Pioneering research from the University of Cambridge

Research

Horizons

www.cam.ac.uk/research

Issue 25

Spotlight

Stem cells

Feature

Trust me, I’m a banker

Feature

Visions of plague

Contents

4 – 5 Researchnews

6 – 7 Trustme,I’mabanker8 – 9 Andnow,thevolcanoforecast

10 – 11 Visionsofplague 12 – 13 Wherethere’smuckthere’saluminium(ifnotbrass) 14 – 15 Fancypantsandthefashionpolice 16 – 17 Lifelonglearningandtheplasticbrain

18 – 19 Treasuredpossessions

20 – 21 The‘ultimate’stemcell 22 – 23 Orchestralmanoeuvres 24 – 25 Themanwithathousandbrains 26 – 27 Stemcellphysical 28 – 29 Testingtimeforstemcells 30 – 31 TakingashotatParkinson’s

News

Features

Things

Spotlight: Stem cells

2 ContentsIssue25,October2014

StemcellsareoneofCambridge’srealsuccessstories.WehavewontwoNobelPrizesinthisarea–SirMartinEvansandSirJohnGurdonwerebothmadelaureatesfortheirdiscoveries.OurWellcomeTrust-MRCCambridgeStemCellInstituteisaworld-leadingresearchcentre,andstemcellresearchhaslongbeenastrategicpriorityforourUniversity. Inthisissue,weexploretheseremarkablecells,whichcanmakeeverytypeoftissueintheembryo,repairthebodythroughoutlifeandrenewthemselvesindefinitely.Now,asresearchersdelvedeeperintotheirbiology,ahostofpotentialusesarecomingtolight,fromsupplyingnewcellstoreplacedamagedtissues,toboostingthebody’sownrepairmechanisms,toprovidingexperimentalmodelsfortestingnewdrugs. FundsarenowbeingraisedforanewbuildingforourexpandingInstitute,scheduledtoopenin2018ontheCambridgeBiomedicalCampus,whereresearchscientists,technologyspecialistsandmedicswillworktogethertomakethemostoftheopportunitiesaffordedbythesebody‘repairkits’. Movingfromtheminitothemassive,Iceland’sBárðarbungavolcanohasrecentlybeenshowingsignsofincreasingunrest.Cambridgescientistshavebeenmonitoringitsactivity,aswellasthatofvolcanoesworldwide,withthehopeofhelpingtounderpinfuturehazardforecasting. Inaratherlessscientificmethodofforecasting,ancientMesopotamiansbelievedthatthegodsinscribedthefutureontheliverofsheep.InourExtremeSleepoverarticle,wehearaboutoneresearcher’stravelstoruralArmeniatoobservewhatliverdivinersmighthaveseen4,000yearsago. Allthisplusarticlesonfashion(atatimewhenitwasafinableoffencetowearSpanishbreeches),thetrustworthinessofbanks,braintraining,visualnarrativesofplague,andtechnologythatcanturntoothpastetubesintoaluminiumandfuelinthreeminutes.Wehopethatyouenjoythisissue.

Professor Lynn GladdenPro-Vice-ChancellorforResearch

32 – 33 Immoralityandinvention

34 – 35 Extremesleepover:DiviningdestinyinruralArmenia

Inside out

EditorDrLouiseWalsh DesignTheDistrict Printers Micropress Contributors CraigBrierley,AlexBuxton,AsiaChoudhry,SarahCollins,FredLewsey,LouiseWalsh T +44(0)1223765443 E research.horizons@admin.cam.ac.ukW cam.ac.uk/research

Welcome

Copyright©2014UniversityofCambridgeandContributorsasidentified.ThecontentofResearch Horizons,withtheexceptionofimagesandillustrations,ismadeavailablefornon-commercialre-useinanotherworkunderthetermsoftheCreativeCommonsAttribution-Non-Commercial-ShareAlikeLicence(http://creativecommons.org/licenses/by-nc-sa/3.0/),subjecttoacknowledgementoftheoriginalauthor/s,thetitleoftheindividualworkandtheUniversityofCambridge.ThisLicencerequiresanynewworkwithanadaptationofcontenttobedistributedandre-licensedunderthesamelicenceterms.Research HorizonsisproducedbytheUniversityofCambridge’sOfficeofExternalAffairsandCommunications.

3 ResearchHorizons

News

01.09.14 Anewstudyshowsthathealthierdietsandreducingfoodwasteareneededtoensurefoodsecurityandavoiddangerousclimatechange.

12.09.14CambridgeUniversityLibraryhasraised£1.1milliontosecureoneofthemostimportantNewTestamentmanuscripts.

News in brief

More information atwww.cam.ac.uk/research

4 News

Green award for ‘unprinting’University of Cambridge spin-out wins award for technology that removes print from paper.

Laser‘unprinters’thatremovetonerfrompaperarealittleclosertocomingtoanofficenearyou. Everyyear,oneofficeemployeecanuseupto10,000sheetsofpaper,mostofwhicharethrownaway.Thisnewtechnologyhasthepotentialtoreducethenumberoftreesusedinthepaperlifecycle,andcouldalsosaveanadditional50–80%incarbonemissionsoverrecycling. Now,Cambridgespin-outcompanyReduse,whichisdevelopingthetechnology,hasbeennamedwinneroftheVentureCompetition,organisedbytheEU’smainclimateinnovationinitiative,Climate-KICUK. The‘Unprinter’wasinventedbyDrDavidLeal,Reduse’sChiefScientist,duringhisPhDresearchwithProfessorJulianAllwoodintheDepartmentofEngineering. “Thisawardismoreproofthatweareontherighttracktosolvingtheincrediblewastethatisbeinggeneratedbyprinting,”saidHidde-JanLemstra,CEOofReduse,whichhasstartedraisingitsfirstroundoffundingtocomplementtheClimate-KICsupportandagrantfromtheTechnologyStrategyBoard.www.reduse.co.uk

Monitoring Bárðarbunga

Cambridge scientists have been at the forefront of monitoring the activity of the Bárðarbunga volcanic eruption in Iceland. Bárðarbungaishuge–itsvolumeofmagmaatthetimeofwritingwasalreadymorethantwicethesizeofthatwhichcausedtheEyjafjallajökulleruptionandashcloudin2010,whichledtothecancellationofmorethan100,000airlineflights. Since2006,researchersledbyProfessorBobWhiteoftheDepartmentofEarthScienceshavebeenmonitoringvolcanismintheregion,fundedbytheNaturalEnvironmentResearchCouncil. Inthelongterm,thedatawillyieldconsiderablenewinsightsintohowmoltenrockmovesundergroundandhowthisrelatestotheriskoferuption:“Analysingthedatacollectedsincetheeruptionstartedprobablyamountstoaround100-person-years’worthofwork,”saidProfessorSimonRedfern,oneoftheresearchers.

But,intheshortterm,theresearchersandPhDstudentshavebeenkeyinthe24/7monitoringoftheprogressofBárðarbunga’svolcanicactivity.WorkingwiththeIcelandicMeteorologicalOffice(IMO)andtheEarthSciencesInstituteoftheUniversityofIceland,theteamhasbeenmeasuringtheactivityofmillionsofcubicmetresofmagmaandtheriftingofahugelengthofdykeasitmovestowardsthenearbyAskjavolcano.TheaviationandcivilhazardwarningsinplaceinIcelanddependheavilyontheIMOtrackingofthisseismicity. “ThemassiveeruptionofAskjain1875ledtothedepopulationofnortheastIcelandasash-fallmadesubsistencefarmingimpossible,”saidWhite.“Thatiswhycontinuedmonitoringissoimportant.”

Follow researchers Tobba Ágústsdóttir @fencingtobba and Simon Redfern @Sim0nRedfern on Twitter for the latest developments

Image Lavafountainsintherecenteruption

Credit:RobGreen

11.08.14 New3Dreconstructionsshowhowsomeoftheearliestanimalsonearthdevelopedandprovidesomeanswersastowhytheybecameextinct.

10.07.14 Undernourishmentduringpregnancycanincreasetheriskofdevelopingobesityandtype2diabetesinchildren,andtheirchildren.

18.06.14 MorethanhalfofEnglishhomesfallshortofmodernspacestandards,callingintoquestionthepremisebehindtheso-calledbedroomtax.

5 ResearchHorizons

Why marvellous isn’t awesome any more‘Marvellous’ has been consigned to the dustbin of vocabulary and replaced by the American ‘awesome’, according to a new study by Cambridge University Press and Lancaster University.‘Marmalade’hasfallenoutoffavour,‘twoweeks’isusedmorefrequentlythan‘fortnight’and‘essentially’hasrisendramatically. ThesearesomeoftheearlyfindingsofastudyusingtheSpokenBritishNationalCorpus2014,averylargecollectionofrecordingsofreal-life,informal,spokeninteractionsbetweenspeakersofBritishEnglishfromacrosstheUnitedKingdom. ResearchersatCambridgeUniversityPressandLancasterUniversity’sFacultyofArtsandSocialScienceshaveembarkedonthefirstlarge-scalestudyindecadestoevaluatehowthelanguageisusedindifferentregions,betweengenders,andacrossagegroupsandsocio-economicstatus. TheresearchersarenowcallingforpeopleallovertheUKtosendMP3filesoftheireveryday,informalconversationstohelpthemdelvedeeperintospokenlanguage. “Weneedtogatherhundreds,ifnotthousands,ofconversationstocreateaspokencorpussowecancontinuetoanalysethewaylanguagehaschangedoverthelast20years,”saidLancaster’sProfessorTonyMcEnery. CambridgeUniversityPressisgreatlyexperiencedatcollectinghugeamountsofdataonhowEnglishisusedandhastheinfrastructureinplacetoundertakesuchalargecompilationproject.LinguistsatLancasterUniversityhavetheexpertisetoensurethattheresourcewillbeasusefulandaccessibleaspossibleforfurtherresearch.

Submit recordings to the research team at corpus@cambridge.org

Ending violenceNew evidence presented at the first Global Violence Reduction Conference, in Cambridge, shows that homicide rates in many countries are falling.

Homicidehashadahigherbodycountthiscenturythanallwarscombined–some8millionpeoplesince2000.Domesticviolencecoststheworld$8trillionannually,andaround30%ofwomenhaveexperiencedit;oneinsevenchildrenontheplanetisthoughttobeavictimofsexualabuse. However,amidthesesoberingfactsthereiscauseforoptimism.NewevidencepresentedbyProfessorManuelEisner,directorofCambridge’sViolenceResearchCentreintheInstituteofCriminology,showsthathomiciderateshavebeendecliningsincethemid-1990sinmanypartsoftheworld–insomecasesdramatically. Thenewfindingsarepartofabodyofresearchintoeffectivepolicingstrategies,rehabilitationmethods,betterchildprotectionservicesandsocietalattitudeshifts–whichhasmanyexpertsagreeing

thatglobalratesofviolencecouldbehalvedbyjust2040iftherightpoliciescanbedefinedandimplemented. NationsasdiverseasEstonia,China,SouthAfrica,PolandandRussiahaveseenaveragerecordedhomicideratesdropby40%ormoreinthecourseofjust15years.Outof88countrieswheretrenddatacouldbefound,67showedadeclineandonly21showedanincreasebetween1995and2010,thenewanalysisofdatafromtheUnitedNationsOfficeonDrugsandCrimehasrevealed. “Examplesofsuccessfulhomicidereductioncanbefoundacrosstheworld.Butifwewanttoachieveaworldwidedeclineinhomicideweneedtolearnfromthesesuccessstoriesandunderstandwhattheydidright,”saidEisner,co-convenerofthefirstGlobalViolenceReductionConference. Eisnerandhisteamwillbeworkingcloselywithresearchersfromeverycontinenttodeveloppolicyrecommendations,andtostrengthentheknowledgebaseandresearchcapacityneededtoaddressviolencemoreeffectivelyinlowandmiddleincomecountries.

n a post- crash economy, the financial industry has taken a severe hammering in the courts

of public approval. Banks have never been trusted less. In a capitalist society, that’s not good news. But now bankers may have some unlikely new saviours: philosophers.

“I’llpayyou,youknow,50,000dollars,100,000dollars…whateveryouwant…I’mamanofmyword.” AUBSinvestmentbankerand‘manofhisword’iscaughttryingtobribeabroker.TakenfromanincriminatingemailuncoveredaftertheLibor-fixingscandal–whentradersillegallymanipulatedLondoninterestrates–thesentenceillustratesaclimatethathasaglobalsectorreeling. Evenbeforenewsofthescandalbroke,PRgiantEdelman’sannualTrustBarometerwasreportingthatpublictrustinbankshadfallenoffacliff,concludingthatbankingisthe“mostdistrustedglobalindustry.” Peopleneedmoney.Oncetheyhaveit,theyneedtoknowit’ssafe.Sopeopleneedtotrustbanks,andbanksneedpeopletotrustthem.Ifthattrustebbs,thesystembecomesdangerouslyunstable.Fortwophilosophers,thecurrentlackoftrustsitslikeatimebombattheheartofglobalcapitalism.

“Oneshouldstartbydistinguishingtrustfromtrustworthiness.Trustisn’talwaysvaluable,sinceitmaybebadlyplaced.Itwouldbefoolishandfoolhardytotrustbankswhentheydon’tmeritit.Trustworthinesscomesfirst,”saidAlexOliver,ProfessorofPhilosophyatCambridge.WithProfessorBoudewijndeBruinfromtheUniversityofGroningen,heisco-leadinga€1million,five-yearprojectonTrustingBanks,fundedbytheDutchResearchCouncil. “WearewaybeyondcheapPRexercises.Ifthepublicaretotrustbanksagain,wemustpromotethekeyinstitutionalvirtuesneededforbankstobetrustworthy.” Themid-1980sderegulationswerebasedontheideathatbankshaveastrong,self-interestedreasontobehavescrupulously.Iftheydonot,sothereasoninggoes,theywillbefoundout,theirreputationswillsufferandtrustwillbelost,leadingtocompetitivedisadvantage.Butthismarket-baseddeterrentmechanismhascomprehensivelyfailed:witnessBernieMadoff’sPonziinvestmentscheme–describedasthelargestfinancialfraudinUShistory–themanipulationofmarkets,moneylaundering,mis-sellingofpaymentprotectioninsuranceandinterestrateswaps,flawedcreditratingsandthe

subprimemortgagecrisis.Wherewillitend? Asthoseatthetopofthesectorcontinuetowalkawayfromfinancialmeltdownwithpersonalfortunesintact,publicangeratperceivedinjusticehasmounted.Whetherornotbanksandtheirstaffdeservethisreputation,inthepost-crasheconomicwintertherearefew,ifany,professionsandinstitutionsasuniversallyreviled. ForOliverandDeBruin,thisposesaveryseriousproblem.Ifcitizensandbusinessesdistrustbanks,theysay,achillingeffectwillspreadaseconomiesslow,unemploymentrisesandcompaniesandcountriesgobust.It’salreadyhappening. “Ifyoutalktobankers,manywillblamethepublicfornottrustingthem,eitherforalackoffinancialunderstanding,orforanunwarrantedcynicismencouragedbyhostileportrayalsinthemedia,”saidDeBruin,“butthisisadefensive‘blametheconsumer’strategy–aformofdenial.Thedeclineinpublictrusttracksadeclineintrustworthinessofthefinancialsector.Trustworthinessneedstoberestoredfirst.Trustwillfollow.” Indevelopingatheoryoftrust-worthinessforbanks,OliverandDeBruinwillnavigatethevariousconflictinginterestsinherentinfinancialrelationships

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Features

“Trust me, I’m a banker”

Left to rightProfessor Alex Oliverado10@cam.ac.ukFacultyofPhilosophyProfessor Boudewijn de BruinUniversityofGroningen

The manipulation of markets, money laundering,

mis-selling of payment protection insurance and

interest rate swaps, flawed credit ratings and the

subprime mortgage crisis. Where will it end?

7 ResearchHorizons

–betweendepositorsandborrowers,betweenbankersandshareholders,andsoon–andwillchartthecomplexkindsofinteractionsneededforsuccessfulandtrustworthyfinancialservices.Tobetrustworthy,onemustbebothableandwillingtoperformtherelevantactions.Thatiswhytheresearchwilladdresskeyquestionsofcompetenceandmotivation,bothofindividualsandoforganisations. OliverandDeBruinareworkingwithateamoftwopostdoctoralresearchersandtwoPhDstudents,aswellasdrawingontheexpertiseofcolleaguesintheirdepartments.Usinginitialresults,theydesigneda‘PhilosophyinBusiness’coursefortheMBAprogrammesatCambridge’sJudgeBusinessSchool,andtheyhaveruntailor-madeworkshopswithbankers,fromtraineesthroughtoboards. Banksaremassivelydiversecorporateagents.Fine-graineddistinctionscanbemadebetweenretailandinvestmentbanking,forexample,whichareeasilyconflatedinthepublicmind.Noteveryonewhoworksforabankisa‘bankster’drivenbya‘greedisgood’mentality,justasnoteveryuniversitystaffmemberisanivorytoweracademic. “Manybankbranchemployeesaretryingtoservecommunities,andaredeeplydisturbedby‘badapple’bankers.Buttheircustomerstendtotarthem

withthesamebroadbrush.It’sagoodquestionwhyroguedoctorsdon’thavethesameeffect.Doctorsalwaystopthetrustpolls,whilebankersarenowinthegutterwithtabloidjournalistsandpoliticians,”saidOliver. Virtues,andhowanorganisationcanembodythem,areacornerstoneoftheproject.Connectingwithcutting-edgeresearchoncorporateentitiesandcorporatedecision-makinginphilosophyandsocialscience,theprojectwillexaminehowinstitutionalstructurescanfosterthevirtuesneededfortrustworthiness,suchasintellectualhonestyandhumility,open-mindedness,curiosityandtruthfulness. “Thesolutioncansometimesbeassimpleasputtingtherightpeopleintherightplace,buttypicallyitisnotthatsimple,”saidDeBruin,“Organisational

changemaywellbeneeded,suchasrotationalpolicies,inwhichemployeesareshiftedaroundtomaintainobjectivityintheirclientrelationships.” OliverandDeBruinarekeentoemphasisethattheirworkisnotasimpleone-waytransferofknowledgefromacademiatothe‘realworld’.“Philosophersandeconomistshaveincreasedourunderstandingof‘virtuemanagement’,buttherearestillmanyopenquestions.Answeringthemrequirescollaborationnotonlywithotherdisciplines,butalsowiththebankingworlditself.Sharingideaswithbankersoftenleadstoreciprocalillumination,whichbenefitsallparties.” Oneoftheproject’soutcomeswillbea‘financialcitizenship’initiative.Ratherthantrytoteachpeopleaboutcomplexfinancialproducts,thiswillfocusonempoweringcitizensthroughidentifyingvirtuesthathelpthemcopewithconflictingfinancialinformation.Aweb-basedinteractivemodulewillenableprospectiveclientstotestwhethertheyarecriticalandsober-mindedenoughtoseethroughthemarketingtricksusedtosellfinancialproducts. “Whereitoncestoodforcautiousfinancialadviceandafirmhandshake,theword‘banker’hasbecomeslangfora‘greedmerchant’whogamblesotherpeople’smoneyinriggedgamessotheyalonegetrich,”saidOliver.“‘Trustme,I’mabanker!’isnowawell-wornjoke.Wewanttoinvestigatehowitcanbemadegoodadvice.”

cientists are using volcanic gases to understand how volcanoes work, and as the basis of a

hazard-warning forecast system.

WhentheUSA’sMountStHelenseruptedin1980,justtwomonthsaftershowingsignsofreawakening,itsblastwasequivalentto1,600timestheenergyoftheatomicbombdroppedonHiroshima.ItremainsthemosteconomicallydestructivevolcaniceventintheUSA’shistory. WhenEyjafjallajӧkulleruptedin2010inIceland,theashclouditemittedstrandedaroundhalfoftheworld’sairtraffic,withanestimatedglobaleconomiccostofUS$5billion.Nowmagmaisonthemoveagain,thistimeunderandbeyondIceland’sBárðarbungavolcano.Atthetimeofwriting,thevolumeofmagmawasalreadymorethantwicethesizeofEyjafjallajökull’s,andateamofscientists(seepageof4thisissue)hasbeencontinuouslymonitoringitsprogress. Volcanoesaretheventsthroughwhichourplanetexhales.Yet,notallvolcanoesexperiencespectacularreleasesofenergy,oreveneruptatall:ofthe500orsovolcanoesthatarecurrentlyactiveworldwide,20mightbeexpectedtoeruptinanyoneyear.But,whenvolcanoes

doerupt,theycancausealmosttotaldestructionintheimmediatevicinityandtheashcloudstheyreleasecanaffectareasthousandsofkilometresaway. Fortunately,theabilitytomonitorvolcanoeshasdramaticallyimprovedinrecentyears,thanksinparttotheworkofscientistslikeDrMarieEdmondsinCambridge’sDepartmentofEarthSciences.

StudyingthebehaviourofvolcanoessuchasSoufrièreHillsinMontserrat,whichcausedthedisplacementoftwo-thirdsoftheisland’spopulation(over8,000people)wheniteruptedin1995,Edmondsandcolleagueshaveaccumulatedhugedatasetsoneverythingfromthetypeandquantityofgasbelchedfromvolcanoes,tothebulginganddeformationofthevolcanoes’shape,tothealtitudeandquantityofashthrownupintothestratosphere. “About600millionpeoplelivecloseenoughtoanactivevolcanotohavetheirlivesdisturbedorthreatened,sothere’saclearneedforhazardassessment,”Edmondssaid.“Weknewthatgasmonitoringdatacouldbeessentialforthis,butmonitoringdependedontheuseofcumbersomeinstrumentsthathadtobedrivenaroundthecrater’sedge.” Intheearly2000s,withfundingfromtheNaturalEnvironmentResearchCouncil(NERC),sheandDrCliveOppenheimerfromtheDepartmentofGeographydevelopedanewgassensor–onethatischeap,miniaturisedandcanbeleftlongtermonthevolcano,relayingthedatabacktotheobservatorybyradiomodem.Today,sensorsliketheseareusedbyscientistsworldwideformonitoringvolcanoes.

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And now, the volcano forecast

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Edmondsandcolleaguesbelievetriggersandfuelstheeruption,anditisthisthatsurfaceSO2levelsareaproxyfor. “Thisisfarfromthetraditionalviewofhowamagmachamberworks,”saidEdmonds.“Itwasthoughttobeballoon-likebutnowwethinkit’sverticallyprotracted,withdifferenttypesofmagmaatdifferentlevels.” “ThesurfaceSO2istellingusaboutlong-scaleprocesses,oftheorderofmonthstoyears,”explainedEdmonds.“Eventhoughtheremaybenoevidenceoflavaatthesummit,ifSO2isstilloutgassingthenthere’spotentialfortheeruptiontoresume.Wecantoanextentuseittoforecastavolcaniceruption.” Recently,EdmondsandcolleaguesjoinedforceswithresearchersatotheruniversitiestounderstandhowbesttomonitorvolcanoesandearthquakesintwonewNERC-fundedprojects.The£2.8millionCentrefortheObservationandModellingofEarthquakes,VolcanoesandTectonics(COMET+)programmerunbytheUniversityofLeedswillprovidenewunderstandingofgeohazardstounderpinnationalriskcapabilities;andthe£3.7millionRiftVolcprojectwillcreatealong-rangeeruptiveforecastforthelargelyunchartedvolcanoesintheEastAfricanRiftValley. ForSoufrièreHills,monitoringisprovidingakeyinputtotheriskassessmentsbytheUKgovernment’sScientificAdvisoryCommitteeforMontserrat,aBritishOverseasTerritory.“Allthesurfacesignsindicatethevolcanicactivityisdecayingawaybut,fromtheSO

2emissions,thevolcanoremainsactiveatdepth.Wethinkthere’sahugemagmareservoir–tensofcubickilometresbeneaththeisland,muchbiggerthantheislanditself.Weknowfromlookingatolderashdepositsontheislandthatthisvolcanoiscapableofmuchlargereruptionsthanwehaveseeninrecentyears,perhapsevenaslargeastheMountStHelensblast.”

“Previousstudieshadshownthatchangesintheemissionrateofgasescorrelatedwithvolcanicactivitybut,becausewehavesuchalongdataset,webegantoseeanotherpatternemerging,”saidEdmonds.“Whatyouseeatthevolcanosurfaceisreallyonlytheendpartofthestory.” Theintensetemperaturesandpressuresdeepintheearthfindreleasethroughfissuresandcracks,whichcarrydissolvedgasessuchascarbondioxide(CO2),sulphurdioxide(SO2),hydrogenchloride(HCl)andsteamupthroughthemantletothecrust. Asthemagmabeginsitsjourneytothesurface,thepressurelowersanddissolvedgasesformtinybubbles,whichstarttoexpand.Closetothesurface,theexpansioncanbesogreatthatitfuelsanexplosiveburstoflava,shootingvolcanicgasestensofkilometresintotheearth’satmosphere. Becauseeachspeciesofgasdissolvesatdifferentpressures,thescientistscanmeasurewhatisreleasedatthesurfaceandusethistoworkoutthedepthatwhichthegasesseparatedfromthe

magmatoformbubbles.“Thegasesarelikemessagesthattellyouhowthevolcanois‘plumbed’andwhatshapethatplumbingisin,”explainedEdmonds. “OneintriguingpatterntoemergeinSoufrièreHillsisthatthetimeseriesforthemagmaeruptionandthatfortheSO2gaseruptionarecompletelyunrelatedtooneanother.Therehavebeenthreebigepisodesoflavaextrusioninthepast15yearsand,althoughHClfluxseemstobeaproxyforeruptionrate,SO2emissionisuncoupledfromwhatishappeningintheeruption.WethinktheSO2fluxistellingusaboutsomethingmuchdeeperinthesystem.” Whentheseresultswerecombinedwithastudyoftherocksspewedfromthevolcano,Edmondsandcolleaguesbegantopiecetogetheranideaofthephysicsandchemistryhappeningwithin. Theybelievethatahotmagnesium-andiron-rich‘mafic’magmaisintrudingfromdepthintotheshallowermagmachamberwhereitmeetsasilica-andcrystal-rich‘andesite’magmathatformsthemainpartoftheeruption.However,itisthegas-richmaficmagmathat

Dr Marie Edmondsme201@cam.ac.ukDepartmentofEarthSciences

9 ResearchHorizons

All ImagesSoufrièreHills,Montserrat

new research project is compiling the largest database of plague imagery ever amassed,

focusing on a pandemic that peaked in the early 20th century and continues to this day. WeareinthemidstoftheworstEbolaoutbreakknowninhumanhistory.Ourscreensarefilledwithnightmarishyetstrangelyfamiliarimagery.Meninspace-ageprotectivesuits,luggingwrapped-upbodiesovertohastilydugpits.Clinicaltentsinpooryetexoticlocations,gleamingincongruously.Bodiesinthestreets.

AsEbolacontinuesitstrailofdeathandterror,manywillbeunawarethatwealsocontinuetolivewithanotherkiller–plague.Themostrecentpandemic(thethird)startedinruralChinain1855butexplodedwhenitreachedHongKongin1894,sweepingtheworldandkillingover12millionpeople.Althoughithasnotbeenconsideredanactivethreatsince1959,recentcasesofplaguehaveoccurredinBolivia,China,MadagascarandtheUSA.

DrChristosLynterisisasocialanthropologistbasedattheCentreforResearchintheArts,SocialSciencesandHumanities(CRASSH).DuringworkonplagueamongmarmotsontheChinese–Russianborder,Lynterisstartedtoconsiderhowplagueisrepresented,howknowledgeaboutplagueiscapturedand

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howweinteractwithwhatweseewhenweencounterthetraitsofplague.

“Thethirdpandemicwasbornaroundthesametimeasmodernphotographictechniques,andtheabilitytocaptureandtransmitimagesofthethirdplaguepandemictransformedpublicconsciousness.Itopenedupanerawherethemeaningofhealthemergenciesispubliclynegotiated,ratherthanpredeterminedbyanysinglescientificorgovernmentalauthority.”

Lastyear,hewasawardedaEuropeanResearchCouncilgranttofind,collateandanalysethelargestdatabaseofplagueimageryinhistory;astheonlyexhaustivevisualrecordofanyinfectiousdiseaseepidemicanditsimpactonsociallifeandthoughtinthemodernera,itwillbeaninvaluableresourcetohistorians,anthropologistsandepidemiologistsalike. TrackingtheimagesdowntakespainstakinginvestigativeworkforLynterisandhisteam(LukasEngelmann,NickEvansandBranwynPoleykett),siftingthroughphotographicremnantsoftheoldcolonialpowerstopickoutthediseased,thedying,thedepictionsofhumanYersinia pestisinfection.“Manyoftheimagesarenotheldintheplaceswhereoutbreaksoccurred.AnarchiveinAlabamamightholdahundredimagesoftheplagueinNorthChinabecausethat’swherethemissionarieswerefrom.Foreigndoctors,missionaries,reportersgotoallcornersoftheplanettoworkwithplagueepidemics;itcanbeatrickywebtountangle.”

Hedescribestheimageryasa“strangecombinationofjournalisticwarreporting,crimescenephotographyandmedicalimagery.”Someofitissographicanddistressingthatpartofthegrantstipulatesthedigitalarchivemustbekeptinalockedroomatalltimes,the‘plagueroom’asLynterischeerfullyreferstoit.Enteringanywherewithsuchamonikerisslightlyunnerving.

“OK,thisnextonereallyisn’tverypretty,”saidLynteris,showingoneofthethousandsofimagestheyhavealreadycollected.Lynterisprobablysaysthisalotthesedays.Thephoto,takeninMadagascarin1899,feelsfamiliar.Thetents.Thepits.Thesuitedspacemen.Ifnotforthesepia,thiscouldbeWestAfricain2014.

“Thereisaclearvisualparadigmofplagueinheritedfromimperialandcolonialhistorythatisemergingaswegathermoreandmoreimages,anexpressionofdiseasedenvironmentswestilllivewith,”explainedLynteris.

“ThevisualparadigmintheMadagascarphotoisreplicatedthroughoutthethirdpandemicandinotheroutbreakssince,

ImagePlagueimagery

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Dr Christos Lynteriscl537@cam.ac.ukCentreforResearchintheArts,SocialSciencesandHumanities(CRASSH)

11 ResearchHorizons

evenoveracenturylater,despitethefactthatthemedicalparadigmhascompletelyshifted–weknowfarmoreaboutinfectiousdiseasesnowthanin1899,sowhyareweseeingthesameimagery?Bytakingtheaestheticregimefromahundredyearsagoandreplicatingittodayyouareinadvertentlyreplicatingalongsurpassedmedicalmodel.”

Askedwhethergovernmentsandmediaarepropagatingtheseportrayalsbecausethisiswhatpeopleexpect,evenneedtosee,Lynterissaid:“I’mnotsure,butsomethingisnotrighthere.It’sthecomponentsandrationalebehindthesevisualparadigmsthatwewillexplore.”

Notalltheimageryisgruesome.Someresembleforensicarchitecturalphotos.“WhentheplaguehittheUSA,investigatorswouldmeticulouslyphotographeveryhouseintheinfectedarea–cellars,floors,beams–lookingforcluesastotheconditionsthatfacilitateplague.”

InanothersetofimagesfromanoutbreakinManchuriain1911thatkilled60,000,Lynterishighlightsanimperialistpropagandawarbeingfoughtoutintheplaguedepictions.RussiaandChinaweretryingtoclaimprovidenceofthearea,with

bothdeterminedtoprovethatitwastheywhowerethemostscientificandcouldtametheplague.

“TheChineseweretryingtopresentanimageofhighscienceandhygienicmodernity,fullofmedicalteamswithmicroscopesandcharts.Theydepictedplagueasanurbanplanningproblemthatcanbescouredbyfire.”Therearemanypicturesofburninghouses,butnotasinglehumanbody.

TheRussianswentadifferentway(“it’sahorrorshow”).Theimagesareentirelymilitaristic,asifanarmyinvadedalandwhereeveryonewasalreadydead.TheaimwastoshowthattheChinesehadnocontrol,thatdeathwasrifeandunstoppablewithoutRussianforce:“itwasintendedtoscare,showorientalbarbaritywithdogseatingcorpsesand

exposedplaguepits.”Imageslikethesearewhythe‘plagueroom’iskeptlocked.

Theteamhashadtocreatealanguageofplaguetomakesurethedatabaseisfullysearchable,andaimtohaveitliveandopenaccessbythetimetheprojectfinishesin2018.Theyareworkingnotjustwithotheranthropologistsandmedicalhistoriansbutwithepidemiologists.Shouldfundamentalquestionsaboutplagueariseamonglifescientists,thearchivemightholdcluesastothehistoryofcertainassumptions. Mostimportantly,theteamisfocusingontherelationshipbetweentheethicsandaestheticsofplaguephotography.“Theimplicationsofthisintheageofsocialmediaareimmense.HowdowecaptureanoutbreaklikeEbolawithourcameras?Howdoesthisreflectourresponsibilitytowardsthevictims,butalsointermsofglobalhealth?”It’salarming,Lynterissays,thatthereseemstobenodifferencebetweenhowwedepictoutbreakstodayandhowwedidahundredyearsago.“Inthepost-colonialworld,epidemicphotographyisstillstubbornlycolonial.”

Cre

dit

: All

imag

es o

n th

is p

age,

Wel

lco

me

Imag

es

echnology developed in Cambridge lies at the heart of a commercial process that can

turn toothpaste tubes and drinks pouches into both aluminium and fuel in just three minutes.

Itstartedwithabaconrollandamicrowaveoven,andnowit’spoisedtotransformtherecyclingofapackagingmaterialthathasbeenasunrecyclableasitisuseful. Thebaconroll,asthestorygoes,wasmicrowavedforsolongitturnedintoacharredmassofcarbonthatbegantoglowred-hot.Whatwashappeningwasanintenseheatingprocesscalledmicrowave-inducedpyrolysis. Onhearingaboutthe‘over-microwaved’baconrollfromanacquaintance,chemicalengineersProfessorHowardChaseandDrCarlosLudlow-Palafox(aPhDstudentatthetime)wonderedwhethertheprocesscouldbeexploitedtorecoverusefulmaterialsfrompackagingwastes. Particulatecarbonisanefficientabsorberofmicrowavesandcantransferthisthermalenergytoadjacentmaterials.Iftheadjacentmaterialisorganic,suchasplasticorpaper,itbreaksapart(orpyrolyses)intosmallerpieces;ifthematerialisametalattachedtotheplasticorpaper,themetalcanberecoveredinacleanformaftertheattachedorganicsarepyrolysed. Fifteenyearslater,andthetechnologytheydevelopedisnowbeingusedinacommercial-scaleplantdesigned,builtandoperatedbyCambridgespin-outEnvalLimited.FoundedbyLudlow-Palafox,withChaseasR&DDirector,Envalisusingtheplanttodemonstratethecapabilitiesandeconomicsoftheprocesstoinvestorsandwastehandlers. Envalhasfocusedonplastic–aluminiumlaminatepackaging.Prizedbymanufacturersforitslightness,cheapnessandabilitytoprotectthecontentsfromlightandair,thepackagingiscommonlyusedforfood,drink,toothpaste,petfoodandcosmeticproducts.

12

Where there’s muck there’s aluminium (if not brass)

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Features

However,thecombinationofplasticandaluminiuminthepackagingpresentsatechnicalrecyclingchallengethatuntilnowhasbeenunsolved;instead,itemspackagedlikethiscontributetothemillionsoftonnesofrubbishdisposedofinlandfilleachyear.Forthebrandswhopackagetheirconsumergoodsthisway,the‘recyclablelogo’onthepackaging,andthesustainabilitycredentialsthatgowiththis,hasbeenall-elusive. “Wehavecarriedoutalife-cycleassessmentofthepackagingandit’sstillenvironmentallybettertousetheselaminateseventhoughtheyarenotrecyclable,justbecausesolittlematerialsandenergygoesintomakingandtransportingthemcomparedwithalternativeslikeglasswareandcans,”saidLudlow-Palafox. “Thereisnorealdrivetoreplacethemandtheirmarketuseisincreasingbyabout10–15%everyyear.IntheUK,roughly160,000tonnesoflaminatesareusedperyearforpackaging,whichmeansatleast16,000tonnesofaluminiumisgoingintotheground.Justimagineifwecouldroutinelyrecyclethis.” ThesolutionheandChasedevelopedwithfundingfromtheEngineeringandPhysicalSciencesResearchCouncilstartedinarelativelysimpleway:theyplacedapileofparticulatecarbonandsomeshreddedlaminatedpackaginginsideaconventional1.2kWkitchenmicrowave,replacedtheairinsidetheovenwithnitrogenandturnedthemicrowaveuptofullpoweruntilthe

temperatureincreasedtoabout600°C. Whentheyopenedthedoortwominuteslater,thelaminatedmaterialhadbeenseparatedintocleanaluminiumflakesandhydrocarbongasesandoil. Thebasicchemistryisstillthesameinthecommercial-scaleplantbuttheovenisnow150kWandlargeenoughtobehousedina100m2industrialunit.Ittakesjustthreeminutestoconvertwasteintoaluminiumforsmelting,andhydrocarbonsforfuel,andwithnotoxicemissions. Nowfullycommissioned,theplantcanrecycleupto2,000tonnesofpackagingayear–which,saytheresearchers,isroughlytheamounthandledbyregionalwastehandlers–anditgeneratesenoughenergytorunitself.Envalnowhasanarrangementwithmanufacturersofplastic–aluminiumlaminatestorecycletheirindustrialscrapatlessthanwhattheywouldhavespentonsendingittolandfill. Theresearchershave,ineffect,turnedintocommercialwastehandlers–somethingtheywouldneverhave

imaginedbackinthe1990s.“Whileweweregettingintotheworldoflaminatesitdidn’tcrossourmindstostartacompany…wejustwantedtheprocesstobecomeareality,”saidLudlow-Palafox.“Intheend,theinvestors[CambridgeCapitalGroupandCambridgeAngels]saidthereisnooneelsewhoknowstheprocessaswellasyou,youmightaswelldoit!” “Weknewthatthepatentedtechnologyofferedagenuinerecyclingrouteforthistypeofpackagingbutthatthewasteindustrycanbeslowtotakeonnewtechnology–themarginsinenvironmentalservicesaresmall,andweneededaworking,fullcommercial-scaleplanttoconvincethemthattheprocesswasviable,”saidChase,whoestimatesthataplantliketheirswouldpayforitselfwithinthreeyears.“Inparallel,wewerebeingcontactedbythebrandswhousethepackaging,askinghowtheycouldhelp.”

Thecommercial-scaleplantispart-fundedbyNestléandKraftFoods/MondelezInternational. “Itwasachickenandeggsituation,”saidLudlow-Palafox.“Nooneisgoingtobuythistechnologyunlessthistypeofwasteisseparatedforrecycling,butthewastewasn’tgoingtobeseparatedbecausetherehasbeennoprocesstorecycleit.Wehadtobreakthatnegativeloopsomehow.Nowwehavethecommercial-scaleplant,wecanshowwastehandlersthebenefitsandencouragelocalauthoritiestoimplementaselectivecollectingsystem.” Meanwhile,thescientistsarekeepinganeyeonfuturerecyclingprospects.ResearchintothemicrowavepyrolysisofdifferenttypesofwastescontinuesinChase’sgroupintheDepartmentofChemicalEngineeringandBiotechnology.“It’scrucialthatwecontinuetolookfornewopportunitiesforrecyclingvaluablematerialswhilesimultaneouslyeliminatingtheneedtosendwastestolandfillorincineration. “We’vedemonstratedthatalotoftroublesomewastematerialscanbepyrolysedusingourmicrowavetechnologybutit’snotalwayseconomicallysensibletodoit;thechallengenowistoidentifywhichprocessesarelikelytobecommerciallyviable,andwhichofthosewillattractthenecessaryinvestmentfundingtobringthemintocommercialreality.Thisisabusinesssectorthatiscomparativelyunfamiliartomostinvestorswhoregularlycommittoinnovationinotherareas.Bydemonstratingthesocietalandeconomicbenefitsofgreentechnologies,wehopetosecurethenecessaryinvestmenttotransforminnovationintosuccessfulcommercialpractice.”

Left to rightProfessor Howard Chasehac1000@cam.ac.ukDepartmentofChemicalEngineeringandBiotechnologyDr Carlos Ludlow-Palafoxcarlos.ludlow@enval.comEnvalLtd

They placed a pile of

particulate carbon and

some shredded laminated

packaging inside a

conventional 1.2 kW

kitchen microwave…

when they opened the

door, the laminated

material had been

separated into clean

aluminium flakes

13 ResearchHorizons

en’s fashion didn’t come cheap in 16th-century Italy. Nor did it go down well with the authorities.

PhD student Giulia Galastro is researching the level of opulence that could be paraded in public – and how the dandies of the day neatly sidestepped the rules.

On15September1595,SalvagiodeAstewasspottedbreakingthelawinGenoa.Therecordinthecity’sstatearchivesdescribeswithremarkableprecisionwhat

hewaswearingashestrolledthroughthesquareofSanSiro.Hemusthavecutadashingfigure.Hesported“anembroideredcap,asilkdoubletofmanycolourswithgoldbuttonsonthesleeves,tworingswithwhitestonesonhisfingers,ajerkinandembroideredhoseinblacksilk.” ThedetailwithwhichSalvagio’sattirewasnotedisnoaccident:hisshowyandcostlyclothingwashiscrime.HiscostumehadfallenfoulofGenoa’sMagistratodellePompe,whoseroleitwastoenforcethe

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Fancy pants & the fashion police

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ithpermissionoftheNationa

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sumptuarylawsthatregulatedwhatmenandwomencouldwear.Patrollingthestreetsandsquaresofthebustlingcityasarbitersofthelevelofostentationthatwasdeemedappropriate,thesumptuarymagistrateswerequitesimplythefashionpolice. Theroleofthesemagistrates,andtheir(largelyunsuccessful)attemptstomoderateexcessivespending,isonestrandofresearchintoclothingandsocietyinearlymodernGenoabeingcarriedoutbyGiuliaGalastro,aPhDcandidateintheFacultyofHistoryworkingwithDrMaryLaven.SumptuarylawsrestrictedtheuseoftheluxurioustextilesforwhichGenoawasfamous,alongwithexpensivedecorationsuchasgoldandsilverembroidery,jewelleryand‘ostentatious’modesoftransport. Italywasn’taloneinhavingsumptuarylaws–theobsessionwithlegislatingagainstcostlyclothesspreadacrossEuropeduringtheMiddleAges.Theaimsofthelawsaresubjecttosomedebate.Theirwordingsuggestsconcernthatluxurygoodscouldmorallydamagethosewhoconsumedthem,thatfashion’stransitorynaturestokedanacquisitivelustfornewgoods. Financialconsiderationstoowereatplay.A15th-centuryGenoeselawbemoaned“agreatquantityofmoneywhichiskeptdeadandwrappedupinclothingandjewels,[and]ifconvertedintotrademightbringgreatreturnandprofits.”Somehistorianshavearguedthatthelawswereanindirecttaxonwealth,workingonthetacitassumptionthattherichwouldbepreparedtopaytogetaroundthem. “Partoftheproblemisthatnotmuchevidenceforhowthelawswereenforcedhasbeenpreserved,soit’sdifficulttoknowhow–andwhether–theyworkedinpractice.That’swhatmakestheGenoesesumptuaryrecordssospecial.Theraresurvivalofnoteskeptbythesumptuarymagistratesgiveusaglimpseofthelawsinaction,andofclothesinuse.Wecanbegintobuildupapictureofwhowaswearingwhat,whenandwhere,”saidGalastro.TherecordssuggestthatresidentsofGenoaroutinelyignoredthesumptuarylaws.Inthefouryearsfrom1594to1598,

themagistratesrecordedmorethan560contraventionsoftheregulations. ThefoppishSalvagiowasamongtherepeatoffenders.Threedaysafterbeingadmonishedon15September1595,hewasbackinSanSiro–wearingexactlythesameoutfit.On5November,hewasthereagain,wearingaleatherjerkinimpregnatedwithmusk. Thesumptuarymagistrateswerecaughtupinagameofcatch-me-if-you-canasGenoa’sdandiesdefiedandsubvertedtherules.ThefecklessSalvagiobrokethelawatleastafurtherfourtimes,suggestingthatwhateverfinewasimposedwasnodeterrenttoamandeterminedtostruthisstuff. “Itislikelythatanyfinesimposedweremodestincomparisonwiththecostoftheoffendinggarments.Awholeoutfitinsilkvelvet,embroideredwithpreciousmetalthreads,couldcomeclosetothepriceofasportscartoday:ifyoucouldaffordtobuytheclothes,youcouldaffordtopaythefine–orthebribe,”saidGalastro. “Contrarytowidelyheldbeliefs,maleoffendersoutnumberfemales.Intermsofoverallsumptuaryoffences,thereare289mento242women.Ifwefocusonoffencesconcerningdress,however,thedisparityismorestriking:269mento99women.Inotherwords,therewerealmostthreetimesasmanymenbreakingthelawonclothingaswomen.” Historianshaveoftenpresumedthat,wheresumptuarylawsmentionmenatall,itisfordressingtoofemininely,butGalastro’sresearchsuggestssomethingdifferent.“It’sinterestingthatthemajorityoftheoffencesrelatetoanoutfitofblacksilk–taffeta,satinorvelvet–ornamentedwithsomesortofpreciousmetalstitchingorwithlace.BlackwasaclearstatussymbolinRenaissanceculturebecauseitwasoneofthemostdifficultdyestofixeffectively,”saidGalastro. “IfyoupairthesumptuaryrecordswithliterarysourcesitseemsthatwhatwasdisquietingtothesumptuarymagistratesinGenoawasaparticularformofvaunting,flauntingmasculinedress.” Inhis1620commentaryontheCharacters of Theophrastus,theGenoesewriterAnsaldoCebadescribesthe

effronteryoftheyoungmanwhowill“whenheiswearingbreechesalla Spagnola,oranembroidereddoublet,circulatearoundthecitysosedulouslythatyoucan’thelpbumpingintohiminchurch,inthesquare,oronthecorner…Youneedn’tthinkofleavinguntilyouhaveadmiredhimfromheadtotoe.Indeedhewillcompelyoutodoso,nowbyopeninghiscloak,nowbyplantinghimselfinfrontofyoulikeabulwark.” Infringementsofthesumptuarylawsweren’tconfinedtotheelite:artisanstoowereunderscrutiny.Somewerecaughtbythesumptuarymagistrateswhilemakingluxuryclothes.On20May1595,thewifeofGioannetinothecheese-makerwasspottedsittingonherdoorstepsewingaman’ssilkshirt,dyedincostlycrimson,withgoldandsilverbraidsthreefingers’thick. “Some60%ofthepopulationwereinvolvedintheproductionoftextilesandclothing–fromthewomenemployedtounwindsilkfilamentfromcocoonsthroughthedyersandweaversintheirworkshopstothehundredsoftailorsandseamstresses,”saidGalastro. Itwasanerawhenpeoplehadahands-onrelationshipwithtextiles,choosingandpurchasingfabricsinconsultationwiththeirtailorsandeagerlyawaitingthearrivalofnewtextilesandtrimmings.Thevocabularyoffabricsandfashionwasfabulouslydiverse–colourssuchas‘incarnadine’(theredofrawflesh)–mostofthesewordslosttoustoday.AsGalastro’sresearchisshowing,whatyouwore,andhowyouworeit,wasamatterofdeepsignificance.

A whole outfit in silk velvet, embroidered with precious metal threads, could come close to the price of a sports car today

15 ResearchHorizons

Giulia Galastro gcg25@cam.ac.uk FacultyofHistory

ImagePaintingofLordJohnStuartandhisbrother,LordBernardStuart,byAnthonyvanDyck

ur brains are plastic. They continually remould neural connections as we learn,

experience and adapt. Now researchers are asking if new understanding of these processes can help us train our brains.

WhenagroupofexperimentalpsychologistsmovedintotheirnewlabspaceinCambridgeearlierthisyear,theytookasomewhatunconventionalapproachtorefurbishingtheirtearoom:theyhadthewallstiledwiththeCaféWallIllusion. Theillusion,so-namedafteritwasspottedonthewallofaBristolcaféinthe1970s,isamuch-debatedgeometricaltrickoftheeyeandbraininwhichperfectlyparallellinesofblackandwhitetilesappearwedge-shapedandsloped. It’salsoanexcellentdemonstrationofhowthebraininterpretstheworldinawaythatmovesbeyondwhattheinputisfromtheeye,asoneoftheexperimentalpsychologists,ProfessorZoeKourtzi,explained.“Ininterpretingtheworldaroundus,ourbrainsarechallengedbyaplethoraofinformation.Thebrainisthoughttointegrateinformationfrommultiplesourcesandsolvethepuzzleofperceptionbytakingintoaccountnotonlythesignalsregisteredbythesensoryorgansbutalsotheircontextinspaceandtime. “IntheCaféWallIllusion,thebraintakesintoaccountthesurroundingtiles,butitalsoreliesonourpreviousknowledgeacquiredthroughtrainingandexperiencewheninterpretinganewsituation.” Fromthedayweareborn,neuronsinthebrainstarttomakeconnectionsthatcombinewhatwecansee,hear,taste,touchandsmellwithourexperiencesandmemories.Neuroscientistsrefertothebrain’s‘plasticity’inexplainingthisabilitytorestructureandlearnnewthings,continuallybuildingonpreviouspatternsofneuronalinteractions. Tounravelthemechanismsthatunderliehowbrainslearn,Kourtzi’s

teamislookingathowbrainsrecogniseobjectsinaclutteredscene.“Thisaspectisvitalforsuccessfulinteractionsinourcomplexenvironments,”sheexplained.“It’showwerecogniseafaceinacrowdoralandmarkduringnavigation.” Visualperceptionisalsohighlytrainable.Thebraincanusepreviousexperienceofsimilarcuestobequickeratidentifyingtheimagefromthe‘noise’–theproverbialneedlefromthehaystack. Butalthoughneuroscientistsrecognisethatthistypeofbrainplasticity

isfundamentaltoourabilitytocopewithcontinuallychangingsettingsathome,school,workandplay,littleisknownabouthowwecanstimulateourbraintoenhancethislearningprocess,rightacrossthelifespan. “Theprocessof‘learningtolearn’isatthecoreofflexiblehumanbehaviours,”explainedKourtzi.“Itunderpinshowchildrenacquireliteracyandnumeracy,andhowadultsdevelopwork-relatedskillslaterinlife.” Oneoftheimportantdeterminantsher

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Lifelong learning and the plastic brain

It’s an excellent demonstration of how the brain interprets the world in a way that

moves beyond what the input is from the eye

Features

therearechildren.TheUK’sOfficeforNationalStatisticspredictsthat,by2020,peopleover50willmakeupalmostathirdoftheworkforceandalmosthalfoftheadultpopulation.TheaveragelifeexpectancyforamanintheUKwillhaverisenfrom65yearsin1951to91yearsby2050.Olderagehasbecomeanincreasinglyactivephaseofpeople’slives,oneinwhichre-trainingandcognitiveresilienceisincreasinglysoughtafter. Kourtziandcolleaguesareusingfunctionalmagneticresonanceimagingtodetectwhenareasofthebrainareactivatedinresponsetoasensoryinputandhowthesecircuitschangewithlearningandexperience.WhileattheUniversityofBirmingham,sheshowedthatthevisualrecognitionabilitiesofyoungandolderadultscanbeenhancedbytraining,butthatthedifferentagegroupsusedifferentneuralcircuitstodothis. Youngadultsuseanteriorbraincentresthatareoftenusedinperceptualdecisions,wheresensoryinformationisevaluatedforadecisiontobemade;olderadults,bycontrast,usetheposteriorpartofthebrain,whichisinchargeoftheabilitytoattendandselectatargetfromirrelevantclutter.“Theclearimplicationofthisisthattrainingprogrammesneedtobegearedforage,”saidKourtzi. Crucially,whatshealsoobservedisthatsomepeoplebenefitfromtrainingmorethanothers:“althoughit’swellknownthatpracticemakesperfect,somepeoplearebetteratlearningandmaybenefitmorefromparticularinterventionsthanothers.Buttodeterminehowandwhy,weneedtogobeyondbiologicalfactors,likecognitionorgenetics,tolookatsocialfactors:whatisitaboutthe

teamhasdiscoveredisthatbeingabletomulti-taskisbetterthanbeingabletomemorise. “Thefasterlearnersarethosewhocanattendtomultiplethingsatthesametimeandrecruitareasofthebrainthatareinvolvedinattention,”sheexplained.“Thosewhoaresloweratlearningtrytomemorise,aswecanseefromgreateractivityinthepartsofthebrainconnectedwithmemory.” “So,infact,beingabletodothesortofmulti-taskingrequiredwheninteractinginbusyenvironmentsorplayingvideogames–whichrequirestheprocessingofmultiplestreamsofinformation–canimproveyourabilitytolearn.” Shealsofindsthatagedoesn’tmatter:“whatseemstomatterisyourstrategyinlife–soifolderpeoplehavereallygoodattentiveabilitiestheycanlearnasfastasyoungerpeople.” Thishasimportantimplicationsforanageingsociety.IntheUK,therearenowmorepeopleoverStatePensionagethan

Professor Zoe Kourtzizk240@cam.ac.ukDepartmentofPsychology

17 ResearchHorizons

ImagesTheCaféWallIllusion–tilesthattricktheeyeandthebrain

wayaparticularindividualhaslearnedtoapproachlearningintheirsocialsettingthatmightaffecttheirabilitytolearn?” Thismultidisciplinaryapproachtounderstandinglearningliesattheheartofherwork.SheleadstheEuropean-Union-fundedAdaptiveBrainComputationsproject,whichbringstogetherbehaviouralscientists,computerscientists,pharmacologistsandneuroscientistsacrosseightEuropeanuniversities,plusindustrialpartners,tounderstandandtesthowlearninghappens. “Inourwork,there’sastrongelementoftranslatingourfindingsintopracticalapplications,socreatingtrainingprogrammesthatareageappropriateisourultimategoal,”sheadded. “ThereasonweliketheCaféWallIllusionsomuchisbecausetricksofvisualperceptiontellusthatthebraincanseethingsinadifferentwaytotheinput.Howthebraindoesthisisinfluencedbycontext,justasthewayweinterpretourenvironmentisinfluencedbylearningandpreviousexperience.”

Credit:TonyKerronFlickr

Credit:fu

nstuffcafe.com/cafe-wall-illusion

collection of ‘possessions’ shows us how people treasured beautiful things before mass production

and a disposable culture irrevocably changed our relationship with the material world.

Theyarenotthemostpracticalfootwear.Theyarenotevenfittedfortheleftandrightfoot.Butthese18th-centurysilkshoes,withtheirpointedtoesandthickcurvingheels,weredesignedwithfashionnotfunctioninmind.Cherished,shownoff,perhapsbequeathed,theywouldhavebeentreasuredbytheirstylishownertoadegreethatmightbehardtofathominthecontextoftoday’smassconsumerism. ThreeCambridgehistorians–DrMaryLaven,ProfessorUlinkaRublackandDrMelissaCalaresu–haveteamedupwithDrVickyAvery,KeeperofAppliedArtsatTheFitzwilliamMuseum,toexplorepossessionfromtheRenaissancetotheEnlightenment.“Ourgoalistoshedlightonthemeaningofobjectstotheirownersinanageofexpandingpossibilities,newtechnologiesandglobalexchange,”explainedLaven.

“Eversincebeautifulandengagingobjectswerefirstcreated,peoplehavewantedtopossessandcherishthem,makingtheir‘favouritethings’partoftheirlives.Possessionsnotonlydefineus,theyalsosaysomethingaboutourpersonalhistories.” Theirresearchwillculminateinasix-monthexhibitionthatwillopeninMarch2015andfeaturemorethan250oftheMuseum’streasures–amongthemamourningseal‘SacredtotheMemoryofanAdoptedChild’,anexquisitetortoiseshellsnuffboxandaDelftwarebirdcage–manyofwhicharerarelydisplayed. “Theexhibitionjuxtaposesiconicartefactswithunfamiliar,quirkyobjectsthatareusuallypassedover,”Lavenadded.“Eachoftheseobjectshadsignificance…It’seasytoforgetthesesecrethistorieswhenyoupassthroughamuseum,viewingobjectsinisolation.”

The collections at The Fitzwilliam Museum explore world history and art from antiquity to the present day.

www.fitzmuseum.cam.ac.uk

Things18

ThingsTreasured possessions

ImagesSomeofthe‘treasuredpossessions’

A

ResearchHorizons19

ImageYellowsilktaffetashoes,madein1749inEngland

Credit:Allimag

es,T

heFitzwilliamM

useu

m

tem cell biologists are a step closer to identifying what some have called the ‘Higgs Boson’ of

the field: the moment in the developing human embryo when everything is possible. Intheearliestmomentsofamammal’slife,thedevelopingballofcellsformedshortlyafterfertilisation‘doesasmothersays’–itfollowsacoursethathasbeenpre-programmedintheeggbythemother.

Extraordinaryasthisis,whathappensthenisevenmoreremarkable.Justbeforeimplantationintheuterus,theballofcells,calledablastocyst,gainsthecapacitytogenerateallofthecelltypesofthesubsequentadult–afeaturecalledpluripotency.Itisatthismomentwheneverythingispossible,whenthehistoryofthepreviousgenerationhasbeenwipedcleanandwhentheembryobeginsitsuniquecourseofdevelopment.

But,althoughthese‘naive’stemcellshavebeenisolatedinmice–andmousecellsatalaterstageofdevelopmentcanbemanipulatedtotakethembacktofullnaivety–thesamehasnotbeenconvincinglyaccomplishedforhumans.

Infact,inanassessmentearlierthisyear,CambridgeresearchersProfessorRogerPedersenandPhDstudentVictoriaMascetticoncludedthattheexistenceofnaivehumanstemcellsrequiredconfirmationbyotherstemcellresearchgroups:“LikeHiggs’Bosontothefieldofparticlephysics,”theyexplained,naivetyinhumanstemcells“waspredictedfromconsiderationsofsymmetryandconservation,[but]weareyettounlockitspotential.”

NowresearchersledbytheWellcomeTrust-MedicalResearchCouncilCambridgeStemCellInstitutehave

20

S

Professor Austin Smithags39@cam.ac.ukDr Jenny Nicholsjn270@cam.ac.ukWellcomeTrust-MRCCambridgeStemCellInstitute

Spotlight:Stemcells

The ‘Ultimate’ Stem Cell

Credit:Jen

nyNicho

ls ImageAmouseblastocystatthepluripotentstage,whencellsgainthecapacitytogenerateallofthecelltypesofthesubsequentadult

21 ResearchHorizons

managedtoinduceagroundstatebyrewiringthegeneticcircuitryinhumanembryonicstem(ES)cellsandinadultcellsthathavebeeninducedintoapluripotentstate.Their‘resetcells’sharemanyofthecharacteristicsofauthenticnaiveEScellsisolatedfrommice,suggestingthattheyrepresenttheearlieststageofdevelopment.

“CapturingEScellsislikestoppingthedevelopmentalclockattheprecisemomentbeforetheybegintoturnintodistinctcellsandtissues,”explainedProfessorAustinSmith,DirectoroftheInstitute,whoco-authoredarecentpaperontheresearch.“Scientistshaveperfectedareliablewayofdoingthiswithmousecells,buthumancellshaveprovedmoredifficulttoarrest.Theyshowsubtledifferencesbetweentheindividualcells.It’sasifthedevelopmentalclockhasnotstoppedatthesametimeandsomecellsareafewminutesaheadoftheothers.”

Headded:“TrulynaivehumanEScelllineswouldnotonlyhelpanswerfundamentalquestionsabouthowwearemade,andbeusefulfordrugscreeningandtissuetherapy,buttheywouldalsoprovideabenchmarkagainstwhichothertypesofstemcellscouldbemeasuredintermsoftheireffectivenessinstemcelltherapyandregenerativemedicine.”

Overthepast20years,researchgroupsledbySmithandDrJennyNicholsattheInstitutehavemadeamajorcontributionbothtounderstandingtheearlystagesofmousedevelopmentandtodetermininghowtomakestablemousestemcelllinesmoreefficiently.Theyknowenoughtorealisethatit’sverydifferentinhumans,asNicholsexplained:“Pluripotentcellsthatseemverysimilartothemousenaivepluripotentcellsappearinthehumanblastocystbefore

Lengthening the journey to joint replacement

Translating scientific discoveries to the clinic can be a major challenge, which is why Austin Smith and orthopaedic surgeon Andrew McCaskie are working together on research that could radically change the way we treat conditions like osteoarthritis.

“Osteoarthritisisarapidlygrowinghealthproblem,withover8millionpeopleaffectedintheUK,”explainedProfessorAndrewMcCaskiefromtheDepartmentofSurgery.“Theconventionalapproachistotreattheconditionwhenthejointisextensivelydamagedbyusingajointreplacement.Wewanttotreattheconditionatanearlierstageusingrepairandregenerativetechniquestoprolongtheuseofthepatient’sownjointandthereforedeferjointreplacement.”

McCaskieisDirectoroftheArthritisResearchUKTissueEngineeringCentre,anationalmulticentrecollaborationfocusedonbothcellandcell-freeapproachestoregenerativetherapiesinosteoarthritis.Healsoleadsanothermulticentreconsortium(SmartStep)thataimstoexplorewaystostimulatethepatient’sownrepairmechanismsbytargetingtheircellpopulations.SmartStepisfundedthroughtheUKRegenerativeMedicinePlatformbytheBiotechnologyandBiologicalSciencesResearchCouncil,EngineeringandPhysicalSciencesResearchCouncilandMedicalResearchCouncil.

“Apivotalpartofresponsibletranslationtothepatientisaclearunderstandingofrelevantadultcellpopulations,”headded.“Austin’sexpertiseinfundamentalstemcellbiologywillallownewinsightsintohowthesecellswork,whichmaytheninfluencetheiruseinsafeandevidence-basedtherapy.”

McCaskieisalsodevelopingmusculoskeletalscienceinCambridgeinamoregeneralway:“Themusculoskeletalsystemisuniquelyreliantonlinkingbiologicalformtomechanicalfunction.WehavestartedanetworkingprocesstodevelopCambridgeMusculoskeletalScienceandfacilitateinteractionbetweenphysicalandbiologicalsciences,technologyandclinicalmedicine,toenhancebenchtobedsideinterdisciplinaryresearch,withtheultimateaimoftransformingpatientcare.”

It is at this moment when everything

is possible

implantationbutwedon’tknowwhathappenstothosecellsforthefollowingweekofdevelopment.Wecanonlymakeassumptionsbasedonwhathappensinthemouse.”

Theirrecentstudy,publishedinSeptember2014inthejournalCell,provesthattheyareclosertocapturingnaivepluripotencyinhumans:“Weknowalmostallweneedtoknowaboutthemolecularrequirementsforcreatingthegroundstateinmice,”Smithsaid.“Wehaveidentifiedthegenesandgrowthfactorsinvolvedand,thankstoacollaborationwithMicrosoftResearch,wecannowcomputationallymodelthecontrolcircuitryinmousecells.It’sreinforcedourviewthatweunderstandenoughtoknowwhattolookforinhumansandwhichcombinationsofgenestofocuson.It’snowonlyamatteroftime.”

Andwhenthathappens,workwillbeginoncomparingthemwithothersourcesofstemcells,throughcollaborationssuchasthePluriMesprojectthatSmithcoordinates,anewlylaunchedconsortiumof10Europeanpartnersfocusedondirectingpluripotentstemcellstobecomeboneandmuscle,andacollaborationwithorthopaedicsurgeonProfessorAndrewMcCaskie(seepanel).

CouldnaivehumanEScellsbethestemcellofchoicefortissuetherapy?“Wedon’tyetknow,”saidSmith.“Thesecellswouldofferthehopeofhavingabroaderandmoreconsistentabilitytodifferentiateintoarangeofcelltypesbecausetheyareatanearlierstageofdevelopment.Butit’salsoentirelypossiblethatcurrentstemcellsaregoodenoughforsomeapplications.Thepointis,weneededthesenewstemcellsinordertofindoutwhatisbest.”

Like conducting an errant orchestra to play together, researchers are guiding processes that go awry in

multiple sclerosis to repair themselves.

Theconductorwalkstothestandandtakeshisplaceinfrontoftheorchestra.Heraiseshisbatonand,withadramaticflourish,onehundredindividualscometolife.Fromnowhere,thestillnessbecomesabeautifulharmonyaseachmembertakestheirpartinacomplexsymphony.

Consider the workings and structure of the human brain – our most complicated organ – in terms of this orchestra

22 Spotlight:Stemcells

Orchestral manoeuvres: multiple sclerosis faces the music

Considertheworkingsandstructureofthehumanbrain–ourmostcomplicatedorgan–intermsofthisorchestra.Whenitworks,itiscapableofsomethingmoreremarkablethanthegreatestmusicalcompositionsinhumanhistory,butwhenitisaffectedbyaconditionsuchasmultiplesclerosis(MS),“thebrain’stightlyorchestratedbiologicalfunctionsbecomediscordant–theconductorbeginstofailattheirjobandseveralinstrumentsgooutoftune,”saidProfessorRobinFranklin,HeadofTranslationalScienceattheWellcomeTrust-MedicalResearchCouncil(MRC)CambridgeStemCellInstituteandDirectoroftheMSSocietyCambridgeCentreforMyelinRepair. HisresearchteamandthoseledbyotherStemCellInstituteresearchersDrsThóraKáradóttir,MarkKotterandStefanoPluchinoareeachlookingatadifferentaspectofthiserrantorchestra.Theyhopethattheircollectiveknowledgewillonedayhelp‘re-tune’thebrainsofMSpatientstoself-repair. Initssimplestterms,MSisadiseaseinwhichtheimmunesystemturnsonitself,destroyingtheoligodendrocytesthatmakeaprotectivesheathcalledmyelin,whichencasesnervefibres.Thishaltsthetransmissionofneuralmessages,andeventuallyleadstonervefibredamage,resultinginaprogressivelossofmovement,speechandvisionforthe100,000peopleintheUKwhohaveMS. However,thecomplexitiesoftreatingthediseasegobeyondsimplystoppingthedestructionofmyelin,saidFranklin:“Themyelindamagecausesabuild-upofdebris,whichneedsremoving,andtheenvironmentsurroundingthecellsneedstobeconducivetoregeneratingthesheath.Whenwethinkaboutrepairingthedamage,weneedtobeconsideringseveraldifferentbiologicalphenomenaatthesametime.” AlthoughtherearedrugsavailableformodifyingtheearlystagesofMS–includingalemtuzumab(Lemtrada),developedinCambridge–therearenotreatmentsthatregeneratethedamagedtissue.Moreover,althoughthediseaseevolvesoverdecades,withperiodsofremissionfollowedbyrelapses,thereisnotreatmentoncepatientshavereachedtheprogressivestage(estimatedtobeabout50%ofcurrentpatients). Oligodendrocytes–themastermanufacturersofmyelin–areformedbyatypeofstemcellinthebraincalledoligodendrocyteprogenitorcells(OPCs),andareresponsibleforre-wrapping,orremyelinating,thebareaxonswithmyelininresponsetoinjuriesordiseases.ButthisregenerativeabilitydecreaseswithageandMS.“Asthediseaseprogresses,

theneedforinterventionthatgalvanisesthenaturalhealingprocessbecomesevermoreimportant,”explainedFranklin.“WorkingwithcolleaguesattheHarvardStemCellInstitute,we’veshownthattheeffectsofageonremyelinationarereversible,whichgivesussomeconfidencethatwecanusethebrain’sownOPCsformyelinregeneration.” However,tounderstandhowtostimulatethebrain’sownrepairmechanismsfirstrequiresanunderstandingofhowthebraindetectsinjuryandinitiatesrepair. ThóraKáradóttirbelievesthatonewaythebrain‘senses’problemsareafootisthroughthedropinhowfastneuralmessagesarepassedacrossthebrain.“Thedifferenceinspeedbetweenanintactneuronandadamagedonecanbelikecomparingthespeedofacheetahtoatortoise,”shesaid.“I’meavesdroppingontheinformationsuperhighwaybyattachingelectrodestoneuronsandOPCs.” Herfindingsshowthatdamagedfibresreleaseamoleculecalledglutamate.“It’stheir‘cryforhelp’toOPCs.Ifitdoesn’thappen,oriftheOPCsdon’t‘hear’,thenrepairisreduced.”SheisworkingwithNumedicus,acompanythatspecialisesindevelopingsecondaryusesforexistingdrugs,totestdrugsthatshehopeswillbeabletoamplifythissignalandincreasetherepairprocess. Meanwhile,RobinFranklin’steamhasshownthatit’spossibletokick-startOPCs,drivingtheformationofoligodendrocytesandsheathformation,usingadrugthattargetsretinoidXreceptor-gamma,amoleculefoundwithinOPCs.TheresultsarepositiveandclinicaltrialswillshortlycommenceincollaborationwithDrAlasdairColesfromtheDepartmentofClinicalNeurosciencesandtheMRCCentreforRegenerativeMedicineattheUniversityofEdinburgh. What’sinterestingabouttherejuvenationofremyelinationisthatthetreatmentprimarilyaffectedinflammationindemyelinatinglesions,andspecificallytherecruitmentofcellscalledmacrophages.Thesearethebody’s‘bigeaters’–theirroleistosearchoutandgobbleuprubbish.“Wehaveidentifiedmyelindebrisasapotentinhibitorofstemcells.Learninghowitisbeingsensedbystemcellsenabledustoovercomethisinhibitionbyusingdrugssuchasibudilast.Aclinicaltrialtotesttheseeffectsiscurrentlyundergoingpreparation,”explainedMarkKotter. FranklinandKotter’sworkisrepresentativeofaninterestingturninMSresearchwithinthefield.Increasingly,investigatorsarelookingathowtheenvironmentaroundthedamagecanbeimprovedtohelpnaturalremyelination.

“It’sacuriousparadox,”saidFranklin.“MSiscausedbytheimmunesystembutcomponentsoftheimmunesystemarealsokeytoitsrecovery.” StefanoPluchino’steam,forinstance,hasshownthatinjectingbrainstemcellsintomicewithMSworksinasurprisingway.Insteadofmakingnewoligodendrocytes(orotherbraincells),thecellsseemtoworkbyre-settingthedamagingimmuneresponse,creatingbetterconditionsforthebrain’sownstemcellstoreplaceorrestorewhathasbeendamaged.Heisnowdevelopingmore-efficientstemcellsandnewdrugs,includingnanomedicines,tofosterthehealingofthedamagedbrain.

GiventhecomplexlandscapeofabnormalactivitieshappeningintheMSbrain,willcombinationtherapiesbethewayforward?“Certainly,”saidFranklin.“OverthenexttenyearswewillseeanincreasedunderstandingofthefundamentalbiologyinMS,wewillidentifymoretargetswhichmayyieldeffectivedrugsandwe’llhavemore-refinedstrategiesforrunningclinicaltrials.WhatmakesCambridgerareisthespectrumofskillshere–fromunderstandingthefundamentalbiologyofmyelinrepairthroughtoclinicaltrials.”

Left to right Professor Robin Franklinrjf1000@cam.ac.ukDr Thóra KáradóttirDr Mark KotterDr Stefano PluchinoWellcomeTrust-MRCCambridgeStemCellInstitute

ResearchHorizons

They hope that their

collective knowledge

will one day help

‘re-tune’ the brains

of MS patients to

self-repair

23

24

FThe man with a thousand brains

The research poses

an interesting ethical

question: when is a

model of a brain

actually human?

orty million people worldwide are living with Alzheimer’s and this is only set to increase. But tiny brains

grown in culture could help scientists learn more about this mysterious disease – and test new drugs.

Itsoundslikesomethingfroma1950s’B-movie:scientistsgrowingbrainsinthelab.Itbringstomindimagesofdimlylit,cobweb-filledroomswithbrainspulsatinginglasstanks.

Spotlight:Stemcells

Thetruth,ofcourse,isfarlessgothic.TheWellcomeTrust/CancerResearchUKGurdonInstitute,wheretheresearchistakingplace,islight,airyandhi-tech.ButalthoughDrRickLivesey,wholeadsthestudy,doesnotliketocallthem‘mini-brains’,thatisinessencewhattheyare:clustersofmillionsofnervecells,electricallyactiveandnetworkedtoeachother,andnobiggerthanafreckle.Whatmakesthese‘brains’particularlyusefulisthattheyarediseased–theyhaveAlzheimer’s.

Almost40millionpeopleworldwidearelivingwithAlzheimer’sdisease,andasmorepeopleliveintooldage,thisnumberissettorise.Foradiseasefirstdescribedin1906,surprisinglylittleisunderstoodaboutitsmechanisms,andtherearenotreatmentoptionstopreventorreverseitsprogress.Wedoknow,however,thatthediseaseischaracterisedbythebuild-upinthebrainoftwotypesofprotein:beta-amyloid,whichclumpstogetherinto‘plaques’,andtau,whichaccumulatesinnervecellstoform‘tangles’.Theseproteinsdisruptthebehaviourofthenervecells,whichlosetheirconnectionsandeventuallydie.

Thestandardwaytostudyadiseaseistouseanimals.Crudelyspeaking,youinsertahumandiseasegeneorseriesofgenesintoamouseandobservethemechanismsthatleadtheanimaltodevelopthedisease.Thisapproachisusefulforaskingspecificquestions,butdoesn’tshowthediseaseprocessinacohesiveway.Itcanleadtothedevelopmentofdrugsthattreatthediseaseinmicebutfailwhenitcomestohumans.

Instead,Liveseyhasturnedtostemcells,buildingonresearchthatwonSirJohnGurdon,themanwhogavehisnametotheinstituteatwhichLiveseynowworks,aNobelPrizein2012.

MostpeoplewhodevelopAlzheimer’sbeginshowingsymptomsinlaterlife,fromtheirsixtiesonwards.However,asmallnumberofpeople–lessthan1%ofcases–haveageneticformofthediseasethatrunsintheirfamilies,causedbyasinglechangeinoneofthreegenes.Ifyoucarrythemutation,youwillgetAlzheimer’s–andonsetistypicallyinone’sthirtiesorforties.

LiveseytakesskincellsfrompatientswiththisfamilialformofAlzheimer’sandreprogrammesthemtobecomeinducedpluripotentstemcells,whichresembleembryonicstemcells,withtheabilitytoturnintoalmostanytypeofcellinthebody.Byguidingthemtodevelopasneuralstemcells,whichcreatethebrain’snervecells,hemakestwo-dimensionalclustersofnervecellsthatmodelthecerebralcortex,theareaofthebrainthatisaffected

byAlzheimer’s.Theseclustersconnecttoeachother,formingcircuits–essentialformodellingearlystagesofAlzheimer’s,whichaffectstheabilityofneuronstocommunicatewitheachother.It’saverylabour-intensive–andfraught–processthattakesmonths.“Wegrowtheminasugarandsaltmixture,andwhatdobacterialovebutsugarandsalt!You’realwaysparanoidyou’regoingtolosethem,”explainedLivesey.

Theseclustersallowtheresearcherstoreplayadiseaseprocessthattakes30or40yearsbutoverthreeorfourmonths.Inhumans,ourimmunesystemdoesitsbesttofightoffthedisease,buteventuallythisclearancemechanismgetsoverwhelmed.“Inthedish,thesespecialistclearancecells,calledmicroglia,areabsentsothediseaseprocessisfaster.Oneofthebeautiesofourmodelsisthatwecanaddmicrogliaandseewhattheeffectoftheimmunesystemisandifwecanuseittomakethingsbetterorworse.”

AswellasallowingLiveseytostudythefundamentalbiologyofthedisease,hismini-brainsarepowerfultoolsforscreeningpotentialdrugcandidates.Touseanimalsforthispurposewouldmeanusingtensofthousandsofmicewhich,asLiveseypointsout,“wouldbebothimpracticalandethicallyindefensible.”Liveseyputstheclustersintoall96wellsofaplatethesizeofamobilephoneandaddsadifferentcompoundtoeachwell.“Wedothiseverytwodaysforamonth,monitoringtoseeifthediseasegetsbetter.Wemighttrydifferentdosesofthesamecompound–wesaywelllook,thisisfinewithwhackinggreatamounts,butwilliteverworkasarealdrugatconcentrationssuitableforhumans?”

Thankstoarecent£2millionawardfromAlzheimer’sResearchUK,Livesey,togetherwithcolleaguesatUniversityCollegeLondon,hasalsobegunworkonmodellingmorecommonformsofthedisease.Thesesharethesamepathologyasthefamilialforms,butmayarisethroughfundamentallydifferentmechanisms.“Weknowthereissomeoverlapbetweenthetwoforms,butthere’sariskthatwedevelopatreatmentforfamilialAlzheimer’swhichwon’tworkinthegeneralpopulationifthediseasedoesn’tstartinthesameway.”

Theresearchdoes,however,poseaninterestingethicalquestion:whenisamodelofabrainactuallyhuman?Livesey’smodelsaremadeupofhumancellsandhavemanyofthepropertiesofrealbrains,buttheycannotlearn,donotthinkandarenotsentient–theyarenot‘human’inthatsense.“Allofthenervecellswemakeareexcitatory–they’relike‘on’switches.Realbrainsalsohaveasecond,inhibitorynervecelltype,whichactslikean‘off’

Dr Rick Liveseyrick@gurdon.cam.ac.ukWellcomeTrust/CancerResearchUKGurdonInstituteandWellcomeTrust-MRCCambridgeStemCellInstitute

25 ResearchHorizons

switchandmodulatestheneuralcircuits.Theseaddanextralayerofcomplexitywhichismissinginourmodels.

“Buthonestly,wesimplydon’tunderstandthecellularbasisforsentience,letaloneconsciousness,soweprobablywouldn’tknowitifwesawit.Norareweclearwhetherit’sascaleoracomplexityissue.Ourneuralclustersaretiny,onlyaroundamillionnervecells,whereasarealbrainhasabout86billion.Ifwemadeitbigenough,sayakilogram,woulditbecomeahumanbrain?Probablynot,aswe’renotcapturingallthecomplexityofthesystem.Sowhatifthebrainmodelwassmaller,butcapturedallthecomplexity,likeamousebrain–wouldthatcauseethicalconcerns?It’saquestionwecannotignoreaswemoveforward.Butwe’restillalongwayoffthereyet.”

These clusters allow the

researchers to replay

a disease process that

takes 30 or 40 years but

over 3 or 4 months

Stem Cell Physical

26

ImageStemcellshaveapeculiarphysicalpropertycalledauxeticity:thenucleusexpands,ratherthanthins,whenit’sstretched Credit:EffigosAG

“You’re not going to perform lots of chemistry

on it in order to decide which is the best one:

you’re going to pick it up and squeeze it”

Spotlight:Stemcells

ooking at stem cells through physicists’ eyes is challenging some of our basic assumptions

about the body’s master cells.

Oneofthemanymysteriessurroundingstemcellsishowtheconstantlyregeneratingcellsinadults,suchasthoseinskin,areabletoachievethedelicatebalancebetweenself-renewalanddifferentiation–inotherwords,bothmaintainingtheirnumbersandproducingcellsthataremorespecialisedtoreplacethosethatareusedupordamaged.

“Whatallofuswanttounderstandishowstemcellsdecidetomakeandmaintainabodyplan,”saidDrKevinChalut,aCambridgephysicistwhomovedhislabtotheUniversity’sWellcomeTrust-MRCCambridgeStemCellInstitutetwoyearsago.“Howdotheydecidewhetherthey’regoingtodifferentiateorstayastemcellinordertoreplenishtissue?Wehavediscoveredalotaboutstemcells,butatthispointnobodycantellyouexactlyhowtheymaintainthatbalance.”

Tounravelthismystery,bothChalutandanotherphysicist,ProfessorBenSimons,arebringingafreshperspectivetothebiologists’work.Lookingatproblemsthroughthelensofaphysicisthelpsthemuntanglemanyofthecomplexdatasetsassociatedwithstemcellresearch.Italso,theysay,makesthemunafraidtoaskquestionsthatsomebiologistsmightconsider‘heretical’,suchaswhetherafewsimplerulesdescribestemcells.“Asphysicists,we’reveryusedtotheideathatcomplexsystemshaveemergentbehaviourthatmaybedescribedbysimplerules,”explainedSimons.

Whattheyhavediscoveredischallengingsomeofthebasicassumptionswehaveaboutstemcells.

Oneofthoseassumptionsisthatonceastemcellhasbeen‘fated’fordifferentiation,there’snogoingback.“Infact,itappearsthatstemcellsaremuchmoreadaptablethanpreviouslythought,”saidSimons.

Byusingfluorescentmarkersandliveimagingtotrackastemcell’sprogression,Simons’grouphasfoundthattheycanmovebackwardsandforwardsbetweenstatesbiasedtowardsrenewalanddifferentiation,dependingontheirphysicalpositioninthetheirhostenvironment,knownasthestemcellniche.

Forexample,somehavearguedthatmammals,fromelephantstomice,requirejustafewhundredbloodstemcellstomaintainsufficientlevelsofbloodinthebody.“Whichsoundscrazy,”saidSimons.“Butiftheself-renewalpotentialofcellsmayvaryreversibly,thenumberofcells

L

Left to rightDr Kevin Chalutkc370@cam.ac.ukWellcomeTrust-MRCCambridgeStemCellInstituteProfessor Ben Simonsbds10@cam.ac.ukDepartmentofPhysicsandWellcomeTrust/CancerResearchUKGurdonInstitute

27 ResearchHorizons

thatretainstemcellpotentialmaybemuchhigher.Justbecauseacertaincellmayhavealowchanceofself-renewaltodaydoesn’tmeanthatitwillstillbelowtomorrowornextweek!”

Chalut’sgroupisalsolookingatthewayinwhichstemcellsinteractwiththeirenvironment,specificallyattherolethattheirphysicalandmechanicalpropertiesmightplayinhowtheymaketheirfatedecisions.It’salittle-studiedarea,butonethatcouldplayakeyroleinunderstandinghowstemcellswork.

“Ifyougotothegrocerystoretobuyanavocado,you’renotgoingtoperformlotsofchemistryonitinordertodecidewhichisthebestone:you’regoingtopickitupandsqueezeit,”saidChalut.“Inessence,thisiswhatwe’retryingtodowithstemcells.”

Chalut’steamislookingattheexactpointwherepluripotency–theabilitytogenerateanyothercelltypeinthebody–arisesintheembryo,anddeterminingwhatrolephysicalormechanicalsignalsplayingeneratingthis‘ultimate’stemcellstate.

Usingfluidpressuretosqueezethestemcellsthroughachannel,aswellasminiaturecantileverstopushdownonthecells,theresearcherswereabletoobserveandmeasurethemechanicalpropertiesofthesemastercells.

Whattheyfoundisthatthenucleiofembryonicstemcellsdisplayabizarreandhighlyunusualpropertyknownasauxeticity.Mostmaterialswillcontractwhenstretched.Ifyoupullonanelasticband,theelasticwillgetthinner.Ifyousqueezeatennisball,itscircumferencewillgetlarger.However,auxeticmaterialsreactdifferently–squeezethemandtheycontract,stretchthemandtheyexpand.

“Thenucleusofanembryonicstemcellisanauxeticsponge–itcanopenupandsoakupmaterialwhenit’spulledonandexpelallthatmaterialwhenit’scompressed,”saidChalut.“Butoncethecellshavedifferentiated,thispropertygoesaway.”

Auxeticityarisespreciselyatthepointinastemcell’sdevelopmentthatitneedstostartdifferentiating,soit’spossiblethatthepropertyexistssothatthenucleusisabletoallowentranceandspacetothemoleculesrequiredfordifferentiation.

“There’salotofdiscussionaboutwhatexactlyitmeanstobepluripotent,andhowpluripotencyisregulated,”saidChalut.“Manydifferentfactorsplayarole,butwebelieveoneofthosefactorsmaybeamechanicalsignal.Thismayalsobethecaseinthedevelopingembryo.”

Bybringingtogetherphysicsandbiology,SimonsandChalutbelievenot

onlythatsomeofthedefiningquestionsinembryonicandadultstemcellbiologycanbeaddressed,butalsothatnewinsightscanbefoundintomechanismsofdysregulationindisease,cancerandageing.

Stem cells are much more adaptable than previously thought

“Oneofthereasonsthatthisbringingtogetherofdisciplinessometimesdoesn’tworksowellisthatphysicistsdon’twanttounderstandthebiologyandbiologistsdon’twanttounderstandthephysics,”saidChalut.“Inasense,biologistsdon’tknowthephysicalquestionstoask,andphysicistsdon’tknowthebiologicalquestionstoask.Asaphysicist,themainreasonIwantedtomovemylabtotheStemCellInstituteisIthoughttherewasnopointworkinginbiologyifIdidn’tunderstandwhichquestionstoask.”

“There’sarealeffortbeingmadetocombinebiologyandphysicsmuchmorethantheyhavebeeninthepast,”addedSimons.“Ittakesabitofaleapoffaithtobelievephysicswillenrichthefieldofbiology,butIthinkit’saveryreasonableleapoffaith.Scientifichistoryisfulloffieldsthathavebeenenrichedbypeoplecominginandlookingatanissuefromdifferentdirections.”

efiniGEN is one of the first commercial opportunities to arise from Cambridge’s expertise in

stem cell research. Here, we look at some of the fundamental research that enables it to supply liver and pancreatic cells for drug screening.

Muchhasbeenwrittenaboutthepromiseofstemcellsformodernmedicine,andcell-basedtherapiestotreatdiseasesarenowbeingdevelopedbycommercialcompaniesinEuropeandacrosstheworld.Butitistheirusebothtoscreenmedicinaldrugsfortoxicityandtoidentifypotentialnewtherapieswhichisincreasinglybeingviewedasonethatcouldhaveanimmediateandfar-reachingimpact. Cambridge-basedcompanyDefiniGENsuppliesthepharmaceuticalindustrywithliverandpancreaticcellsthathavebeenreprogrammedfromhumanskincells.Thesecells,knownasinducedpluripotentstem(IPS)cells,areusedtotestpotentialnewdrugs,andcanalsobeusedasin vitromodelsfordisease. ThecompanyspunoutoftheUniversityin2012andisoneofthefirstcommercialopportunitiestoarisefromCambridge’sexpertiseinstemcellresearch.ItsportfolioofproductsisbasedontheresearchofDrLudovicVallier,ProfessorRogerPedersen,DrTamirRashid,DrNickHannanandDrCandyChoattheAnneMcLarenLaboratoryforRegenerativeMedicine(LRM)inCambridge.

“Drugfailureinthelatephaseofclinicaldevelopmentisamajorchallengetofindingnewtherapeuticswhichareurgentlyneededbyabroadnumberofpatientswithmajorhealth-careproblemssuchasdiabetes,”saidVallier.“Agreatdealoftimeandmoneyareoftenlostfollowingthesefalseleads,andthislimitsthecapacityofpharmaceuticalcompaniestoexplorenoveltherapies.So,identifyingtoxicdrugsasearlyaspossibleisvitaltotheefficiencyandsafetyofthedrugdiscoveryprocess.” “Becauseweusehumancells,ourlabhasaspecificphilosophythatallthedatawegenerateisusednotonlyforfundamentalresearch,butalsorelatesbacktotheclinic,”addedVallier,whoholdsajointappointmentattheLRMandtheWellcomeTrustSangerInstitute,andisalsoChiefScientificOfficeratDefiniGEN.“Weareinterestedinhowstemcellsworkbutwealsoalwaysaskhowtheresearchwe’redoingmighthaveaclinicalortranslationalinterest.” IPScellscanbegrownoutsidethebodyindefinitely,butcanalsodevelopintoalmostanyothercelltype,providingtheopportunitytohaveareadysourceofhumancellsfortestingnewdrugs.

28

D

Testing time for stem cells

Spotlight:Stemcells

Dr Ludovic Vallierlv225@cam.ac.ukAnneMcLarenLaboratoryforRegenerativeMedicineandWellcome-MRCCambridgeStemCellInstitute

29 ResearchHorizons

Vallier’slabiscombiningbasicknowledgeindevelopmentalbiologyandstemcellstodevelopmethodsfordifferentiatingIPScellsintoliverandpancreaticcells.Despitebeinggeneratedinadish,thesecellsshowmanyofthesamecharacteristicsasthosegeneratedthroughnaturaldevelopment. Inparticular,thegroupusesamixofIPScellsandhumanembryonicstem(ES)cellstounderstandthemolecularmechanismsthatcouldgoverntheonsetofvariousmetabolicdiseasessuchasthosethataffecttheliverandpancreas. Theliverisalargeandcomplexorganandplaysanumberofimportantrolesinthebody,includingdigestionandthesecretionandproductionofproteins.Itisalsothekeyorganformetabolisingdrugsandremovingtoxicsubstancesfromthebody.Forthisreason,demonstratingthatadrugcandidateisnottoxictotheliverisacrucialstageinthedevelopmentofnewdrugs.Itisalsoatestthatmostnewdrugcandidatesfail–increasingthecostanddecreasingtheefficiencyofthedrugdevelopmentprocess. Alackofhigh-qualityhumanlivercells,orprimaryhepatocytes,meansthatinferiormodelsareoftenusedfortestingpotentialnewdrugs.ThecellsgeneratedinVallier’slab,however,showmanyofthesamefunctionalcharacteristicsasprimaryhepatocytes,bothfortoxicologytestingandasmodelsofliverdisease,includingthemostcommonlyinheritedmetabolicconditionssuchasfamilialhypercholesterolaemiaandalpha1-antitrypsindisorder. Vallier’steamisalsoabletousethesecellstomodeladiverserangeofinheritedliverdiseases,offeringthepotentialtoacceleratethedevelopmentofnewtherapiesfortheseconditions.“Thereisnocureforend-stageliverdiseaseapartfromtransplantation,”saidVallier.“Duetoanacuteshortageofdonors,manyresearchgroupshavebeenlooking

atalternativemeansoftreatingliverfailure,includingstem-cell-basedtherapy.” Understandingthebasicmechanismsbehindthegenesisanddevelopmentofliverdiseaseishelpinghisteamdevelopnewwaystogeneratefunctionallivercellsthatcouldbeusedtotreattheseconditionsinfuture. Theresearchersaretakingasimilarapproachtothepancreas,withaparticularfocusondiabetes.AccordingtoDiabetesUK,3.2millionpeopleintheUKhavebeendiagnosedwithdiabetes,andanestimated630,000peoplehavethecondition,butdon’tknowit. Apromisingtherapytotreattype1diabetesistransplantingtheinsulin-producingisletcellsofthepancreas,butthereareonlyenoughdonatedisletstotreatfewerthan1%ofdiabeticpatientswhomightbenefitfromthisformoftreatment. Vallier’sgroupisworkingtogeneratelargenumbersofpancreaticisletcellsfromstemcells,whichcouldbeusedfortransplantation-basedtherapy.Inaddition,theyarebuildingin vitromodelstostudythemolecularmechanismsthatcontrolpancreaticspecificationintheembryo.Vallier’sgrouphasidentifiedseveralgenesthatcouldbeimportantforpancreaticdevelopmentandindetermininganindividual’sresistancetodiabetes. “UsingIPScells,we’retryingtounderstandhowindividualgeneticscaninfluencedevelopment,insulinproductioncapacityanddiseaseonset,”saidVallier.“Essentially,humanIPScellscanbeused

tomodelhumangeneticsinadish,whichhasn’tbeenpossibleuntilnow. “ThankstoIPScells,we’renowabletodiscoverthingsthatarenotpossibletodousinganimalmodelsoranyin vitrosystem.Notonlywillthishelpusunderstandmoreaboutthemechanismsbehindhumandevelopment,suchashowcellsinthehumanembryodevelopintoorgans,butitwillalsohelpwithdrugscreeningandwithmakingmore-precisedrugs,whichiswhat’sreallyneededfortheliverandpancreas.Thesetypesofin vitroapplicationsarepossiblenow,whilecell-basedtreatmentsaremoreinthelongerterm.Butyouhavetowalkbeforeyoucanrun.”

A great deal of time and money are often lost following these false leads

ust one shot of dopamine cells derived from stem cells could be enough to reverse many of the features of

Parkinson’s disease for decades – and the barriers to developing such a treatment are finally being overcome.

ProfessorRogerBarkerhasadream:bythetimeheretiresin15years,hewouldliketoseestemcelltransplantsforParkinson’sdiseaseavailableontheNHS. Fifteenyearsmayseemlikeplentyoftimetorealisethisdream,buttherearesomanycontingenciesthatevenheadmitsthismaybeoptimistic.“Itassumesthatallourclinicaltrialsgosmoothly,thatindustrytakesupthetechnology–andthat‘stemcelltourism’doesn’tsetusback,”hesaid. It’snotdifficulttounderstandwhypeopleresorttostemcelltourism–goingabroad,usuallytocountriessuchasIndiaandChina,toreceiveprivate,unregulatedstemcelltherapies(howeverexperimental)totreatincurableconditionssuchasParkinson’sormultiplesclerosis.Therehasbeenmuchhypesurroundingstemcellsand,withnothingtolose,isn’titworthatleasttryingoneofthesetreatments?Thetroubleisthattheyarebasedonverylimited–ifany–evidenceandhavethepotential“togopear-shaped”,saidBarker.Thiscoulddamagepublic–and,more

importantly,regulators’–confidenceinthefieldandleadtoinappropriaterestrictionsonlegitimateresearch. TheideaofcelltransplantstotreatParkinson’sisnotnew.Oneofthekeycharacteristicsofthedisease,whichaffectsaroundonein800peoplebythetimetheyareelderly,isthedeathofdopamine-producingcellsinthebrain.Findingawaytoreplacethesecellscould,intheory,leadtodramaticimprovementsinthepatient’shealth. Anadulttypicallyhasaroundhalfamilliondopaminecellsinthesubstantianigraoneachsideofthebrain.Whenhalfofthesecellshavedied,thepatientwillbeginshowingsymptoms,whichincludearestingtremor,slownessofmovementandrigidity.“OneofthereasonsParkinson’sdiseaseissoattractiveforcelltherapies,”explainedBarker,“isthatitisatractableproblem.Ifwecangetjust100,000propernigraldopaminecellsinthere,itshouldmakeadifference.” Eversincethe1980s,scientistshavebeentriallingwaysofreplacingdopaminecellswithcellstakenfromabortedfetuses–apracticewhich,asidefromethicalconcerns,isnotpracticalonascaleneededtotreatthehundredsofthousandsofpatientsintheUKalone. Thetrialshadmixedsuccess.Insome,

30

Taking a shot at Parkinson’s

J Cell therapies are relatively straight-forward to administer, through a small hole in the skull, and just one shot should last decades

Spotlight:Stemcells

patientscontinuedtoseeimprovementsover15years;however,inothers,thetreatmentnotonlyfailed,butpatientssufferedsideeffects.Inpart,thiswasduetoaninconsistencyinprotocols,forexampletheageofparticipants,theclinicaltechniquesusedforcelldeliveryandthenumberofcellstransplanted. Now,withfundingfromtheEuropeanUnion,BarkerandcollaboratorsinEuropehavedevelopedaprotocolthatismorelikelytoprovidesafe,consistentandclinicallyeffectivebenefitsforpatients.HeisleadingatrialinEuropetousefetalcellstotreatpatients,withtheaimof“puttingcelltherapiesforParkinson’sdiseasebackonthemap.” Ifthetrialissuccessful,by2018theresearchershopetobegintriallingtheuseofdopaminecellsderivedfromembryonicstemcellsthroughanewcollaborationwithteamsacrossEurope,theUSAandJapan.(ThecollaboratorsinJapanhopetoconductasimilartrialusinginducedpluripotentstemcells–thepatients’ownskincells,reprogrammedtobecomestemcells.) Thebeautyofusingstemcellsisthattheycanbeprogrammedtobecomealmostanytypeofcellwithinthebody.Therisk,ofcourse,isthattheybecomethewrongkindofcellor‘runawaywiththemselves’tobecomecancerous.EarlierthisyearinLisbon,anexperimentalstemcelltreatment–partofanapprovedtrial

tocureparalysis–reportedlyledtoaparaplegicwomangrowinganasaltumouronherback.However,Barkerisconfidentthatnewprotocolshaveallbuteliminatedsafetyconcerns–thoughthisriskmaybeveryrealincasesofstemcelltourism. Ithasstillbeenachallengetoprogrammethestemcellstobecomenigraldopaminecells.“Youtakestemcellsandprogrammethemtobecome‘neuralprecursorcells’.Thesecellsmakebrain;somewillturnintodopaminecellsandotherswillwanttobecomeforebrain–butifyoualreadyhaveaforebrain,growinganotheroneisnotgoingtohelpyou!Fortunately,we’vefoundawayroundthistoallowustocommittheprecursorcellstobecometherightdopaminecellswithouttheothercellsappearingaftergrafting.” Pre-clinicalstudiesinmicehaveshownsuccessintreatingParkinson’sdiseasewithdopaminecellsderivedfromstemcells,butthemiceareobservedonlyoveramatterofmonths:Parkinson’s,bycontrast,isadiseasethatprogressesoverdecades.Indeed,postmortemsofsomeofthepeoplewhohadpreviouslyreceivedfetalcelltransplantsfoundevidenceofthediseaseinsomeofthecellsinthegraftasthoughtheproteininvolvedinParkinson’shadcauseddiseaseinthetransplant.“Ifthat’sthecase,thenevenwithstemcelltherapieswecouldstarttoseepathology.Butevenifthatistrue,weknowitwillbe

decadesbeforewestarttoseeaneffectandsothisshouldnotpreventthembeingadoptedfortreatingpatients.” “Ofcourse,justbecausewecandosomethingdoesn’tnecessarilymeanweshould,”addedBarker.TreatmentsalreadyexistforParkinson’sdisease.ThedrugL-dopacanreplacelostdopamineandreversesymptoms–butmedicationneedstobetakenregularly,cancausesideeffectsandeventuallybecomesrelativelyineffective.Deepbrainstimulation–electrodesimplantedintothebrain–canlikewisepreventtremorsandreducesomeofthemotorfeaturesexperiencedbyParkinson’ssufferers,butpatientsneedtocarryaroundbatterypacksundertheirskin.Celltherapies,ontheotherhand,arerelativelystraightforwardtoadminister,injectedthroughasmallholeintheskull,andjustoneshotshouldlastdecades. Evenso,Barkerisrealisticaboutwhatstemcelltherapiescanachieve.“Theyarelikelytobenomoreeffectivethanexistingtreatments.Wecertainlywon’tbecuringanyone.”Heisalsoawarethattoproducecellsonascalelargeenoughforwidespreaduse,thetechnologywillneedtobepickedupbyindustry.“Andoncethisbecomesacommercialtreatment,pricemaybecomethebiggestissue.”

31 ResearchHorizons

Professor Roger Barker rab46@cam.ac.uk JohnvanGeestCentrefor BrainRepair,DepartmentofClinical Neuroscience,andWellcomeTrust- MRCCambridgeStemCellInstitute

New protocols have all but eliminated safety concerns

Butusinghumanembryonicstem(ES)cellstoimprovethehealthofotherhumanshasalsobeenthesubjectofcomment,criticismandevencourtcases.Time magazinedubbedthe“complexityanddrama”surroundingthesecellsasthe“GreatDebate”. Mostnotably,thefieldwitnessedthe2001restrictiononfundingforEScellresearchintheUSAbyPresidentBushandtheliftingofthebanin2009byPresidentObama.Thenin2011,theCourtofJusticeoftheEuropeanUnion(CJEU)bannedthepatentingofinventionsderivedfromhumaneggsortheirequivalentonthebasisthattheywerehumanembryos,thecommercialexploitationofwhich“wouldbecontraryto…morality.” Whilereligiousbodiesandgreenlobbyistsusepatentlawtoelevatethestatusoftheembryo,scientistsarguethatdoingsothreatensresearchthatmightbenefitthehealthofmillions.

uman stem cell research holds promise for combating some of the most recalcitrant of diseases

and for regenerating damaged bodies. It is also an ethical, legal and political minefield.

Humanstemcellresearchisathrivingfieldofscienceworldwide–holdingpromisefortreatingdiseasessuchasdiabetes,multiplesclerosisandParkinson’sdisease,aswellasforfurtheringourunderstandingofhowwedevelopfromtheveryearlieststagesoflife.

32

H IMMOrALITy AnD InVEnTIOn: the “great stem cell debate”

Internationallawpermitsstatestorefusepatentswherenecessarytoprotectmoralityintheirterritory.“Yet,howdoesapatentexamineroracourtassesswhetheraninventionisimmoraltothepointthat,unlikeotherinventions,itcan’tbepatented?Thatisaparticularlydifficultquestion,”saidDrKathyLiddellfromtheFacultyofLaw.“Itisaconundrumthatrunsheadlongintothecomplexintersectionoflawandmorality,intellectualpropertyandphilosophy.” ItispreciselythisintersectionthatanewresearchcentreintheFacultywillinvestigate.Thenewcentre–fundedbytheHattonTrustandtheWYNGFoundation–willfocusonmedicallaw,ethicsandpolicyrelatingtocontroversialissuessuchaspatentinginventionsinvolvingDNAandbodyparts,theregulationofmedicalresearchandtechnologies,assistedreproductionandsurrogacy,andthegovernanceof‘bigdata’inthemedicalfield,aswellastheregulatoryandlegislativeissuesthatstemcellresearchislikelytomeetenroutefromthelabtotheclinic. “Theseareasneedtobeconsiderednotasapost hocrationalisationofeventsthathavealreadyhappened,butalongsideandaheadoftechnologicaladvances,”saidLiddell,whoiscentrallyinvolvedinthenewcentre,aswellasbeingDeputyDirectoroftheFaculty’sCentreforIntellectualPropertyandLaw.“Tocomplementtheextraordinarysciencethatishappening,weneedtoconsidertheramificationsofbiomedicaladvancesinathoroughandtimelyway.” Liddell’sownresearchinterestsrelatetothepathwaythatleadsfromtheresearchbenchtoclinicallyeffectivetreatments.Sheseesthelaw’sroleas

“We need to consider

the ramifications of

biomedical advances

in a thorough and

timely way”

Spotlight:Stemcells

Dr Kathy Liddellk.liddell@law.cam.ac.ukFacultyofLaw

33 ResearchHorizons

facilitatingandsupportingthispathwayinmorallyresponsibleways. EScellsareusefulbecausetheyareattheearliestpointofhumandevelopmentandpossessthefull‘regenerativetoolkit’.Inotherwords,theycandevelopintoanytypeofcellinthehumanbody.Althoughstemcellsfoundintheadulthumanalsoretaintheself-renewingabilitytodevelopintospecifictissues,theycannotdevelopintoallthetissuetypesneededforregenerativemedicine;thegeneticinformationneededforsomedevelopmentalpathwayshasalreadybeenshutdown. “TheCJEUwasveryreluctanttoengagewiththeethicalandpublicpolicydebatessurroundinghumanembryos.Soitendedupansweringthepatentlawquestionswithverylittlereasoning,”addedLiddell. “Forme,thiswasthebiggestproblemwiththejudgment.TheCourthastohavethecourage,skills,wisdomandaccountabilitytofaceuptothedegreeofjudicialactivismandpolicyshapingthatisinevitableinthesecontroversialareas.Likewise,citizens,researchersandNGOshavetoacceptthatjudgeshavetomakedifficult‘calls’inthefaceofmoralandscientificuncertainty.Theysimplycan’tpleaseeveryoneinamorallypluralistsociety.” JulianHitchcock,aspecialistinlifescienceintellectualpropertyatLondonlawfirmLawfordDaviesDenoon,whoadvisesgovernmentandtheWellcomeTrustonstemcelllaw,agrees:“TheproblemIseeisthattheCJEU’sdecisionsendsthemessagethatscientistsengagedinstemcellresearchareimmoral.Moreover,theCJEU’sdecisionisbeingusedtoattemptwiderassaultsonresearch,suchasinaCitizens’Initiativecalled‘OneofUs’whichsuggestedthattheprincipleofhumandignityappliesfromthepointofconception.Hadthisinitiativesucceeded,notonlywouldithaveunderminedresearchfunding,butitwouldalso

haveimpededthefulfilmentofurgentMillenniumDevelopmentGoals.” Meanwhile,thegreatstemcelldebatecontinues,witharecentchallengeintheHighCourtbytheInternationalStemCellCorporationoveradecisionbythePatentOfficethatunfertilisedhumaneggsthathavebeenstimulatedtodivide(turningthemintoso-calledparthenotes)beincludedintheterm‘humanembryos’.TheimplicationisthatparthenoteinventionswouldalsofallwithintheCJEU’szoneofunpatentableinventions.TheHighCourtreferredtheissuetotheCJEUand,inJulythisyear,theCourtwasadvisedtorejectpartofthedecisionbytheAdvocateGeneral. “It’saverycomplexareaofthelaw–bothhighlytechnicalandhighlycontroversial.Bysupportingpeopletodevelopexpertiseinthelifesciencesandthelaw,wecanbetterrespondtotheseimportantdiscussions,”saidLiddell. Hitchcockadded:“Formulatinglawsandpoliciesthatareresponsivetotheneedsofresearch,andwhichcarrythesupportofthepublic,requiresadeepunderstandingofthewaysthatbiologyandlawintersect,aswellasimaginativethinking,powerfuladvocacyandthecouragetofightanoftenembattledcorner.” “Thequintessentialjustificationforpatentprotectionhasalwaysbeenthat

it’simportantforprotectinginvestmentinresearchandcommercialisation,”saidLiddell. “Wehaveyettoseewhetherthelackofpatentprotectionforinventionsinvolvinghumanembryoshashadachillingeffectonthetransitionofideastoclinicalrealities,orwhetherithasnudgedresearchinnew,butsimilarlyeffective,directionsthatavoidthemoraldilemmasandlegaluncertaintiesofusingembryos.Wemayneverknow–itisverydifficulttogatherthissortofempiricaldata.Butforsocietytobenefitproperlyandfullyfrommedicaladvances,wedoknowthatweneedtobereadytoenteranyandalldebatesthatwrestlewiththeirethicalandmoralimplications.”

Using human

embryonic stem cells

has been the subject of

comment, criticism and

even court cases

our thousand years ago, ancient Mesopotamians believed that the gods inscribed the future on

sheep livers. Alex Loktionov travelled to rural Armenia to investigate what liver diviners might have seen.

Thedustrisesastheflocktrudgesthroughtheheathaze,outofthedarkramshacklestableandintothebrightArmeniansun.Thetemperatureissoaring;itiswellover40oC,andthefewstuntedtreeshavelongceasedtoofferanyshade.Evenso,theanimalsmoveon,wellawareofthehugesheepdogtrackingtheireverymovement. Theypassoldbombcratersand,astheyellowishpastureopensupahead,theherderapproacheswitharopeandknife.Dzhamalisverytiredtoday:hehasthreeherdstolookafter–noeasytaskintheseconditions.Helungesatthenearestsheep.Thereisabriefandsilentscuffle,twoknotsaretiedandoneblowisstruck.Halfaminutelater,hesuspendsthedeadsheepfromatreeandstartsdismemberingbecauseitisneededforfoodandfleece.Fiveminuteson,andI’m

recordingsurfacemarkingsonthefreshlyremovedliver.Helooksbackatmeandsays“we’vegotagoodonetoday.” I’manMPhilstudentintheDivisionofArchaeology,andI’mhereaspartofmyresearchintodecision-makingprocessesoftheAncientNearEast. AncientMesopotamiansbelievedthatthegodsdepictedthefutureonthesurfaceofasheep’sliver:itssize,colourandthepresenceofanygroovesorspotscouldallbeinterpretedassigns.I’vebeenworkingonacorpusof4,000-year-oldclaytabletsmarkedwithcuneiformscriptdetailingwhatomensthedifferentliversurfacepatternswerethoughttoentail.Thisismychancetoseetheliversforrealandtocomparethetextswithgenuineanatomy. ThesheepinArmeniaarecloselyrelatedtoMesopotamianvarietiesandhavehigherlevelsofnaturalparasiteexposure.Althoughtheparasitesusuallydon’tharmthesheep,theycreatepatternsontheliversurfacethatwereimportantinthefortune-tellingprocess. AsIphotographaparticularlystrikingparasiticlesion,Ifeelthecontentof

theclaytabletscometolife.It’salwaysrewardingwhenafeaturedescribedintheomencorpuscanbetracedingenuinelivermorphology,butherewehaveaparticularlynicecase.Dzhamal’scommentaboutthesheepbeinga“goodone”wasdefinitelyjustified–althoughheclearlymeantsomethingaltogethermoregastronomic.TheancientMesopotamiansmayhavetakenthisparticularsetofmarksasagoodomenforthelifeoftheKing. Thenoiseofanenginesendstheherdrunningoffintothepasture,andabatteredwhitejeeppullsuponthedirttrackbehindme.Threemenstepout–theoldest,Hakob,isthefarmowner.HismainfocusisonsellinglivestocktotradingpartnersinnearbyIran,andhe’sjustreturnedfromthere.Full-timeshepherdslikeDzhamallookafterhisflocks.Theothers,VazgenandRafayel,areinvolvedwithArmeniantelevisionandarecollectingfootageforadocumentaryabouttheproject.AllthreefoughtinthesameregimentduringtherecentwaragainstAzerbaijanandthebondsbetweenthemarestrong. AsVazgenandRafayelgoofftofilmtheherd,I’mleftalonewithHakob.Themanisburstingwithenthusiasmfortheprojectandcan’twaittohearwhatIthinkabouthissheep’slivers.We’vehadarangeofresults,withmorphologicalalterationbyparasitesbeingveryseriousinsomecases,andalmostentirelyabsentinothers. Generally,theyoungersheephave‘cleaner’liversasparasiticmarkscanaccumulatewithage,butit’snotthissimple.Livercolourandtexturearealsoimportant,andtheseareprimarilyaffectedbythedietoftheanimalbeforeslaughter. AsItellthistoHakob,henodsvigorouslyandnotesdownthekeypoints.Thenhejokinglyasksifhecanfeedhissheepinaparticularwaytogetmorefavourableomens–ArmeniansareChristian,andactuallyhavetheoldestestablishedChurchintheworld,buttheinterestinearlierculturesisstill

34 Insideout:AlexLoktionov

Extreme sleepover:Divining destiny in

rural Armenia

F

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www.cambridge.org/research-horizons

Co

ward

and

Wells

Textbo

ok o

f CLIN

ICA

L EMB

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LOG

Y

Textbook of

CLINICAL EMBRYOLOGY

EDITED BY Kevin Coward and Dagan Wells

Cover illustration: images © Nuffi eld Department of Obstetrics & Gynaecology, University of Oxford.

The success of assisted reproductive technology is critically dependent upon the use of well-optimized protocols, based upon sound scientifi c reasoning, empirical observations and evidence of clinical effi cacy. Recently, the treatment of infertility has experienced a revolution, with the routine adoption of increasingly specialized molecular biological techniques and advanced methods for the manipulation of gametes and embryos.

This textbook – inspired by the postgraduate degree programme at the University of Oxford – guides students through the multi-disciplinary syllabus essential to ART laboratory practice, from basic culture techniques and micromanipulation to laboratory management and quality assurance, and from endocrinology to molecular biology and research methods.

Written for all levels of IVF practitioners, reproductive biologists and technologists involved in human reproductive science, it can be used as a reference manual for all IVF laboratories, and as a textbook by undergraduates, advanced students, scientists and professionals involved in gamete, embryo or stem cell biology.

Kevin Coward is Principal Investigator and Director of the MSc Clinical Embryology, Nuffi eld Department of Obstetrics & Gynaecology, University of Oxford, Oxford, UK.

Dagan Wells is a Scientifi c Leader at Oxford NIHR Biomedical Research Centre Programme, Nuffi eld Department of Obstetrics & Gynaecology, University of Oxford, Oxford, UK.

Other titles of interest:

How to Improve your ART Success Rates: An Evidence-Based Review of Adjuncts to IVFEdited by Gab Kovacs (ISBN 9781107648326)

In-Vitro Fertilization, 3rd EditionKay Elder and Brian Dale (ISBN 9780521730723)

Preimplantation Genetic Diagnosis, 2nd EditionEdited by Joyce Harper (ISBN 9780521884716)

Cover designed by Zoe Naylor.

Cow

ard & W

ells 9780521166409 Cover. C

M Y

K

Stem Cells in Reproductive MedicineBasic Science and Therapeutic Potential

EdiTEd By

Carlos Simón, Antonio Pellicer and Renee Reijo Pera

Third EdiTion

Stem cell science has the potential to impact human reproductive medicine significantly – cutting-edge technologies might allow the production and regeneration of gametes from human stem cells and differentiated cells, offering potential treatment to infertile patients. Written by leading experts in the field Stem Cells in Reproductive Medicine brings together chapters on the genetics and epigenetics of both the male and female gametes and advice on the production and regeneration of reproductive tissues and cells in men and women, trophoblasts, and endometrium from stem cells of various sources. Although it focusses mainly on the practical elements of the use of stem cells in reproductive medicine, the book also contains a section on new developments in stem cell research. The book is essential reading for reproductive medicine clinicians, gynecologists, and embryologists who want to keep abreast of practical developments in this rapidly developing field.

Carlos simón MD PhD is Professor and Scientific Director of Instituto Valenciano de Infertilidad (IVI), Valencia University, Valencia, Spain.

anTonio PElliCEr MD PhD is Professor and President of Instituto Valenciano de Infertilidad (IVI), Valencia University, Valencia, Spain.

rEnEE rEijo PEra PhD is Professor and Director of Human Embryonic Stem Cell Research and Education, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Palo Alto, CA, USA.

Cover designed by hart mcleod ltd

9781

1070

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, PE

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& R

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StE

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imón, P

ellicer and R

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edicine

Cover image: Bridle path. Photo by Jeffrey T. Siliko 2012. Cover design by Alice Soloway

Bioethics and the Future of Stem Cell Research

HY

UN

Bioethics and the Future of Stem Cell R

esearch

“Finally we have a very useful volume that takes us well beyond the ethical issues surrounding embryonic stem cells to a set of important ethical concerns that arise as soon as we mobilize clinical trials using stem cells from any source.” – Harold T. Shapiro, Princeton University

“At last we have a comprehensive review of the crucially important yet enduringly controversial fi eld of stem cell research. Ranging across topics as diverse as philosophy of science, ancient mythology, modern biology, the meaning of language, and the intricacies of FDA requirements for the compassionate use of investigational biologic drugs, Hyun weaves together a story of humanity’s latest effort to defi ne, heal, and even regenerate itself.” – R. Alta Charo, University of Wisconsin Law School

“As the caravan of stem cell science has raced ahead at breakneck pace over the last decade, Insoo Hyun has been riding shotgun, facilitating some of our fi eld’s most critical deliberations, and challenging us to set a socially responsible course for this transformative research. In this wonderfully accessible book for both expert and layman, Hyun navigates the dynamic relationship between philosophical and research ethics to dissect stem cell research with the philosopher’s scalpel, applying the incisive edge of pure reason in perfect balance with the practical imperatives that his new science offers our society. Hyun speaks with an authoritative voice on science, medicine, policy, and realms philosophical where answers are harder to come by than in the laboratory.” – George Q. Daley, Director, Stem Cell Transplantation Program, Hospital

and Dana Farber Cancer Institute, and Professor, Harvard Medical School

Despite years of heated social controversy over the use of human embryos in embryonic stem cell research, the caravan of stem cell science continues to proceed at an unrelenting pace all around the world. Bioethics and the Future of Stem Cell Research urges readers to look beyond the embryo debate to a much wider array of ethical issues in basic stem cell science and clinical translational research, including research involving adult and induced pluripotent stem cells. Insoo Hyun offers valuable insights into complex ethical issues ranging from preclinical animal studies to clinical trials and stem cell tourism, all presented through a unique blend of philosophy, literature, and the history of science, as well as with Dr. Hyun’s extensive practical experiences in international stem cell policy formation. This thoughtful book is an indispensible resource for anyone interested in the science of stem cells and the practical and philosophical elements of research ethics.

INSOO HYUN is Associate Professor of Bioethics and Philosophy at Case Western Reserve University School of Medicine. He is an internationally recognized authority on stem cell research ethics. Dr. Hyun is the past Chairperson of the Ethics and Public Policy Committee for the International Society for Stem Cell Research (ISSCR). His bioethics articles have appeared in Science, Nature, Cell Stem Cell, the Journal of Clinical Investigation, the Hastings Center Report, among many other publications. His bioethics articles have appeared in Science, Nature, Cell Stem Cell, the Journal of Clinical Investigation, the Hastings Center Report, and the Cambridge Quarterly of Healthcare Ethics, among many other publications.

INSOO HYUN

Atkins,Amor, Fletcher and M

illsThe Biology of M

ultiple Sclerosis

Multiple sclerosis is the most common debilitating

neurological disease in people under the age of 40

in the developed world.

Many publications cover medical and clinical

approaches to the disease; however, The Biology

of Multiple Sclerosis provides a clear and concise

up-to-date overview of the scientifi c literature on

the various theories of MS pathogenesis.

Covering the main elements of scientifi c

research into multiple sclerosis, the book

contains chapters on the neuropathology of the

disease, as well as a detailed account of the most

extensively used animal model experimental

autoimmune encephalomyelitis.

The book contains chapters regarding the

role of viruses in the development of multiple

sclerosis. Viruses have long been implicated,

and chapters on animal models based on virus

infection, as well as on their possible role in the

etiology of MS are included.

Of interest to MS researchers, the book is

written to also be of value to postgraduate and

medical students.COV

ER D

ESIG

N:

JACK

IE T

AYL

OR

Multiple Sclerosis

The Biology of

Gregory Atkins Sandra Amor Jean M. Fletcher Kingston H. G. Mills

GREGORY ATKINS DSc is a Fellow Emeritus of the Department of Microbiology, Moyne Institute of Preventive Medicine, Trinity College Dublin, Dublin, Ireland.

SANDRA AMOR PhD is a Professor and Head of MS Research, Pathology Department, VU Medical Center, Amsterdam, the Netherlands and has an honorary position at QMUL, London, UK.

JEAN M. FLETCHER PhD is an Assistant Professor at the Schools of Medicine and Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.

KINGS TON H. G. MILLS PhD is a Professor at the School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.

OTHER TITLES OF INTERES T:

Multiple Sclerosis TherapeuticsEdited by Jeffrey A. Cohen and Richard A. Rudick (ISBN 9780521766272)

Demyelinating Disorders of the Central Nervous System in ChildhoodEdited by Dorothée Chabas and Emmanuelle L. Waubant (ISBN 9780521763493)

Multiple Sclerosis: Recovery of Function and NeurorehabilitationEdited by Jürg Kesselring, Giancarlo Comi, and Alan J. Thompson (ISBN 9780521888325)

C O V E R I L L U S T R AT I O N : Macrophage engulfi ng a damage myelinated axon in the CNS © 2012 Steve Gschmeissner

Atkins Et Al 97805211968002 PPC. C M Y K

Cover illustration: Masson’s trichrome staining and immunohistochemical staining for DSP of human dental pulp stem cell scaffold constructs implanted subcutaneously in nude mice for 8 weeks, on NF-PLLA scaffolds.

Biomaterials and

Regenerative Medicine

Written by world-leading experts, this book focuses on the role of biomaterials in stem cell research and regenerative medicine. Emphasizing basic principles and methodology, it covers stem cell interactions, fabrication technologies, design principles, physical characterization, and biological evaluation, across a broad variety of systems and biomaterials. Topics include:

• Stem cell biology, including embyonic stem cells, iPS cells, HSCs, and progenitor cells

• Modern scaffold structures, including biopolymer, bioceramic, micro- and nanofi ber, ECM, and biohydrogel

• Advanced fabrication technologies, including computer-aided tissue engineering and organ printing

• Cutting-edge drug delivery systems and gene therapy techniques• Medical applications spanning hard and soft tissues, the cardiovascular

system, and organ regeneration

With a contribution by Nobel laureate Shinya Yamanaka, this is a must-have reference for anyone in the fi eld of biomaterials, stem cell biology and engineering, tissue engineering and regenerative medicine.

Peter X. Ma is the Richard H. Kingery Endowned Collegiate Professor at the University of Michigan. A recent winner of the Clemson Award (2013) from the Society of Biomaterials and a Distinguished Scientist Award (Isaac Schour Memorial Award 2013) from the International Association for Dental Research, he is a Fellow of the American Institute for Medical and Biomedical Engineering (AIMBE), a Fellow of the International Union of Societies for Biomaterials Science and Engineering (IUSBSE), and a Fellow of the American Association for the Advancement of Science.

Cover designed by Zoe Naylor

Biomaterials and Regenerative

MedicineEdited by Peter Ma

Ma

Ma 9781107012097 PPC

. C M

Y K

“Professor Ma, an internationally-known materials scientist, leads an impressive collection of experts in documenting the state of the art in biomaterials design and synthesis for regenerative medicine.”

W. Mark Saltzman, Yale University

Scientific research highlights

from Cambridge

enormous.He’sraisedavalidpointhere.Isaythatit’sworthatry–wecan’tbecertainthattheancientMesopotamiansknewthatsheepdietaffectedtheirentrailmorphology,butit’saninterestingthought. Meanwhilethemenhavefinishedtheirworkfortheday,heraldedbythesmellofroastlambwaftingonthewarmeveningbreeze.Aswesitbythefireandconsumethetendermeat,thesheepdogjoinsourmeal.Nobodydriveshimaway,andasthewineispoured,Inoticethatthedogisgivensomeaswell.Iaskmyfriendsaboutthis,buttheylooksurprised.AsHakobputsit,“everybodywhocomestoafeastshouldeatanddrinkastheywish.”Whymakeanexceptionhere? Andsoanotherdaydrawstoacloseinthisincrediblecountry,wheremorphologicallyaccuratesheeplivers,ancientChristianritesandinebriatedsheepdogslivetogetherinharmony.Andyet,asthenearbybombcraterstestify,20yearsagothislandwasawarzonethatclaimedover30,000lives.It’sasoberingthought,andasIthinkofreturningtoCambridgeandanalysingmybeautifulliverphotos,itjustcan’tsinkinthateveryonesittingaroundourfiremightbekilledinwar.Myfriendssmileandjokeinreturn–“theliveromensaregood,sowe’llbefine.”

Alex is a Benefactors’ Research Scholar at St John’s College Cambridge.

35 ResearchHorizons

Alex Loktionov al621@cam.ac.uk DepartmentofArchaeology andAnthropology

T +44(0)1223765443 E research.horizons@admin.cam.ac.uk W cam.ac.uk/research f facebook.com/cambridge.university twitter.com/cambridge_uni youtube.com/cambridgeuniversity

ContactResearchHorizonsOfficeofExternalAffairsandCommunicationsThePittBuilding,TrumpingtonStreetCambridge,CB21RP

CoverDevelopmentoftheembryo(suchasthismouseembryo)intoanadultdependsontheabilityofstemcellstodevelopintoanycelltype;findoutmoreaboutourresearchonstemcellsintheSpotlightfocusthisissue.

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