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1、Gajdusek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,The Nobel Prize in Physiology or Medicine 1976 for their discoveries concerning new mechanisms for the origin and dissemination of infectious diseases,Baruch S. Blumberg,D. Carleton Gajdusek,Daniel Carleton Gajdusek,1997,http:/en.wikipedia.org/wiki/L
2、ist_of_Nobel_laureates,Daniel Carleton Gajdusek an American physician and medical researcher who was the co-recipient (with Baruch S. Blumberg) of the Nobel Prize in Physiology or Medicine in 1976 for work on Kuru, the first human prion disease demonstrated to be infectious.,http:/en.wikipedia.org/w
3、iki/List_of_Nobel_laureates,诺贝尔奖论文,非常规型病毒（朊病毒）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非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,Daniel Carlton Gajdusek 丹尼尔卡里顿盖达塞克 1923 出生New York 1955 参与Kuru研究工作(33岁)
4、 1976 获诺贝尔医学奖(53岁) for work on Kuru, the first human Prion disease Stanley B. Prusiner 1997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白质或 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
5、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( transmissible spongiform encephalopathies, TSE) , 是一组由传染性朊蛋白侵袭人类及多种动物中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, 又称朊蛋白病。,概念 -朊蛋白病 （Prion diseases）,JOHNSON R T. Prion diseases . Lancet Neurol, 2005, 4 (10) : 635-642,海绵状脑病,Human diseases: 1. Kuru病或
6、库鲁病 2. 克-雅病 (CJD) 3. Gerstmann Strussler 综合征 4. 致死性家族失眠症,Animal diseases: 1. 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 Nervous System Failure,Long Incubation Period,No Cure,Death,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 1921 1968 家族型 1924 变异型 1996 库鲁病（Kuru） 1
7、955 1966 Gerstmann Strussler 综合征 1936 1981 致死性家族性失眠症 1986 1995,Kuru is a rare and fatal brain disorder that occurred at epidemic levels during the 1950s-60s among the Fore people in the highlands of New Guinea.,Kuru region in New Guinea,A map of Kuru prevalence in early fifties. Courtesy of Dr. D.C.
8、Gajdusek, Paris, France,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New Guinea 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。 中期阶段：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。死前伴随大笑。 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，最后不省人事而死亡。
9、,Carleton Gajdusek in Agakamatasa in 1978,A man with early stage Kuru. (a) His gait is broad-based and he is holding his walking stick. (b) The patient shows difficulty with fingernose testing. (c) Enlargement of panel (b), patient unable to touch the tip of myindex finger. (d ) The patient has diff
10、iculty with heelshin testing.,A woman with advanced Kuru. (a) For stability, the patient holds a steel rod implanted in the ground. She shows frontal lobe release signs, including (b) snout reflex, (c) hand grasp and (d ) foot grasp., 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
11、 ？,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 D.Carleton Gajdusek,1923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。”,1943: from the University of Rochester
12、(New York), where he studied Physics, Biology, Chemistry and Mathematics Yonkers, New York (20 Years old) 1946: obtained M.D. from Harvard University. postdoctoral research at Columbia, Caltech and Harvard a research virologist at the Walter Reed Army Medical Service Graduate School military service
13、 1952-1953: a position at the Institut Pasteur in Tehran, offered by urgent opportunistic investigations of epidemiological problems in exotic and isolated populations. (30 years old) 1954: as a visiting investigator at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia.
14、,1954: received the award in recognition of his study of the disease Kuru (a Fore word for “trembling”) 1956: Vincent Zigas, a district medical officer in the Fore Tribe region of New Guinea first introduced Gajdusek to Kuru. (34 years ) 1957: provided the first medical description of this unique ne
15、urological disorder, which was miscast in the popular press as the “laughing sickness” because some patients evinced risus sardonicus as a symptom. (35 years old) lived among the Fore, studied their language and culture and performed autopsies on Kuru victims.,1958: became head of laboratories for v
16、irological and neurological research at the National Institutes of Health (NIH) ,USA 1974：inducted to the National Academy of Sciences in the discipline of microbial biology. 1976: Notable awards: Nobel Prize in Physiology or Medicine (53 years old ),诺贝尔奖论文,T,非常规型病毒（朊病毒）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
