诺贝尔医学奖论文剖析 27页

诺贝尔医学奖论文剖析科学假说和验证假说具有重要作用启示2传染病的假说流行病学调查禁止食人葬俗预防库鲁病发病假说社会习俗调查库鲁病人脑组织中可能存在感染因子的假说动物实验验证感染因子的存在广泛联系拓展思路启示3在发现了库鲁病的慢病毒感染以后并不停留在这只是个别原始民族的疾病问题而是和人类和动物其他更为广泛的某些原因不明的神经系统和非神经系统的疾病相联系提出这类疾病也可能由慢性病毒引起的假说为研究这类疾病提出新的方向采用类比方法解决病因研究中的主要科学矛盾启示41矛盾一是从流行病学调查证据看是传染病而从个体症状和实验室检查证据看菲典型传染病只有解决这个矛盾才能发现慢病毒在库鲁病中的病原作用这个矛盾的解决需耍做动物实验验证因而是Gajdusek决心进行动物实验的动因通过类比研究证实库鲁病和羊蚤痒病可能是同一个病原体引起的SmalllaboratoryanimalsTransmitkurutosmalllaboratoryanimailsortoisolateabacteriumleptospirumfungusrickcttsiaorvirususingtissueculturesorembryonatedhenseggswereunsuccessfulEpidemiologyinfectiousEtiologicalhypothesisofKuru Clinicalpatientsnoobvioussignsofinfection1nomcningo-encephaliticsignsorsymptomsfeverconfusionconvulsionsorcoma2nocerebrospinalfluidplcocytosisorelevatedpTotcinlevelPathologybyautopsynoperivascularcuffingsorothersignsofinflmmnatorybrainpathologyEnvironmentalinvestigationsneitherexhaustivegeneticanalysesnorthesearchfornutritionaldeficienciesorenvironmcntaitoxinsresultedinatcnablchypothesisLiberskiPPBrownPKuruitsramificationsafterfiftyyearsExperimentalGerontology2008doi101016jexger200805010MisinterpretationsofKuruScholarswhofirststudiedthediseasehadmajormisconceptionsconcerningitsnatureTheyfirstincorrcctlypostula’tcdthatitwasageneticdisorderasithadatendencytooccuramongfamilymembersThispossibilitywaseventuallyruledoutbecauseKuruwastoocommonandtoofatalsuchalethalgeneticdisorderwou1ddrasticallyreducethefitnessofapopulationandsoondieoutofthegenepool2矛盾二是库魯病的病原体和典型病毒的才盾问题盖求塞克通过实验性前瞻性调查和动物实验证明库鲁病是由病原体引起的传染病然而这种病原体和典型的病毒不同因此只能称感染因子由于Dienner等人发现植物类病毒将库鲁病病原体和植物 类病毒类比发现库鲁病的慢性毒原来是和一般病毒不同的类病毒Gajdusck教授善于应用类比的方法和他的知识结构有密切关系他是美国神经病和中风研究所的研究员乂是病毒学的专家这种知识结构帮助他善于把人类致病慢病毒和植物类病毒类比启示5背景知识动物模型证据科学新发现实验室调查证据临床观察发现背景知识不能解释的科学问题其他发现分析类比联想灵感分析实验室检杳流行病学调查问题假说其他发现分析类比联想灵感分析科学发现是科学假说提出和证明相互作用的动态过程及其结果不断产生问题解决问题是科学发现的内在动力金大劫1987基于家庭扩展家庭疾病表型定义质量数量中间衣型疾病表型的人群家庭环境因素选择核心家庭双生子养子病例对照样本量估计样品保存数据收集家族史临床资料环境测定DXA收集流行病学设计与方法选择单纯病例基因分型科研整体思路基I大I分析数据分析Defineinteractionsenvironment-genegene-genePhysicalmappingGeneidentificationIdentifytestandmapregionsofinterestTrait-modeldependentLODscoreanalysisTrait-modelindepcndentsib-pairanalysisaffectedrclativcpairanalysisAssociationstudiescase-controlfamily-based启示6浓厚的研究兴趣辛勤的敬业精神敢于冒风险奉献精神如果你喜欢到未开化的地区去探险那么你有可能获诺贝尔奖Gajdusek教授儿乎是在没有任何资助的情况下开始他的课题研究的为了查明一•种蔓延在南太平洋土著人中的库鲁病的病因盖达塞克多次深人到新几内亚土著人屮间进行调查其间饱尝了失败的苦涩和他人的嘲讽美国国内研究院的同事们开玩笑地称他是研究库鲁病着 了迷的疯子把他所从事的工作称为由考察库鲁病引起的续发性感染Gajdusek教授的导师斯麦迪尔说这是一种强烈的冒险精神是以自己的时间精力和科学声誉以致金钱作为投资从事风险事业的探索精神而且盖达塞克的研究经费曾儿度告罄有时不得不靠口己的积蓄來维持生计但一个真止有作为的科学家所具有的可贵品质就在于他一旦确定了FI标就会执着地去追求锲而不舍直至成功参加第42届诺贝尔医学获奖者年会1996年德国林道Lindua参加诺贝尔医学获奖者有18位GertrudeBElion1918-1999PhysiologyorMedicine1988FortheirdiscoveriesofimportantprinciplesfordrugtreatmentEdmondHFischer1920-PhysiologyorMedicine1992ForPhosphorylationDoctoralstudentsEdwinGKrebsBornShanghaiChina与克雷布斯共同发现可逆的蛋口质磷酸化作用是牛物的最基木功能Z—理论而获奖发现和描述了细胞中蛋白质的调控活动机制有助于开发治疗平衡失调症的新型药物这将导致人类找到根治癌症的方法RichardJRoberts1943一PhysiologyorMedicine1993ForintronsFieldsmolecularbiologistBornDerbyEnglandUK与夏普发现既可致病亦可治病的基因分裂现象通过对一种普通感冒病毒的研究发现基因并非铁板一块而是由不同的片断构成紧接着又发现基因可分裂并重新拚接基因的重新拚接是对自身的更新但拚接的失误也在所难免基因可分裂性已成为现代生物学研究的基础基因治疗方法也是在此基础上产生的ChristianeNusslein-Volhard1942-PhysiologyorMedicine1995FortheirdiscoveriesconcerningthegeneticcontrolofearlyembryonicdevelopmentPhysiologyorMedicine1978Hamilton0Smith 23August1931NewYorkNYUSAAffiliationatthetimeoftheawardJohnsHopkinsUniversitySchoolofMedicineBaltimoreMDUSAPrizemotivation/zforthediscoveryofrestrictionenzymesandtheirapplicationtoproblemsofmoleculargenetics"创造性思维基本特性突破性新颖性突发性多向性形象性深刻性独立性敏捷性风险性综合性Gajdusek教授在揭示人类退行性脑病的研究思路主要什么实现创新的路径希望打破常规的人实现创新有效的创新思维相关的技术知识创新理论和规律谢谢发现的问题及其实验假说发现的问题及其实验假说Kuril病理变化与CJDScrapie有相似海棉状脑病变具有慢性传性传染物质到底是什么早期认为是一•种迟发性感染Slowinfection慢病毒与一般病毒感染认为为Slowvirusinfection传染物质一直未被分离为非常规型病毒发病者参加Kuru病丧葬仪式且食入患者组织的不良习俗发现的问题及其实验假说Kuru病理变化与CJDScrapie右相似海棉状脑病变具有慢性传性传染物质到底是什么早期认为是一•种迟发性感染Slowinfection慢病毒与一般病毒感染认为为Slowvirusinfection传染物质一直未被分离为非常规型病毒发病者参加Kuru病丧葬仪式且食入患者组织的不良习俗推测Kuru病亲属的脑组织含有非常规病毒-丧葬仪式食入-传播发病提出的实验方案死者的脑子研碎滤洗除去微生物核酸分解酶处理将蛋片粒子移入到黑猩猩脑中死者的脑子实验结果AchimpanzeebrainwithexperimentalkuruAphotograph67-10825-2-1261214courtesyofDCGajdusekParisFranceSlowinfectionsofmancausedbyconventionalviruses非常规病毒物理化学特性的比较人类致病慢病毒和植物类病毒类的比 较CJDScrapie动物传播实验和KuruCJDScrapie和TME非常规病毒的潜伏期时间实验结果18-38个月后黑猩猩发生与Kuru病临床相似的表现首次证实Kuru病为传染性疾病再用这只黑猩猩的脑了提取出蛋白粒了移植到另一只健康的黑猩猩脑中仍然发病若将蛋门粒子经过蛋口分解酶处理就不会发病盖达塞克教授的研究结论库鲁病是由一•种侵害人的脑子和神经系统的慢性病毒所致其慢病毒以寄生于脑组织可长期潜伏为特征既非微生物也非常规型病毒禁止Foar族丧葬食人肉和脑的不良风俗后库鲁病随即预防库鲁病为代表的人类TSE病人和羊瘙病羊各器官组织屮感染因子主要分布在屮枢神经系统和眼球脾脏淋巴结等也有分布宿主组织人类库鲁病感染性绵羊山羊瘙病感染性脑脊髓脑脊液眼球周围神经0垂体腺NT脾淋巴结白细胞NT宿主组织人类库鲁病感染性绵羊山羊瘙病感染性血清00血球血浆0土骨髓00肺土肝肾0肠0卵巢NT子宫NT注总是存在经常不规律土罕见0未发现少量样本结果NT示检查人的海绵状脑病震颤病或库鲁病Kuru克-雅病CJD或克-雅病变种V飭iantCJDGcrstmann-Strausslcr综合征GSS致死性家族失眠症fatalfamilialinsomniaFFI肮病毒的传播途径-食物传播如CJD库鲁病等的流行病调杳库鲁病病人AspecimenfromaGSScasestainedagainstPrPNoteinnumerableplaquesreminiscentofkuruplaques1997kuruplaqueAspecimenreversedfromaparaffinblocktotransmissionelectronmicroscopyAspecimencourtcsyofDrDCGajdusckParisFrance1997Amicrophotographshowingaspecimenofcerebellarcortexstainedagainstprionproteinantibodies3F4tovisualizekurunumerousplaquesSpecimencourtesyof DrDCGajdusekParisFranceTheimmunohistochemicalstudywasperformedcourtcsybyProfHerbertBudkaViennaAustriaHainfcllncrctal1997Kuru病与肮病毒反病毒对人类最大的威胁是可以导致人类和家畜患中枢神经系统退化性病变最终不治而亡Kuru病是人类发现的第一个致死性航蛋白病随着阮病毒的侵入复制在神经元树突和细胞本身尤其是小脑星状细胞和树枝状细胞内发牛进行性空泡化星状细胞胶质增生灰质中出现海绵状病变肮病毒病属慢病毒性感染皆以潜伏期长病程缓慢进行性脑功能紊乱无缓解康复终至死亡为特征The1stNobelPrizeforprionstudy1976CarletonGajdusek1923rctiredaschiefofthelaboratoryofCNSatNIHDemonstratedKurusetiologyaninfectiousinvisibleslow30yincubationperiodvirusasthatofScrapieNeversawanyinflamination反病毒Prp一类能侵染动物并在宿主细胞内复制的小分子无免疫性疏水蛋白质它与一般病毒不一样只有蛋白质而无核酸但却既有感染性又有遗传性H具有和一切已知传统病原体不同的异常特性阮病毒Prp阮病毒又称普里昂蛋口它可加速进化蚯蛋白可能对酵母进化提供了一个加速度正常的血病毒位于神经细胞的表面大约是最小病毒尺寸的1100它是折叠为两种形式之一的蛋口质航病毒Prp正常的Prp富含a螺旋称为PrPcPrPc在某种未知蛋白质的作用下可转变成全为0折叠的PrPsc从而致病蛋白感染索月元蛋白也告诫人类无论是分食族人尸体的陋习人吃人述是用粉碎了的动物尸体和内脏作饲料喂养那些食草的牛羊牛吃牛羊吃羊都会产生不祥的后果因此放弃进食同类蛋白食人族习俗还有中医的进食胎盘大补说从工业化农业恢复到自然生态农业也许是战胜疯牛羊 病和疯人病的最根本的途径•研究思路之一病因发病机制控制措丿施病策略1策略2策略3-问题树-策略树病理学病毒学实验动物流行病学临床学环境因素预防医学•研究思路Z二病因发病机制控制措施病策略1策略2策略3-问题树-策略树病理学病毒学实验动物流行病学临床学环境因素预防医学目录一研究背景与科学难点二论文研究思路的剖析三对科学研究工作的启示1950年美国人类学家罗伯特•葛拉斯RobertGlasse夫妇记录ForeI大I害怕大灭绝而举行的无数次集会1957年新儿内亚公共一卫生署长官吉加斯医生说服在澳大利亚完成传染性肝炎研究的途经新几内亚回国的Gajdusek研究Kuril病华盛顿的斯马德尔老师寻找神经病理解剖专家8月克拉索发现患者小脑损伤严重怀疑接触了某种有毒的物质所致9月发现儿童患者脑部老化性改变的淀粉样蛋白斑唯一与此和似的人类疾病只有克雅二氏综合症CJD综合症1959年拍摄第一部关于Kuru症的科学片并在美英展出1959年9川英国研究羊搔痒症病理学兽医海徳娄观后迅速撰写比较两病的论文并发往《柳叶刀》医学朵志同时将论文寄给Gajdusek因羊搔痒症可以从绵羊传给山羊山羊再回传给绵羊可设法在实验室条件下将Kuru症传递给动物如灵长类以验证Kuru症是否也是传染病昆虫媒介病毒的专家吉布斯ClarenceJosephGibbs确定为实验动物负责人地方性疾病传染病或母亲传递给子女的遗传性病Gajdusek研究思维的发展过程和研究团队的形成传染病模型Gajdusek研究Kufu病昆虫媒介病毒的专家吉布斯ClarenceJosephGibbs实验动物负责人Gajdusek研究思维的发展过程和研究团队的形成1965年6月28H吉布斯的助手苏利玛MikeSulima首先发现被称为乔琪的猩猩行为界常有点发 抖似冷风袭击它一般到7月中句该异常己更明显来自澳洲的研究人员阿尔波斯医生在作记录观察时机械的写下临床印象Kuru症他立刻被自己写下的东西震惊并找到吉布斯说猩猩得Kuru症但吉布斯认为-•种想象吉布斯为了尽可能的客观拒绝看任何Kuru症病例以免先入为主的概念影响了动物观察但阿尔波斯坚持要吉布斯把Gajdusek从新几内亚找冋來吉布斯只得发电报给Gajdusek要他冋来看看7月20HGajdusek赶到时乔琪的情况更糟了几乎已经不能行走一而走一而摔跤就在24小时前Gajdusek还和Kuru症患者接触现在看到这只猩猩的症状实在是和Kuru症患者太相似了到这时大家都同意猩猩可能真的感染上了Kuru病Gajdusek研究思维的发展过程和研究团队的形成10刃神经病理学家贝克亲自到现场直接将乔琪的脑部带回了伦敦观察其病理变化变化在焦灼中等待了三个多星期后贝克从伦敦发来电报内容简捷而有力乔琪病理与人类Kuru症无法分辨在收到贝克的电文后Gajdusek吉布斯阿尔波斯开始撰写整个实验的总结性论文于1966年2月发于Nature向同彳亍们宣布已经确认在实验条件下将Kuru症接种移植到狎狎上自从确认了Kuru症是传染性疾病后确认英在Fora族中是如何的传播的就成了紧耍问题同年12月贝克发表了详尽的乔琪脑部病理报告认定乔琪大脑神经元大量损失海绵状改变十分明显受损部位的神经兀几乎丧失殆尽到1968年阿尔波斯突然顿悟了这其中的奥妙可以解释以前的困惑Z处那就是丧葬食Kuru感染者组织的传播模式可解释Kuru症传播所涉及的年龄和性别难题到此对Kuru症这种疾病终于有了一个比较满意的结果1957-1976-主要成果-高质量论文1459GAJDUSEKDCZIGASVDegenerativeDiseaseOfTheCentralNervousSystemInNew-Guinea-TheEndemicOccurrenceOfKuruInTheNativePopulation NewEnglandJournalOfMedicine25720974-9781957GAJDUSEKDCGIBBSCJATTEMPTSTODEMONSTRATETRANSMISSIBLEAGENTINKURUAMYOTROPHICLATERALSCLEROSISOTHERSUB-ACUTECHRONICNERVOUSSYSTEMDEGENERATIONSOFMANNATURE204495257-2671964BECKEGAJDUSEKDCVARIABLESIZEOFSEPTALNUCLEIINMANNATURE21050431338-13481966GAJDUSEKDCGIBBSCJALPERSMEXPERIMENTALTRANSMISSIONOFAKURU-LIKESYNDROMETOCHIMPANZEESNATURE2095025794-8041966BECKEDANIELPMALPERSMGAJDUSEKDCGIBBSCJEXPERIMENTALKURUINCHIMPANZEES-APATHOLOGICALREPORTLANCET27472105619661957-1976-高质量的论文1459KAKULASBALECOURSARGAJDUSEKDCLATENTVIRUSESINCHIMPANZEESWITHEXPERIMENTALKURUNATURE21651144461967GAJDUSEKDCSLOW-VTRUSINFECTIONSOFNERVOUSSYSTEMNEWENGLANDJOURNALOFMEDICINE2767392-4021967GAJDUSEKDCGIBBSCJALPERSMTRANSMISSIONAXDPASSAGEOFEXPERIMENTALKURUTOCHIMPANZEESSCIENCE155IS3759212-2221967GIBBSCJGAJDUSEKDCASHERDMALPERSMPBECKEDANIELPMMATTHEWSWBCREUTZFELDT-JAKOBDISEASESPONGIFORMENCEPHALOPATHY-TRANSMISSIONTOCHIMPANZEESCIENCE161IS38393881968GAJDUSEKDCGIBBSCJASHERDMDAVIDETRANSMISSIONOFEXPERIMENTALKURUTOSPIDERMONKEYATELESGEOFFREYISCIENCE162385469319681957-1976-高质量的论文1459GAJDUSEKDCGIBBSCJTRANSMISSIONOF2SUBACUTESPONGIFORMENCEPHALOPATHIESOFMANKURUANDCREUTZFELDT-JAKOBDISEASETONEWWORLDMONKEYSNATURE2305296588-5971971GAJDUSEKDCGIBBSCJROGERSNGBASNIGHTMHOOKSJPERSISTENCEOFVIRUSESOFKURUANDCREUTZFELDT-JAKOBDISEASEINTISSUE-CULTURESOFBRAINCELLSNATURE23533104-1141972GAJDUSEKDCGIBBSCJTRANSMISSIONOFKURUFROMMANTORHESUS-MONKEYMACACA-MULATTA812YEARSAFTERINOCULATIONNATURE2405380351-3571972GIBBSCJGAJDUSEKDCEXPERIMENTALSUBACUTESPONGIFORMVIRUSENCEPHALOPATHIESINPRIMATESANDOTHERLABORATORY-ANIMALSSCIENCE182767-681973疾病人群临床的发现1I现场调查与实验室研究13I现场干预效果观察科研思路启示1-研究团队和创新性成果-一流杂志论文45传染性海绵状脑病克-雅病皮质-纹状体-脊髓变性绵羊瘙痒病67展望亚急性海绵状脑病自然史推测自然绵羊瘙痒病是克-雅病库鲁病和貂传染性脑病的假设起源菲常规型病毒肮病毒与库鲁病的起源与消除1致亚急性海绵状脑病的非曲规型病毒2當规型病毒通过缺陷性或非缺陷性复制引起慢性疾病0前言研究背景-库魯病-慢病毒感染-与 人和动物3库鲁病4传染性海绵状脑病克-雅病皮质-纹状体-脊籠变性5绵羊瘙痒病6亚急性海绵状脑病自然史推测自然绵羊瘙痒病是克-雅病库鲁病和貂传染性脑病的假设起源7展槊诺贝尔奖论文研究思路思路一A基础研究-病毒学B病理学研究C实验动物研究D临床学研究E流行病学研究F环境因素调查J干预试验思路二A临床学研究B流行病学研究C环境因素调杳D病理学研究E基础研究-病毒学F实验动物研究J干预试验目录一研究背景与科学难点二论文研究思路的剖析三对科学研究工作的启示创造性思维方法创造性思维方法逻辑思维直觉思维形象思维幻想思维联想思维灵感思维相似联想关系联想接近联想对比联想丹尼尔•卡里顿•盖达塞克DCarletonGajdusek查明致库鲁病发生的元凶和控制措施的科学思维是什么•研究思路之一病因发病机制控制措施病策略1策略2策略3-问题树-策略树病理学病毒学实验动物流行病学临床学环境因索预防医学•研究思路Z二病因发病机制控制措施病策略1策略2策略3-问题树-策略树病理学病毒学实验动物流行病学临床学环境因素预防医学以1976年获得诺贝尔医学和生理学奖的论文内容为主检索该论文相关的文献59162篇1957-1976年1957-2004年按时间排序盖达塞克教授作为第一作者或作者Z—研究思维的剖析1957-1965-临床流行病学和病理学1957ZIGASVGAJDUSEKDCKuruClinicalstudyofanewsyndromeresemblingparalysisagitansinnativesoftheEasternHighlandsofAustraliariNewGuineaMEDJOURAUSTRALIA4421745-754GAJDUSEKDCZTGASV DegenerativcDiseaseOfTheCentralNervousSystemInNew-Guinea-TheEndemicOccurrenceOfKuruInTheNativePopulationNewEnglandJournalOfMedicine25720974-9781958GAJDUSEKDCZIGASVUntersuchungenUberDiePathogeneseVonKuruKlinischeWochenschrift3610445-4591959GAJDUSEKDCZTGASVKURU-CLINICALPATHOLOGICALANDEPTDEMTOLOGTCALSTUDYOFANACUTEPROGRESSIVEDEGENERATIVEDISEASEOFTHECENTRALNERVOUSSYSTEMAMONGNATIVESOFTHEEASTERNHIGHLANDSOFNEW-GUINEAAMERICANJOURNALOFMEDICINE263442-469KLATZOIGAJDUSEKDCZIGASVPathologyOfKuruLaboratoryInvestigation84799-7811957-1965-临床流行病学和病理学1961GAJDUSEKDCREIDLHSTUDIESONKURU4KURUPATTERNINMOKEAREPRESENTATIVEFOREVILLAGEAMERICANJOURNALOFTROPICALMEDICINEAXDHYGIENE104628-634GAJDUSEKDCBAKERJZIGASVSTUDIESONKURU3PATTERNSOFKURUINCIDENCE-DEMOGRAPHICANDGEOGRAPHICEPIDEMIOLOGICALANALYSISAMERICANJOURNALOFTROPICALMEDICINEANDHYGIENE104599-609GAJDUSEKDCZIGASVSTUDIESONKURU1ETHNOLOGICSETTINGOFKURUAMERICANJOURNALOFTROPICALMEDICINEANDHYGIENE10180-90CURTAINCCZIGASVGAJDUSEKDCSTUDIESONKURU2SERUMPROTEINSINNATIVESFROMKURUREGIONOFNEWGUINEAAUSOAMERICANJOURNALOFTROPICALMEDICINEANDHYGIENE10192-1021962SIMMONSRTGAJDUSEKDCBloodgroupgeneticalstudiesonKuru-afflietednativesoftheEasternHighlandsofNewGuineaandcomparisonswithunaffected neighboringtribesinPapua-NewGuineaBiblllaemeitol13255-2591962GAJDUSEKDCKURU-ANAPPRAISALOF5YEARSOFINVESTIGATIONEUGENICSQUARTERLY9169-701963GAJDUSEKDCARLETONKuruTRANSROYSOCTROPMEDANDHYG573151-1691964NEUMANNMAGAJDUSEKDCZIGASVNEUROPATHOLOGICFINDINGSINEXOTICNEUROLOGICDISORDERSAMONGNATIVESOFHIGHLANDSOFNEWGUINEAJOURNALOFNEUROPATHOLOGYANDEXPERIMENTALNEUROLOGY233486-496GAJDUSEKDCGIBBSCJATTEMPTSTODEMONSTRATETRANSMISSIBLEAGENTINKURUAMYOTROPHIC DEGENERATIONSOFMANNATURE204495257-2671965ALPERSMGAJDUSEKCDCHANGINGPATTERNSOFKURU-EPIDEMIOLOGICALCHANGESINPERIODOFINCREASINGCONTACTOFFOREPEOPLEWITHWESTERNCIVILIZATIONAMERICANJOURNALOFTROPICALMEDICINEANDHYGIENE145852-862GAJDUSEKDCPhysiologyorMedicine1976314Itcontainsmorethan35000peoplelivingin160villagescensusunitsthathaveexperiencedkuruAllkuru-affectedhamletslienestledamongrainforestcoveredmountainsfrom1000to2500mabovesealevelIntheForecultureandlinguisticgroupamongwhomover80ofthecasesoccurithadayearlyincideneerateandprevalenceratioofabout1ofthepopulationFigure5Kurucoincidedwiththeheightoftheepidemic5aGurumortalityrateindeathsperthousandpopulationperarmumin1957-59and1961-19635BMalefemalepopulationratioineachtribalgroupofthekururegion1958and1962Figure4Riverdrainagesofthekururegionwithsuperimposedlocationsofthe160villagesinwhichkuruhaseveroccurredIn1957itwasfoundtoaffectallagesbeyondinfantsandtoddlersitwascommoninmaleandfemalechildrenandinadultfemalesbutrareinadultmalesThismarkedexcessofdeathsofadultfemalesovermaleshasledtoa male-to-femaleratioofover31insomevillagesandof21forthewholeSouthForegroupAlldiedoftheirdiseasewithin1yearafterthisphotographweistakenEverypatientrequiredsupportfromtheothersinordertostandwithouttheaidofthestickstheyhadbeenaskedtodiscardforthephotographSixwomenwithKurusoadvancedthattheyrequiretheuseofoneortwosticksforsupportbutstillabletogotogardenworkontheirownTheclinicalcourseofKuruisremarkablyuniformwithcerebellarsymptomatologyprogressingtototalincapacitalionanddeathusuallywithinthreetoninemonthsTwoormoreForechildrenwithadvancedkuruin1957whosedentaryforseveralmonthsandwerereachingthetermineilstageofthedisease1966-1969-实验动物学病毒学营养学1966BECKEGAJDUSEKDCVARIABLESIZEOFSEPTALNUCLEIINMANNATURE21050431338-1348GAJDUSEKDCGTBBSCJALPERSMEXPERIMENTALTRANSMISSIONOFAKURU-LIKESYNDROMETOCHIMPANZEESNATURE2095025794-804BECKEDANIELPMALPERSMGAJDUSEKDCGIBBSCJEXPERIMENTALKURUINCHIMPANZEES-APATHOLOGICALREPORTLANCET2747210561967KAKULASBALECOURSARGAJDUSEKDCFURTHEROBSERVATIONSONPATHOLOGYOFKURU-ASTUDYOF2CEREBRATNSERIALSECTIONJOURNALOFNEUROPATHOLOGYANDEXPERIMENTALNEUROLOGY26185-95ROGERSNGBASNIGHTMGIBBSCJGAJDUSEKDCLATENTVIRUSESINCHIMPANZEESWITHEXPERIMENTALKURUNATURE2165114446GAJDUSEKDCSLOW-V1RUSINFECTIONSOFNERVOUSSYSTEMNEWENGLANDJOURNALOFMEDICINE2767392-402GAJDUSEKDCGIBBSCJALPERSMTRANSMISSIONANDPASSAGEOFEXPERIMENTALKURUTOCHIMPANZEESSCIENCE155IS3759212-222 1968GIBBSCJGAJDUSEKDCASHERDMALPERSMPBECKEDANIELPMMATTHEWSWBCREUTZFELDT-JAKOBDISEASESPONGIFORMENCEPHALOPATHY-TRANSMISSIONTOCHIMPANZEESCIENCE161IS38393881966-1969-实验动物学病毒学营养学1968GajdusckDCGibbsCJSlowlatentandtemperatevirusinfectionsofthecentralnervoussystemResPublAssocResNervMentDis44254-480GAJDUSEKDCGIBBSCJASHERDMDAVIDETRANSMISSIONOFEXPERIMENTALKURUTOSPIDERMONKEYATELESGEOFFREYISCIENCE16238546931969BeckEDanielPMAlpersMGajdusckDCGibbsCJNcuropathologicalcomparisonsofexperimentalkuruinchimpanzeeswithhumankuruIntArchAllergyApplImmunol36Suppl55362-68GAJDUSEKDCROGERSNGBASNIGI1TMG1BBSCJALPERSMTRANSMISSIONEXPERIMENTSWITHKLRUINCHIMPANZEESANDISOLATIONOFLATENTVIRUSESFROMEXPLANTEDTISSUESOFAFFECTEDANTMALSANNALSOFTHENEWYORKACADEMYOFSCIENCES1621529GibbsCJGajdusckDCAlpersMPAttemptstotransmitsubacuteandchronicneurologicaldiseasestoanimeilsIntArchAllergyApplImmunol36Suppl51952LAMPERTPWEARLEKMGIBBSCJGAJDUSEKDCEXPERIMENTALKURUENCEPHALOPATHYINCHIMPANZEESANDSPIDERMONKEYS-ELECTRONMICROSCOPICSTUDIESJOURNALOFNEUROPATHOLOGYANDEXPERIMENTALNEUROLOGY283353ReidLIIGajdusekDCNutritionintheKururegionIIAnutritional evaluationoftraditionalForedietinMokevillagein1957ActaTrop264331-345传染病家族性遗传病现场人群调查病理学流行病学临床学实验室检查无典型的病毒引起的传染病的炎症反应和免疫反应患者无持续性发热脑脊液屮无典型的传染病前期表现和淋巴细胞增多蛋白质升高的异常现彖病理改变乂只限于神经系统表现为星形细胞增生和肥大神经元胞体树突和轴突有进行性空泡变性表现为神经系统的变性改变不支持是传染病病例非病例血液遗传学调查菲典型传染病脑病现场人群调查病理学流行病学临床学实验室检查无典型的病毒引起的传染病的炎症反应和免疫反应不是典型传染病患者无持续性发热脑脊液屮无典型的传染病前期表现和淋巴细胞增多蛋白质升高的界常现象病理改变乂只限于神经系统表现为星形细胞增生和肥大神经元胞体树突和轴突有进行性空泡变性表现为神经系统的变性改变不支持是传染病发现矛盾GajdusekspentalmostayearlivingwithandstudyingtheForeandcollectingtissuesamplesfromvictimsofKuruin1957WhenGajdusekreturnedtotheUnitedStatesin1958hewasabletocarryoutlaboratorystudiesofKuruattheNationalInstituteofNeurologicalandCommunicativeDisordersandStrokewhereheeventuallyestablishedtheLaboratoriesofS1owLatentandTemperateVirusInfectionsandofCentralNervousSystcmStudicsThebraintissueobtainedfromvictimsofKururevealedmanylesionsandatrophybutnottheexpectedsignsofinfectionWillicimHadlowoftheNIIIRockyMountainlabomtorypointedoutthesimilaritybetweenKuruandaviraldiseaseofsheepknownasscrapieEllisFayJarosh2009TotestthepossibilitythatKuruwasaviraldiseaseGajdusekandhisassociateClareneeJGibbsinoculatedchimpanzeeswithbraintissuefromKuruvictimsAll cookingincludingthatofhumanfleshfromdiseasedkinsmenwasdoneinpitswithsteammadebypouringwateroverthehotstonesorcookedinbambooevlindersinthehotashesInfectionwiththekuruviruswasmostprobablythroughthecutsandabrasionsoftheskinorfromnose-pickingryerubbingormucosalinjuryFore族特殊葬礼仪式-FamilycookandatedeceasedfamilymembersbodytissueandbrainFore部落土著有亲人死后用死者的脑涂抹丁•口周及眼周并食用死者的身体组织和脑的不良风俗而使该病广泛传播尤其妇女及儿童食物性传播地区分布distributionofdiseasebyplace1国家间及国家内的分布2城乡分布3影响地区分布的因素1特姝风俗习惯和遗传特征2自然地理因素3生物因素4社会经济环境2地方性由当地的卫生习惯和卫生条件所造成的某病在某地区或人群中长期存在如伤寒痢疾及KURU病Figure7Theoverallincidenceofkurudeathsinmaleandfemalepatientsbyyearsinceitsdiscoveryin1957through1975干预效果依据Gajdusck研究1968年停止食人葬俗后库鲁病得到控制而逐渐消除从而拯救了一个部落的人群1970-1972-流行病学遗传和病理比较1970GAJDUSEKDCSORENSONERMEYERJACOMPREHENSIVECINEMARECORDOFDISAPPERARINGKURUBRAIN9365-69GIBBSCJGAJDUSEKDCISOLATEDANDMIGRATORYPOPULATIONGROUPSHEALTHPROBLEMSANDEPIDEMIOLOGICSTUDIES4KURUPATHOGENESISANDCHARACTERIZATIONOFVIRUSAMERICANJOURNALOFTROPICALMEDICINEANDHYGIENE191138-1441971GAJDUSEKDCSLOWVIRUSDISEASESOFCENTRALNERVOUSSYSTEMAMERICANJOURNALOFCLTNTCALPATHOLOGY563320-337GAJDUSEKDCGIBBSCJTRANSMISSIONOF2SUBACUTESPONGIFORMENCEPHALOPATHIESOFMANKURUAXDCREUTZFELDT-JAKOBDISEASETONEWWORLDMONKEYSNATURE2305296588-597GibbsCJGajdusekDCTransmissionandcharacterizationoftheagentsofspongiformvirus encephalopathieskuruCreutzfeldt-JakobdiseasescrapieandminkencephalopathyResPublAssocResNervMentDis49383-410LAMPERTPHOOKSJGIBBSCJGAJDUSEKDCALTEREDPLASMAMEMBRANESINEXPERIMENTALSCRAPIEACTANEUROPATHOLOGICA19281-861972GajdusekDCSpongiformvirusencephalopathiesJClinPatholSupplRCollPathol678-83GAJDUSEKDCGIBBSCJROGERSNGBASNTGHTMHOOKSJPERSISTENCEOFVIRUSESOFKURUANDCREUTZFELDT-JAKOBDISEASEINTISSUE-CULTURESOFBRAINCELLSNATURE23533104-1141970-1972-动物模型遗传和病理比较1972GAJDUSEKDCGIBBSCJTRANSMISSIONOFKURUFROMMANTORHESUS-MONKEYMACACA-MULATTA812YEARSAFTERINOCULATIONNATURE2405380351-357GajdusekDCAlpersMGeneticstudiesinrelationofkuruICulturalhistoricalanddemographicbackgroundAmJHumGenet24Suppl138-45GibbsCJGajdusekDCIsolationandcharacterizationofthesubacutespongiformvirusencephalopathiesofmankurucindCreutzfeldt-JakobdiseaseJClinPatholSupplRCollPathol684-96KitchinFDBearnAGAlpersMGajdusekDCGeneticstudiesinrelationtokuru3Distributionoftheinheritedserumgroup-specificproteinGephenotypesinNewGuineansanassociationofkuruandtheGcAbphenotypeAmJHumGenet24Suppl7285-84AULAMPERTPWGAJDUSEKDCGIBBSCJSUBACUTESPONGIFORMVIRUSENCEPHALOPATHIES-SCRAPIEKURUANDCREUTZFELDT-JAKOBDISEASE-AREVIEWAMERICANJOURNALOFPATHOLOGY683626-634PlatoCCGajdusekDCGeneticstudiesinrelationtokuruIVDermatoglyphicsoftheForeandAngapopulationsoftheEasternHighlandsofNewGuineaAmJHumGenet24Suppl8694-99SimmonsRTGraydonJJGajdusekDCAlpersMPHornabrookRWGeneticstudiesinrelationtokuruIIBlood-groupgeneticpatternsinkurupeitientsandpopulationsoftheEasternHighlandsofNewGuineaAmJHumGenet24Suppl3971SteinbergAGGajdusekDCAlpersMGeneticstudiesinrelationtokuruVDistributionofhumangammaglobulinallotypesinNewGuineapopulationsAmJHumGenet24Suppl95110-115患者厂检病理改变乂只限于神经系统 表现为星形细胞增生和肥大神经元胞体树突和轴突有进行性空泡变性表现为神经系统的变性改变不支持是传染病传播途径致病因子非典型传染病脑病病因Theincubationperiodthetimeittakesuntilsymptomsdevelopforthisdiseasecanbeupto30yearsorlongerDeathhoweverusuallyoccurswithinayearaftertheonsetofsymptoms潜伏期达30年以上微生物-常规病毒-患者水土-食物-金属-盖达塞克和福鲁族人同吃同住生活在一起无异常发现遗传家庭聚集性调查不是家族遗传病发现孑盾1973-1974-动物模型血清学1973ASHERDMGAIDUS11EKDKGIBBSKIRECENTACHIEVEMENTSINTHESTUDYOFSUBACUTESPONG1OUSENCEPHALOPATHIESVestnikAkademiiMeditsinskikhNaukSSSR28234-43BECKEDANIELPMASHERDMGAJDUSEKDCGTBBSCJEXPERIMENTALKURUINCHIMPANZEE-NEUROPATHOLOGICALSTUDYBRAIN96441-450GAJDUSEKDCKURUAXDCREUTZFELDT-JAKOBDISEASE-EXPERIMENTALMODELSOFNONINFLAMMATORYDEGENERATIVESLOWVIRUSDISEASEOFCENTRALNERVOUS-SYSTEMANNALSOFCLINICALRESEARCH55254-261GIBBSCJGAJDUSEKDCEXPERIMENTALSUBACUTESPONGIFORMVIRUSENCEPHALOPATHIESTNPRIMATESANDOTHERLABORATORY-ANIMALSSCIENCE182767-681974BENFANTERJTRAUBRDLIMKAHOOKSJGIBBSCJGAJDUSEKDCIMMUNOLOGICALREACTIONSINKURU-ATTEMPTSTODEMONSTRATESEROLOGICALRELATIONSHIPSBETWEENKURUANDOTHERKNOWNINFECTIOUSAGENTSAMERICANJOURNALOFTROPICALMEDICINEANDHYGIENE233476-488BROWNPGAJDUSEKDCNOMOUSEPMNLEUKOCYTEDEPRESSIONAFTERINOCULATION WITHBRAIN-TISSUEFROMMULTIPLE-SCLEROSISORSPONGIFORMENCEPHALOPATHIESNATURE247438217-218PetersonDAWolfeLGDeinhardtFGajdusekDCGibbsCJTransmissionofkuruandCreutzfeldt-JakobdiseasetomarmosetmonkeysIntervirology2114-19与人和动物的海绵状脑病比较Kuruincludecongestionofbloodvcsselsandinlong-standingcasescorticalatrophynotobviousherebrush-likeplaqueswhicharealsocalledspikeballscindfoundinthecerebellum1974-1976-动物模型病理学亚临床和病毒学1974YURKLEDEENRWGAJDUSEKDCGIBBSCJGANGLIOSIDECHANGESINSLOWVIRUSDISEASES-ANALYSESOFCHIMPANZEEBRAINSINFECTEDWITHKURUAXDCREUTZFELDT-JAKOBAGENTSBRAINRESEARCH701103-1121975BECKEBAK1JCHRISTJFGAJDUSEKDCGIBBSCJHASSLERREXPERIMENTALKURUINSPIDERMONKEY-HISTOPATHOLOGICALANDULTRASTRUCTURALSTUDIESOFBRAINDURINGEARLYSTAGESOFINCUBATIONBRAIN98595605GajdusckDCAlpersMPRecentdataonthepropertiesofthevirusesofkuruandtransmissiblevirusdementiasPNGMedJ184207-213GajdusekDCGibbsCJFandlidlandsporadicchronicneurologicaldegenerativedisorderstransmittedfrommantoprimatesAdvNeurol10291-317LAMPERTPWGAJDUSEKDCGIBBSCJPATHOLOGYOFDENDRITESINSUBACUTESPONGIFORMVIRUSENCEPHALOPATHIESADVANCESINNEUROLOGY12465-470WIESENFELDSLGAJDUSEKDCGENETICSTUDIESINRELATIONTOKURU6EVALUATIONOFINCREASEDLIABILITYTOKURUINGCAB-ABINDIVIDUALSAUSOAMERICANJOURNALOFHUMANGENETICS274498-5041976AsherDMGibbsCJGajdusekDCPathogenesisofsubacutespongiformencephalopathiesAnnClinLabSci6184-103MASTERSCLALPERSMPGAJDUSEKDCGIBBSCJEXPERIMENTALKURUINGIBBONANDSOOTYMANGABEYANDCREUTZFELDT-JAKOBDISEASEINPIGTAILEDMACAQUE-WITHASUMMARYOFHOSTRANGEOFSUBACUTESPONGIFORMVIRUSENCEPHALOPATHIESJOURNALOFMEDICALPRIMATOLOGY54205-209MASTERSCLKAKULASBAALPERSMPGAJDUSEKDCGIBBSCJPRECLINICALLESIONSANDTHEIRPROGRESSIONINEXPERIMENTALSPONGIFORMENCEPHALOPATHIESKURUANDCREUTZFELDT-JAKOBDISEASEINPRIMATESJOURNALOFNEUROPATHOLOGYANDEXPERIMENTALNEUROLOGY356593-605Gajdusek获诺贝尔奖的研究思路 郭雄教授西安交通大学医学院公共卫生系诺贝尔奖论文剖析TheNobelPrizeinPhysiologyorMedicine1976fortheirdiscoveriesconcerningnewmcchanisinsfortheoriginanddisseminationofinfectiousdiseasesBaruchSBlumbergDCeirletonGajdusekBornSeptember91923YonkersNewYorkDiedDecember122008aged85TromsNorwayNationalityUniledStatesFieldsMedicineDanielCarletonGajdusek1997KnownforPrionNotableawardsNobelPrizeinPhysiologyorMedicine1976httpenwikipediaorgwikiList_of_Nobel_laureatesDanielCarletonGajdusekanAmericanphysicianandmedicalresearcherwhowastheco-rccipicntwithBaruchSBlumbergoftheNobelPrizeinPhysiologyorMedicinein1976forworkonKuruthefirsthumanpriondiseasedemonstratedtobeinfcctioushttpcnwikipcdiaorgwikiListofNobellaurcatcsGajdusckhadsuggestedtheexistenceof"slowviruses"novelvirusesthatseemedtoremaindormantforlongperiodsoftimebeforeattackingthebodyTheconceptofslowvirusesemergedfromGajduseksstucliesofKuruadegenerativebraindiseasefoundamongtheForepeopleofPapuaNewGuineaTheslowviruseswerecvcntuallyimplicatedasthecausativeagentsofotherdiseasesincludingCreutzfeldt-Jakobdiseaseandmad-cowdisease克雅氏病和疯牛病的病原休研究巴布亚新儿内亚的一种脑部退化疾病-库鲁病慢病毒侵袭机体一个较长的不发病潜伏期诺贝尔奖论文非常规型病毒阮病毒与库鲁病的起源与消除1致亚急性海绵状脑病的非常规型病毒2常规型病毒通过缺陷性或卄缺 陷性复制引起慢性疾病0前言研究背景-库鲁病-慢病毒感染-与人和动物3库鲁病4传染性海绵状脑病克-雅病皮质-纹状体-脊髓变性5绵羊瘙痒病6亚急性海绵状脑病自然史推测自然绵羊瘙痒病是克-雅病库鲁病和貂传染性脑病的假设起源7展望诺贝尔奖论文DanielCarltonGajdusek丹尼尔•卡里顿•盖达塞克1923出生NewYork1955参与Kuru研究工作33岁1976获诺贝尔医学奖53岁forworkonKuruthefirsthumanPriondiseaseStanleyBPrusiner1997年获诺贝尔医学奖主55岁1942美国中西部出生1972神经科住院医师30岁1982年发表于Science的论文『引起羊搔症的传染性新蛋白质粒子』Prion一种不含核酸的传染性蛋口质或少量核酸外围包有紧密的蛋白质外壳目录一•研究背景与科学难点二论文研究思路的剖析三对科学研究工作的启示•主要科学问题新几内亚发生的一种严重危害人群健康的呈地方性分布的疾病病因发病机制有效控制措施病策略1策略2策略3-问题树-策略树海绵状脑病transmissiblespongiformencephalopathiesTSE是一组rfl传染性航蛋口侵袭人类及多种动物小枢神经系统所致的致死性退行性脑病以病变区域广泛神经元缺失和神经胶质增生伴有明显空泡形成海绵状态为特征乂称肮蛋白病概念-月元蛋门病PriondiseasesJOHNSONRTPriondiseasesLancetNeurol2005410635-642海绵状脑病Humandiseases1Kuru病或库鲁病2克-雅病CJD3GersImann-Strussler综合征4致死性家族失眠症Animaldiseases1羊瘙痒病2牛海绵脑病疯牛病3大耳鹿慢性消耗病4传染性雪貂白质脑病Central NervousSystemFailureLongIncubationPeriodNoCureDeath海绵状脑病的特征人类可传播性海绵样脑病疾病名称第一次报告时间证明可传播时间克-雅氏病Creutzfeldt-Jakob病散发型19211968家族型1924变异型1996库鲁病Kuru19551966Gcrstmann-Strussler综合征19361981致死性家族性失眠症19861995Kuruisarareandfatalbraindisorderthatoccurredatepidemiclevelsduringthe1950s—60samongtheForepeopleinthehighlandsofNewGuineaKururegioninNewGuineaAmapofKuruprevalenceinearlyfiftiesCourtesyofDrDCGajdusekParisFrance地方性分布•库鲁病Kuru病Kuru在该部落意为恐惧或寒颤故称该病为库鲁病•地方性分布主要在发生NewGuinea的Fore部落区•患者总数约3万1957-1961年发生1000例以女性和未成年儿童居多成年男性为2•死亡率高19世纪50年代200例年病死率达50-100最初阶段病人感到头疼和关节疼屮期阶段数周之后出现行走困难并伴随着肢体颤抖晚期阶段病人会丧失记忆死前伴随人笑震颤共济失调脑退化痴呆竭而死亡丧失运动能力言语含糊及无意识地狂笑最后不省人事而 夕匕亡CarletonGajdusekinAgakamatasain1978AmanwithearlystageKuruaHisgaitisbroad-basedandheisholdinghiswalkingstickbThepatientshowsdifficultywithfinger-nosetestingcEnlargementofpanelbpatientunab1etotouchthetipofmyindexfingerdThepatienthasdifficultywithheel-shintestingAwomanwithadvancedKuruaForstabilitythepatientholdsasteelrodimplantedinthegroundSheshowsfrontallobereleasesignsincludingbsnoutreflexchandgraspanddfootgrasp•主要科学问题新儿内亚发生的一种严重危害人群健康的呈地方性分布的疾病病因发病机制有效控制措施病策略1策略2策略3-问题树-策略树研究思路思路一A基础研究-病毒学B病理学研究C实验动物研究D临床学研究E流行病学研究F环境因素调查J干预试验思路二A临床学研究B流行病学研究C环境因素调查D病理学研究E基础研究-病毒学F实验动物研究J干预试验丹尼尔•卡里顿•盖达塞克DCarletonGajdusek1923年出生于美国哈佛大学毕业由于查明库鲁病病因而获得1976年诺贝尔医学奖如果你喜欢到未开化的地区去探险那么你有可能获诺贝尔奖1943fromtheUniversityofRochesterNewYorkwherehestudiedPhysicsBiologyChemistryandMathematicsYonkersNewYork20Yearsold1946obtainedMDfromHarvardUniversitypostdoctoralresearchatColumbiaCaltechandHarvard aresearchvirologistattheWalterReedArmyMedicalServiceGraduateSchoolmilitaryservice1952-1953apositionattheInstitutPasteurinTehranofferedbyurgentopportunisticinvestigationsofepidemiologicalproblemsinexoticandisolatedpopulations〃30yearsold1954asavisitinginvestigatorattheWalterandElizaHallInstituteofMedicalResearchinMelbourneAustralia1954receivedtheawardinrecognitionofhisstudyofthediseaseKuruaForewordfortrembling1956VincentZigasadistrictmedicalofficerintheForeTriberegionofNewGuineafirstintroducedGeijdusektoKuru34years1957providedthefirstmedicaldescriptionofthisuniqueneurologicaldisorderwhichwasmiscastinthepopularpressasthelaughingsicknessbecausesomepeitientsevincedrisussardonicusasasymptom35yearsold1ivedamongtheForestudiedtheirlanguageandcultureandperformedautopsiesonKuruvictims1958becameheadoflaboratoriesforvirologicalandneurologicalresearchattheNationalInstitutesofHealthNil!USA1974inductedtotheNationalAcademyofSciencesinthe disciplineofmicrobialbiology1976NotableawardsNobelPrizeinPhysiologyorMedicine53yearsold诺贝尔奖论文T非常规型病毒航病毒与库鲁病的起源与消除0研究背景诺贝尔奖论文1比较自然存在致海绵状脑病的病毒特征致人类2种致动物2种致亚急性海绵状脑病的非常规型病毒23库鲁病常规型病毒通过缺陷性或非缺陷性复制引起慢性疾病