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生物芯片技术、产业现况与趋势邱创泛工业技术研究院生物医学工程中心TEL:03-5912111E-mail:cfchiou@itri.org.tw中华民国九十一年二月二十一日2Sequencingcostshavedropped100-foldoverthelast10years,correspondingtoaroughlytwofolddecreaseevery18months.Thisrateissimilarto`Moore'slaw'concerningimprovementsinsemiconductormanufacture.Inbothsequencingandsemiconductors,suchimprovementdoesnothappenautomatically,butrequiresaggressivetechnologicalinnovationfuelledbymajorinvestment.Nature409,860-921(15February2001)3Proteomesizesandnumberofgenessharedwitheachofthehumanproteinsets(withaBlastcutoffof1010)OrganismsNumberofproteinsNumbermatchingEnsemblproteomeNumbermatchingCeleraproteomeHuman–31,78026,544Bacteria/Archaea85,8244,3883,915Yeast9,0307,5087,103nematodeworm19,40013,77012,660fruitfly14,08015,32414,302mustardweed25,4709,1519,081Parasites11,6065,1464,756SCIENCEVOL2928JUNE2001,MicrobialGenesintheHumanGenome:LateralTransferorGeneLoss?,p19034基因序列的特性•是一种信息。•所有生物具有共通的语法。•具有跨平台执行的能力。•具有自我演化、自我繁殖、自我扩充的能力。5•生物芯片是「微小化」、「整合化」之风潮，表现在生技领域之结果。•运用分子生物学、分析化学、生化反应等原理；•以硅芯片、玻璃或高分子为基材；•配合微机电、自动化或其他精密加工技术，所制作之高科技元件与系统；•用于进行快速之生化分析检验。6生物芯片范畴mTASmicroTotalAnalysisSystemLab-on-a-ChipcDNA/DNAmicroarrayGeneChipMicrofluidicChipBioMEMS(BioNEMS)ProteinChipHighThroughputScreeningChip7生物芯片(Biochips)基因芯片(genechip)蛋白质芯片(proteinchip)细胞芯片(cellchip)组织芯片(tissuechip)人类芯片(humanchip)电泳分析芯片(electrophresischip)检体前处理芯片(samplepreparationchip)组合化学芯片(combinatorychemistryonachip)8生物芯片应用范围基础研究、新药开发医疗诊断、环境检测食品安全、军事预警法医鉴定、制程控制9改变相关产业的竞争力改变生活方式生物芯片的重要性10未来的生技研发，是整合「知识」、「信息」与「工具」的竞争。「工具」的更新与应用，将直接影响实验室的生产力。传统仰赖高级人力，以「超工时」努力换取成果之方式，将丧失竞争力。11分子检测与治疗(MolecularDiagnosticsandTherapy)个人化医疗(PersonalizedMedicine)预防医学(PreventiveHealthcare)检测「工具」将由配角地位，成为产业「主角」之一。生物芯片将是新世代医疗之基础！12DNAMicroarray/GeneChip/DNAChipAAACCTCGTTTCGGGAAAACCTCGTTTCGGGA13应用领域•基础研究、新药开发与筛选、生技研发•基因表现程度监测•基因型鉴定•毒理、药理、治疗标的与机制•医疗诊断•个人医药、预防医学•食品安全、环境检测•法医鉴定•农渔畜牧•居家生活14基因表现程度检测GeneExpressionProfilingDNARNAProteinBiochemicalReactionsDNAReplication复制Transcription转录Translation转译ReverseTranscription逆转录cDNA15个人化医疗未来血压胆固醇运动习惯+基因型（SNPprofile）风险评估药物反应+基因表现（Expressionprofile）生理状态目前血压胆固醇运动习惯+家族病史基因型疾病16AffymetrixGlaxoWellcomeAffymaxGlaxoSmithKlineAffymetrix1988成立，新药开发1995-2001，并购隶属于GlaxoWellcome2001，再度成为独立公司核心技术Combinatorialsolidphasechemistry1993成立，研发生物芯片GlaxoWellcome占有30%以上股权，于1996IPO核心技术：Photolithography17ATCAATTCCACTTTCATCGADNAchipAAAAAAAAAAAACAAAC132456AAAC7AAAC8AAAAC9AAffymetrix18AffymaxTechnologyUSP5,571,639,November5,1996(May24,1994)Computer-aidedengineeringsystemfordesignofsequencearraysandlithographicmasksAffymetrixUnitedStatesPatent5,744,305,April28,1998(June6,1995)ArraysofmaterialsattachedtoasubstrateAffymetrix重要专利分析19UnitedStatesPatent5,744,305Anarrayofoligonucleotides,thearraycomprising:aplanar,non-poroussolidsupporthavingatleastafirstsurface;andapluralityofdifferentoligonucleotidesattachedtothefirstsurfaceofthesolidsupportatadensityexceeding400differentoligonucleotides/cm2,whereineachofthedifferentoligonucleotidesisattachedtothesurfaceofthesolidsupportinadifferentpredefinedregion,hasadifferentdeterminablesequence,andisatleast4nucleotidesinlength.Affymetrix重要专利分析20AffymetrixR&DExpansesYear20001999199819971996Totalrevenues$200,830$109,074$52,413$19,765$11,972R&Dexpenses$57,384$43,524$38,433$28,590$18,762Netloss$(53,990)$(25,504)$(26,800)$(22,780)$(12,227)Netlosspershare$(0.98)$(0.54)$(0.62)$(0.50)$(0.30)(inthousands,exceptpershareamounts)21Affymetrix,1998-2000核心技术：光罩法/Oligonucleotide4-20bases重点产品：感染性疾病、新药开发产业策略：封闭系统重要客户：EasyAccess™专案Warner-LambertCompanyAmericanHomeProducts/GeneticsInstituteEosBiotechnology,Inc.Hoffmann-LaRocheLtd.HoechstMarionRoussel,Inc.HowardHughesMedicalInstituteRhone-PoulencRorer22基因芯片专利诉讼HighDensityArray,1998/15,445,9345,744,3055,800,992SequencebyHybridization5,202,2315,525,4645,695,940ChemicalSynthesis2000/7SouthernDNAArrayAffymetrixOxfordGeneTech.PEHyseqIncyte/SynteniSequencebyHybridization5,795,716HighDensityArray5,744,305侵权抵触无效侵权无效侵权23基因芯片量产制程原位合成in-situsynthesis微影光罩法Photolithography(Light-directedin-situsynthesis)四色印刷法4-baseink-jetin-situsynthesis預先合成ex-situsynthesis噴墨法Ink-jetprinting點陣法Blot-printing/Spotting探针密度高(50,000/cm2)低(6,000/cm2)探针长度短(10-50mers)长(10-100mers)orhigher24Affymetrix,2001-•专利诉讼互有胜负。•Affymetrix-OxfordGenetechnology，负•Affymetrix-Hyseq，和•Affymetrix-Incyte，未定•市场成长缓慢，且占有率蚕食鲸吞，节节下滑。•制程技术瓶颈无法突破，成本居高不下。•产品设计错误，造成客户损失。•封闭系统，客户群有限。•无法与客户分享信息，抱怨连连。25Affymetrix,2000-•购入GeneticMicroSystems(GMS)，提供客户自制芯片服务•努力改善客户关系。•转移公司运行方向•成立PerlegenSciences建立SNP资料库•与Hyseq和解，并成立CallidaGenomics,Inc专责芯片业务•Ayymetrix可能转型成为新药开发公司264-BaseInk-Jetin-situSynthesis•富有弹性•适合小量试产•可以发展成实验室使用之产品•RosettaInphamatics+AgilentFlexJetTMDNAMicroarraysChangearraydesignatwill.Synthesizedifferentlengtholigonucleotidesonthesamearray.Movefromdesigntoarrayinhours.Workonnewlycharacterizedorganismsandhavethearraydesignchangeandgrowwithyourknowledgeofthegenome.274-baseInkjetin-situSynthesisACGATCGATCGATCGATCGATCGAACATCGATCGATCGATCGATCGA28微流体生物芯片mTAS/Lab-on-a-ChipsBiochipSystemInformationSpecimensReagents/SubstratesInformation平行检测：提供完整信息。迅速正确：节省时间，降低人为错误。降低成本：容易普及化。“sample-in