘Medicine in Context’exhibitions at London’s ScienceMuseum, such as this year’s on pain,have provided unique interpretationsof fascinating topics;• Page 30: The Engaging ScienceProgramme has brought new bloodinto the field, with fresh ideas andenthusiasm;• Page 31: The award-winning ‘Livingand Dying’ exhibition at the BritishMuseum illustrates how differentcultures perceive their health;• Page 32: Innovative medical trainingat the Peninsula Medical Schoolshows how the sciences can gainfrom the arts;• Page 32: The Eden Project hasbenefited from a visitor centre grantsscheme to rejuvenate its exhibits;• Page 33: The poignant FoundlingMuseum is a reminder of the socialcontext in which medicine is delivered.The experience gained from theseand other projects will be invaluableas plans are laid for a new publicventure at 183 Euston Road, London,due to open in 2006.

PUBLIC ENGAGEMENT29PUBLICENGAGEMENT

PUBLIC ENGAGEMENT30PLEASURE AND PAINCombining art, history and science at a scientific venue – London’sScience Museum – has proven a popular mix.GREAT ANDSMALLProjects of vastly different scaleshave been funded through the newEngaging Science Programme.“Beautifully organised... intelligentlycurated… The exhibition weavesbetween the witty, the horrific, thechallenging and the banal.” Thiswas The Spectator’s verdict on Pain:Passion, compassion, sensibility –a Wellcome Trust exhibition at theScience Museum.The exhibition – which attracted nearly100 000 visitors – highlighted how,despite its universality as a humanexperience, the meaning of painhas changed over time and acrossdifferent cultures.Pain has variously been seen as ameans of salvation, a route to selfenhancement– or a sign of injury orillness. People’s responses to pain varyaccordingly: sometimes we suffer it,sometimes we contemplate or study it,and sometimes we try to alleviate it. Atother times, willingly or not, we inflict it.Pain: Passion, compassion, sensibility,curated by Professor Javier Moscoso,explored the ceaselessly shifting culturalplace of pain, and how science andother ways of thinking have shapedour beliefs and responses to it.Reflecting the compelling nature of theexhibition, the CD-ROM catalogue forPain was short-listed for the 2004 AXAArt Exhibition Catalogue Award.Pain and other Science Museumexhibitions have provided evidence ofa wide public enthusiasm for a ‘culturallyintegrated’ view of biomedical science.This approach will be picked up furtherin the redeveloped Wellcome Building,due to open in 2006, which will bea public venue dedicated to theexploration of science and its socialand historical contexts.Since its launch in September 2003,the Engaging Science Programme hasenabled a diverse range of people andorganisations to get involved in publicengagement.The £3 million programme has beengeared around flexibility, with small,fast-turnaround People Awards offeringthe chance for people to turn ideas intoaction and larger Society Awardsavailable for bigger, longer-term andnationally important ventures. A wholerange of applicants has been temptedto apply – including health practitioners,community workers, teachers,postgraduate students, as well asacademics and science communicators.And quirky or ‘off-beat’ projects havebeen supported as well as the worthy.The year’s smallest award, for example,went to Dr Jonathan Cox, a postdoc atthe University of Bath. His People Awardof £786 enabled him to bring Sir AlecJeffreys – the inventor of DNAL to R‘Ecce homo’ by Nicholásde Bussy, a centrepieceof the Pain exhibition.Leg amputation in the18th century, by ThomasRowlandson.Playwright Simon Turleyand Rebecca Gouldat the Theatre RoyalPlymouth are involvedin a drama project fundedby a Society Award.The Living and Dyingexhibition in theWellcome Trust Galleryat the British Museum.

PUBLIC ENGAGEMENT31LIVING AND DYINGBeautiful objects from all over the globe illustrate how differentcultures perceive and protect their health and well-being.fingerprinting – to an event for membersof the local community, schools andthe university.At the other end of the scale, SocietyAwards support research or significantpublic activities – and focus on specificareas of public engagement. Youngpeople’s education was a theme through2004, and was the focus of a £415 000Society Award to the science centreAt-Bristol.A team from the centre will work closelywith teachers and a range of experts(including scientists, policy makers andconsumer group representatives) todevelop a suite of tools that teacherscan use to get young people thinkingand talking about science and its widerimpact. New techniques might includevideo conferencing, drama and filming,role-play, internet research tasks andethics committees. The most successfulapproaches will be disseminated widelywithin the UK’s teaching community.Living and Dying – the first exhibitionin the Wellcome Trust Gallery at theBritish Museum, London – exploredthe different ways in which peoplearound the world seek well-beingfor themselves or their communities,and how they deal with the harshrealities of life.Different societies have differentunderstandings of the causes andsymptoms of sickness, and differentways of averting or confronting sorrowor need. This diversity is reflected inthe objects produced by differentcultures. Living and Dying dramaticallyillustrated this fascinating diversitywith material from all over the world –from the Andes to Zimbabwe.The centrepiece of the exhibition,however, had its roots closer to home.The specially commissioned artinstallation, ‘Cradle to Grave’,produced by the Pharmacopoeiacollective (artists Susie Freeman andDavid Critchley, and GP Liz Lee),resembles a shop counter, runningthe length of the gallery. Inside, it showsthe medicines a typical British man andwoman take during their lives, stitchedinto two 13-metre pieces of fabricmesh. These are surrounded by familyphotographs with handwritten captions,and various medical objects, such asa mammogram, an X-ray and ahearing aid.Living and Dying, which opened inNovember 2003, won a prestigiousMuseums and Heritage Show 2004Award for Excellence for bestpermanent exhibition.The Wellcome Trust Gallery at the BritishMuseum will house a series of long-termexhibitions examining life’s challengesand the ways people from differentcultural backgrounds deal with them.Using objects from vastly different timesand places as a window onto commonhuman experience, the gallery will offera distinctively fresh perspective on theoutstanding ethnography collectionsof the British Museum.The Pharmacopoeia collective was formed thanksto one of the Wellcome Trust’s first-ever Sciartawards. www.pharmacopoeia-art.net

PUBLIC ENGAGEMENT32MEDICALINNOVATIONArt is well known to benefit fromscience. Less well appreciatedis that science can gain from art.PARADISE GAINSCornwall’s Eden Project aims to combine science, art and dramato create a rich sensory experience for its visitors.Working with artist Helen Storey –on a Sciart project exploring the natureof creativity – was a life-changingepisode in Professor John McLachlan’slife. He was strongly struck by thehumanising influence of art. And beingresponsible for developing the coursesat the new Peninsula Medical School(PMS), he was also able to put theoryinto practice.The PMS aims to encourage medicalstudents to see patients as individualsin particular social and cultural contexts.The arts and humanities – includingpoetry writing, life-drawing, sculptureand photography – are an importantpart of this programme.Among its many innovations, thePMS teaches anatomy without usingcadavers, relying on imaging andexamination of living bodies instead.Medical students first experiencepatients as living people rather than asdevitalised corpses. Similarly, the courseis case-based and students encounterpatients in normal settings, fromhospitals to family planning clinics.The Eden Project site is dominatedby 2.2 hectares of covered ‘biomes’,themed around tropical andMediterranean landscapes, alongsidea further 15 hectares of outdoortemperate displays. The adjacentVisitor Centre contains exhibits thatexplore contemporary issues inscience, especially relevant to foodand health – including its advances,decisions, dilemmas and impacts.In 2004, the Eden Project receiveda £734 000 Rediscover award fromthe Millennium Commission and theWellcome Trust to redevelop itsexhibition space. To engage visitors,the exhibits have the air of a fairgroundattraction with extensive use of automataand arcade game style exhibits.All, however, illuminate the connectionsbetween people and plants, wild placesand cultures, across the globe.But the Rediscover award is onlyone way in which the Eden Projecthas attempted to use innovativeapproaches to tackle scientific issues.In 2002 it hosted an exhibition ofthe dresses produced by the Sciartpartnership of Helen and Kate Storey,which were inspired by earlyembryonic development.And it has actively drawn upon dramato engage young people, thanksto a Wellcome Trust Pulse award.Graham Mitchell’s Signs of Life,which explored people’s responsesto genetic modification, was developedin collaboration with students ona foundation degree course inperformance at Truro College.Accompanied by associated role-playworkshops, it toured secondaryschools in the south-west, and fromJuly 2004 was performed to schoolgroups and the general public atEden’s Visitor Centre.The Rediscover initiative was a £33 million jointventure between the Millennium Commission,the Wellcome Trust and the Wolfson Foundation.Drama and role play form a key partof students’ training, and dramaperformances are even being takeninto local schools to encourage studentsto consider a career in medicine.The medical school also draws uponhistorical contexts, collaborating withthe historians at the University of Exeter,a group supported by a WellcomeHistory of Medicine Strategy Award.L to RTeaching anatomywithout cadavers atthe Peninsula MedicalSchool.The biomes of the EdenProject in Cornwall.‘March of the guardsto Finchley’, one ofHogarth’s contributionsto the Foundling Hospital.

PUBLIC ENGAGEMENT33FOUNDLING FATHERA new exhibition provides an insight into the lives of abandonedchildren in the eighteenth century.A DRAMATICYEARVisitors to London’s FoundlingMuseum, which opened in June2004, can learn the remarkable storybehind the Foundling Hospital,which, like an early-day Live Aid,used artistic creativity to publiciseshocking social ills.In the mid-18th century thousands ofunwanted children were left to die onthe streets of London. In 1719, aftera life spent as a successful ship-builderand sailor in the New World, retired seacaptain Thomas Coram tripped overone such baby left in a gutter.Stunned by the appalling socialconditions all around him, he spentthe rest of his life establishing a refugefor abandoned children. His effortswere rewarded in 1739, when GeorgeII granted a Royal Charter for theestablishment of a Foundling Hospital,to provide a home and education foryoung children.Coram solicited the help of a talentedset of friends. Handel wrote thehospital anthem; Hogarth contributedpaintings, and persuaded manyof his contemporaries, includingGainsborough and Reynolds, todo likewise. At that time there wereno public places for artists to exhibit,so the Foundling Hospital becamethe first British public art gallery.In the 1920s the Foundling Hospitalwas demolished, but its artistictreasures were saved and movedto 40 Brunswick Square. The FoundlingMuseum houses the internationallyimportant Foundling HospitalCollection, which includes paintingsby Hogarth, Gainsborough, Hudsonand Roubilliac, and material relatingto Handel.The Wellcome Trust provided fundsfor an exhibition on the life and welfareof these unfortunate youngsters.The Museum includes many objectsreflecting the social and personalhistory of its children, includinghundreds of personal mementosor ‘tokens’ left by mothers in the hopethat they might one day be ableto return and identify their child.These tokens, including a hazelnutshell, a label from an ale bottle,and pieces of ribbon, are poignantreminders of past anguish.The Foundling Museum, at 40 Brunswick Square,London WC1N 1AZ, is open Tuesday – Sunday,10.00–18.00.Drama is highly effective at engagingyoung people, providing a way in forstudents who may be put off by ‘pure’science. And it provides muchinspiration for people whose firstinterest is in the performing arts.• Many Pulse performances took placeduring the year. Among the mostnotable performances, the TrestleTheatre Company premièred theirpuppetry work, The Smallest Person,at the Edinburgh Fringe festival –“Visually ingenious and delightful”,said the Guardian – while studentsfrom Sir John Colfox School inBridport collaborated with hospitalstaff and artists to create animaginative and occasionally surrealsite-specific work, Visiting Time,performed at a variety of locationswithin Dorset County Hospital.•‘Imagining the Future’, held at theTheatre Royal Plymouth in February2003, brought together playwrights,theatre practitioners and scientistsfor a week-long workshop. At leasttwo new works emerged from theworkshop – Simon Turley’s SeeingWithout Light, about immunity andthe impact of HIV, and Peter Morgan’sSpecial, which explored the medicaland cultural history of eugenics.• The Theatre Royal Plymouth wenton to apply for a £250 000 SocietyAward to build on the success ofthese two plays. The theatre will workwith professional casts and localcommunity groups to develop theplays and educational projects.• A reading of Peter Morgan’s play tookplace at the EuroScience Open Forum(Stockholm, August 2004). The playdeals with Sweden’s policy ofcompulsory sterilisation of the‘mentally defective’ – which onlyceased in the 1970s. The readingwas followed by a discussion involvingthe author and artist and commentatorEva Dahlgren, who has writtenextensively about the Swedish policy.

A YEAR AT THE WELLCOME TRUST34A YEAR AT THEWELLCOME TRUSTA brief overview of corporate activities in 2003/04.UK scienceWe worked closely with the UKGovernment in the run-up to the launchof its ten-year framework for Scienceand Innovation. We welcomed theGovernment’s decision to increaseframework spending from £3.9 billionin 2004 to £5 billion in 2008.We have agreed to work jointly withthe Government in key areas, suchas international health and public healthin the UK. We were also pleased to notethe Government’s acknowledgementof the contribution made by charitiesto research in UK higher educationinstitutes, and its decision to provideadditional funds through the dualsupport system.Open accessWe have continued to promote the ‘openaccess’ model of science publishing,to help ensure that scientific researchfindings are shared as widely and asrapidly as possible. In April 2004, wepublished the findings of research carriedout by the consultants SQW, Costs andBusiness Models in Scientific ResearchPublishing, which analysed the economicconsequences of different modelsof academic science publishing.The research suggested that openaccess publishing was economicallyviable and offered the potential forsignificant cost savings.Human Tissue BillDuring the year, we liaised with legislatorsand other parties to address issues raisedby the draft Human Tissue Bill, which inits original form would have posed seriousproblems to medical research in the UK.The Human Tissue Bill was a responseto cases in which the organs of deceasedchildren were taken and stored withoutthe consent or knowledge of parentsor families. While supportive of the aimsof the bill, we and others feared that inits original form it could have put majorobstacles in the way of potentially lifesavingresearch. The revised billaddressed many of the medical researchcommunity’s concerns, while still providingimportant protection to individuals’ rights.Public health researchA working group commissioned by theWellcome Trust called for a nationalstrategy to foster and enhance researchinto major public health problems facingthe UK population. The study wascarried out by an independent workingparty chaired by Professor StephenFrankel, Professor of Epidemiology andPublic Health at the University of Bristol.The group’s report, Public HealthSciences: Challenges and Opportunities,addresses a major issue identified in therecent Treasury-led Wanless Report,which recommended that the NHS shouldfocus more on health improvement anddisease prevention rather than justtreatment of ill-health.Consultation submissionsDuring the year, we submitted 27 formalresponses to consultations launchedby the UK Government and other bodies,including the draft charities bill, the Ten-Year Science and Innovation InvestmentFramework and the ScientificPublications Inquiry.StreamsIn October 2004, we introduced afunding ‘streams’ model for our researchfunding activities. The new streams cover:Immunology and Infectious Disease;Populations and Public Health;Neuroscience and Mental Health;L to RThe Gibbs Building –new headquartersof the Wellcome Trust.Colour-enhancedelectron micrographof the norovirus.Detail of a spectacularsculpture by the ThomasHeatherwick Studio,in the Gibbs Building.Dorsal root ganglionnerve cells.Frances Norton, whojoined the Trust as Headof the Wellcome Libraryin July 2004.

A YEAR AT THE WELLCOME TRUST35Physiological Sciences; Molecules,Genes and Cells; and MedicalHumanities. These streams arecomplemented by ‘cross-cutting’ strandsof activity such as technology transferand public engagement. The aim of thereorganisation is to focus more stronglyon research priorities and strategy, ratherthan on the funding process. FundingCommittees and Strategy Committeesare being set up to assess grants andconsider strategy issues in each area.Flexible fundingIn 2004, we made a number of changesto our grants management processes,with the aim of providing greater flexibilityfor grantholders and reducingadministrative burdens for grantholders,universities and the Trust. The changesallow grantholders to move fundsbetween budget headings (exceptsalary costs), and grants now includea ‘flexible funding award’ to provide forunanticipated direct costs and to provideadditional flexibility to researchers.New GovernorsThree new Governors were appointedin 2003/04: Dame Patricia Hodgson,former Chief Executive of the IndependentTelevision Commission; Ronald Plasterk,Professor of Developmental Geneticsat the University of Utrecht; and PeterSmith, Professor of Tropical Epidemiologyat the London School of Hygiene andTropical Medicine.Sir David SteelSir David Steel, former Chairman of theWellcome Trust, died on 9 August 2004.Sir David, previously Chairman of BP,was the Wellcome Trust’s Chairmanfrom 1982 to 1989.New staffFour new senior members of staff wereappointed during the year: Dr Ken Arnold,Head of Public Programmes; Dr DavidLynn, Head of Strategic Planning andPolicy; Frances Norton, Head of theWellcome Library; and Dr JimmyWhitworth, Head of International Activities.New headquartersThe Wellcome Trust moved into newpurpose-built accommodation, the GibbsBuilding at 215 Euston Road, during2004. The new building brings togetherall Wellcome Trust staff under one roof,except for Wellcome Library personnel,who have moved to 210 Euston Roadwhile the Wellcome Trust’s previousheadquarters building at 183 EustonRoad is refurbished. The refurbished183 building will be opened as a publicvenue in 2006.New corporate identityA new logo and corporate identity werelaunched during the year. The newidentity, launched to coincide with theoccupation of the new headquartersbuilding, is being rolled out gradually.The new identity is also reflected in theWellcome Trust website, which wasrelaunched in 2004 in a more userfriendlyformat.

FINANCIAL SUMMARY36FINANCIAL SUMMARY1 October 2003 to 30 September 2004Grants awarded: £251 millionDirect activities: £86 millionApplications: 2988; 1141 awardsTotal charitable expenditure: £378 millionInvestment assets: £10.5 billion(as at 30 September 2004)Additional financial information can be foundin the Wellcome Trust’s Annual Report andFinancial Statements 2004.Charitable resources expended (£ million)Grants awarded 251Direct activities 86Support and administration costs 41Total charitable expenditure 378Breakdown of grants awarded (£ million)*UK funding 101.4 †Careers 70.2International 38.8Infrastructure and equipment 28.4 ‡Medicine, Society and History 11.9Total 250.7In the year to 30 September 2004,the Wellcome Trust’s total charitableexpenditure was £378 million. Thisrepresents a drop on the figure for2002/03 (£516 million), due primarilyto the decline in infrastructure fundingthrough the Joint Infrastructure Fundand Science Research Investment Fundas these initiatives drew to a close.Of the total charitable expenditure, grantsworth £251 million were awarded.Although grants expenditure was downon last year, the number of grantapplications received also decreasedsignificantly – from 4312 in 2002/03to 2988, a drop of 30 per cent.Outstanding grant commitments againshrank slightly this year, but remainin excess of £1 billion.As in previous years, the bulk of grantsupport was for investigator-ledproposals in biomedical science.Fellowships and other careers fundingalso continued to be a major area ofsupport (27.5 per cent of grants spend).International expenditure (fundingfor schemes focused on the needsof developing and restructuring countries)increased as a proportion of total spend(15.5 per cent of grants spend).Grants for the medical humanities (historyof medicine and biomedical ethics) andpublic engagement with scienceamounted to £26.1 million. This consistsof £11.9 million for response-modefunding (2002/03: £13 million) plus capitalawards to the Natural History Museum(£10 million) and for the National ScienceLearning Centre (£4.2 million).Expenditure on direct activities, thoseorganised by the Wellcome Trust, roseslightly to £86 million. The bulk of thesecosts were for research at the WellcomeTrust Sanger Institute, which received£64 million in grants in 2003/04. Alsoincluded is £11 million committed tothe Diamond synchrotron project at theChilton/Harwell Science Campus. Directactivity costs also include support for theWellcome Library.Administration and support costs fellagain, from £44 million to £41 million.Wellcome Trust subsidiaries suchas the Genome Campus accountedfor £6.7 million of this expenditure.InvestmentsThe Wellcome Trust’s investmentsare managed to preserve (at least) thepurchasing power of its long-term assetbase and to provide an income streamto support ongoing activities. This year,the Trust’s asset base increased from£10.1 billion to £10.5 billion.Grants awarded (£ million)48038841 93952 5 12000 2001 2002 2003 2004* An additional £76.6 million was awarded toWellcome Trust subsidiaries, mainly to supportactivities at the Wellcome Trust Sanger Institute.† Including £86.9 million awarded through the UKSubject Panels; £12.4 million awarded throughthe Functional Genomics Development Initiative.‡ Includes £14.2 million of capital awards in Medicine,Society and History.Grants paid and outstanding (£ million)2239792741093327118 5412116839110282000 2001 2002 2003 2004Grants paidOutstanding grant commitmentsGrants awarded (left) represent the total funds committedto successful applications during the Trust’s financialyear. Most awards are made to researchers’ hostinstitutions, which then claim monies from the Trust.The light purple in the figure above (grants paid)represents the amounts claimed by host institutionsduring the year for expenses incurred, while the darkpurple (outstanding grant commitments) representsthe total sums committed by the Trust to projects whichhad not been claimed by the end of the financial year.The gap between committed funds and cash paid isdue to the long-term nature of many grants, and to thetime lag between a grant award and the subsequentclaim for funds from an institution.

THE FUNDING YEAR37THE FUNDING YEARA summary of major awards and key Wellcome Trust expenditurefor 2003/04.The Wellcome Trust supports researchand other activities in four main areas:• Biomedical Science• Technology Transfer• Medical Humanities• Public Engagement with ScienceIn biomedical science, project andprogramme support continued toaccount for the bulk of the WellcomeTrust’s support in the UK. Research isprimarily funded through response-modemechanisms, with support provided forinvestigator-led proposals in almost allareas of biomedical science and for awide range of basic and applied studies.The following pages describe some ofthe major projects funded in 2003/04.Career development support is providedat all levels from PhD (through Four-yearPhD Programmes) to professorial-levelPrincipal Research Fellowships. The12 UK Four-year PhD Programmes allreceived five-year renewals during theyear. Eight new Senior ResearchFellowships were awarded (six BasicBiomedical Science and two ClinicalScience), and eight fellowships wererenewed. Three Principal ResearchFellowships were renewed.Infrastructure investment has returnedto levels seen before the surge ofspending through the Joint InfrastructureFund and Science Research InvestmentFund. Funding of £11 million wasapproved for phase 2 of the Diamondsynchrotron project.The Wellcome Trust’s internationalfunding is primarily focused on regionalcentres of excellence, particularlyin South-east Asia (Thailand and Vietnam),Kenya, Malawi and South Africa. TheMalawi programme received a £2.3 milliongrant, to enable it to continue its researchon malaria and other infections.A £1.86 million grant was awardedto support research on women’s healthand ageing populations in Lebanonand elsewhere in the Middle East. Fourawards totalling £3.8 million were madeto countries in Latin and Central America– Brazil (two awards), Costa Rica and theWest Indies.In 2003/04, 12 International SeniorResearch Fellowships were awarded(seven in India, four in central/easternEurope, and one in South Africa); tenwere renewed (eight in India, onein central/ eastern Europe, and onein South Africa).Technology TransferThis year was the first in which awardswere made through the Wellcome Trust’snew technology transfer schemes.University Translation Awards providesupport for early-stage developmentof promising lines of research. The 16awards made this year covered a rangeof areas, including therapeutics, vaccines,diagnostics and medical devices.Strategic Translation Awards are largeawards in areas of strategic importanceto the Trust. Four awards are currentlyat advanced stages of consideration.Medical HumanitiesIn the history of medicine, the year’ssole Strategic Award went to theUniversity of Oxford, for a programmeof work on the history of tropical diseaseand medicine. Twentieth-century historycontinued to provide a major focus, withtopics being studied ranging from Unanipractice in India to the history ofmyxomatosis in the UK.Funding continued for BiomedicalEthics studies, in the UK and thedeveloping world. Studies supportedare of practical relevance, including thefunction of clinical ethics committees andan assessment of the impact of researchon health policy makers in Kenya.Public EngagementPublic engagement funding is primarilythrough the Engaging Scienceprogramme. Rediscover funding –a partnership with the MillenniumCommission and the Wolfson Foundation– has enabled public venues such as theEden Project in Cornwall and ThinkTankin Birmingham to update exhibits.A £10 million award to the Natural HistoryMuseum, for phase 2 of its DarwinProject, was confirmed. A £4.2 millionaward was made to the White RoseConsortium (an alliance between theuniversities of Leeds, Sheffield and York),to support construction of the NationalScience Learning Centre at York.Direct activitiesAs well as funding others, the WellcomeTrust organises activities directly, eitherindependently or in partnership withothers. The Wellcome Trust SangerInstitute accounted for £64 million forits ongoing highly productive researchprogrammes in genome sequencingand analysis.Partnerships lay at the heart of severalpublic engagement projects, includingthe Imagine photographic competitionrun with the BBC, and the Pain exhibitionat the Science Museum.Looking forwardIn October 2004, the Wellcome Trustintroduced a ‘streams’ model of funding.This is intended to provide a greaterfocus on the needs and opportunitieswithin particular areas.Funding Committees and StrategyCommittees are being establishedto assess grant applications andto consider how the Trust might bestmake an impact in these areas.Future Annual Reviews will reporton the progress made by the streamsin funding and developing strategy.The Diamondsynchrotron, whichreceived a fundingboost in 2004.

IMMUNOLOGY AND INFECTIOUS DISEASE38IMMUNOLOGY ANDINFECTIOUS DISEASEThe Immunology and Infectious Disease stream aims to increase our knowledgeand understanding of the infectious organisms that cause disease in humansand animals, and of the immune system that fights these organisms.During the year, 70 immunology andinfectious disease awards were made,including 15 new programme grantsor renewals, to a total value of£26.6 million.Research funded in the immunologyand infectious disease area rangedfrom fundamental and applied researchin basic immunology and infectiousdiseases conducted in the UK throughto field, epidemiological and clinicalresearch based in developing countries.Professor Brian Spratt, Imperial College,had the programme grant associated withhis Principal Research Fellowship renewedat a cost of £1.7 million. Professor Spratt,who has been a Principal Research Fellowsince 1989, studies the epidemiology andevolution of bacterial populations, and haspioneered the use of multi-locussequence typing as a scientific andepidemiological tool.Senior Research Fellowships in BasicBiomedical Science were awarded toDr Allison Green, University of Cambridge,for studies into inflammation andautoimmune disease, and to Dr Danielvan Aalten, University of Dundee, forhis studies on structural biology andinhibitor design in chitin metabolism.Fifteen programme grants were awarded,including grants to:• Professor Jose Vazquez-Boland, whomoved from the University of Leon inSpain to take up the Chair of VeterinaryMolecular Microbiology at the Universityof Bristol, for his studies of themolecular and cellular pathogenesis ofListeria infection. Listeriosis has one ofthe highest hospitalisation and mortalityrates of all food-borne infections.Professor Vazquez-Boland isinvestigating the actin-basedmechanism of cell–cell spread usedby the bacterium.• Dr Gavin Wilkinson, University of WalesCollege of Medicine, Cardiff, for studiesinto human cytomegalovirus. Thisherpesvirus is able to evade theimmune system of healthy but infectedpersons, but in immunocompromisedindividuals it presents a major clinicalproblem. Using clinical isolates,Dr Wilkinson will look at how the virusinteracts with natural killer cells, themain weapon in fighting viral disease.The team will use whole genomecloning techniques to investigate therole of different viral genes in evadingthese immune cells.• Professor David Wraith, Universityof Bristol, for research on thedifferentiation and stability of inducedregulatory T cells. Professor Wraith’sresearch is aimed at the developmentof therapies to control autoimmuneconditions, such as multiple sclerosis.Under the Tropical MedicineProgramme, awards included a SeniorClinical Fellowship in Tropical Medicineto Dr Elizabeth Corbett, London Schoolof Hygiene and Tropical Medicine, fortrials of TB case-finding strategies in anurban community in Zimbabwe severelyaffected by HIV, and a CareerDevelopment Fellowship to Dr CameronSimmons, University of Oxford, for hisstudies in Vietnam on cellular immuneresponse and disease pathogenesisduring dengue infection. Dr Corbettwas awarded the 2004 Chalmers medalby the Royal Society of Tropical Medicineand Hygiene for her contributions totropical medicine.An interim review was carried out of theWellcome Trust/Burroughs WellcomeFund Infectious Diseases Initiative.Launched in 1999, the initiative awarded£18 million to support 13 projects, eachinvolving partners in the UK, USA and adeveloping country, and has played animportant role in fostering internationalpartnerships and developing capacity.While many projects have yet to cometo full fruition, it is clear that they havedelivered major benefits to the participantsand host institutions, and in some caseshave had a direct impact on publichealth. For example, the project basedin Bangladesh has raised the profileof neonatal healthcare locally, attractingthe interest of the Ministry of Health andother NGOs/charities (see page 27).Major Overseas ProgrammesFollowing a favourable review in 2004,an award of £2.3 million was madeto the University of Liverpool for theMalawi–Liverpool–Wellcome TrustClinical Research Programme. Theprogramme, which is led by ProfessorMalcolm Molyneux and is based in theWellcome Trust Research Laboratoriesat the University of Malawi College ofMedicine, Blantyre, conducts researchinto malaria, HIV, TB and other bacterialand viral infections, and anaemia.In addition to research costs, the awardprovides funds to support the trainingof local researchers associated with theprogramme (see page 25).In Kenya building work began on newlaboratories in Kilifi for the WellcomeTrust/Kenya Medical Research InstituteResearch Programme, led by ProfessorKevin Marsh. The building has beenfunded by a Wellcome Trust grant of£2.75 million to the Kenya MedicalResearch Institute. The building shouldbe completed by August 2005.Research highlights from the Kenyaprogramme include:• The completion of a survey of epilepsyin over 160 000 people and theidentification of all cases of activeepilepsy, the largest study of its kindever conducted in Africa.

IMMUNOLOGY AND INFECTIOUS DISEASE39• Analysis of data on the spectrumof bacteraemia in children, with datafrom over 20 000 children admittedto hospital. Of all hospital deaths,14 per cent were attributable toStreptococcus pneumoniae andHaemophilus influenzae, for whicheffective vaccines are available butonly partially implemented.• Dr Sam Kinyanjui and Dr Faith Osierwere awarded Research TrainingFellowships for Scientists fromDeveloping Countries to conductresearch at the KEMRI–WellcomeTrust programme in Kilifi.In South-east Asia, whichencompasses research centres inThailand (led by Professor Nick Day)and Vietnam (Professor Jeremy Farrar),research highlights include:• Demonstration that variable horizontalgene acquisition by Burkholderiapseudomallei is an important featureof its recent genetic evolution.• Continued translation of theProgramme’s research results intohealth policy. Biological, economicand clinical evidence from the researchpublications of the programme haveprovided a basis for a change in globalantimalarial treatmentrecommendations to artemisinincombination therapies (ACTs)(see page 24).• A mathematical–economic modelof drug resistance has been usedas a basis for the globalrecommendations on antimalarialdrug policy issued in a recentInstitute of Medicine report (SavingLives, Buying Time).• In Vietnam, the Programme hascompleted the largest-ever studyof TB meningitis (see page 26).• The Vietnam Programme has beenat the forefront of the battle againstthe outbreak of avian flu (seepage 23).• The New Adult Intensive CareUnit at the Hospital for TropicalDiseases opened in 2004, fundedjointly by the Vietnamese Governmentand the Wellcome Trust.The Wellcome Trust Centrefor Molecular ParasitologyThe Wellcome Trust Centre for MolecularParasitology at the University of Glasgow,led by Professor Dave Barry, carries outresearch on basic features of parasites,using genetic and molecular technologyallied with organismal biology. One aimis that such studies will lead to novelcontrol approaches.Much of the research at the Centreconcerns African trypanosomes,microscopic parasites that cause humansleeping sickness and the wastingdisease nagana in domestic animals.The malaria parasite, Plasmodium,and a related parasite, Theileria, whichinfects cells of the cattle immune system,are also studied at the Centre.In 2004, the Centre established a newpartnership with INSERM, the nationalmedical research agency of the FrenchGovernment. INSERM has begun tolocate its researchers in universitiesabroad, and the first of these INSERMResearch Units, led by ProfessorChristian Doerig, has been establishedat the Centre.During the year, a programme grantwas awarded to Professor Andy Taitat the Centre, based on his applicationof genetics to the identification ofimportant trypanosome genes. ProfessorTait’s mapping and annotation of thetrypanosome genome has beeninvaluable to the genome sequencingwork on the parasite being carried outat the Wellcome Trust Sanger Instituteand elsewhere.www.gla.ac.uk/centres/wcmp/index.htmlAdenovirus particles.

MOLECULES, GENES AND CELLS40MOLECULES, GENES AND CELLSThe Molecules, Genes and Cells stream aims to support high-quality researchthat will further our understanding of the fundamental molecular, cellular and geneticprocesses involved in health and disease.During the year, 75 awardswere made, including nine newprogramme grants or renewals,to a total value of £21.8 million.Two Principal Research Fellowshipswere renewed: to Professor AngusLamond (University of Dundee),for his structural and functionalanalysis of the mammalian cellnucleus, and to Professor BillEarnshaw (University of Edinburgh)for his studies of non-histonechromosomal proteins in mitosisand apoptosis.Membrane trafficking and proteinfolding were notable themes in thisyear’s molecular and cell biologyfunding. Professor Margaret Robinson(University of Cambridge) had theprogramme grant associated withher Principal Research Fellowshipon coated vesicle adaptors renewed.She is characterising the adaptorprotein complexes that facilitatethe transport of cargo betweenintracellular organelles. A new lineof investigation will focus on how thehuman immunodeficiency virus (HIV)may exploit adaptor proteins to evadethe immune response.Professor Colin Stirling (Universityof Manchester) received continuedprogramme grant funding for studiesof protein biogenesis in the yeastendoplasmic reticulum. By using boththe powerful genetic systems of yeastand biochemical approaches, hisgroup will investigate the partitioningof proteins into the secretory pathwayvia the endoplasmic reticulum andthe role of the translocon complexand associated chaperones.Professor Neil Bulleid (Universityof Manchester) was awarded aprogramme grant to continuehis studies on oxidative foldingin the mammalian endoplasmicreticulum. His group studies the redoxconditions within the endoplasmicreticulum that allow proteins, particularlythose containing disulphide bonds,to fold correctly.Professor Christopher Dobson(University of Cambridge) receivedcontinued programme grant fundingto study protein folding and misfoldingusing an array of biophysicaltechniques and theoretical simulations.Several important and innovativegrants were also funded in the areaof epigenetics and gene silencing.Jane Mellor (University of Oxford) wasawarded a programme grant toelucidate the role of a novel chromatinremodelling ATPase in gene silencingand gene regulation.Professor Constanze Bonifer (Universityof Leeds) received continued projectgrant funding for her studies on theepigenetic mechanisms regulating theexpression of the lysozyme gene, whileDr Brian Hendrich (University ofEdinburgh) was awarded a grant,complementing his ongoing Wellcomefellowship support, to investigate theepigenetic silencing mechanisms in cellfate decisions. Dr Maria Vogelauerreceived a Research CareerDevelopment Fellowship to study themolecular mechanisms by whichhistone acetylation regulates the timingof replication origin firing.Biological chemistryThe partnership with the Royal Societyof Chemistry to encourage the areaof chemical biology continued duringthe year. A successful workshop on‘Chemistry at the Biological Interface’was held at the University of Warwickin September 2004. The participants,from universities in and around theMidlands, enthusiastically discussedcollaborative projects and it is likely thatseveral new grants will be submittedfrom ideas first aired at the workshop.Wellcome Trust Centrefor Cell BiologyThe Wellcome Trust Centre for CellBiology at the University of Edinburgh,led by Professor Adrian Bird, seeksto understand the fundamentalcharacteristics of living things at thecellular level, such as growth, movement,self-replication and development.It has particular strengths in the studyof RNA, including its transcription,processing, transport and destruction;the cell division cycle; and geneexpression in developing systems,particularly epigenetic processes suchas DNA methylation.During the year Professor Bill Earnshaw’sPrincipal Research Fellowship wasrenewed (see left), as was Dr KennethSawin’s Senior Research Fellowshipin Basic Biomedical Science (Regulationof eukaryotic microtubule nucleationand microtubule-mediated cell polarity).A Research Career DevelopmentFellowship was awarded to Dr MariaVogelauer (see left).Professor David Tollervey, a WellcomePrincipal Research Fellow at the Centre,was elected to the Royal Society, whileProfessor Jean Beggs was awardedthe Royal Society Darwin TrustResearch Professorship.www.wcb.ed.ac.uk/intro.htm• RNA-based gene silencing: see page 19Wellcome Trust Centrefor Human GeneticsThe Wellcome Trust Centre for HumanGenetics at the University of Oxford,led by Professor Tony Monaco, studiesthe mechanisms controlling geneticsusceptibility to human disease. Thisincludes the localisation and identificationof disease genes; functional analysis ofgene variants responsible for

MOLECULES, GENES AND CELLS41susceptibility; and understandinghow gene variants contribute to riskof disease in the population and howgenetic factors contribute biologicallyto a disease process.The Centre, located in the HenryWellcome Building of Genomic Medicine,houses multidisciplinary research teamsin human genetics, functional genomics,bioinformatics, statistical genetics andstructural biology. The Centre is focusingon three main disease areas in its geneticsresearch programme: neurogenetics,genetics of inflammation and immunity,and the genetics of cardiovasculardisease/metabolic syndrome.A Senior Research Fellowship in ClinicalScience was awarded to Dr Julian Knight(Characterisation of genetic variationregulating gene expression within theMHC class III region). A Senior ResearchFellowship in Basic Biomedical Sciencewas renewed: Dr Dominique Gauguier(Functional genomics of type 2 diabetesquantitative trait loci in rat models).A Research Career DevelopmentFellowship was awarded to Dr RichardWade-Martins (Functional analysisof the tau genomic locus and its rolein neurodegeneration).Dr Kalim Mir, a Wellcome CareerDevelopment Fellow, received aTechnology Development Grant (Ultrathroughputparallel DNA sequencing usinga heuristic single molecule array strategy).Researchers at the Centre also receivedtwo clinical training fellowships.www.well.ox.ac.uk• Population genetic structure: see page 6Wellcome Trust Centrefor Cell-Matrix ResearchThe Wellcome Trust Centre for Cell-Matrix Research, led by Professor MartinHumphries, is an interdisciplinary researchcentre embedded within the Facultyof Life Sciences at the Universityof Manchester. Its long-term aims areto elucidate the structure and functionof the extracellular matrix (ECM) andcell–matrix adhesions, define thecontribution of cell–matrix interactionsto human diseases, and developapproaches for preventing and treatingthese diseases.Research within the Centre is organisedas four integrated programmes:(1) molecular basis and cellular controlof ECM assembly, (2) organisationof signalling at the cell–ECM interface,(3) microenvironmental determinationof cell fate, and (4) cell–ECM engineeringand tissue regeneration. While eachprogramme is highly focused onextracellular matrices and cell–matrixinteractions, the long-term promiseof the work overlaps with some of themost important areas of biomedicalresearch – signalling, tissue engineeringand medical genetics.In 2001, the University of Manchesterwas awarded £15 million from the JointInfrastructure Fund (JIF) to help set upa new Integrative Centre for MolecularCell Biology. An additional £35 million fromthe university was used to create a largeresearch facility for biomedical researchsited at a central location in theuniversity’s biomedical corridor, adjacentto the Manchester Royal Infirmary andthe Wellcome Trust Clinical ResearchFacility. This building, named in honourof Professor Michael Smith, was occupiedin 2004 and now houses the WellcomeTrust Centre for Cell-Matrix Research.During the year a Senior ResearchFellowship in Basic Biomedical Sciencewas awarded to Richard Kammerer(Elucidating the mechanisms ofangiopoietin function and amyloidformation by protein engineering andde novo design). A Research CareerDevelopment Fellowship was awardedto Dr Eleni Tzima (Role of cell–celljunctions and integrins in endothelialcell responses to fluid shear stress).A programme grant was awardedto Professor Neil Bulleid (see left).www.wtccmr.man.ac.ukWellcome Trust/Cancer ResearchUK Gurdon InstituteThe Wellcome Trust/Cancer ResearchUK Gurdon Institute of Cancer andDevelopmental Biology at the Universityof Cambridge, chaired by ProfessorJim Smith, focuses on two inter-relatedaspects of cell biology: how cells acquireand maintain their normal function duringdevelopment, and how they escape fromnormal controls and become cancerous.The Institute adopted its new nameduring the year, in recognition of thepioneering scientific contributions madeby its founding Director, Sir John Gurdon.Sir John was also awarded the RoyalSociety’s Copley Medal, its top honour.In 2004, the Institute also occupied itsnew building, constructed with supportfrom the Joint Infrastructure Fund.www.gurdon.cam.ac.uk• Research resources: see page 19Normal red blood cells.

NEUROSCIENCE AND MENTAL HEALTH42NEUROSCIENCE ANDMENTAL HEALTHThe Neuroscience and Mental Health stream aims to support high-qualityresearch into the function of the nervous system in health and disease.During the year, 62 neuroscienceawards were made, including 11new programme grants or renewals,to a total value of £26.6 million.One Principal Research Fellowshipwas renewed, to Professor Chris Frith(Institute of Neurology) for his studiesof social interactions (see page 8).Neuroscience awards continued to covera wide range of both basic and clinicalresearch topics throughout 2003/04.Two examples of the diversity of fundingare awards to Dr Lucia Sivilotti (UniversityCollege London), for a highly detailedstudy of the subunits of the nicotinicacetylcholine receptor, and Dr Mariannevan den Bree (University of Wales,Cardiff) who is carrying out a longitudinalstudy in adolescents of the risk factorsassociated with substance abuse.Two significant awards were madein the field of child psychiatry. The firstwas to Professor Alan Stein (Universityof Oxford) for his ongoing work whichaims to understand how maternalpostnatal psychiatric disorders can affectthe development of a child, even afterthe mother has recovered. His groupwill be looking at how interactionsbetween mother and child are affectedby postnatal depression, following infantsin the first years of life to see how theysubsequently develop.In a related study, Professor Ian Goodyer(University of Cambridge) will be lookingat how genetic and environmental riskfactors in infancy affect the occurrenceof psychiatric disorders during the keychanges accompanying adolescence.His group will be carrying out alongitudinal study of 13 and 14 year-oldsto find associations of selected genesand childhood adversity with depressionand associated conditions.Several awards were for basic researchprojects aiming to increase our knowledgeof how neurons communicate witheach other – essential for ourunderstanding of the nervous system.Two awards were made to groups atUniversity College London, to ProfessorsDavid Attwell and Stuart Cull-Candy.Professor Attwell’s group will be involvedin studies into how neurotransmittersfunction in ways distinct fromconventional fast synaptic transmissionbetween neurons, looking particularlyat their communication with glia cells.Professor Cull-Candy’s research willexamine how changes in receptorsubunits define the nature ofneurotransmission at glutamateand GABA synapses.Other research projects are lookingat chemicals that are not classicalneurotransmitters but have a major rolein neuronal transmission. One suchaward was made to Professor AlanNorth (University of Manchester), whois studying the role of ATP, classicallyknown as a molecule which transfersenergy within cells, which interactswith specific receptors on neurons.Furthering our understanding of howthese molecules enable neurons tocommunicate is important in their furtherdevelopment as targets for drugs fordiseases of the nervous system.A number of projects are aiming to clarifyhow the very complex connections inthe nervous system develop. Dr UweDrescher (King’s College London), forexample, is examining how neurons canbe directed to their targets, which areoften a great distance away, by guidancemolecules. Dr Drescher is studying thedifferential expression of genes at criticaltimes of development which assist inguiding neuronal projections from theretina to the tectum.Professor Kristjan Jessen (UniversityCollege London) was awarded a grantto study the development of Schwanncells within the nervous system. Thesevery specialised cells form the myelinsheath which insulates nerve axonsand are essential for normal nervefunction. However, following injury theycan revert to an immature state, leadingto demyelination of the axon and lossof function. Professor Jessen’s groupis examining the signals that controlSchwann cell differentiation and theprocess of myelination, and will alsolook at mechanisms that may allowthe Schwann cells to form new myelinsheaths and thus aid nerve repairfollowing injury.

PHYSIOLOGICALSCIENCESThe Physiological Sciences stream aims to support high-quality basic and clinicalresearch relevant to the understanding of biological processes at the cell, organ,system and whole-animal level in health and disease.During the year, 63 physiologicalsciences awards were made, includingseven new programme grants orrenewals, to a total value of£20.2 million.Physiological science awards covereda broad range of basic and clinicalresearch. Awards were made in areasas diverse as epidemiology – forexample, to Dr Louise Parker (Universityof Newcastle), for an analysis of a historicalbirth cohort to explore the effect of preandpost-natal exposure to airborneparticulate matter on subsequentmortality and health – and organtransplantation – such as the awardto Professor Peter Friend (Universityof Oxford), for the development of anovel preservation technique for donorlivers involving warm perfusion.One notable theme during the yearcentred on appetite control, nutritionand body size, obesity and theirimpact on health, particularly diabetes.Awards included a programme grantto Professor Stephen Bloom (ImperialCollege London) for his studies aimedat exploiting the discovery that guthormones physiologically controlappetite. This programme will examinehow different gut hormones producetheir effects and interact in obese andlean volunteers. The research shouldprovide a better understanding of thecomplex interactions in appetiteregulation and provide new strategiesto treat and prevent obesity.Another significant award in a relatedarea was made to Professor PatrikRorsman (University of Oxford), forhis studies into the physiology andpathophysiology of beta-cell exocytosisand insulin secretion. Greater insight intothe control of insulin secretion has thepotential to inform both our fundamentalknowledge of the defects involved intype 2 diabetes and the developmentof novel therapies to treat this debilitatingand widespread condition. This awardwas of further importance as it aidedthe recruitment and retention ofProfessor Rorsman, an internationallyrenowned scientist previously workingoutside the UK.In this same general theme, an awardwas made to Professor David Dungerand colleagues (University of Cambridge)for a study looking at the effect of geneticvariation in the insulin gene on birthweight and perinatal survival in Africanpopulations. This study will, for the firsttime, test the hypothesis that genesrelating to size at birth influence fetaland postnatal survival.A significant amount of multidisciplinaryresearch was also funded through theyear. This included an award to ProfessorDavid Paterson and colleagues at theUniversities of Oxford and Auckland (NewZealand) for a heart ‘physiome’ project.The aim of their project is to demonstratethe use of integrative multi-scale modelling– at the levels of atoms, proteins, cells,tissues and organs – to relate detailedgenomic information to a model of thestructure and function of the human heart.Since biological systems are extremelycomplex, the team will develop speciallydesigned instrumentation, databasesand software to help understand thegenetic basis of mechanisms underlyingPHYSIOLOGICAL SCIENCES43arrhythmia in the heart. These toolswill be accessible on the web for otherinvestigators to use in further studies.Another award for multidisciplinaryresearch was made to Dr David Webb(Aston University) and colleagues atthe University of Birmingham. They aredeveloping a ‘smart vest’ which, whenworn next to the skin, will collect clinicallyuseful information related to respiration.Such information should aid cliniciansin the diagnosis of respiratory disease.As well as grant funding, a joint MRC/Wellcome Trust workshop was organisedon integrative physiology. The workshop,held in May 2004, brought together basicand clinical physiologists and exploredhow an appropriate strategy to furtherencourage integrative physiology mightbe developed.L to RNeurons in the brain.Professors DavidPaterson (left) and PeterHunter of the HeartPhysiome Project.

POPULATIONS AND PUBLIC HEALTH44POPULATIONS ANDPUBLIC HEALTHThe Populations and Public Health stream aims to improve our understandingof the determinants of disease and quality of life in populations. It promotesthe use of this understanding to improve public health and healthcare delivery.During the year, 53 awards were madein this area, principally through theHealth Consequences of PopulationChange Programme, to a total valueof £12.7 million.Latin AmericaAn initiative to support Centres ofExcellence in Latin America culminatedin the award of four programmes (totalling£3.8 million) to support multidisciplinaryresearch on the impact on healthof demographic and socioeconomicchanges in the region. Professor MauricioBarreto (Univesidade da Bahia, Salvador,Brazil) will study the impact ofurbanisation, migration and lifestylechanges on allergic diseases (atopyand asthma). A parallel study in Quito,Ecuador, in collaboration with Dr PhilipCooper (a Wellcome Trust SeniorResearch Fellow), will compare theprevalence of allergic diseases, and riskfactors, in rural and urban populations.Also in Brazil, Professor Cesar Victora(Federal University of Pelotas) willcompare two large birth cohorts toexplore how early life factors – such asnutrition, socioeconomic, cultural andhealthcare issues – influence adolescentand adult health.Professor Luis Rosero-Bixby’s team(Universidad de Costa Rica) will addressthe role of social, nutritional andhealthcare factors in longevity and activelife expectancy in the country, whilecollaborations with Cuba and Mexicowill study how different public healthapproaches affect ageing in the region.Finally, Dr Elsie Le Franc (University of theWest Indies) will examine the possiblecauses of family and interpersonalviolence, especially among adolescentsand young adults. The project will assessa number of possible risk factors,including family structure, social networks,and instabilities resulting from migration.Major centresDr Michael Bennish at the Africa Centrefor Health and Population Studies,University of KwaZulu-Natal, South Africahas been awarded funding for a feasibilitystudy to examine different approachesto using antiretroviral drugs against HIVinfections in resource-poor settings.These drugs are normally used on a longtermbasis to suppress disease, withcareful monitoring of patients – presentingmajor challenges where the numbers ofpeople in need are large and resourcesare scarce.The Trust-funded building housing theAfrica Centre at Somkhele has beenwidely praised – a tribute to a distinctivebuilding that reflects the Centre’scommitment to community-based healthresearch. A series of regional and nationalawards culminated in the South AfricanInstitute of Architects Award of Excellencefor 2002, where the building wasdescribed as one of the best ever builtin South Africa.Professor Huda Zurayk, Center forResearch in Population and Health,American University of Beirut, wasawarded a £1.86 million programme grantto continue her studies on reproductivehealth of women, health of adolescentsand the elderly in the Middle East.The award reflects the progress madesince it was awarded a ‘regional centreof excellence’ grant in 2001.TrainingThe Master’s-level Research TrainingFellowship scheme was reviewed duringthe year. The awards consist of a taughtcourse, followed by a research projectin the applicant’s home country. In all,67 individuals received Masters’ supportbetween 1998 and 2002. Most havethrived professionally and still appearto be working in their home country,attesting to the success of the schemein strengthening research capacity.Other notable awardsTwo awards under the HealthConsequences of Population ChangeProgramme address key areas in ageingresearch – diet and vision. ProfessorRicardo Uauy (London School of Hygieneand Tropical Medicine, with the Universityof Chile) will be evaluating a nutritionalsupplementation and exercise programmeinitiated by the Government of Chile.Professor Astrid Fletcher (London Schoolof Hygiene and Tropical Medicine, withthe All India Institute of Medical Sciences)will continue research into age-relatedeye disease in India, following asuccessful Trust-funded pilot study.This is a population-based study to mapprevalence rates for macular degenerationand cataract, the impact of theseconditions on quality of life, and possiblerisk factors such as diet, smoking and useof cooking fuels.UK BiobankThe UK Biobank project, a partnershipbetween the Wellcome Trust, the MedicalResearch Council and the Departmentof Health, will collect current health,lifestyle and medical history data on500 000 volunteers aged 40–69. The datawill be a powerful tool for researchersexploring the origins of complex diseases.In November 2003, UK Biobank Ltd wasestablished as a charitable company andin January 2004 the Board of Directors,chaired by Sir Alan Langlands, Principaland Vice-Chancellor of the Universityof Dundee, held its first full meeting.In August 2004, Alastair Campbell,Professor of Ethics in Medicine at theUniversity of Bristol’s School of Medicine,was appointed chair of the UK BiobankEthics and Governance Council.

MEDICAL HUMANITIES45MEDICAL HUMANITIESThe Medical Humanities stream aims to enhance understanding of the historicaland social context of medicine and biomedical science. It supports researchprogrammes in history of medicine and biomedical ethics, and encouragesuse of research findings, for example to inform public policy making.In the history of medicine, a StrategicAward was made to Dr Mark Harrison(University of Oxford) for his study‘The history of infectious disease, andmedicine in the tropics’. EnhancementAwards were made to ProfessorVirginia Berridge (London Schoolof Hygiene and Tropical Medicine),Professor Anne Crowther (Universityof Glasgow) and Dr Nick Hopwood(University of Cambridge).Two University Awards were made,to Dr Tim McHugh (Oxford BrookesUniversity; Rural medical charity andsociety in Brittany, 1598–1789) andDr Rosemary Elliot (University ofGlasgow; Smoking and health inGermany from occupation toreunification, 1945–1995). Fellowshipand project support covered a widerange of topics, from Unani practicein India to fungal diseases inmodern medicine.PreservationThe Research Resources in MedicalHistory scheme was set up to improveaccess to documentary collections thatare important to historians of medicine,by funding preservation, conservation,cataloguing and digitisation projects.In June 2004, the scheme wasextended for a further two years, withfunds of £500 000 available each year.In its first four years, the scheme hasfunded 58 projects to a total value of£2 million.An evaluation of the scheme carried outin 2004 discovered that institutions thathave received funding for cataloguingnow urgently require second-stagefunding for preservation andconservation. As a result, the newscheme is focusing primarily onpreservation and conservation, althoughproposals for cataloguing projects willstill be accepted.Biomedical ethicsResearch is supported on issuesrelevant to policy and practice in the UKand the conduct of biomedical researchin the developing world. A total of 50awards in biomedical ethics were madein 2003/04, primarily project grantsbut including six fellowships, ninestudentships and 17 symposia.The Wellcome Trust also organiseda workshop, ‘Investigating ethicsand mental disorders’.Among the research projects funded,Dr Sheila McLean (University ofGlasgow) was awarded a project grantto review and evaluate clinical ethicscommittees in the UK. Dr RobinWilliams (University of Durham) receivedproject grant funding for follow-up to hisprevious study on the UK National DNAdatabase, this time reviewing forensicdatabasing in support of criminalinvestigation in the EU states, and howDNA data are being shared acrossnational borders.Dr Mike English, a clinician at theKEMRI/Wellcome Trust Major OverseasProgramme in Kenya, was awardedproject grant support to investigatethe research-to-policy-to-practicepathway in Kenya. He will explorethe environment in which health policydecisions are made, mapping out thelinkages and information flow betweenkey stakeholder groups.The development of novel diagnostics,therapeutics and health services isincreasingly predicated on the searchfor significant biological differenceswithin and between populations.Dr Paul Martin (University of Nottingham)was funded to investigate how thecategories of race/ethnicity are usedin research and what their practicalimpact might be.Wellcome Trust Centre for theHistory of MedicineResearch at the The Wellcome TrustCentre for the History of Medicine atUniversity College London, led byProfessor Hal Cook, spans a widerange of topics, eras and countries.The Centre also organises outreachactivities and teaching at undergraduate,Master’s and PhD levels. The Centrebegan a new MA course in 2004,recruiting 13 students from a varietyof backgrounds.Professor Janet Browne continued toadd to the prizes awarded to her bookCharles Darwin: Volume 2 – The powerof place (Jonathan Cape), including theW H Heinemann prize from The RoyalSociety of Literature. Her book was alsoshort-listed for the British Academy BookPrize 2003.Professor Vivian Nutton’s AncientMedicine was published by Routledgein 2004, while six Wellcome Witnessesto Twentieth Century Medicine, publishedby the Centre, are now available online.The Centre has a varied outreachprogramme. Professor Roger Cooterbegan a column in the Lancet on‘Keywords in the history of medicine’,while members of the Centre appearedin the six-part Radio 4 programme TheOther Medicine presented by Anna Ford.Dr Sanjoy Bhattacharya and Dr AndrewHull advised and appeared on the recentChannel 4 documentary The Great AsianInvasion discussing the role of Asiandoctors in the formation of the NHS.Professor Kan-wen Ma contributedto parliamentary consultations on theregulation of complementary andalternative medicine.www.ucl.ac.uk/histmedL to RBoys in Kenya.Dr Mark Harrisonof the Universityof Oxford.

TECHNOLOGY TRANSFER46TECHNOLOGY TRANSFERTechnology Transfer at the Wellcome Trust seeks to maximise the impact of researchinnovations on health by facilitating the development of early-stage projects to a pointat which they can be further developed by the market.For the Wellcome Trust to achieve itsmission, it is important that the basicdiscoveries made by the scientificcommunity are translated into practicalinnovations that can be utilised directlyor indirectly to improve human andanimal health. To be effective intranslating scientific advances intohealth products, scientists needto engage with the business andinvestment community. Bridging thegap between academic research andcommercial R&D is difficult becauseof the risks inherent to early-stagetranslation. This is a particular problemin the healthcare sector, where thetechnical and regulatory hurdles area significant challenge on the pathto market.Technology Transfer at the WellcomeTrust seeks to mitigate the risks of earlystagetranslation by funding projectsthat are too early to attract venture capitalor to be seen by industry as crediblein-licensing opportunities. Up to 2003,it achieved this through the £20 millionDevelopment Fund. Over a period of fiveyears, this has supported around 40projects from 14 institutions. Many ofthese have raised additional investmentand two have developed products already(see pages 22 and 27), although it is stilltoo early to appreciate the full impactof the funding provided.In March 2003 the Wellcome Trustannounced two new forms of translationaward. University Translation Awardsprovide a response-mode funding stream.As such, they are used to support adiverse array of technologies, not onlyfrom biology but also from the physicalsciences and mathematics. The commonrequirements are that the research isaimed at the improvement of health andthat the project can be advanced to apoint at which it represents an attractiveproposition for follow-on support by athird party. Both academic institutionsand associated early-stage companiesare eligible to apply for these translationawards. Managing projects to a successfuloutcome is the responsibility of theinstitution or company management.Technology Transfer has just completedthe first full year of funding of UniversityTranslation Awards. Of 58 applicationsreceived from 30 institutions, 25 per centwere awarded. An equivalent number ofawards were made to universitydepartments and small businesses.The mean value of these awards was£276 000 (range: £48 000 to £594 000).In keeping with the response-mode natureof the scheme, projects were funded thataddressed a wide range of potentialapplications – including therapeutics,vaccines, diagnostics and medicaldevices, as well as new platformtechnologies. One award was madeto investigate the effectiveness of policytools for promoting translation inneglected diseases, such as malariaand African sleeping sickness.Strategic Translation Awards area second form of funding designedto support translational research in areasof key importance to the Wellcome Trust.These may be technologies that havea particular role in support of the Trust’smission and address an unmet needin healthcare, and where TechnologyTransfer can add value by providingproject management support or securingfollow-on funding.Four Strategic Translation Awardapplications have been considered sincethe scheme was announced. Theserelated to diagnostics, vaccination and anovel genotyping technology. The meanvalue of the awards was £1.3 million.Further developments in strategicallyimportant translational research are likelyto be announced in the coming year.There has been encouraging progressin a number of the projects supportedthrough the Development Fund. CellTran,a spin-out company from the Universityof Sheffield, launched a ‘smart bandage’product called ‘Myskin’ for the treatmentof serious burns (see page 27). Anotherearly-stage company, Diagnostics forthe Real World, has developed dipsticktechnology for the diagnosis of Chlamydiainfection (see page 22).The year also saw important developmentsin a drug discovery project, basedat the Institute of Cancer Research, ona mutant form of the B-Raf kinaseassociated with malignant melanoma.The project is being taken forward bya partnership that includes the Instituteitself, Cancer Research Technology, theWellcome Trust Sanger Institute, theWellcome Trust and Astex Technology,a biotech company with expertise in drugdiscovery, especially structure–activityrelationship research. With the expandedteam, the programme is set to progressthrough the critical phases of leadselection and lead optimisation overthe coming year.L to RZebrafish embryos.Scientists at the SangerInstitute.

WELLCOME TRUST GENOME CAMPUSThe Wellcome Trust Genome Campus, at Hinxton, near Cambridge, is home to theWellcome Trust Sanger Institute, the Wellcome Trust Conference Centre and WellcomeTrust Advanced Courses. The Genome Campus is currently being extended to provideadditional laboratory and ancillary space.WELLCOME TRUST GENOME CAMPUS47Wellcome Trust Sanger InstituteThe Wellcome Trust Sanger Instituteis one of the world’s leading scientificestablishments, generating and providingdata and resources to the global scientificcommunity. Genome sequence and themultitude of variants present in apopulation are responsible for manyof the differences between individuals,from cognition to cancer predispositionin humans to virulence in pathogens.Hence DNA sequence provides anessential platform for much ofbiomedical research.The Sanger Institute produced the largestcontribution to finished human genomesequence (see page 6), and has alsodeveloped tools such as the Ensemblgene browser which enable hundredsof thousands of researchers to view andutilise genome sequence data from 17different species via the web, with humanand mouse the most popular.In 2004, papers from the Sanger Institutedescribing the sequence content ofchromosomes 6, 9 and 10 – a totalof nearly 400 million base pairs – werepublished. The Sanger Institute has nowproduced some 2.5 billion base pairsof finished sequence.The Sanger Institute has increased itsfaculty strength to 35, as its programmesevolve to place a greater emphasis ongene function through genetic analysisin humans and model organisms.High-volume sequencing continues to fuelmany of these activities: during last yearthe zebrafish genome was a priority,but there was an increasing emphasison re-sequencing in humans, miceand pathogens to document variationand identify disease-causing alleles.In the past year the Sanger Institute hasidentified genes that play a role indiabetes and lung cancer (see pages12, 22), while the genome of MRSA(methicillin-resistant Staphylococcusaureus) was decoded. The SangerInstitute plays a leading role in identifyingvariation in the major histocompatibilitycomplex – a key part of the immunesystem which is also involved inautoimmune diseases such as arthritisand type 1 diabetes.Teams from the Sanger Institute havebeen funded by the US National Institutesof Health to contribute to the ENCODE(Encyclopedia of DNA Elements) project,a consortium that aims to put in place thebest technologies to map all functionalelements of the genome. In its initial pilotphase, 1 per cent of the human genomeis being evaluated.The Sanger Institute now has establishedmajor activities in mouse genetics andthis year announced the developmentof SITGR and MICER, two resources formouse functional genomics. These freelyavailable resources are dramaticallyaccelerating the process of discoveringgene function in mice in laboratoriesacross the globe.Wellcome Trust Conference CentreThe Conference Centre continuedto expand its activities, hosting some200 meetings and more than 7500delegates. Highlights of the year includedfive large Wellcome Trust Conferences –Functional Genomics, Days of MolecularMedicine, Genomes 2004, FunctionalGenomics of Host–PathogenInteractions, and Genome Informatics.The latter two events were held jointlywith Cold Spring Harbor Laboratory.International collaboration was alsoa feature of Days of Molecular Medicine(coorganised with the Universityof California San Diego and NatureMedicine) and Genomes 2004 (withThe Institute for Genomic Researchand Institut Pasteur).These events have been well attendedand well received, and more will beorganised for 2004/05 and beyond.Wellcome Trust Advanced CoursesThe Wellcome Trust Advanced Coursesprogramme provides postdoctoralresearchers with hands-on trainingin emerging research techniques.The courses, which are attended byresearchers from all over the world,are held in dedicated laboratories inthe Wellcome Trust Sanger Institute.During the year four Advanced Courseswere held – Genotype to Protein, DNAMicroarrays, Functional Genomics andHuman Genome Analysis. In addition fourbioinformatics Open Door Workshopswere held, giving participants hands-onexperience of working with human andpathogen genome sequences.The Advanced Courses programmewas positively reviewed in 2003,and new courses will be added from2004/05 onwards in key areas.South Field ProjectThe South Field Project, the £95 milliondevelopment of the Genome Campus,remained on schedule to be completedin 2005.The 13 000 square metre developmentwill provide additional researchlaboratories and data-handlingfacilities for the Sanger Institute andimproved ancillary facilities for allGenome Campus staff. The laboratorieswill provide additional space for genomicand molecular biology research, while thedata centre will provide a substantialincrease in the computing power of theSanger Institute, making it one of themost advanced in Europe. The ancillarybuilding houses a new lecture room,restaurant facilities and sports hall andgymnasium. Completion and handover ofthe project is scheduled for spring 2005.

PUBLIC ENGAGEMENT48PUBLIC ENGAGEMENTThe Wellcome Trust’s Public Engagement activities aim to raise awarenessand understanding of biomedical science, its social and ethical implicationsand its historical context.GrantsA total of 41 Society Awards wereawarded under the £3 million EngagingScience grants programme. These largeawards of £50 000 or more supportpublic engagement projects in designatedareas – in 2003/04, ‘broadening access’,‘young people’s education’ and ‘Sciart’.Society Awards under the ‘broadeningaccess’ theme included an award toDr Guto Roberts to introduce biomedicalscience to the National Eisteddfod ofWales, the most important annual culturalfestival of Wales, and one to Dr CarolynStephens at the London School ofHygiene and Tropical Medicine, to seewhether children’s participation inepidemiological research can stimulatean interest in medical science.Ten Research and Development Awardsof up to £15 000 were awarded underthe Sciart theme, as were four ProductionAwards of around £100 000: The FluentHeart, an original music and dance workinspired by the cardiovascular system,created by composer Sir John Tavener,heart imaging specialist Dr Philip Kilnerand choreographer Wayne McGregor;Projected Worlds, an exhibition andevents season at Camden Arts Centreexploring how scientific interventiontransforms our surroundings; How ToLive, a live performance by Bobby Baker,inspired by her experience of dialecticalbehavioural therapy and created withpsychologist Professor Richard Hallam;and Tomorrow Belongs to Me, a seriesof filmed interviews with scientific andmedical professionals researchinginherited genetic disorders, by artistJacqueline Donachie and geneticistDr Darren Monckton.A notable award under the YoungPeople’s theme was for a project at theUniversity of Bristol, which will createyoung people’s Research EthicsCommittees. School students willconsider real grant applications andfeed back comments to the actualpanels considering the applications.A total of 31 People Awards – a fastresponsemechanism to support smallerprojects – were also funded under theEngaging Science programme.In 2003, 27 awards were made throughthe Pulse initiative, which encouragedyouth theatre and dance companies todevelop new performance arts projectsto engage young people with science.The projects embraced a huge spectrumof themes, including the bioscienceof light, neuroscience, cloning, eugenics,ageing and vaccination programmes.This year saw many performancesbased on projects funded through Pulse.In addition, a two-day conferenceat the University of Manchester (25–26June 2004) featured performances andenabled participants to share thoughtsabout their experiences. The initiativehas been so successful that a secondcompetition is planned for 2005.Grants worth £2.5 million were madeby the Wellcome Trust through the£33 million Rediscover initiative.This partnership with the MillenniumCommission and the Wolfson Foundationprovided funds for science centres andmuseums to redevelop their exhibits.Recipients of Trust funds included theCentre for Life in Newcastle upon Tyne,W5 at Odyssey, Belfast, Sensation inDundee and the Eden Project in Cornwall(see page 32).Public participationIn September 2004 the Wellcome Trustand BBC Science launched the secondImagine photographic competition toencourage school groups, young peopleand adults to explore ‘how is sciencechanging us?’The Wellcome Trust organised a seriesof online debates and public eventswith Spiked, an online publisher anddiscussion forum (www.spikedonline.com).The opening debate in theseries, ‘Fearing the Unknown: Are wetoo risk averse?’ questioned whethersociety was excessively preoccupiedwith exaggerated risks. The seconddebate, ‘Human Body Parts’, focusedon issues around the Human Tissue Bill,including consent and the use of humantissue and organs in research. Debateswere also organised with the Instituteof Contemporary Arts. The firstdebate looked at privacy and questionsof how personal biomedical dataare used; the second at the pathwayfrom research to the media.ExhibitionsPain: Passion, compassion, sensibilityran from 13 February to 20 June 2004at the Medicine in Context Gallery at theScience Museum (see page 30). Toaccompany the exhibition, a public event,The Heartache of St Valentine's Day, washeld at the Dana Centre on 11 February2004, while a series of films and debatesabout pain were organised at the Instituteof Contemporary Arts (ICA) in London.An innovative multimedia CD-ROMcatalogue was produced for theexhibition, featuring a gallery of worksfrom the exhibition, audio and video clips,and specially commissioned essays. TheCD-ROM catalogue was shortlisted forthe prestigious 2004 AXA Art ExhibitionCatalogue Award, run by the ArtNewspaper and specialist insurer AXA Art.Woodland ecology.

PUBLIC ENGAGEMENT49The Wellcome Trust Gallery at the BritishMuseum, funded by a £5.4 million grantto the British Museum, opened on3 November 2003 with Living and Dying(see page 31).Pharmakon ran from 17 October 2003to 6 February 2004 at the TwoTen Galleryon Euston Road. The exhibition featuredworks from the US artist Beverly Fishman.Wonderful: Visions of the near future,a major collaborative science and artventure exploring the languages andassumptions of art and science and whathappens when these research interestsfuse, opened at the Arnolfini Gallery inBristol in February 2004. Supported bythe Wellcome Trust and other partners,Wonderful comprises a national touringexhibition, new commissions, live work,an education CD-ROM, conference,publication and interpretative film.EducationConstruction work began on the newNational Science Learning Centreat the University of York, part of the£51 million national network of ScienceLearning Centres being funded by theWellcome Trust and the Departmentfor Education and Skills. The nationalcentre, which is due to open in autumn2005, will be run by the White RoseConsortium. The national network aimsto provide enhanced professionaldevelopment opportunities for scienceteachers and technicians.Life Study, a research report describingthe views and attitudes of a rangeof stakeholders and interested partiestowards A-level biology, was publishedin October 2003. The research wascommissioned by the Wellcome Trustand carried out by the Centre forEducation and Industry at the Universityof Warwick.Two editions of LabNotes: New biologyand society – a publication providingteachers with up-to-date informationon research findings in biomedicine andtheir wider social implications – werepublished during the year. Ageingcovered the science and socialimplications of increased longevity, whileDying for change: Infectious diseasein the developing world examinedthe reasons underlying the huge impactof infectious disease in resourcepoorcountries.Wellcome LibrarySignificant progress was made on thecataloguing of the Wellcome FoundationLtd archive (which was transferred to theWellcome Library from GlaxoSmithKlinein 2001). The cataloguing project will helpilluminate both the early developmentof the Wellcome pharmaceuticalcompany and the wider history of thepharmaceutical industry in the UK.Public outreach, particularly withschools and young people, was a featureof the Wellcome Library’s year. Fourteenstudents from South Camden CommunitySchool, all refugees, embarked on theRemedies and Recipes project. Aftervisiting the Wellcome Library to examinea range of recipe books they compiledtheir own books of home cures fromboth the UK and their home countries.Two GCSE Medicine Through TimeINSET days were run by the WellcomeLibrary in partnership with the SchoolsHistory Project (www.tasc.ac.uk/shp) withthe aim of improving teachers’ knowledgeand increasing their confidence inteaching the history of medicine. Thefirst, held in January 2004, examinedwhy Victorian industrial towns were sounhealthy; the second, held in June 2004,explored changes in medicine, surgeryand our understanding of the humanbody over this period.The Wellcome Library ran a programmeof 40-minute video-conference sessionsfor schools. Topics included ‘What’s theDifference?’, looking at medical advancesin the 19th and 20th centuries, and ‘WhatWas it Like?’, exploring Tudor andVictorian healthcare. During the sessionschildren could see unique items fromthe Wellcome Library collections (suchas Louis Pasteur’s notebooks from histime as a student in Paris) via a video link.They then had the opportunity to askquestions about the material and thesubject. This enabled them to get firsthandexperience of historically significantobjects without needing to make aspecial trip.The Wellcome Trust contributed£750 000 to a project promoting openaccess to published scientific papers.Run by the Wellcome Library, the JointInformation Systems Committee andthe US National Library of Medicine,the new project will digitise the full textof every issue of a number of importantmedical journals.PublicationsTalking Heads: Cognitive behaviouraltherapy comes of age, the latestWellcome News Supplement, waspublished in June 2004. It featuredarticles exploring the latest thinkingon cognitive behavioural therapy –and how it is being applied to a widerange of disorders, including depression,social phobia, post-traumatic stressdisorder, schizophrenia and borderlinepersonality disorder.An evaluation of The Human Genomemicrosite – which provides keyinformation about the human genome –indicated that the site is a valuable andwidely used resource; it attractedaround 280 000 visitors in the year.A microsite was also developed toaccompany the Pain exhibition,providing articles on the science,medicine, culture and history of pain.An Advocacy and Training InteractiveGuide was produced in 2004 for theSchistosomiasis Control Initiative (SCI).The CD-ROM was produced incollaboration with the SCI at ImperialCollege, London, which is funded bythe Bill and Melinda Gates Foundation.The CD-ROM delivers programmeorientedadvocacy messages andtraining materials to those responsiblefor implementing the programme.A French translation of a LymphaticFilariasis CD-ROM was published inAugust 2004. In the Topics in InternationalHealth series of CD-ROMs, a revisededition of HIV/AIDS was launchedin November 2003.

FUNDING COMMITTEES50FUNDINGCOMMITTEESAnimal Healthin the DevelopingWorld CommitteeProfessor H R P Miller(Chair) University of EdinburghProfessor R H Gilman(Vice-Chair) John HopkinsUniversity, USAProfessor M BobrowGovernor, Wellcome TrustProfessor C R W EdwardsGovernor, Wellcome TrustProfessor P A ConradUniversity of California-Davis, USAProfessor M C M De JongWageningen University, The NetherlandsDr C HeffernanUniversity of ReadingDr M JeggoCSIRO Livestock Industries, AustraliaDr R KockOrganisation of AfricanUnity/Inter African Bureaufor Animal Resources, KenyaProfessor G PalmerWashington State University, USADr C PeacockFARM-Africa, LondonProfessor D U PfeifferRoyal Veterinary College, HatfieldDr M J WittyPfizer UK, SandwichBasic ScienceInterest GroupProfessor J N P Rawlins(Chair) University of OxfordProfessor A P BirdGovernor, Wellcome TrustProfessor Dame Jean ThomasGovernor, Wellcome TrustProfessor G Banting(Chair of Research CareerDevelopment Fellowship Committee)University of BristolProfessor P Brophy*University of EdinburghProfessor T J ElliottUniversity of SouthamptonProfessor D B GoldsteinUniversity College LondonProfessor P InghamUniversity of SheffieldDr J Langhorne(to April 2004) National Instituteof Medical Research, LondonProfessor A MayesUniversity of LiverpoolProfessor L H PearlInstitute of Cancer Research, LondonProfessor D F SmithImperial College of Science,Technology and Medicine, LondonProfessor R C TrembathUniversity of LeicesterProfessor B TurnerUniversity of Birmingham Medical SchoolProfessor M J WhitakerUniversity of Newcastle upon TyneProfessor J G WilliamsUniversity of Dundee* Member for the PhD Advisory Board onlyBioarchaeology PanelProfessor M K Jones(Chair) University of CambridgeProfessor D J Ortner(Vice-Chair) Smithsonian NationalMuseum of Natural History, USAProfessor J O ThomasGovernor, Wellcome TrustProfessor L C AielloUniversity College LondonDr D G BradleyTrinity College Dublin, Republic of IrelandProfessor J E BuikstraUniversity of New Mexico, USADr P HalsteadUniversity of SheffieldProfessor M StonekingMax Planck Institute for EvolutionaryAnthropology, GermanyBiomedical Ethics PanelMr A Tomei(Chair) Nuffield Foundation, LondonMr E Walker-ArnottGovernor, Wellcome TrustDr C BartonPapworth Hospital, CambridgeProfessor A V CampbellUniversity of BristolDr D ColesEuropean Commission, BrusselsProfessor N L G EastmanSt George’s Hospital MedicalSchool, LondonProfessor P KaufertUniversity of Manitoba, CanadaProfessor S McLeanUniversity of GlasgowProfessor S MendusUniversity of YorkProfessor N NevinQueen’s University of BelfastProfessor M ReissInstitute of Education, LondonProfessor M RichardsUniversity of CambridgeProfessor S YearleyUniversity of YorkClinical Interest GroupProfessor R E Phillips(Chair) University of OxfordProfessor M BobrowGovernor, Wellcome TrustProfessor J J B JackGovernor, Wellcome TrustProfessor M R Bennett(from January 2004) Universityof CambridgeProfessor C Black(to January 2004) Royal Free HospitalSchool of Medicine, LondonProfessor T J Elliott*University of SouthamptonProfessor J Franklyn(from January 2004) Universityof BirminghamProfessor I GriffithsUniversity of GlasgowProfessor C HaslettUniversity of EdinburghProfessor D KelleherTrinity College Dublin, IrelandProfessor P F LiddleUniversity of NottinghamProfessor P Openshaw(to January 2004) Imperial CollegeSchool of Medicine, LondonProfessor M J Owen(to October 2003) University of WalesCollege of Medicine, CardiffProfessor L ReganImperial College Schoolof Medicine, LondonProfessor A J Silman(from January 2004) Universityof ManchesterProfessor P M Stewart(to January 2004) Universityof BirminghamProfessor R C TrembathUniversity of LeicesterProfessor D M Turnbull(from January 2004) Universityof NewcastleProfessor H Watkins(to October 2003) University of OxfordProfessor A P WeetmanUniversity of SheffieldProfessor M K B Whyte(to January 2004) Royal HallamshireHospital, Sheffield* Senior fellowships onlyFunctional GenomicsDevelopment InitiativeBiomedical Resources PanelProfessor P J Donnelly(Chair) University of OxfordProfessor Dame Jean ThomasGovernor, Wellcome TrustDr D R ApweilerEuropean BioinfomaticsInstitute, HinxtonProfessor M S BaileyUniversity of OxfordProfessor N J CraddockUniversity of Wales Collegeof Medicine, CardiffProfessor N J DimmockUniversity of Warwick, CoventryProfessor M A J FergusonUniversity of DundeeProfessor D B GoldsteinUniversity College LondonProfessor K GullUniversity of OxfordProfessor M C HolleyUniversity of SheffieldProfessor C G P MathewKing’s College LondonProfessor C S PeckhamInstitute of Child Health, LondonProfessor D J PorteousWestern General Hospital,University of EdinburghDr L RechaussatINSERM, FranceDr D ShepherdUniversity of SouthamptonProfessor B G SprattImperial College Schoolof Medicine, LondonFunctional GenomicsDevelopment PanelDr R G Hill(Chair) Merck Sharp & DohmeUK, HarlowProfessor Sir Michael RutterGovernor, Wellcome TrustDr L BeeleyPfizer Central Research, SandwichDr R BrentUniversity of California, USAProfessor L R CardonUniversity of OxfordProfessor B CharlesworthUniversity of EdinburghProfessor J DarlingtonImperial College of Science,Technology and Medicine, LondonDr P GrindrodNumbercraft Ltd, OxfordDr P JeffreysUniversity of OxfordProfessor K LindpainterBasel Institute of Immunology,SwitzerlandHealth Consequences ofPopulation Change PanelProfessor W Graham(Chair) University of AberdeenProfessor C R W EdwardsGovernor, Wellcome TrustProfessor N ChaturvediImperial College Schoolof Medicine, LondonProfessor J H DarbyshireMRC Clinical Trials Unit, LondonProfessor S B J EbrahimUniversity of BristolDr A C EzehAfrican Population PolicyResearch Centre, KenyaProfessor J FalkinghamSouthampton UniversityDr A FontanetInstitut PasteurProfessor A GlasierEdinburgh Healthcare NHS TrustDr S HarperOxford Institute of Ageing

FUNDING COMMITTEES51The Wellcome Trust is committed to the principles of peer review. We are indebtedto 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 providecomments on grant applications. The following pages list the membershipof our advisory committees during 2003/04.Professor K HillJohns Hopkins University, USADr S JejeebhoyThe Population Council, IndiaProfessor R MartorellEmory University, USAProfessor R SauerbornHeidelberg University, GermanyProfessor G ThornicroftInstitute of Psychiatry, LondonHistory of Medicine PanelProfessor M A Jackson(Chair) University of ExeterProfessor J J B JackGovernor, Wellcome TrustDr J AndrewsOxford Brookes UniversityProfessor V BerridgeLondon School of Hygieneand Tropical MedicineProfessor M A CrowtherUniversity of GlasgowDr M HarrisonUniversity of OxfordMr J N P B HordenUniversity of LondonDr T TanseyUniversity College LondonProfessor T TreasureGuy’s Hospital, LondonProfessor P van der EijkUniversity of NewcastleInfection andImmunity PanelProfessor N A R Gow(Chair) University of AberdeenProfessor A C Hayday(Vice-Chair) Guys, Kings andSt Thomas’ Schools of Medicineand Dentistry, LondonProfessor A P BirdGovernor, Wellcome TrustProfessor M J AlldayImperial College Schoolof Medicine, LondonDr B ArnoldGerman Cancer ResearchCentre, HeidelbergProfessor G S BesraUniversity of BirminghamProfessor I N ClarkeUniversity of SouthamptonProfessor A DesseinUniversité de la Méditerranée, FranceProfessor N J KleinInstitute of Child Health, LondonDr J P LatgeInstitut Pasteur, FranceDr A McLeanUniversity of OxfordProfessor H R P MillerUniversity of EdinburghProfessor K H G MillsTrinity College Dublin, IrelandProfessor P MorganUniversity of Wales College of MedicineProfessor J H NaismithUniversity of St AndrewsProfessor J R SaundersUniversity of LiverpoolProfessor C M R TurnerUniversity of GlasgowDr A P WatersLeiden University, The NetherlandsInternationalBiomedical PanelProfessor A Tait(Chair) University of GlasgowProfessor C R W EdwardsGovernor, Wellcome TrustProfessor V CrunelliCardiff UniversityProfessor G E GriffinSt George’s Hospital MedicalSchool, LondonProfessor B H HirstUniversity of Newcastle upon TyneProfessor V HorejsiAcademy of Sciencesof the Czech RepublicProfessor M J HumphriesUniversity of ManchesterProfessor O A KrishtalBogomoletz Instituteof Physiology, UkraineProfessor R M MaizelsUniversity of EdinburghProfessor M McCarthyOxford Centre for Diabetes, Endocrinoloyand MetabolismProfessor W RichardsonUniversity College LondonDr H le Breton SkaerUniversity of CambridgeProfessor A SpisniUniversity of Parma, ItalyProfessor M YanivInstitut Pasteur, FranceLibrary Advisory CommitteeMr P K Fox(Chair) Cambridge University LibraryMr E Walker-ArnottGovernor, Wellcome TrustDr P AyrisUniversity College London LibraryDr C FieldBritish Library, LondonMr N KingsleyGloucestershire County Records OfficeMs J WilkinsonUniversity of Leeds LibraryMolecular and Cell PanelProfessor M J P Arthur(Chair) University of SouthamptonProfessor M Tuite(Vice-Chair) University of Kent,CanterburyProfessor J J B Jack(to February 2004) Governor,Wellcome TrustDr V AllanUniversity of ManchesterProfessor P R AvnerInstitut Pasteur, FranceProfessor P CullenUniversity of BristolProfessor R A DixonJohn Innes Centre, NorwichProfessor P S FreemontImperial College of Science,Technology and Medicine, LondonDr A J GreenfieldMedical Research Council MammalianGenetics Unit, HarwellProfessor D G HardieUniversity of DundeeProfessor C L MummeryNetherlands Institute forDevelopmental Biology, UtrechtProfessor S NeidleSchool of Pharmacy,University of LondonProfessor M S PoveyUniversity College LondonProfessor A J ReesUniversity of AberdeenProfessor M S RobinsonUniversity of CambridgeDr J-P VincentNational Institute for MedicalResearch, LondonProfessor J P WalthoUniversity of SheffieldProfessor D I WilsonUniversity of SouthamptonNeurosciences PanelProfessor D A S Compston(Chair) University of CambridgeProfessor J Rothwell(Vice-Chair) University College LondonProfessor M BobrowGovernor, Wellcome TrustDr C D BenhamGlaxoSmithKline, HarlowProfessor A BjorklundLund University, SwedenProfessor V J BrownUniversity of St AndrewsProfessor N J BuckleyUniversity of LeedsProfessor N J CraddockUniversity of Wales Collegeof Medicine, CardiffProfessor I D ForsytheUniversity of LeicesterProfessor G G R GreenUniversity of YorkProfessor R C HarringtonUniversity of ManchesterProfessor J M HenleyUniversity of BristolProfessor P B JonesUniversity of CambridgeProfessor E JoyceImperial College of Science,Technology and Medicine, LondonProfessor E A KuipersInstitute of Psychiatry, LondonProfessor A P MonacoUniversity of OxfordProfessor V H PerryUniversity of SouthamptonProfessor D J PriceUniversity of EdinburghProfessor G P RichardsonUniversity of SussexProfessor M J RiddochUniversity of BirminghamProfessor B RobertsonUniversity of StrathclydeProfessor P J ShawUniversity of SheffieldProfessor A W StittQueen’s University of BelfastPhysiology andPharmacology PanelProfessor P Vallance(Chair) University College LondonProfessor S H Ralston(Vice-Chair) University of AberdeenProfessor Dame Jean ThomasGovernor, Wellcome TrustProfessor D BeechUniversity of LeedsProfessor R DimalineUniversity of LiverpoolProfessor S DimmelerUniversity of Frankfurt, GermanyProfessor D J FitzgeraldRoyal College of Surgeons in IrelandDr A GalioneUniversity of OxfordProfessor A T HattersleyUniversity of ExeterProfessor D HeinegardLund University, SwedenProfessor I T HuhtaniemiImperial College Schoolof Medicine, LondonProfessor K-T KhawUniversity of CambridgeProfessor M S MarberKing’s College LondonProfessor G MilliganUniversity of GlasgowProfessor I C A F RobinsonNational Institute for MedicalResearch, LondonProfessor G WalzUniversity Hospital Freiburg, GermanyProfessor M K B WhyteUniversity of Sheffield

FUNDING COMMITTEES52FUNDINGCOMMITTEESPublic EngagementStrategic Advisory GroupMs C Matterson(Chair) Wellcome TrustMr E Walker-ArnottGovernor, Wellcome TrustDr D BellAssociation for Science EducationMr P DoddInstitute of Contemporary Art, LondonMs C FoxInstitute of Ideas, LondonProfessor A IrwinBrunel UniversityProfessor M JacksonUniversity of ExeterDr R PersaudMaudsley Hospital, LondonProfessor K SykesUniversity of BristolMr A TomeiThe Nuffield FoundationDr J TurneyPenguin PressDr G WattsBBC Radio 4Dr S WebsterImperial College of Science,Technology and Medicine, LondonProfessor Lord Robert WinstonImperial College of Science, Technologyand Medicine, LondonRediscover Advisory BoardDr P-E Persson(Chair) Heureka Science Centre, FinlandDr B AprisonMuseum of Science and Industry,Chicago, USADr A BandelliInternational ConsultantMr D BromfieldBBC, LondonMr C CableThe Imaginarium, Anchorage, USADr G DelacoteThe Exploratorium, San Francisco, USAMr T R DevittUniversity of Wisconsin-Madison, USADr S DuensingUniversity of California, USAProfessor G DurantAustralian National Science andTechnology Centre, Questacon, AustraliaProfessor R DuschlRutgers University, USAMs R EdwardsQualifications and CurriculumAuthority, LondonDr A FriedmanNew York Hall of Science, USAMr D SchatzPacific Science Center, Seattle, USAMs G ThomasMiami Museum of Scienceand Planetarium, USARediscover JointFunders’ CommitteeProfessor M BobrowGovernor, Wellcome TrustMs C MattersonWellcome TrustMr E Walker-ArnottGovernor, Wellcome TrustDr H CouperThe Millennium CommissionMr M D’AnconaThe Millennium CommissionMs J DonovanThe Millennium CommissionMr M O’ConnorThe Millennium CommissionSir Eric AshTrustee, The Wolfson FoundationDr V HarrisonThe Wolfson FoundationLord Randolph QuirkTrustee, The Wolfson FoundationSir Derek RobertsTrustee, The Wolfson FoundationResearch Resources inMedical History CommitteeMr P K Fox(Chair) Cambridge University LibraryMr E Walker-ArnottGovernor, Wellcome TrustMs H FordeLovells, LondonProfessor M A JacksonUniversity of ExeterProfessor H KingUniversity of ReadingMr N KingsleyGloucestershire County Records OfficeD PearsonWellcome Library for the Historyand Understanding of MedicineJ SheppardWellcome Library for the Historyand Understanding of MedicineDr A SummersBritish Library, LondonSociety Awards Panel(Broadening Access andYoung People’s Education)Dr D Bell(Chair) Association for Science EducationMs S AddinellCity and Islington College SixthForm Centre, LondonProfessor P AggletonInstitute of Education, LondonMs K HamptonGlasgow Caledonian UniversityDr R JarmanQueen’s University of BelfastDr J LewisJoseph Rowntree FoundationProfessor A McFarlaneUniversity of BristolDr A MooreEuropean MolecularBiology OrganisationSociety Awards Panel(Sciart production awards)Dr M Greenhough(Chair) University of CardiffMs M EllisFilm LondonMs M FlemingArtist and WriterDr L GoodmanCentral St Martins Collegeof Art and Design, LondonMs K R HuffmanCornerhouse, ManchesterProfessor B HurwitzKing’s College LondonMs A MorrisSoho Theatre, LondonDr J TurneyPenguin PressTropical MedicineInterest GroupProfessor D G Colley(Chair) University of Georgia, USAProfessor Z A Bhutta(Vice-Chair) Aga KhanUniversity, PakistanProfessor C R W EdwardsGovernor, Wellcome TrustDr J S FriedlandImperial College Schoolof Medicine, LondonProfessor R H GilmanJohn Hopkins University, USA ProfessorK P KlugmanEmory University, USAProfessor D P KwiatkowskiUniversity of OxfordProfessor G LewisUniversity of BristolProfessor N G SaraviaCentro Internacional de Entrenamiento eInvestigaciones Medicas, ColombiaProfessor M TannerSwiss Tropical Institute, SwitzerlandProfessor J WhitworthLondon School of Hygiene and TropicalMedicineProfessor M E J WoolhouseUniversity of Edinburgh

AcknowledgementsWe are grateful to everyone whoagreed to be reviewed in this issue,everyone who supplied picturesor gave us permission for theirpictures to be used, and the manymembers of Wellcome Trust staffwho helped produce this volume.EditorIan JonesProject ManagerLucy MooreWritersPenny BaileyDr Lisa MeltonDr Giles NewtonDesign ManagerAlan StevensDesignJoanna PollardPicture researchAnne Marie MargetsonPrinted byEmpress LithoComments on The Wellcome TrustAnnual Review are welcomed andshould be sent to:Ian Jones, PublisherPublishing GroupThe Wellcome TrustGibbs Building215 Euston RoadLondon NW1 2BE UKF +44 (0)20 7611 8270E publishing@wellcome.ac.ukThe Wellcome Trust Annual Reviewis distributed via a mailing list heldby the Wellcome Trust. If you wouldlike to be added to this list, or if youhave a colleague who would liketo receive The Wellcome TrustAnnual Review, please contact:The Wellcome TrustFREEPOSTANG 6754Ely CB7 4YE, UKT +44 (0)20 7611 8651F +44 (0)20 7611 8242E publishing@wellcome.ac.ukISBN 1 84129 055 6The Wellcome Trust is a registeredcharity, no. 210183. Its sole Trusteeis The Wellcome Trust Limited, acompany registered in England,no. 2711000, whose registeredoffice is 215 Euston Road, LondonNW1 2BE.First published by the WellcomeTrust, 2005.© The Trustee of the WellcomeTrust, London.All rights reserved. No part of thispublication may be reproduced,stored in a retrieval system, ortransmitted by any meanselectronic, mechanical,photocopying, recording orotherwise without the priorpermission of the Wellcome Trust.The Wellcome TrustGibbs Building215 Euston RoadLondon NW1 2BE, UKT +44 (0)20 7611 8888F +44 (0)20 7611 8545E (general information)contact@wellcome.ac.ukwww.wellcome.ac.ukAll images are courtesy of theWellcome Library, except as follows:contents and p. 1 (L–R) Escherichiacoli (D Gregory, D Marshall), Africanchild (C Penn), Human embryo (YNikas), twins (D Teplica); p. 2 MarkWalport (M Chew); pp. 4–5 (L–R)Zebrafish embryo neuron (S Wilson);pp. 6–7 chromosome 1 (T JMcMaster); pp. 8–9 (L–R) serotonintransporter protein (M Johnson,L Sharp), MRI scanning (SPL); pp.10–11 (L–R) child with leishmaniasis(© R Killick-Kendrick, courtesyof International Health ImageCollection), sand fly (© R Lane,courtesy of International HealthImage Collection), African peoplein the rain (Panos Pictures), malariain red blood cells (SPL), Soay sheep(Rex Features); pp. 16–17 womanwith Huntington’s (SPL), paper-clips,archivist (Lothian Health ServiceArchive); p. 18 aerial view ofchemistry building, Oxford (KarlHarrison); pp. 20–21 gatheringwood in Kenya (C Penn); pp. 22–23melanoma cells (P J Smith,R Errington), mosquito (© LiverpoolSchool of Tropical Medicine,by A Stich, courtesy of InternationalHealth Image Collection), chickens(Rex Features), South-east Asianscene (M Chew); pp. 24–25 (L–R)Artemisia annua (SPL), Kevin Marsh,Kenyan children (C Penn); pp.26–27 (L–R) Edinburgh ClinicalResearch Facility (Universityof Edinburgh), Mycobacteriumtuberculosis (SPL), developing ‘livingbandages’ (CellTran Ltd);pp. 32–33 Eden Project (SPL), lifemodel (L Russell/ Peninsula MedicalSchool) Hogarth painting (FoundlingMuseum); pp. 34–35 Gibbs Building(Nick Kane), Norovirus (D Gregory, DMarshall), ganglion (K Nobes,M Shipman);p. 37 synchrotron (JacobsGIBBLtd/Crispin Wride ArchitecturalDesign Studio); p. 38 adenovirus(D Gregory, D Marshall); p. 40 redblood cells (Royal Free MedicalSchool); p. 42 neurons (Universityof Wales College of Medicine);p. 44 Kenyan boys (C Penn).Cover: Pyramidal neurons forminga network in the brain. J ClarkeDC-3236.p/15k/01-2005/JP

The Wellcome Trust is an independentresearch-funding charity, establishedunder the will of Sir Henry Wellcomein 1936. It is funded from a privateendowment, which is managed withlong-term stability and growth in mind.Its mission is to foster and promoteresearch with the aim of improvinghuman and animal health. Its workcovers four areas:Knowledge – improving ourunderstanding of human and animalbiology in health and disease,and of the past and present roleof medicine in society.Resources – providing exceptionalresearchers with the infrastructuraland career support they need to fulfiltheir potential.Translation – ensuring maximumhealth benefits are gained frombiomedical research.Public engagement – raising awarenessof the medical, ethical and socialimplications of biomedical science.www.wellcome.ac.uk