nanomedicine - philosophie · 4 robert a. freitas (1999): nanomedicine, volume i: basic...

Nanomedicine•ABriefHistoryofNanomedicine•Theranostics•TargetedDrug-Delivery•PolymerTherapeutics•RegenerativeMedicine•Ethicalandsocietalissues

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The Images: Courtesy of the Molecular Biophysics Group at Delft University of Technology

Theaimofthisbriefingpaperistoprovideconcise,correctandbalancedinformationtoadvancepublicdebateamongconsumers,media,policymakers,producersandresearchersaspartoftheEuropeanCommission-fundedNanobio-RAISEproject.1Itresultsfromthecombinedcontributionsofnaturalandsocialscientists,industrialists,andgovernmentalandpublicinterestorganisationsacrossEurope.ItisintendedtoprovideinformationanddoesnotrepresenttheviewsorpolicyoftheEuropeanCommissionoranyotherbody.

IntroductionAbroadarrayofpresentandfutureresearchdevelopmentsaregenerallylumpedtogetheras“nanotechnology.”Acommonfeatureisonlythattheyareconcernedwithlargeandsmallthingswhereatleastsomerelevantmeasuresareinthenanometrerange(10-9to10-7metres)andthusinthesize-rangeofDNA-moleculesorviruses.Morestringentdefinitionsrequirethatnanotechnologicalresearchberestrictedtothescientificinvestigationandtechnicalexploitationofnovelpropertiesthatappeardiscontinuouslyatthenanoscale:atonofgoldhasthesamechemicalpropertiesasamilligram,butagoldnanoparticleshowsinterestingandinitiallysurprisingnewbehaviours.Thismorestringentdefinitionofnanotechnologicalresearchremainsquiteunspecificregardingtechnologicalapplications:nanotechnologyisallthatthesenewlydiscoveredpropertiesandprocessesmightbegoodfor.Andhere,theimaginationrunswild,challengingustoidentifyandsupportpromising,feasibleaswellasbeneficialshort-andmedium-termdevelopments.

Onfirstsight,nanomedicineistherathermorewell-definedapplicationofnanotechnologyintheareasofhealthcareanddiseasediagnosisandtreatment.Buthere,too,oneencountersabewilderingarrayofprogrammesandprojects.Artificialboneimplantsalreadybenefitfromnanotechnologicallyimprovedmaterials.Nanostructuredsurfacescanserveasscaffoldingforcontrolledtissue-growth.Of

course,allkindsofmedicaldevicesprofitfromtheminiaturisationofelectroniccomponentsastheymovebeyondmicrotonano.Thisaffectsdiagnostictools,pace-makers,“camerasinapill,”etc.Nanoparticulatepharmaceuticalagentscanpenetratecellsmoreeffectivelyaswellasbeingabletocrosstheblood-brain-barrier.Afterinjectingnanoparticlesintotumours,thesecanbestimulatedelectromagneticallyfromoutsidethebody–byemittingheat,thestimulatedparticlescanthendestroythetumourcells.Antibacterialsurfacesincorporatingphotocatalyticorbiocidalnanoparticlesreducetheriskofinfectionindoctors’officesandpublicbuildings.Portabletestingkitsallowforself-monitoringandspeedydiagnosis.Newcontrastagentsandvisualisationtoolsprovideacloserlookatcellularprocesses.Butthis,too,isnanotechnologyinaction:nanoparticulatesteroidsareintroducedintothebody’sownredbloodcells;asthecellsdietheirnaturaldeaths,thesteroidsarereleasedtothebodyinverysmalldoses,thusminimising,ifnotexcludingtheside-effectsofmanysteroidtreatments.2

Theseexamplesandmanymoreofongoingdevelopmentscanbefoundinvariousreportsontheprospectsandpromisesofnanomedicine.Butthoughtheseexamplesarenothingtofrownat,nanomedicinehasbeenconceivedasafarmoreambitiousenterprise:"Nanomedicine comes into being where a molecular understanding of cellular processes is strategically combined with capabilities to produce nanoscale materials in a controlled manner."3Withthesegreaterambitionscomestheformidablechallengetoassessmorevisionaryprogrammesnotonlyfortheir

mean more people on Earth. But how many more people can the Earth sustain?"22Inasimilarvein,theEuropeanTechnologyPlatformnotesthatonelargeimpactofnanomedicinewillbe"increased costs of social security systems due to ageing of population."23

Itisimportanttobeclearabouttheachievablegoalsofnanomedicinethatareinthepublicinterest.Popularfascinationwithenvisionedtechnologiesoflifeextensiondoesnotrenderlongevityapublicgood.Conversely,beforeworryingaboutincreasedlife-expectancyasoneofthepotentialimpactsofnanomedicine,oneshouldensurethatnanomedicinegetsoffthegroundandmeetstheformidablechallengetoconvertevenitsmoremodestambitionsintoreality.

Asitisconvertedfromvisiontoreality,thenotionofcellrepairwillbeatestinggroundfortheveryideathatcellularprocessesinvolveananotechnologicalmachinerythatcanbreakdownandthatcanalsoberepaired.Thismetaphorofnanomachineryhasprovenproductiveforunderstandingcellularmechanismsbutitisunclearasofyethowfarthismetaphorcarrieswhenitcomestotheprecisioncontrolofhighlycomplexbiologicalrealities.24Italsoleadstotheethicalquestionofwhetherwemaymechanicallyreducethehumanbeingtoasumofphysicaltraits.25

Ethical and societal issuesTraditionally,medicalethicsispatient-andtreatment-centredratherthanresearch-anddisease-centred.Inotherwords,mostmedicalethicsisfocusedondoctor-patientrelations,onend-of-lifedecisions,onresource-allocation,ontreatmentchoices,informedconsent,andthelike.Biomedicalresearchbecomessignificantonlyasitentersclinicaltrials.Accordingly,medicalethicshasbeenratherindifferenttothelevelofmedicalintervention.Whiletheremovalofthecausesofdiseaseisgenerallypreferabletosymptomatictreatments,itdoesnotappeartomattermuchwhetherdiseasesareaddressedatamolecularorcellularorwhole-organlevel.

Astheprevioussectionsindicated,however,thenanomedicalresearchprogrammeraisesissuesthatservetoexpandthescopeofmedicalethics.Thisconcerns,forexample,thedistinctionbetweendruganddeviceanditsregulatoryimplications.Italsoconcernstherecognitionandacknowledgmentoflimitsofknowledgeandcontrol,inotherwords,caretoavoidhypeandtostateachievablegoalscrediblyandresponsibly.Regenerativemedicineintheserviceofpublichealthandqualityoflifeshouldbedistinguishedfromthenotionthatlife-extensionisapublicgood.Finally,nanomedicalresearchraisesquestionsofdistributivejusticeandglobalequityas

majorpublicinvestmentsaredirectedatcancertreatmentsandthusatattemptsfurthertoreducemortalityindevelopedsocietieswhereitisalreadycomparativelylow.

Nanomedicalethicsshouldnotservetovalidateanuncertainfuture,forexample,byassumingtooreadilyanincreaseofdiagnosticpowersoranimpactonlife-expectancy.Instead,itmightcontributetopublicdeliberationontheresearchagendafornanomedicine.Onceonestartsquestioningitsprimaryfocusoncancerandcardiovasculardiseases,onemighthavetoconsidertheverydefinitionsofillnessandhealthandthemedicalisationofsociety.Similarly,onemightconsiderthemetaphorsweusetodescribethehumanbeingorthechangingboundariesofhumanbodiesasthebody'sowntissueorinsulin,forexample,mightbegeneratedoutsidethebodyorbywayofanimplanteddevice.

ConclusionA2007nanomedicalbulletinofferedthefollowingnewsitem:"Working with an organic semiconductor, researchers at the University of Arkansas have fabricated and tested two similar but slightly different biosensors that can measure physiological signs. Integrated into 'smart' fabrics – garments with wireless technology – the sensors will be able to monitor a patient's respiration rate and body temperature in real time."26Inmanyways,thisappearstobenanotechnologyatitsbestandisthereforenotatalluniquetotheUniversityofArkansas.Itisanexampleofhighlyinterdisciplinaryresearchthatintegratesfunctionalitiesatthenanoscale,namelytheotherwiseseparatenanotechnologicalfieldsofpoint-of-carediagnosticsand'smart'fabrics.Thiskindofmedical nanotechnologymayenableaprofoundreconfigurationoftherelationsbetweendoctors,patients,andhospitals.Itcanalsopromotethefurthermedicalisationofsociety,thatis,ofbringingsocialbehaviours(risktaking,dietarypractices,stressandanger)intotherealmofmedicalsupervision.Thesedevelopmentsarelikelytobecontestedandcallforthedebateoftheirethicalandsocietalimplications.

Itisunlikelythatnanomedicinewillbeastransformative.Itdefinesitselfasbasicmedicalresearch,andisapplication-orientedlikeallmedicalresearch.Assuch,nanomedicinecanrealiseitspromises

References1 Nanobiotechnology:ResponsibleActiononIssuesinSocietyandEthics:http://nanobio-raise.org/2 MauroMagnani Eythrocyte Engineering for Drug Delivery and Targeting.NewYork:Kluwer,2003.3 VolkerWagnerandAxelZweckNanomedizin:Innovationspotenziale in Hessen für Medizintechnik und Pharmazeutische Industrie Wiesbaden:HessischesMinisteriumfürWirtschaft,2006.4 RobertA.Freitas(1999): Nanomedicine, Volume I: Basic Capabilities,Georgetown,TX:LandesBioscience.5 Cancer NANOTECHNOLOGY: Going Small for Big Advances – Using Nanotechnology to Advance Cancer Diagnosis, Prevention and Treatment.Washington,DC:U.S.DEPARTMENTOFHEALTHANDHUMANSERVICES,National InstitutesofHealth,NationalCancerInstitute,2004.6 Nanomedicine: Nanotechnology for Health – European Technology Platform.Brussels:EuropeanCommission, ResearchDG,2006,p.12.7 Ibid.,p.10,seealsop.6andespeciallyp.12.8 Nanomedicine: An ESF – European Medical Research Councils (EMRC) Forward Look report.Strasbourg:European ScienceFoundation,2006.9 Likesyntheticbiology,nanomedicineisthuspoisedtobecomeanoff-shootofnanotechnologythatclaimsitsown, atleastpartlyseparateidentityandintegrity.–TwooftheauthorsoftheESF-reportreflectonthisquiteexplicitly, seeRingsdorfandDuncan"nanogamesgainingground"2006.10 TheEuropeanTechnologyPlatformsubsumesnewpharmaceuticalsunder"targeteddelivery":"Seamlessly connectingDiagnostics,TargetedDeliveryandRegenerativeMedicine:Diagnostics,targeteddeliveryand regenerativemedicineconstitutethecoredisciplinesofnanomedicine.TheEuropeanTechnologyPlatformon NanoMedicineacknowledgesandwishestoactivelysupportresearchattheinterfacebetweenitsthreescience areas."Thisresearchattheinterfacecanestablishtheranostics(p.9).11 AlfredNordmann"KnotsandStrands:AnArgumentforProductiveDisillusionment,"Journal of Medicine and Philosophy,32:3,2007,pp.217-236.12 ESF-report,p.11.13 Thisconstructiveprinciplealsodistinguishesnanomedicine(asakindofnanotechnology)frombiotechnologywhich isdevelopinganddeployingproteinsasactiveagents.14 ETP,p.16.15MatthiasAdam"Whattoexpectfromrationaldrugdesign,"Expert Opinion on Drug Discovery2(6),2007, 773-776.16 JoachimSchummer"TheImpactofNanotechnologiesonDevelopingCountries,"inFritzAllhoff,PatrickLin,,James Moor,JohnWeckert,eds., Nanoethics: The Ethical and Social Implications of Nanotechnology,Wiley,2007.17AndreasJordan"FromSciencetoBusinessin15Years"intheProceedingsofEuroNanoForum 2005: Nanotechnology and the Health of the EU Citizen in 2020,editedbyMichaelMason,SophiaFantechi,Renzo Tomellini,Brussels:ECDGResearch,2006,p.16.18 TheEuropeanGrouponEthicsinScienceandNewTechnologiestotheEuropeanCommission"Opiniononthe ethicalaspectsofNanomedicine(OpinionN°21),"January17,2007,section5.5.1,p.57.19WhiletheEuropeanTechnologyPlatformconsidersregenerativemedicineoneofnanomedicine'sthreecore disciplines,theESF'sForwardLooktreatsitonlyundertheheadingofnewmaterials(inparticular,scaffoldingfor tissuegrowthandrepair).TheUS-reportonCancerNanotechnologydoesnotrefertoitatall.20 ETP,p.6.21 PaulMillerandJamesWilsdon“Themanwhowantstoliveforever”inPaulMillerandJamesWilsdon(eds.)Better Humans? The Politics of Human Enhancement and Life Extension,London:DEMOS,2006,pp.51-58.22 IvanAmatoNanotechnology - Shaping the World Atom by Atom,Washington:NationalScienceandTechnology Council,InteragencyWorkingGrouponNanoscience,EngineeringandTechnology,1999,p.8.23 ETP,p.24.24RichardJonesSoft MachinesOxford:OxfordUniversityPress,2004.25 Jean-PierreDupuyinJournal of Medicine and Philosophy,32:3,2007.26NanoMedicineNews(www.euronanotechnews.com),#71,July20,2007.

onlyinthelongerterm.Whileitmakesacompellingcaseforthesepromises,italsoasksforourpatience.Andaswithallbasicresearch,somethingisboundtocomeofit,thoughnotperhapsthefullmasteryofphysiologicalcomplexitiesthatisenvisionedinthenameoftheranostics,individualisedmedicine,andcellrepair.Someofitsmostimportantcontributionswillconsistofprogressininstrumentationandanalyticmethodsthatisnowconsideredprimarilyastepping-stonetowardsbiggerandbetterthings.

Oneshouldthereforenotexpectnanomedicinetorevolutionisemedicine.Itisonepromisingavenuebywhichmedicinecanadvance.Attheendoftheday,itwillhavecontributednewtreatment-optionsforcertaindiseases,somenewnanomedicines,betterimaging-techniquesandotherdiagnostictools.Thesewilladdsignificantlytothecurrentlyavailablearsenaloftherapiesandmedicines,raisingsimilarethicalandsocietalconcernsasdidthemedicaladvancesofthepast.Demonstrationsofefficacyhavetobeconsideredtogetherwithphysiologicalandenvironmentalside-effectsandgeneralquality-of-lifeissues,comparingallofthesetoalternativetreatmentoptions.Andlikealldisease-orientedresearch,itrequirespublicdeliberationonwhichdiseasesshouldbeprioritisedinthecontextofglobalhealthcare.

Nanomedical sectors •Drugdelivery•Biomaterials• In vivoimaging• In vitrodiagnostics• Activeimplants•Drugs&therapy

NanoBio-RAISECo-ordinationoffice:Julianalaan672628BCDelftTheNetherlandst+31(0)152786626f+31(0)152782355info@nanobio-raise.orgwww.nanobio-raise.org

feasibility,butalsofortheproperbalancingofpublicinvestmentandsocietalneed,and,thusfortheirlikelybenefits.Theseambitionsrevolvemainlyaroundtheconcepts“theranostics(i.e.thecombinationofdiagnosisandtherapeuticfunctionalityinonedevice,enablingpre-symptomatictreatment)”,“polymer therapeutics(rationaldesignofnanomedicines)”,“targeted drug-delivery (individualisedmedicine)”,“regenerative medicine(cellrepair).”Thepromiseassociatedwiththesetermsisthatoftherapeuticallymoreeffective,individualised,dosereducedandmoreaffordablemedicine.Beforeconsideringtheseambitionsandpromisesonebyone,ithelpstoplacetheminthelargerhistoricalcontextofthedevelopmentofnanomedicine.

A Brief History of NanomedicineNanomedicinehasbeenanimportantpartofnanotechnologyfromtheverybeginning.Andsincenanotechnologybeganasavisionaryenterprise,nanomedicinestartedbyapplyingmainlynanomechanicalconceptstothebody.Inhis1999bookonNanomedicine,RobertFreitasassembledanimpressivearrayofingeniousideasthatderivefromongoingdevelopmentsandinevitablyleadtoextravagantspeculations.4Freitas'sconflationoftheshort-termwiththelong-termandevenwithtechnicalimpossibilitiesremainscharacteristicevenofthefarmorerestrainedtechnicalpapersoftoday.The2004presentationofthecancernanotechnologyinitiativeintheUnitedStatesrevolvesaroundthegoalof“eliminating death and suffering from cancer by 2015”.5The2006EuropeanTechnologyPlatformonNanomedicineismoresubtlethanthis.Itspeaksofa

“revolution in molecular imaging in the foreseeable future, leading to the detection of a single molecule or a single cell in a complex biological environment.”6Thisstatementelegantlyglossesoverthefactthattheproblemsofdetectingmoleculesandcellsaremagnitudesapart:Cellsareahundredtoathousandtimeslargerthanmoleculesanditiscertainlymucheasiertoimagineacontrastagentormarkerattachedtoorinsideacell.Inthesamereport,thespeculativespiritofEricDrexlerandRobertFreitasinformsavisionofcell-monitoringandrepair:Thedetectionofdiseasewillhappenasearlyaspossibleand“ultimately this will occur at the level of a single cell, combined with monitoring the effectiveness of therapy.7”

ThemostbalancedoverviewofnanomedicinetodateistheEuropeanScienceFoundation’s2006Forward Look on Nanomedicine.8Itisfirmlygroundedincurrentresearch.Asitdistancesitselffromspeculationandhype,itseekstogiveshapetoananomedicalresearchagendathatisclearlysetapartfromthegrab-bagofnanotechnologies.9Ineffect,thereportdrivesawedgebetweenscientific nanomedicineandsomethinglesserthatmightbecalledmedical nanotechnology.Nanomedicineisbasedonmolecularknowledgeofthehumanbodyanditinvolvesmoleculartoolsforthediagnosisandtreatmentofdisease.Medicalnanotechnologyencompassesalltheotherwaysinwhichnanotechnologyaffectshealthcare,especiallyallthatcomesfromtheminiaturisationofdevicesandtheintegrationofinformationandcommunicationtechnologiesindiagnostictoolsandhealthmonitoring–includingaradicaltransformationofthepresentday

hospitalwithitstraditionaldoctor-patientrelationships.

Nanomedicine,inotherwords,isdisease-centred,tryingtodobetterandonamolecularlevelwhatphysiology,pathology,andthevariousspecialisedmedicalscienceshavebeendoingsofar.Becauseitisdisease-centred,nanomedicineleavestomedicalnanotechnologiesthemoregeneralandperhapsmoreprofoundtransformationsofhealthcare:theseconcernpublichealthmonitoring,theintegrationofmedicalpracticesintodailypatternsofworkandleisure,theredefinitionofthephysiologicalbodyasabodyofdata,andthereorganisationofthetherapeuticcontextwithitsmedicalexperts,insurancecompanies,stateinterests,andhealth-careinstitutions.Bythesametoken,nanomedicineinheritsitsfocusoncertaindiseasesfromongoingmedicalresearch.Accordingly,itisprimarilyconcernedtoreducemortalityfromnon-infectiousdisease,especiallycancer.Thatis,itaimstoincrementallyreducemortalitywhereitisalreadylow,namelyinthehighlydevelopedworldwherecancerandcoronarydiseasehavebecomethemostprominentphysiologicalcausesofdeath.

AnotherpotentiallimitationofthenarrowlydefinednanomedicalfocusisbroughttolightbytheEuropeanTechnologyPlatform:itisexplicitlyaddressedtoanincreasinglysedentaryageingpopulationanditsmedicalproblems.Throughthelensofdisease-centrednanomedicine,thistranslatestothetreatmentofpainfullyarthriticjoints.Inawiderperspective,ofcourse,thehealthofjointsinvolvesquestionsofnutrition,mobility,andanintegratedapproachtotheproblemofobesity.Thestrictlynanomedicalalleviationofchronicpaininthejointsshouldbeasmallpart,indeed,ofa“treatmentpackage”thatincludesmedicalnanotechnologiesformonitoringandfeedback,alongwithphysicaltherapy,geriatricandsocio-psychologicalapproaches,togetherwitheveneconomicorpoliticalincentivesforincreasedexercise,nanotechnologicallyimprovedfootwearandsurfaces.

TheranosticsAsdistinctfrommedicalnanotechnologies,scientificnanomedicineconcentratesonfourareasofresearchanddevelopment:theranostics,anewclassofpharmaceuticals,targeteddrug-delivery,and

regenerativemedicine.10Theprospectsandproblemsofeachwarrantabriefreview.

Asindicatedbytheterm"theranostics,"itspromiseconsistsinthefusionoftherapyanddiagnostics.Asdiagnosticcapabilitiesimprove,onemightcomeupwithtreatmentswellbeforeadiseasemanifestsitselfsymptomatically.Ideally,diagnosisandtreatmentcouldbeperformedinasinglestepthroughamonitoringprocessthatautomaticallyintroducesappropriatecorrections(e.g.,plaquedetectionandremovalforthepreventionofcardiovasculardiseases).Thebenefitofbeginningtreatmentbeforethereisadiseasedependsonthequalityofdiagnosticinformation.Here,thelengthyhistoryofgenetherapyoffersasoberinglessonwithitsinitial,butasyetonlypartiallyfulfilled,promiseofrepairingspecificgenesthatareresponsibleforspecificdiseases.

Ratherthanlookingforgeneticcausesofdisease,nanomedicalexpectationsrestonvastimprovementsinimagingandmeasuringtechniques.Indeed,considerableprogressismadeontheroadtowardsin vivoimagingaswellaslab-on-a-chiptechnologiesthatsimultaneouslydeterminethousandsofparametersinatinydropofblood.Butaccesstovastamountsofinformationdoesnottranslateautomaticallyintodiagnosticcapabilities.Aswithgenetherapy,thiswillhappenonlyinapiecemealmannerandinconjunctionwithresearchinbioinformaticsorsystemsbiology.Indeed,beforewecanknowwhetheralltheadditionalphysiologicalinformationhasanydiagnosticuse,itwillhavetobeobtainedinorderforbioinformaticsandsystemsbiologytoconstructsufficientlyrobustmodelsofthehighlycomplexdynamicsattheoriginsof

disease–inthehopethatthesemodelscanonedaybeoperationalisedforthediagnosisandtreatmentofindividualpatients.Likeallbasicscientificresearch,therefore,nanomedicinerequireslong-termfundingstrategies.Itisonlyinthelongrunthatonemightrealisethepromisedhealthcaresavingsthatwouldresultfromearlierinterventionintothediseaseprocess.

Targeted Drug-DeliveryTheideathatpharmaceuticalagentsshouldbedeliveredspecificallytodiseasedcellsholdsthepromiseofavarietyofbenefits.Especiallyif,inaddition,thepharmaceuticalagentweretobeadaptedtothecell'sgenome,thesebenefitswouldbegroupedundertheheading"personalisedmedicine."However,"individualisedmedicine"isthemoreappropriatetermsincethisformoftreatmentisaddressedataspecificdisease-process,perhapsanindividualgenome,butdisregardsthebiographic,cultural,andlegalparticularsthatdefineaperson.

Thepromiseofindividualisedmedicineisthatitisefficient.Targeteddrug-deliveryallowsdoctorsandpatientstobenefitfromsmalldosagesatjusttherightplaceandthusfromfewerside-effects.Evenwithouthavingtounderstandthecauseofthedisease,medicalresearchersexpecttodealwithitjustasthingsstartgoingwrongwiththemolecularmachineryinsidethecell.Smallerdosages,earlyandefficienttreatmentarefinallysaidtotranslateintolowerhealthcarecosts.Ofcourse,ascloselyastheyappeartohangtogether,itisimportanttoevaluatethesevariousclaimsfortheefficiencyofnanomedicineoneatatime.11Especiallythepromiseofcost-efficiencymightsendawrongsignal:likeallofnanomedicine,thisisbasicresearchwith

anuncertain,thoughpotentiallyprofoundimpact.Itneedspublicsupportonitsmeritsandnotonthepromiseofashort-ormedium-termreturn.

Polymer TherapeuticsTheprogrammeoftargeteddrugdeliveryrequiresnewnanomedicineswhichconsistofatleasttwocomponents:oneofthemtheactiveingredient,theotheratransportdeviceorconjugatethatattachesitscargoattherightplace.12Itisthisconstructionofatechnicalsystemthatcombinesdifferentfunctionalitieswhichbringliposomes,polymer-proteinconjugates,dendrimers,andothernanoparticlesintotherealmofnanotechnologyproper,asopposedtotraditionalpharmacologyorsupramolecularchemistry.13Also,itisthismodularitywhichanswersnanomedicine'scallfor"design on a disease-specific basis."

WhileEUandUSreportsonnanomedicineemphasisethenotionofdesign,theEuropeanTechnologyPlatformtakespainstopointoutthattherelevantdesignfeaturescanbeachievedby "rational design or by high throughput screening or even by a combination of the two."14Indeed,theambitiontoconstructnanomedicinesisreminiscentofpreviousprogrammesof"rationaldrugdesign,"suchasattemptstopreventdiseasebyinhibitingRNAexpressionandproteinformation.Ifnanomedicineseekstokeepacautiousdistancetotheseprogrammes,thisisbecausetheysendasoberingmessage,havingprovedunabletocompetewithrandomisedhigh-throughputscreeningasthefarmoresuccessfulapproachtodrugdevelopment.15Similarly,theconstructivedesignambitionsofscientificnanomedicinefaceatremendouschallengetomasterphysiologicalcomplexity.Underthebestofcircumstances,itisamatter"only"ofpackaginganactiveingredientwithasuccessfultargetingagent.Thoughtheiroriginspredatetheadventof"nanotechnology,"somenanomedicineshavealreadybeenapprovedforroutineuseandnowhavetoprovethemselvesincompetitionwithsometimeslessexpensivealternatives.16

Ifonlybecauseofthelengthofthemulti-stageapprovalprocess,onlytimewilltellthesuccess-storyofnanomedicines.Theirdefinitionasdesignedtwo-componentsystemssuggestsashort-cut,namelytoconsiderthemmedicaldevicesratherthanpharmacologicalsubstances,especially

whentheactiveingredientisalreadyknown.Sincetheapprovalofmedicaldevicesproceedsataconsiderablyfasterpace,thiscouldspeedupnanomedicaldevelopment.Inoneinstance,atleast,thisroutehasbeenchosensuccessfully.Bycreatingironoxidenanoparticlesthatareaccumulatedbycancercellsandthenapplyingtothemanexternalmagneticfield,tumourscanbedestroyedveryeffectively.Thecoatednanoparticlesareheretakentobecomponentsofatechnicaldevice,aspartsofthemachinethatcreatesthemagneticfieldandthusinducesavibratorymotioninthoseparticleswhichthenleadstotheheatinganddestructionofthetumour.Sincetheparticlesarenotintroducedfortheirchemicalpropertiesoraspharmacologicallyactiveagents,theydonotneedtoberegulatedasdrugs.Itislargelybecauseofthisthattheproceduremovedswiftly"FromSciencetoBusinessin15Years."17

Ontheotherhand,nanoparticulateironoxidemaywellposeriskstothepatient'shealthor,aftersecretion,totheenvironment.Whilethisriskmaybeacceptableinthetreatmentofanotherwisedeadlydisease,theapprovaloftheseironoxidesasdrugsmaystillbecalledfor.ThedifficultyofthisdilemmaisillustratedbytherecommendationoftheEuropeanGrouponEthicsinitsopiniononnanomedicine:"The mechanism of action is a key factor in deciding whether a product should be regulated as a medicinal product or a medical device."18Inthecaseatissue,theregulatoryquestioncannotbedecidedbyreferringtoamatteroffact.Itwillbecontested,afterall,whatthemechanismofactionis:isittheactionoftheironoxideparticlesascomponentsofthedeviceorisittheiractioninandbeyondthehuman

bodyafterdestructionofthecancercells?Initspublishedreports,thenanomedicalcommunitygenerallyurgescautionandcloseethicalaswellasregulatoryreview.

Regenerative MedicineAfterdiagnosticsandtheranostics,individualisedmedicineandthenanomedicinesrequiredforit,regenerativemedicineremainsasthelastofnanomedicine'scoreinterests.Tobesure,regenerativemedicineisnotasingledisciplinebutdrawstogetheravarietyofmedium-andlong-termtechnicalapproaches,rangingfromtissueengineeringandwoundrepairallthewaytovariousvisionsofcelltherapy.Sincetheseapproachespredateanddonotrelyonnanotechnology,regenerativemedicineshouldnotbesubsumedundernanomedicineandoneshouldratherspeakofnanomedicalcontributionstoit.19

Regenerativemedicineaimstostrengthentheself-healingprocessesofthehumanbodyeitherbystimulatingoremulating

them.Inthecaseoftissueengineering,forexample,thismighttaketheformofgrowingtissueonanexternalscaffoldsuchthatthepatient'sbodyrecognisesitasitsown,thusavoidingtheneedtosuppressanimmuneresponse.Diabetespatientscouldbehelpedbyrestoringinsulinproductionwithinthebody.AmongthemostambitiousgoalsofregenerativemedicineistostimulatethegrowthandtoreconnectseverednervesortorestoreneuralfunctioninneurodegenerativediseasessuchasAlzheimer'sorParkinson's.InthewordsoftheEuropeanTechnologyPlatform,"The challenge is to convert this to a reality."20

Tobesure,somewouldpositevenmoreambitiousgoalsforregenerativemedicine,namelyakindofcell-repairthatmightprevent,evenreverseageing.Thoughthisideaattractsmuchattentioninpopulardiscourse,21itdoesnotoccurinthereportsofnanomedicalworkinggroups.Itisimportanttonotethiscleardemarcationofnanomedicalambitionsfromspeculativevisions.However,themoremodestaimtounderstandandtreatdegenerativediseaseprocessesrequiresafurtherdemarcation:Supportofmedicalresearch,ingeneral,andnanomedicalresearch,inparticular,shouldbededicatedtotheadvanceofpublichealthandqualityoflifebutnottheincreaseoflongevityasanendinitself.Increasedaveragelife-expectanciesshouldbeconsideredasnothingbutwelcomeside-effectsofimprovedaccesstohealthcareandbetterhealthmaintenanceoverall.Indeed,someproponentsofnanomedicineprematurelyanticipatejustthisside-effect.Oneoftheearliestpublicdocumentstoacquaintageneralaudiencewithnanotechnologysinglesoutasasocietalissuethat"longer average lifetimes will

feasibility,butalsofortheproperbalancingofpublicinvestmentandsocietalneed,and,thusfortheirlikelybenefits.Theseambitionsrevolvemainlyaroundtheconcepts“theranostics(i.e.thecombinationofdiagnosisandtherapeuticfunctionalityinonedevice,enablingpre-symptomatictreatment)”,“polymer therapeutics(rationaldesignofnanomedicines)”,“targeted drug-delivery (individualisedmedicine)”,“regenerative medicine(cellrepair).”Thepromiseassociatedwiththesetermsisthatoftherapeuticallymoreeffective,individualised,dosereducedandmoreaffordablemedicine.Beforeconsideringtheseambitionsandpromisesonebyone,ithelpstoplacetheminthelargerhistoricalcontextofthedevelopmentofnanomedicine.

A Brief History of NanomedicineNanomedicinehasbeenanimportantpartofnanotechnologyfromtheverybeginning.Andsincenanotechnologybeganasavisionaryenterprise,nanomedicinestartedbyapplyingmainlynanomechanicalconceptstothebody.Inhis1999bookonNanomedicine,RobertFreitasassembledanimpressivearrayofingeniousideasthatderivefromongoingdevelopmentsandinevitablyleadtoextravagantspeculations.4Freitas'sconflationoftheshort-termwiththelong-termandevenwithtechnicalimpossibilitiesremainscharacteristicevenofthefarmorerestrainedtechnicalpapersoftoday.The2004presentationofthecancernanotechnologyinitiativeintheUnitedStatesrevolvesaroundthegoalof“eliminating death and suffering from cancer by 2015”.5The2006EuropeanTechnologyPlatformonNanomedicineismoresubtlethanthis.Itspeaksofa

“revolution in molecular imaging in the foreseeable future, leading to the detection of a single molecule or a single cell in a complex biological environment.”6Thisstatementelegantlyglossesoverthefactthattheproblemsofdetectingmoleculesandcellsaremagnitudesapart:Cellsareahundredtoathousandtimeslargerthanmoleculesanditiscertainlymucheasiertoimagineacontrastagentormarkerattachedtoorinsideacell.Inthesamereport,thespeculativespiritofEricDrexlerandRobertFreitasinformsavisionofcell-monitoringandrepair:Thedetectionofdiseasewillhappenasearlyaspossibleand“ultimately this will occur at the level of a single cell, combined with monitoring the effectiveness of therapy.7”

ThemostbalancedoverviewofnanomedicinetodateistheEuropeanScienceFoundation’s2006Forward Look on Nanomedicine.8Itisfirmlygroundedincurrentresearch.Asitdistancesitselffromspeculationandhype,itseekstogiveshapetoananomedicalresearchagendathatisclearlysetapartfromthegrab-bagofnanotechnologies.9Ineffect,thereportdrivesawedgebetweenscientific nanomedicineandsomethinglesserthatmightbecalledmedical nanotechnology.Nanomedicineisbasedonmolecularknowledgeofthehumanbodyanditinvolvesmoleculartoolsforthediagnosisandtreatmentofdisease.Medicalnanotechnologyencompassesalltheotherwaysinwhichnanotechnologyaffectshealthcare,especiallyallthatcomesfromtheminiaturisationofdevicesandtheintegrationofinformationandcommunicationtechnologiesindiagnostictoolsandhealthmonitoring–includingaradicaltransformationofthepresentday

hospitalwithitstraditionaldoctor-patientrelationships.

Nanomedicine,inotherwords,isdisease-centred,tryingtodobetterandonamolecularlevelwhatphysiology,pathology,andthevariousspecialisedmedicalscienceshavebeendoingsofar.Becauseitisdisease-centred,nanomedicineleavestomedicalnanotechnologiesthemoregeneralandperhapsmoreprofoundtransformationsofhealthcare:theseconcernpublichealthmonitoring,theintegrationofmedicalpracticesintodailypatternsofworkandleisure,theredefinitionofthephysiologicalbodyasabodyofdata,andthereorganisationofthetherapeuticcontextwithitsmedicalexperts,insurancecompanies,stateinterests,andhealth-careinstitutions.Bythesametoken,nanomedicineinheritsitsfocusoncertaindiseasesfromongoingmedicalresearch.Accordingly,itisprimarilyconcernedtoreducemortalityfromnon-infectiousdisease,especiallycancer.Thatis,itaimstoincrementallyreducemortalitywhereitisalreadylow,namelyinthehighlydevelopedworldwherecancerandcoronarydiseasehavebecomethemostprominentphysiologicalcausesofdeath.

AnotherpotentiallimitationofthenarrowlydefinednanomedicalfocusisbroughttolightbytheEuropeanTechnologyPlatform:itisexplicitlyaddressedtoanincreasinglysedentaryageingpopulationanditsmedicalproblems.Throughthelensofdisease-centrednanomedicine,thistranslatestothetreatmentofpainfullyarthriticjoints.Inawiderperspective,ofcourse,thehealthofjointsinvolvesquestionsofnutrition,mobility,andanintegratedapproachtotheproblemofobesity.Thestrictlynanomedicalalleviationofchronicpaininthejointsshouldbeasmallpart,indeed,ofa“treatmentpackage”thatincludesmedicalnanotechnologiesformonitoringandfeedback,alongwithphysicaltherapy,geriatricandsocio-psychologicalapproaches,togetherwitheveneconomicorpoliticalincentivesforincreasedexercise,nanotechnologicallyimprovedfootwearandsurfaces.

TheranosticsAsdistinctfrommedicalnanotechnologies,scientificnanomedicineconcentratesonfourareasofresearchanddevelopment:theranostics,anewclassofpharmaceuticals,targeteddrug-delivery,and

regenerativemedicine.10Theprospectsandproblemsofeachwarrantabriefreview.

Asindicatedbytheterm"theranostics,"itspromiseconsistsinthefusionoftherapyanddiagnostics.Asdiagnosticcapabilitiesimprove,onemightcomeupwithtreatmentswellbeforeadiseasemanifestsitselfsymptomatically.Ideally,diagnosisandtreatmentcouldbeperformedinasinglestepthroughamonitoringprocessthatautomaticallyintroducesappropriatecorrections(e.g.,plaquedetectionandremovalforthepreventionofcardiovasculardiseases).Thebenefitofbeginningtreatmentbeforethereisadiseasedependsonthequalityofdiagnosticinformation.Here,thelengthyhistoryofgenetherapyoffersasoberinglessonwithitsinitial,butasyetonlypartiallyfulfilled,promiseofrepairingspecificgenesthatareresponsibleforspecificdiseases.

Ratherthanlookingforgeneticcausesofdisease,nanomedicalexpectationsrestonvastimprovementsinimagingandmeasuringtechniques.Indeed,considerableprogressismadeontheroadtowardsin vivoimagingaswellaslab-on-a-chiptechnologiesthatsimultaneouslydeterminethousandsofparametersinatinydropofblood.Butaccesstovastamountsofinformationdoesnottranslateautomaticallyintodiagnosticcapabilities.Aswithgenetherapy,thiswillhappenonlyinapiecemealmannerandinconjunctionwithresearchinbioinformaticsorsystemsbiology.Indeed,beforewecanknowwhetheralltheadditionalphysiologicalinformationhasanydiagnosticuse,itwillhavetobeobtainedinorderforbioinformaticsandsystemsbiologytoconstructsufficientlyrobustmodelsofthehighlycomplexdynamicsattheoriginsof

disease–inthehopethatthesemodelscanonedaybeoperationalisedforthediagnosisandtreatmentofindividualpatients.Likeallbasicscientificresearch,therefore,nanomedicinerequireslong-termfundingstrategies.Itisonlyinthelongrunthatonemightrealisethepromisedhealthcaresavingsthatwouldresultfromearlierinterventionintothediseaseprocess.

Targeted Drug-DeliveryTheideathatpharmaceuticalagentsshouldbedeliveredspecificallytodiseasedcellsholdsthepromiseofavarietyofbenefits.Especiallyif,inaddition,thepharmaceuticalagentweretobeadaptedtothecell'sgenome,thesebenefitswouldbegroupedundertheheading"personalisedmedicine."However,"individualisedmedicine"isthemoreappropriatetermsincethisformoftreatmentisaddressedataspecificdisease-process,perhapsanindividualgenome,butdisregardsthebiographic,cultural,andlegalparticularsthatdefineaperson.

Thepromiseofindividualisedmedicineisthatitisefficient.Targeteddrug-deliveryallowsdoctorsandpatientstobenefitfromsmalldosagesatjusttherightplaceandthusfromfewerside-effects.Evenwithouthavingtounderstandthecauseofthedisease,medicalresearchersexpecttodealwithitjustasthingsstartgoingwrongwiththemolecularmachineryinsidethecell.Smallerdosages,earlyandefficienttreatmentarefinallysaidtotranslateintolowerhealthcarecosts.Ofcourse,ascloselyastheyappeartohangtogether,itisimportanttoevaluatethesevariousclaimsfortheefficiencyofnanomedicineoneatatime.11Especiallythepromiseofcost-efficiencymightsendawrongsignal:likeallofnanomedicine,thisisbasicresearchwith

anuncertain,thoughpotentiallyprofoundimpact.Itneedspublicsupportonitsmeritsandnotonthepromiseofashort-ormedium-termreturn.

Polymer TherapeuticsTheprogrammeoftargeteddrugdeliveryrequiresnewnanomedicineswhichconsistofatleasttwocomponents:oneofthemtheactiveingredient,theotheratransportdeviceorconjugatethatattachesitscargoattherightplace.12Itisthisconstructionofatechnicalsystemthatcombinesdifferentfunctionalitieswhichbringliposomes,polymer-proteinconjugates,dendrimers,andothernanoparticlesintotherealmofnanotechnologyproper,asopposedtotraditionalpharmacologyorsupramolecularchemistry.13Also,itisthismodularitywhichanswersnanomedicine'scallfor"design on a disease-specific basis."

WhileEUandUSreportsonnanomedicineemphasisethenotionofdesign,theEuropeanTechnologyPlatformtakespainstopointoutthattherelevantdesignfeaturescanbeachievedby "rational design or by high throughput screening or even by a combination of the two."14Indeed,theambitiontoconstructnanomedicinesisreminiscentofpreviousprogrammesof"rationaldrugdesign,"suchasattemptstopreventdiseasebyinhibitingRNAexpressionandproteinformation.Ifnanomedicineseekstokeepacautiousdistancetotheseprogrammes,thisisbecausetheysendasoberingmessage,havingprovedunabletocompetewithrandomisedhigh-throughputscreeningasthefarmoresuccessfulapproachtodrugdevelopment.15Similarly,theconstructivedesignambitionsofscientificnanomedicinefaceatremendouschallengetomasterphysiologicalcomplexity.Underthebestofcircumstances,itisamatter"only"ofpackaginganactiveingredientwithasuccessfultargetingagent.Thoughtheiroriginspredatetheadventof"nanotechnology,"somenanomedicineshavealreadybeenapprovedforroutineuseandnowhavetoprovethemselvesincompetitionwithsometimeslessexpensivealternatives.16

Ifonlybecauseofthelengthofthemulti-stageapprovalprocess,onlytimewilltellthesuccess-storyofnanomedicines.Theirdefinitionasdesignedtwo-componentsystemssuggestsashort-cut,namelytoconsiderthemmedicaldevicesratherthanpharmacologicalsubstances,especially

whentheactiveingredientisalreadyknown.Sincetheapprovalofmedicaldevicesproceedsataconsiderablyfasterpace,thiscouldspeedupnanomedicaldevelopment.Inoneinstance,atleast,thisroutehasbeenchosensuccessfully.Bycreatingironoxidenanoparticlesthatareaccumulatedbycancercellsandthenapplyingtothemanexternalmagneticfield,tumourscanbedestroyedveryeffectively.Thecoatednanoparticlesareheretakentobecomponentsofatechnicaldevice,aspartsofthemachinethatcreatesthemagneticfieldandthusinducesavibratorymotioninthoseparticleswhichthenleadstotheheatinganddestructionofthetumour.Sincetheparticlesarenotintroducedfortheirchemicalpropertiesoraspharmacologicallyactiveagents,theydonotneedtoberegulatedasdrugs.Itislargelybecauseofthisthattheproceduremovedswiftly"FromSciencetoBusinessin15Years."17

Ontheotherhand,nanoparticulateironoxidemaywellposeriskstothepatient'shealthor,aftersecretion,totheenvironment.Whilethisriskmaybeacceptableinthetreatmentofanotherwisedeadlydisease,theapprovaloftheseironoxidesasdrugsmaystillbecalledfor.ThedifficultyofthisdilemmaisillustratedbytherecommendationoftheEuropeanGrouponEthicsinitsopiniononnanomedicine:"The mechanism of action is a key factor in deciding whether a product should be regulated as a medicinal product or a medical device."18Inthecaseatissue,theregulatoryquestioncannotbedecidedbyreferringtoamatteroffact.Itwillbecontested,afterall,whatthemechanismofactionis:isittheactionoftheironoxideparticlesascomponentsofthedeviceorisittheiractioninandbeyondthehuman

bodyafterdestructionofthecancercells?Initspublishedreports,thenanomedicalcommunitygenerallyurgescautionandcloseethicalaswellasregulatoryreview.

Regenerative MedicineAfterdiagnosticsandtheranostics,individualisedmedicineandthenanomedicinesrequiredforit,regenerativemedicineremainsasthelastofnanomedicine'scoreinterests.Tobesure,regenerativemedicineisnotasingledisciplinebutdrawstogetheravarietyofmedium-andlong-termtechnicalapproaches,rangingfromtissueengineeringandwoundrepairallthewaytovariousvisionsofcelltherapy.Sincetheseapproachespredateanddonotrelyonnanotechnology,regenerativemedicineshouldnotbesubsumedundernanomedicineandoneshouldratherspeakofnanomedicalcontributionstoit.19

Regenerativemedicineaimstostrengthentheself-healingprocessesofthehumanbodyeitherbystimulatingoremulating

them.Inthecaseoftissueengineering,forexample,thismighttaketheformofgrowingtissueonanexternalscaffoldsuchthatthepatient'sbodyrecognisesitasitsown,thusavoidingtheneedtosuppressanimmuneresponse.Diabetespatientscouldbehelpedbyrestoringinsulinproductionwithinthebody.AmongthemostambitiousgoalsofregenerativemedicineistostimulatethegrowthandtoreconnectseverednervesortorestoreneuralfunctioninneurodegenerativediseasessuchasAlzheimer'sorParkinson's.InthewordsoftheEuropeanTechnologyPlatform,"The challenge is to convert this to a reality."20

Tobesure,somewouldpositevenmoreambitiousgoalsforregenerativemedicine,namelyakindofcell-repairthatmightprevent,evenreverseageing.Thoughthisideaattractsmuchattentioninpopulardiscourse,21itdoesnotoccurinthereportsofnanomedicalworkinggroups.Itisimportanttonotethiscleardemarcationofnanomedicalambitionsfromspeculativevisions.However,themoremodestaimtounderstandandtreatdegenerativediseaseprocessesrequiresafurtherdemarcation:Supportofmedicalresearch,ingeneral,andnanomedicalresearch,inparticular,shouldbededicatedtotheadvanceofpublichealthandqualityoflifebutnottheincreaseoflongevityasanendinitself.Increasedaveragelife-expectanciesshouldbeconsideredasnothingbutwelcomeside-effectsofimprovedaccesstohealthcareandbetterhealthmaintenanceoverall.Indeed,someproponentsofnanomedicineprematurelyanticipatejustthisside-effect.Oneoftheearliestpublicdocumentstoacquaintageneralaudiencewithnanotechnologysinglesoutasasocietalissuethat"longer average lifetimes will

feasibility,butalsofortheproperbalancingofpublicinvestmentandsocietalneed,and,thusfortheirlikelybenefits.Theseambitionsrevolvemainlyaroundtheconcepts“theranostics(i.e.thecombinationofdiagnosisandtherapeuticfunctionalityinonedevice,enablingpre-symptomatictreatment)”,“polymer therapeutics(rationaldesignofnanomedicines)”,“targeted drug-delivery (individualisedmedicine)”,“regenerative medicine(cellrepair).”Thepromiseassociatedwiththesetermsisthatoftherapeuticallymoreeffective,individualised,dosereducedandmoreaffordablemedicine.Beforeconsideringtheseambitionsandpromisesonebyone,ithelpstoplacetheminthelargerhistoricalcontextofthedevelopmentofnanomedicine.

A Brief History of NanomedicineNanomedicinehasbeenanimportantpartofnanotechnologyfromtheverybeginning.Andsincenanotechnologybeganasavisionaryenterprise,nanomedicinestartedbyapplyingmainlynanomechanicalconceptstothebody.Inhis1999bookonNanomedicine,RobertFreitasassembledanimpressivearrayofingeniousideasthatderivefromongoingdevelopmentsandinevitablyleadtoextravagantspeculations.4Freitas'sconflationoftheshort-termwiththelong-termandevenwithtechnicalimpossibilitiesremainscharacteristicevenofthefarmorerestrainedtechnicalpapersoftoday.The2004presentationofthecancernanotechnologyinitiativeintheUnitedStatesrevolvesaroundthegoalof“eliminating death and suffering from cancer by 2015”.5The2006EuropeanTechnologyPlatformonNanomedicineismoresubtlethanthis.Itspeaksofa

“revolution in molecular imaging in the foreseeable future, leading to the detection of a single molecule or a single cell in a complex biological environment.”6Thisstatementelegantlyglossesoverthefactthattheproblemsofdetectingmoleculesandcellsaremagnitudesapart:Cellsareahundredtoathousandtimeslargerthanmoleculesanditiscertainlymucheasiertoimagineacontrastagentormarkerattachedtoorinsideacell.Inthesamereport,thespeculativespiritofEricDrexlerandRobertFreitasinformsavisionofcell-monitoringandrepair:Thedetectionofdiseasewillhappenasearlyaspossibleand“ultimately this will occur at the level of a single cell, combined with monitoring the effectiveness of therapy.7”

ThemostbalancedoverviewofnanomedicinetodateistheEuropeanScienceFoundation’s2006Forward Look on Nanomedicine.8Itisfirmlygroundedincurrentresearch.Asitdistancesitselffromspeculationandhype,itseekstogiveshapetoananomedicalresearchagendathatisclearlysetapartfromthegrab-bagofnanotechnologies.9Ineffect,thereportdrivesawedgebetweenscientific nanomedicineandsomethinglesserthatmightbecalledmedical nanotechnology.Nanomedicineisbasedonmolecularknowledgeofthehumanbodyanditinvolvesmoleculartoolsforthediagnosisandtreatmentofdisease.Medicalnanotechnologyencompassesalltheotherwaysinwhichnanotechnologyaffectshealthcare,especiallyallthatcomesfromtheminiaturisationofdevicesandtheintegrationofinformationandcommunicationtechnologiesindiagnostictoolsandhealthmonitoring–includingaradicaltransformationofthepresentday

hospitalwithitstraditionaldoctor-patientrelationships.

Nanomedicine,inotherwords,isdisease-centred,tryingtodobetterandonamolecularlevelwhatphysiology,pathology,andthevariousspecialisedmedicalscienceshavebeendoingsofar.Becauseitisdisease-centred,nanomedicineleavestomedicalnanotechnologiesthemoregeneralandperhapsmoreprofoundtransformationsofhealthcare:theseconcernpublichealthmonitoring,theintegrationofmedicalpracticesintodailypatternsofworkandleisure,theredefinitionofthephysiologicalbodyasabodyofdata,andthereorganisationofthetherapeuticcontextwithitsmedicalexperts,insurancecompanies,stateinterests,andhealth-careinstitutions.Bythesametoken,nanomedicineinheritsitsfocusoncertaindiseasesfromongoingmedicalresearch.Accordingly,itisprimarilyconcernedtoreducemortalityfromnon-infectiousdisease,especiallycancer.Thatis,itaimstoincrementallyreducemortalitywhereitisalreadylow,namelyinthehighlydevelopedworldwherecancerandcoronarydiseasehavebecomethemostprominentphysiologicalcausesofdeath.

AnotherpotentiallimitationofthenarrowlydefinednanomedicalfocusisbroughttolightbytheEuropeanTechnologyPlatform:itisexplicitlyaddressedtoanincreasinglysedentaryageingpopulationanditsmedicalproblems.Throughthelensofdisease-centrednanomedicine,thistranslatestothetreatmentofpainfullyarthriticjoints.Inawiderperspective,ofcourse,thehealthofjointsinvolvesquestionsofnutrition,mobility,andanintegratedapproachtotheproblemofobesity.Thestrictlynanomedicalalleviationofchronicpaininthejointsshouldbeasmallpart,indeed,ofa“treatmentpackage”thatincludesmedicalnanotechnologiesformonitoringandfeedback,alongwithphysicaltherapy,geriatricandsocio-psychologicalapproaches,togetherwitheveneconomicorpoliticalincentivesforincreasedexercise,nanotechnologicallyimprovedfootwearandsurfaces.

TheranosticsAsdistinctfrommedicalnanotechnologies,scientificnanomedicineconcentratesonfourareasofresearchanddevelopment:theranostics,anewclassofpharmaceuticals,targeteddrug-delivery,and

regenerativemedicine.10Theprospectsandproblemsofeachwarrantabriefreview.

Asindicatedbytheterm"theranostics,"itspromiseconsistsinthefusionoftherapyanddiagnostics.Asdiagnosticcapabilitiesimprove,onemightcomeupwithtreatmentswellbeforeadiseasemanifestsitselfsymptomatically.Ideally,diagnosisandtreatmentcouldbeperformedinasinglestepthroughamonitoringprocessthatautomaticallyintroducesappropriatecorrections(e.g.,plaquedetectionandremovalforthepreventionofcardiovasculardiseases).Thebenefitofbeginningtreatmentbeforethereisadiseasedependsonthequalityofdiagnosticinformation.Here,thelengthyhistoryofgenetherapyoffersasoberinglessonwithitsinitial,butasyetonlypartiallyfulfilled,promiseofrepairingspecificgenesthatareresponsibleforspecificdiseases.

Ratherthanlookingforgeneticcausesofdisease,nanomedicalexpectationsrestonvastimprovementsinimagingandmeasuringtechniques.Indeed,considerableprogressismadeontheroadtowardsin vivoimagingaswellaslab-on-a-chiptechnologiesthatsimultaneouslydeterminethousandsofparametersinatinydropofblood.Butaccesstovastamountsofinformationdoesnottranslateautomaticallyintodiagnosticcapabilities.Aswithgenetherapy,thiswillhappenonlyinapiecemealmannerandinconjunctionwithresearchinbioinformaticsorsystemsbiology.Indeed,beforewecanknowwhetheralltheadditionalphysiologicalinformationhasanydiagnosticuse,itwillhavetobeobtainedinorderforbioinformaticsandsystemsbiologytoconstructsufficientlyrobustmodelsofthehighlycomplexdynamicsattheoriginsof

disease–inthehopethatthesemodelscanonedaybeoperationalisedforthediagnosisandtreatmentofindividualpatients.Likeallbasicscientificresearch,therefore,nanomedicinerequireslong-termfundingstrategies.Itisonlyinthelongrunthatonemightrealisethepromisedhealthcaresavingsthatwouldresultfromearlierinterventionintothediseaseprocess.

Targeted Drug-DeliveryTheideathatpharmaceuticalagentsshouldbedeliveredspecificallytodiseasedcellsholdsthepromiseofavarietyofbenefits.Especiallyif,inaddition,thepharmaceuticalagentweretobeadaptedtothecell'sgenome,thesebenefitswouldbegroupedundertheheading"personalisedmedicine."However,"individualisedmedicine"isthemoreappropriatetermsincethisformoftreatmentisaddressedataspecificdisease-process,perhapsanindividualgenome,butdisregardsthebiographic,cultural,andlegalparticularsthatdefineaperson.

Thepromiseofindividualisedmedicineisthatitisefficient.Targeteddrug-deliveryallowsdoctorsandpatientstobenefitfromsmalldosagesatjusttherightplaceandthusfromfewerside-effects.Evenwithouthavingtounderstandthecauseofthedisease,medicalresearchersexpecttodealwithitjustasthingsstartgoingwrongwiththemolecularmachineryinsidethecell.Smallerdosages,earlyandefficienttreatmentarefinallysaidtotranslateintolowerhealthcarecosts.Ofcourse,ascloselyastheyappeartohangtogether,itisimportanttoevaluatethesevariousclaimsfortheefficiencyofnanomedicineoneatatime.11Especiallythepromiseofcost-efficiencymightsendawrongsignal:likeallofnanomedicine,thisisbasicresearchwith

anuncertain,thoughpotentiallyprofoundimpact.Itneedspublicsupportonitsmeritsandnotonthepromiseofashort-ormedium-termreturn.

Polymer TherapeuticsTheprogrammeoftargeteddrugdeliveryrequiresnewnanomedicineswhichconsistofatleasttwocomponents:oneofthemtheactiveingredient,theotheratransportdeviceorconjugatethatattachesitscargoattherightplace.12Itisthisconstructionofatechnicalsystemthatcombinesdifferentfunctionalitieswhichbringliposomes,polymer-proteinconjugates,dendrimers,andothernanoparticlesintotherealmofnanotechnologyproper,asopposedtotraditionalpharmacologyorsupramolecularchemistry.13Also,itisthismodularitywhichanswersnanomedicine'scallfor"design on a disease-specific basis."

WhileEUandUSreportsonnanomedicineemphasisethenotionofdesign,theEuropeanTechnologyPlatformtakespainstopointoutthattherelevantdesignfeaturescanbeachievedby "rational design or by high throughput screening or even by a combination of the two."14Indeed,theambitiontoconstructnanomedicinesisreminiscentofpreviousprogrammesof"rationaldrugdesign,"suchasattemptstopreventdiseasebyinhibitingRNAexpressionandproteinformation.Ifnanomedicineseekstokeepacautiousdistancetotheseprogrammes,thisisbecausetheysendasoberingmessage,havingprovedunabletocompetewithrandomisedhigh-throughputscreeningasthefarmoresuccessfulapproachtodrugdevelopment.15Similarly,theconstructivedesignambitionsofscientificnanomedicinefaceatremendouschallengetomasterphysiologicalcomplexity.Underthebestofcircumstances,itisamatter"only"ofpackaginganactiveingredientwithasuccessfultargetingagent.Thoughtheiroriginspredatetheadventof"nanotechnology,"somenanomedicineshavealreadybeenapprovedforroutineuseandnowhavetoprovethemselvesincompetitionwithsometimeslessexpensivealternatives.16

Ifonlybecauseofthelengthofthemulti-stageapprovalprocess,onlytimewilltellthesuccess-storyofnanomedicines.Theirdefinitionasdesignedtwo-componentsystemssuggestsashort-cut,namelytoconsiderthemmedicaldevicesratherthanpharmacologicalsubstances,especially

whentheactiveingredientisalreadyknown.Sincetheapprovalofmedicaldevicesproceedsataconsiderablyfasterpace,thiscouldspeedupnanomedicaldevelopment.Inoneinstance,atleast,thisroutehasbeenchosensuccessfully.Bycreatingironoxidenanoparticlesthatareaccumulatedbycancercellsandthenapplyingtothemanexternalmagneticfield,tumourscanbedestroyedveryeffectively.Thecoatednanoparticlesareheretakentobecomponentsofatechnicaldevice,aspartsofthemachinethatcreatesthemagneticfieldandthusinducesavibratorymotioninthoseparticleswhichthenleadstotheheatinganddestructionofthetumour.Sincetheparticlesarenotintroducedfortheirchemicalpropertiesoraspharmacologicallyactiveagents,theydonotneedtoberegulatedasdrugs.Itislargelybecauseofthisthattheproceduremovedswiftly"FromSciencetoBusinessin15Years."17

Ontheotherhand,nanoparticulateironoxidemaywellposeriskstothepatient'shealthor,aftersecretion,totheenvironment.Whilethisriskmaybeacceptableinthetreatmentofanotherwisedeadlydisease,theapprovaloftheseironoxidesasdrugsmaystillbecalledfor.ThedifficultyofthisdilemmaisillustratedbytherecommendationoftheEuropeanGrouponEthicsinitsopiniononnanomedicine:"The mechanism of action is a key factor in deciding whether a product should be regulated as a medicinal product or a medical device."18Inthecaseatissue,theregulatoryquestioncannotbedecidedbyreferringtoamatteroffact.Itwillbecontested,afterall,whatthemechanismofactionis:isittheactionoftheironoxideparticlesascomponentsofthedeviceorisittheiractioninandbeyondthehuman

bodyafterdestructionofthecancercells?Initspublishedreports,thenanomedicalcommunitygenerallyurgescautionandcloseethicalaswellasregulatoryreview.

Regenerative MedicineAfterdiagnosticsandtheranostics,individualisedmedicineandthenanomedicinesrequiredforit,regenerativemedicineremainsasthelastofnanomedicine'scoreinterests.Tobesure,regenerativemedicineisnotasingledisciplinebutdrawstogetheravarietyofmedium-andlong-termtechnicalapproaches,rangingfromtissueengineeringandwoundrepairallthewaytovariousvisionsofcelltherapy.Sincetheseapproachespredateanddonotrelyonnanotechnology,regenerativemedicineshouldnotbesubsumedundernanomedicineandoneshouldratherspeakofnanomedicalcontributionstoit.19

Regenerativemedicineaimstostrengthentheself-healingprocessesofthehumanbodyeitherbystimulatingoremulating

them.Inthecaseoftissueengineering,forexample,thismighttaketheformofgrowingtissueonanexternalscaffoldsuchthatthepatient'sbodyrecognisesitasitsown,thusavoidingtheneedtosuppressanimmuneresponse.Diabetespatientscouldbehelpedbyrestoringinsulinproductionwithinthebody.AmongthemostambitiousgoalsofregenerativemedicineistostimulatethegrowthandtoreconnectseverednervesortorestoreneuralfunctioninneurodegenerativediseasessuchasAlzheimer'sorParkinson's.InthewordsoftheEuropeanTechnologyPlatform,"The challenge is to convert this to a reality."20

Tobesure,somewouldpositevenmoreambitiousgoalsforregenerativemedicine,namelyakindofcell-repairthatmightprevent,evenreverseageing.Thoughthisideaattractsmuchattentioninpopulardiscourse,21itdoesnotoccurinthereportsofnanomedicalworkinggroups.Itisimportanttonotethiscleardemarcationofnanomedicalambitionsfromspeculativevisions.However,themoremodestaimtounderstandandtreatdegenerativediseaseprocessesrequiresafurtherdemarcation:Supportofmedicalresearch,ingeneral,andnanomedicalresearch,inparticular,shouldbededicatedtotheadvanceofpublichealthandqualityoflifebutnottheincreaseoflongevityasanendinitself.Increasedaveragelife-expectanciesshouldbeconsideredasnothingbutwelcomeside-effectsofimprovedaccesstohealthcareandbetterhealthmaintenanceoverall.Indeed,someproponentsofnanomedicineprematurelyanticipatejustthisside-effect.Oneoftheearliestpublicdocumentstoacquaintageneralaudiencewithnanotechnologysinglesoutasasocietalissuethat"longer average lifetimes will

Nanomedicine•ABriefHistoryofNanomedicine•Theranostics•TargetedDrug-Delivery•PolymerTherapeutics•RegenerativeMedicine•Ethicalandsocietalissues

For Pictures: © copyright CEA

Design: Gerritsma Vormgeving bno, Leiden, e vormg@planet.nl, w www.1enof2.nl

The Images: Courtesy of the Molecular Biophysics Group at Delft University of Technology

Theaimofthisbriefingpaperistoprovideconcise,correctandbalancedinformationtoadvancepublicdebateamongconsumers,media,policymakers,producersandresearchersaspartoftheEuropeanCommission-fundedNanobio-RAISEproject.1Itresultsfromthecombinedcontributionsofnaturalandsocialscientists,industrialists,andgovernmentalandpublicinterestorganisationsacrossEurope.ItisintendedtoprovideinformationanddoesnotrepresenttheviewsorpolicyoftheEuropeanCommissionoranyotherbody.

IntroductionAbroadarrayofpresentandfutureresearchdevelopmentsaregenerallylumpedtogetheras“nanotechnology.”Acommonfeatureisonlythattheyareconcernedwithlargeandsmallthingswhereatleastsomerelevantmeasuresareinthenanometrerange(10-9to10-7metres)andthusinthesize-rangeofDNA-moleculesorviruses.Morestringentdefinitionsrequirethatnanotechnologicalresearchberestrictedtothescientificinvestigationandtechnicalexploitationofnovelpropertiesthatappeardiscontinuouslyatthenanoscale:atonofgoldhasthesamechemicalpropertiesasamilligram,butagoldnanoparticleshowsinterestingandinitiallysurprisingnewbehaviours.Thismorestringentdefinitionofnanotechnologicalresearchremainsquiteunspecificregardingtechnologicalapplications:nanotechnologyisallthatthesenewlydiscoveredpropertiesandprocessesmightbegoodfor.Andhere,theimaginationrunswild,challengingustoidentifyandsupportpromising,feasibleaswellasbeneficialshort-andmedium-termdevelopments.

Onfirstsight,nanomedicineistherathermorewell-definedapplicationofnanotechnologyintheareasofhealthcareanddiseasediagnosisandtreatment.Buthere,too,oneencountersabewilderingarrayofprogrammesandprojects.Artificialboneimplantsalreadybenefitfromnanotechnologicallyimprovedmaterials.Nanostructuredsurfacescanserveasscaffoldingforcontrolledtissue-growth.Of

course,allkindsofmedicaldevicesprofitfromtheminiaturisationofelectroniccomponentsastheymovebeyondmicrotonano.Thisaffectsdiagnostictools,pace-makers,“camerasinapill,”etc.Nanoparticulatepharmaceuticalagentscanpenetratecellsmoreeffectivelyaswellasbeingabletocrosstheblood-brain-barrier.Afterinjectingnanoparticlesintotumours,thesecanbestimulatedelectromagneticallyfromoutsidethebody–byemittingheat,thestimulatedparticlescanthendestroythetumourcells.Antibacterialsurfacesincorporatingphotocatalyticorbiocidalnanoparticlesreducetheriskofinfectionindoctors’officesandpublicbuildings.Portabletestingkitsallowforself-monitoringandspeedydiagnosis.Newcontrastagentsandvisualisationtoolsprovideacloserlookatcellularprocesses.Butthis,too,isnanotechnologyinaction:nanoparticulatesteroidsareintroducedintothebody’sownredbloodcells;asthecellsdietheirnaturaldeaths,thesteroidsarereleasedtothebodyinverysmalldoses,thusminimising,ifnotexcludingtheside-effectsofmanysteroidtreatments.2

Theseexamplesandmanymoreofongoingdevelopmentscanbefoundinvariousreportsontheprospectsandpromisesofnanomedicine.Butthoughtheseexamplesarenothingtofrownat,nanomedicinehasbeenconceivedasafarmoreambitiousenterprise:"Nanomedicine comes into being where a molecular understanding of cellular processes is strategically combined with capabilities to produce nanoscale materials in a controlled manner."3Withthesegreaterambitionscomestheformidablechallengetoassessmorevisionaryprogrammesnotonlyfortheir

mean more people on Earth. But how many more people can the Earth sustain?"22Inasimilarvein,theEuropeanTechnologyPlatformnotesthatonelargeimpactofnanomedicinewillbe"increased costs of social security systems due to ageing of population."23

Itisimportanttobeclearabouttheachievablegoalsofnanomedicinethatareinthepublicinterest.Popularfascinationwithenvisionedtechnologiesoflifeextensiondoesnotrenderlongevityapublicgood.Conversely,beforeworryingaboutincreasedlife-expectancyasoneofthepotentialimpactsofnanomedicine,oneshouldensurethatnanomedicinegetsoffthegroundandmeetstheformidablechallengetoconvertevenitsmoremodestambitionsintoreality.

Asitisconvertedfromvisiontoreality,thenotionofcellrepairwillbeatestinggroundfortheveryideathatcellularprocessesinvolveananotechnologicalmachinerythatcanbreakdownandthatcanalsoberepaired.Thismetaphorofnanomachineryhasprovenproductiveforunderstandingcellularmechanismsbutitisunclearasofyethowfarthismetaphorcarrieswhenitcomestotheprecisioncontrolofhighlycomplexbiologicalrealities.24Italsoleadstotheethicalquestionofwhetherwemaymechanicallyreducethehumanbeingtoasumofphysicaltraits.25

Ethical and societal issuesTraditionally,medicalethicsispatient-andtreatment-centredratherthanresearch-anddisease-centred.Inotherwords,mostmedicalethicsisfocusedondoctor-patientrelations,onend-of-lifedecisions,onresource-allocation,ontreatmentchoices,informedconsent,andthelike.Biomedicalresearchbecomessignificantonlyasitentersclinicaltrials.Accordingly,medicalethicshasbeenratherindifferenttothelevelofmedicalintervention.Whiletheremovalofthecausesofdiseaseisgenerallypreferabletosymptomatictreatments,itdoesnotappeartomattermuchwhetherdiseasesareaddressedatamolecularorcellularorwhole-organlevel.

Astheprevioussectionsindicated,however,thenanomedicalresearchprogrammeraisesissuesthatservetoexpandthescopeofmedicalethics.Thisconcerns,forexample,thedistinctionbetweendruganddeviceanditsregulatoryimplications.Italsoconcernstherecognitionandacknowledgmentoflimitsofknowledgeandcontrol,inotherwords,caretoavoidhypeandtostateachievablegoalscrediblyandresponsibly.Regenerativemedicineintheserviceofpublichealthandqualityoflifeshouldbedistinguishedfromthenotionthatlife-extensionisapublicgood.Finally,nanomedicalresearchraisesquestionsofdistributivejusticeandglobalequityas

majorpublicinvestmentsaredirectedatcancertreatmentsandthusatattemptsfurthertoreducemortalityindevelopedsocietieswhereitisalreadycomparativelylow.

Nanomedicalethicsshouldnotservetovalidateanuncertainfuture,forexample,byassumingtooreadilyanincreaseofdiagnosticpowersoranimpactonlife-expectancy.Instead,itmightcontributetopublicdeliberationontheresearchagendafornanomedicine.Onceonestartsquestioningitsprimaryfocusoncancerandcardiovasculardiseases,onemighthavetoconsidertheverydefinitionsofillnessandhealthandthemedicalisationofsociety.Similarly,onemightconsiderthemetaphorsweusetodescribethehumanbeingorthechangingboundariesofhumanbodiesasthebody'sowntissueorinsulin,forexample,mightbegeneratedoutsidethebodyorbywayofanimplanteddevice.

ConclusionA2007nanomedicalbulletinofferedthefollowingnewsitem:"Working with an organic semiconductor, researchers at the University of Arkansas have fabricated and tested two similar but slightly different biosensors that can measure physiological signs. Integrated into 'smart' fabrics – garments with wireless technology – the sensors will be able to monitor a patient's respiration rate and body temperature in real time."26Inmanyways,thisappearstobenanotechnologyatitsbestandisthereforenotatalluniquetotheUniversityofArkansas.Itisanexampleofhighlyinterdisciplinaryresearchthatintegratesfunctionalitiesatthenanoscale,namelytheotherwiseseparatenanotechnologicalfieldsofpoint-of-carediagnosticsand'smart'fabrics.Thiskindofmedical nanotechnologymayenableaprofoundreconfigurationoftherelationsbetweendoctors,patients,andhospitals.Itcanalsopromotethefurthermedicalisationofsociety,thatis,ofbringingsocialbehaviours(risktaking,dietarypractices,stressandanger)intotherealmofmedicalsupervision.Thesedevelopmentsarelikelytobecontestedandcallforthedebateoftheirethicalandsocietalimplications.

Itisunlikelythatnanomedicinewillbeastransformative.Itdefinesitselfasbasicmedicalresearch,andisapplication-orientedlikeallmedicalresearch.Assuch,nanomedicinecanrealiseitspromises

References1 Nanobiotechnology:ResponsibleActiononIssuesinSocietyandEthics:http://nanobio-raise.org/2 MauroMagnani Eythrocyte Engineering for Drug Delivery and Targeting.NewYork:Kluwer,2003.3 VolkerWagnerandAxelZweckNanomedizin:Innovationspotenziale in Hessen für Medizintechnik und Pharmazeutische Industrie Wiesbaden:HessischesMinisteriumfürWirtschaft,2006.4 RobertA.Freitas(1999): Nanomedicine, Volume I: Basic Capabilities,Georgetown,TX:LandesBioscience.5 Cancer NANOTECHNOLOGY: Going Small for Big Advances – Using Nanotechnology to Advance Cancer Diagnosis, Prevention and Treatment.Washington,DC:U.S.DEPARTMENTOFHEALTHANDHUMANSERVICES,National InstitutesofHealth,NationalCancerInstitute,2004.6 Nanomedicine: Nanotechnology for Health – European Technology Platform.Brussels:EuropeanCommission, ResearchDG,2006,p.12.7 Ibid.,p.10,seealsop.6andespeciallyp.12.8 Nanomedicine: An ESF – European Medical Research Councils (EMRC) Forward Look report.Strasbourg:European ScienceFoundation,2006.9 Likesyntheticbiology,nanomedicineisthuspoisedtobecomeanoff-shootofnanotechnologythatclaimsitsown, atleastpartlyseparateidentityandintegrity.–TwooftheauthorsoftheESF-reportreflectonthisquiteexplicitly, seeRingsdorfandDuncan"nanogamesgainingground"2006.10 TheEuropeanTechnologyPlatformsubsumesnewpharmaceuticalsunder"targeteddelivery":"Seamlessly connectingDiagnostics,TargetedDeliveryandRegenerativeMedicine:Diagnostics,targeteddeliveryand regenerativemedicineconstitutethecoredisciplinesofnanomedicine.TheEuropeanTechnologyPlatformon NanoMedicineacknowledgesandwishestoactivelysupportresearchattheinterfacebetweenitsthreescience areas."Thisresearchattheinterfacecanestablishtheranostics(p.9).11 AlfredNordmann"KnotsandStrands:AnArgumentforProductiveDisillusionment,"Journal of Medicine and Philosophy,32:3,2007,pp.217-236.12 ESF-report,p.11.13 Thisconstructiveprinciplealsodistinguishesnanomedicine(asakindofnanotechnology)frombiotechnologywhich isdevelopinganddeployingproteinsasactiveagents.14 ETP,p.16.15MatthiasAdam"Whattoexpectfromrationaldrugdesign,"Expert Opinion on Drug Discovery2(6),2007, 773-776.16 JoachimSchummer"TheImpactofNanotechnologiesonDevelopingCountries,"inFritzAllhoff,PatrickLin,,James Moor,JohnWeckert,eds., Nanoethics: The Ethical and Social Implications of Nanotechnology,Wiley,2007.17AndreasJordan"FromSciencetoBusinessin15Years"intheProceedingsofEuroNanoForum 2005: Nanotechnology and the Health of the EU Citizen in 2020,editedbyMichaelMason,SophiaFantechi,Renzo Tomellini,Brussels:ECDGResearch,2006,p.16.18 TheEuropeanGrouponEthicsinScienceandNewTechnologiestotheEuropeanCommission"Opiniononthe ethicalaspectsofNanomedicine(OpinionN°21),"January17,2007,section5.5.1,p.57.19WhiletheEuropeanTechnologyPlatformconsidersregenerativemedicineoneofnanomedicine'sthreecore disciplines,theESF'sForwardLooktreatsitonlyundertheheadingofnewmaterials(inparticular,scaffoldingfor tissuegrowthandrepair).TheUS-reportonCancerNanotechnologydoesnotrefertoitatall.20 ETP,p.6.21 PaulMillerandJamesWilsdon“Themanwhowantstoliveforever”inPaulMillerandJamesWilsdon(eds.)Better Humans? The Politics of Human Enhancement and Life Extension,London:DEMOS,2006,pp.51-58.22 IvanAmatoNanotechnology - Shaping the World Atom by Atom,Washington:NationalScienceandTechnology Council,InteragencyWorkingGrouponNanoscience,EngineeringandTechnology,1999,p.8.23 ETP,p.24.24RichardJonesSoft MachinesOxford:OxfordUniversityPress,2004.25 Jean-PierreDupuyinJournal of Medicine and Philosophy,32:3,2007.26NanoMedicineNews(www.euronanotechnews.com),#71,July20,2007.

onlyinthelongerterm.Whileitmakesacompellingcaseforthesepromises,italsoasksforourpatience.Andaswithallbasicresearch,somethingisboundtocomeofit,thoughnotperhapsthefullmasteryofphysiologicalcomplexitiesthatisenvisionedinthenameoftheranostics,individualisedmedicine,andcellrepair.Someofitsmostimportantcontributionswillconsistofprogressininstrumentationandanalyticmethodsthatisnowconsideredprimarilyastepping-stonetowardsbiggerandbetterthings.

Oneshouldthereforenotexpectnanomedicinetorevolutionisemedicine.Itisonepromisingavenuebywhichmedicinecanadvance.Attheendoftheday,itwillhavecontributednewtreatment-optionsforcertaindiseases,somenewnanomedicines,betterimaging-techniquesandotherdiagnostictools.Thesewilladdsignificantlytothecurrentlyavailablearsenaloftherapiesandmedicines,raisingsimilarethicalandsocietalconcernsasdidthemedicaladvancesofthepast.Demonstrationsofefficacyhavetobeconsideredtogetherwithphysiologicalandenvironmentalside-effectsandgeneralquality-of-lifeissues,comparingallofthesetoalternativetreatmentoptions.Andlikealldisease-orientedresearch,itrequirespublicdeliberationonwhichdiseasesshouldbeprioritisedinthecontextofglobalhealthcare.

Nanomedical sectors •Drugdelivery•Biomaterials• In vivoimaging• In vitrodiagnostics• Activeimplants•Drugs&therapy

NanoBio-RAISECo-ordinationoffice:Julianalaan672628BCDelftTheNetherlandst+31(0)152786626f+31(0)152782355info@nanobio-raise.orgwww.nanobio-raise.org

Nanomedicine•ABriefHistoryofNanomedicine•Theranostics•TargetedDrug-Delivery•PolymerTherapeutics•RegenerativeMedicine•Ethicalandsocietalissues

For Pictures: © copyright CEA

Design: Gerritsma Vormgeving bno, Leiden, e vormg@planet.nl, w www.1enof2.nl

The Images: Courtesy of the Molecular Biophysics Group at Delft University of Technology

Theaimofthisbriefingpaperistoprovideconcise,correctandbalancedinformationtoadvancepublicdebateamongconsumers,media,policymakers,producersandresearchersaspartoftheEuropeanCommission-fundedNanobio-RAISEproject.1Itresultsfromthecombinedcontributionsofnaturalandsocialscientists,industrialists,andgovernmentalandpublicinterestorganisationsacrossEurope.ItisintendedtoprovideinformationanddoesnotrepresenttheviewsorpolicyoftheEuropeanCommissionoranyotherbody.

IntroductionAbroadarrayofpresentandfutureresearchdevelopmentsaregenerallylumpedtogetheras“nanotechnology.”Acommonfeatureisonlythattheyareconcernedwithlargeandsmallthingswhereatleastsomerelevantmeasuresareinthenanometrerange(10-9to10-7metres)andthusinthesize-rangeofDNA-moleculesorviruses.Morestringentdefinitionsrequirethatnanotechnologicalresearchberestrictedtothescientificinvestigationandtechnicalexploitationofnovelpropertiesthatappeardiscontinuouslyatthenanoscale:atonofgoldhasthesamechemicalpropertiesasamilligram,butagoldnanoparticleshowsinterestingandinitiallysurprisingnewbehaviours.Thismorestringentdefinitionofnanotechnologicalresearchremainsquiteunspecificregardingtechnologicalapplications:nanotechnologyisallthatthesenewlydiscoveredpropertiesandprocessesmightbegoodfor.Andhere,theimaginationrunswild,challengingustoidentifyandsupportpromising,feasibleaswellasbeneficialshort-andmedium-termdevelopments.

Onfirstsight,nanomedicineistherathermorewell-definedapplicationofnanotechnologyintheareasofhealthcareanddiseasediagnosisandtreatment.Buthere,too,oneencountersabewilderingarrayofprogrammesandprojects.Artificialboneimplantsalreadybenefitfromnanotechnologicallyimprovedmaterials.Nanostructuredsurfacescanserveasscaffoldingforcontrolledtissue-growth.Of

course,allkindsofmedicaldevicesprofitfromtheminiaturisationofelectroniccomponentsastheymovebeyondmicrotonano.Thisaffectsdiagnostictools,pace-makers,“camerasinapill,”etc.Nanoparticulatepharmaceuticalagentscanpenetratecellsmoreeffectivelyaswellasbeingabletocrosstheblood-brain-barrier.Afterinjectingnanoparticlesintotumours,thesecanbestimulatedelectromagneticallyfromoutsidethebody–byemittingheat,thestimulatedparticlescanthendestroythetumourcells.Antibacterialsurfacesincorporatingphotocatalyticorbiocidalnanoparticlesreducetheriskofinfectionindoctors’officesandpublicbuildings.Portabletestingkitsallowforself-monitoringandspeedydiagnosis.Newcontrastagentsandvisualisationtoolsprovideacloserlookatcellularprocesses.Butthis,too,isnanotechnologyinaction:nanoparticulatesteroidsareintroducedintothebody’sownredbloodcells;asthecellsdietheirnaturaldeaths,thesteroidsarereleasedtothebodyinverysmalldoses,thusminimising,ifnotexcludingtheside-effectsofmanysteroidtreatments.2

Theseexamplesandmanymoreofongoingdevelopmentscanbefoundinvariousreportsontheprospectsandpromisesofnanomedicine.Butthoughtheseexamplesarenothingtofrownat,nanomedicinehasbeenconceivedasafarmoreambitiousenterprise:"Nanomedicine comes into being where a molecular understanding of cellular processes is strategically combined with capabilities to produce nanoscale materials in a controlled manner."3Withthesegreaterambitionscomestheformidablechallengetoassessmorevisionaryprogrammesnotonlyfortheir

mean more people on Earth. But how many more people can the Earth sustain?"22Inasimilarvein,theEuropeanTechnologyPlatformnotesthatonelargeimpactofnanomedicinewillbe"increased costs of social security systems due to ageing of population."23

Itisimportanttobeclearabouttheachievablegoalsofnanomedicinethatareinthepublicinterest.Popularfascinationwithenvisionedtechnologiesoflifeextensiondoesnotrenderlongevityapublicgood.Conversely,beforeworryingaboutincreasedlife-expectancyasoneofthepotentialimpactsofnanomedicine,oneshouldensurethatnanomedicinegetsoffthegroundandmeetstheformidablechallengetoconvertevenitsmoremodestambitionsintoreality.

Asitisconvertedfromvisiontoreality,thenotionofcellrepairwillbeatestinggroundfortheveryideathatcellularprocessesinvolveananotechnologicalmachinerythatcanbreakdownandthatcanalsoberepaired.Thismetaphorofnanomachineryhasprovenproductiveforunderstandingcellularmechanismsbutitisunclearasofyethowfarthismetaphorcarrieswhenitcomestotheprecisioncontrolofhighlycomplexbiologicalrealities.24Italsoleadstotheethicalquestionofwhetherwemaymechanicallyreducethehumanbeingtoasumofphysicaltraits.25

Ethical and societal issuesTraditionally,medicalethicsispatient-andtreatment-centredratherthanresearch-anddisease-centred.Inotherwords,mostmedicalethicsisfocusedondoctor-patientrelations,onend-of-lifedecisions,onresource-allocation,ontreatmentchoices,informedconsent,andthelike.Biomedicalresearchbecomessignificantonlyasitentersclinicaltrials.Accordingly,medicalethicshasbeenratherindifferenttothelevelofmedicalintervention.Whiletheremovalofthecausesofdiseaseisgenerallypreferabletosymptomatictreatments,itdoesnotappeartomattermuchwhetherdiseasesareaddressedatamolecularorcellularorwhole-organlevel.

Astheprevioussectionsindicated,however,thenanomedicalresearchprogrammeraisesissuesthatservetoexpandthescopeofmedicalethics.Thisconcerns,forexample,thedistinctionbetweendruganddeviceanditsregulatoryimplications.Italsoconcernstherecognitionandacknowledgmentoflimitsofknowledgeandcontrol,inotherwords,caretoavoidhypeandtostateachievablegoalscrediblyandresponsibly.Regenerativemedicineintheserviceofpublichealthandqualityoflifeshouldbedistinguishedfromthenotionthatlife-extensionisapublicgood.Finally,nanomedicalresearchraisesquestionsofdistributivejusticeandglobalequityas

majorpublicinvestmentsaredirectedatcancertreatmentsandthusatattemptsfurthertoreducemortalityindevelopedsocietieswhereitisalreadycomparativelylow.

Nanomedicalethicsshouldnotservetovalidateanuncertainfuture,forexample,byassumingtooreadilyanincreaseofdiagnosticpowersoranimpactonlife-expectancy.Instead,itmightcontributetopublicdeliberationontheresearchagendafornanomedicine.Onceonestartsquestioningitsprimaryfocusoncancerandcardiovasculardiseases,onemighthavetoconsidertheverydefinitionsofillnessandhealthandthemedicalisationofsociety.Similarly,onemightconsiderthemetaphorsweusetodescribethehumanbeingorthechangingboundariesofhumanbodiesasthebody'sowntissueorinsulin,forexample,mightbegeneratedoutsidethebodyorbywayofanimplanteddevice.

ConclusionA2007nanomedicalbulletinofferedthefollowingnewsitem:"Working with an organic semiconductor, researchers at the University of Arkansas have fabricated and tested two similar but slightly different biosensors that can measure physiological signs. Integrated into 'smart' fabrics – garments with wireless technology – the sensors will be able to monitor a patient's respiration rate and body temperature in real time."26Inmanyways,thisappearstobenanotechnologyatitsbestandisthereforenotatalluniquetotheUniversityofArkansas.Itisanexampleofhighlyinterdisciplinaryresearchthatintegratesfunctionalitiesatthenanoscale,namelytheotherwiseseparatenanotechnologicalfieldsofpoint-of-carediagnosticsand'smart'fabrics.Thiskindofmedical nanotechnologymayenableaprofoundreconfigurationoftherelationsbetweendoctors,patients,andhospitals.Itcanalsopromotethefurthermedicalisationofsociety,thatis,ofbringingsocialbehaviours(risktaking,dietarypractices,stressandanger)intotherealmofmedicalsupervision.Thesedevelopmentsarelikelytobecontestedandcallforthedebateoftheirethicalandsocietalimplications.

Itisunlikelythatnanomedicinewillbeastransformative.Itdefinesitselfasbasicmedicalresearch,andisapplication-orientedlikeallmedicalresearch.Assuch,nanomedicinecanrealiseitspromises

References1 Nanobiotechnology:ResponsibleActiononIssuesinSocietyandEthics:http://nanobio-raise.org/2 MauroMagnani Eythrocyte Engineering for Drug Delivery and Targeting.NewYork:Kluwer,2003.3 VolkerWagnerandAxelZweckNanomedizin:Innovationspotenziale in Hessen für Medizintechnik und Pharmazeutische Industrie Wiesbaden:HessischesMinisteriumfürWirtschaft,2006.4 RobertA.Freitas(1999): Nanomedicine, Volume I: Basic Capabilities,Georgetown,TX:LandesBioscience.5 Cancer NANOTECHNOLOGY: Going Small for Big Advances – Using Nanotechnology to Advance Cancer Diagnosis, Prevention and Treatment.Washington,DC:U.S.DEPARTMENTOFHEALTHANDHUMANSERVICES,National InstitutesofHealth,NationalCancerInstitute,2004.6 Nanomedicine: Nanotechnology for Health – European Technology Platform.Brussels:EuropeanCommission, ResearchDG,2006,p.12.7 Ibid.,p.10,seealsop.6andespeciallyp.12.8 Nanomedicine: An ESF – European Medical Research Councils (EMRC) Forward Look report.Strasbourg:European ScienceFoundation,2006.9 Likesyntheticbiology,nanomedicineisthuspoisedtobecomeanoff-shootofnanotechnologythatclaimsitsown, atleastpartlyseparateidentityandintegrity.–TwooftheauthorsoftheESF-reportreflectonthisquiteexplicitly, seeRingsdorfandDuncan"nanogamesgainingground"2006.10 TheEuropeanTechnologyPlatformsubsumesnewpharmaceuticalsunder"targeteddelivery":"Seamlessly connectingDiagnostics,TargetedDeliveryandRegenerativeMedicine:Diagnostics,targeteddeliveryand regenerativemedicineconstitutethecoredisciplinesofnanomedicine.TheEuropeanTechnologyPlatformon NanoMedicineacknowledgesandwishestoactivelysupportresearchattheinterfacebetweenitsthreescience areas."Thisresearchattheinterfacecanestablishtheranostics(p.9).11 AlfredNordmann"KnotsandStrands:AnArgumentforProductiveDisillusionment,"Journal of Medicine and Philosophy,32:3,2007,pp.217-236.12 ESF-report,p.11.13 Thisconstructiveprinciplealsodistinguishesnanomedicine(asakindofnanotechnology)frombiotechnologywhich isdevelopinganddeployingproteinsasactiveagents.14 ETP,p.16.15MatthiasAdam"Whattoexpectfromrationaldrugdesign,"Expert Opinion on Drug Discovery2(6),2007, 773-776.16 JoachimSchummer"TheImpactofNanotechnologiesonDevelopingCountries,"inFritzAllhoff,PatrickLin,,James Moor,JohnWeckert,eds., Nanoethics: The Ethical and Social Implications of Nanotechnology,Wiley,2007.17AndreasJordan"FromSciencetoBusinessin15Years"intheProceedingsofEuroNanoForum 2005: Nanotechnology and the Health of the EU Citizen in 2020,editedbyMichaelMason,SophiaFantechi,Renzo Tomellini,Brussels:ECDGResearch,2006,p.16.18 TheEuropeanGrouponEthicsinScienceandNewTechnologiestotheEuropeanCommission"Opiniononthe ethicalaspectsofNanomedicine(OpinionN°21),"January17,2007,section5.5.1,p.57.19WhiletheEuropeanTechnologyPlatformconsidersregenerativemedicineoneofnanomedicine'sthreecore disciplines,theESF'sForwardLooktreatsitonlyundertheheadingofnewmaterials(inparticular,scaffoldingfor tissuegrowthandrepair).TheUS-reportonCancerNanotechnologydoesnotrefertoitatall.20 ETP,p.6.21 PaulMillerandJamesWilsdon“Themanwhowantstoliveforever”inPaulMillerandJamesWilsdon(eds.)Better Humans? The Politics of Human Enhancement and Life Extension,London:DEMOS,2006,pp.51-58.22 IvanAmatoNanotechnology - Shaping the World Atom by Atom,Washington:NationalScienceandTechnology Council,InteragencyWorkingGrouponNanoscience,EngineeringandTechnology,1999,p.8.23 ETP,p.24.24RichardJonesSoft MachinesOxford:OxfordUniversityPress,2004.25 Jean-PierreDupuyinJournal of Medicine and Philosophy,32:3,2007.26NanoMedicineNews(www.euronanotechnews.com),#71,July20,2007.

onlyinthelongerterm.Whileitmakesacompellingcaseforthesepromises,italsoasksforourpatience.Andaswithallbasicresearch,somethingisboundtocomeofit,thoughnotperhapsthefullmasteryofphysiologicalcomplexitiesthatisenvisionedinthenameoftheranostics,individualisedmedicine,andcellrepair.Someofitsmostimportantcontributionswillconsistofprogressininstrumentationandanalyticmethodsthatisnowconsideredprimarilyastepping-stonetowardsbiggerandbetterthings.

Oneshouldthereforenotexpectnanomedicinetorevolutionisemedicine.Itisonepromisingavenuebywhichmedicinecanadvance.Attheendoftheday,itwillhavecontributednewtreatment-optionsforcertaindiseases,somenewnanomedicines,betterimaging-techniquesandotherdiagnostictools.Thesewilladdsignificantlytothecurrentlyavailablearsenaloftherapiesandmedicines,raisingsimilarethicalandsocietalconcernsasdidthemedicaladvancesofthepast.Demonstrationsofefficacyhavetobeconsideredtogetherwithphysiologicalandenvironmentalside-effectsandgeneralquality-of-lifeissues,comparingallofthesetoalternativetreatmentoptions.Andlikealldisease-orientedresearch,itrequirespublicdeliberationonwhichdiseasesshouldbeprioritisedinthecontextofglobalhealthcare.

Nanomedical sectors •Drugdelivery•Biomaterials• In vivoimaging• In vitrodiagnostics• Activeimplants•Drugs&therapy

NanoBio-RAISECo-ordinationoffice:Julianalaan672628BCDelftTheNetherlandst+31(0)152786626f+31(0)152782355info@nanobio-raise.orgwww.nanobio-raise.org