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1、Chapter One:Introduction of Molecular Biology,Definition of Molecular Biology（*）Brief history of Molecular Biology Relationship between Molecular Biology and other disciplines（*）Prospects of Molecular Biology,Key Points:,1 Definition of Molecular Biology,The attempt to understand the biological phen
2、omena in molecular terms.The study on the process of DNA replication,transcription,translation and expression regulation and related proteins or enzymes.,The study of gene structure and function at the molecular level.-Robert Weaver,Stage 1:Preparation准备和酝酿阶段 Stage 2:Establishing and developing of c
3、ontemporary Molecular Biology现代分子生物学的建立和发展阶段 Stage 3:Primary understanding of the nature of life and modification of life-deep development stage初步认识生命本质并开始改造生命的深入发展阶段 Stage 4:Post-genome era后基因组时代,Brief History of Molecular Biology,Molecular biology is a hybrid discipline,it grew out of the discipli
4、nes of genetics and biochemistry.,From late 1900s to early 1950s(19世纪后期到20世纪50年代初)Confirmed that protein is one of the fundamental materials of life.确定了蛋白质是生命的主要基础物质(经典生物化学的贡献)Confirmed that DNA is the nature of genetic material.确定了生物遗传的物质基础是DNA(经典遗传学的贡献),Stage 1:Preparation,In 1989,Buchner brothers
5、 confirmed that yeast cell-free extracts could make glucose fermentation and produce alcoholIn 1926,J.B.Sumner obtained urokinase crystal from jack bean 从刀豆获得了结晶的尿酶In 1955,F.Sanger sequenced the amino acids of calf insulin 牛胰岛素的氨基酸序列分析Kendrew&peruts obtained the structure of whale muscle hemoglobin
6、and horse hemoglobin by x-ray diffraction analysis or x-ray crystallography 用X-射线分析得到鲸肌红蛋白与马血红蛋白的空间结构,In 1869,Miescher isolated DNA from used patient badges for the first time and named it nuclein.In 1910,Kossel from Germany isolated the adenine,thymine and histidine 腺嘌呤、胸腺嘧啶和组氨酸。In late 1890,bioche
7、mists already knew the components and the structure of RNA,In 1865,Austrian scientists Gregor Mendel published a paper entitled Experiments on Plant Hybrids,and put forward two laws:Principles of Independent Segregation and Independent Assortment;,How Mendels first law(independent segregation)explai
8、ns the 3:1 ratio of dominant to recessive phenotypes among the F2 progeny,The inheritance of flower color in the snapdragon.,How Mendels second law(independent assortment)operates?,In 1900,Hugo de Vries,Carl Correns,Erich von Tschermak rediscovered Mendelian inheritance law.In 1909,丹麦geneticists W.J
9、ohannsen dubbed“Gene”to substitute Mendels genetic unit.By the end of 1900,chromosome theory of inheritance was put forwarded.In 1910,American scientists Thomas H.Morgan confirmed gene is located on chromosome and discovered genetic recombination phenomenon.,Thomas Hunt Morgan,The inheritance of a s
10、ex-linked gene in Drosophila.,The genetic map of chromosome 2 of Drosophila melanogaster.,In 1931,Harriet Creighton&Barbara McClintock found the evidence of gene recombination,Whats the nature of genetic material？,1928,Frederick Griffith:transformation in bacteria:Streptococcus pneumoniae1944,Oswald
11、 Avery,Colin MacLeod,and Maclyn McCarty confirmed that,DNA,the transforming material,Conclusion:the genetic material of bacteria is DNA.,In 1952,&Martha Chase used labels sulfur-35(35S)for protein and phosphorus-32(32P)for DNA。,By definition,the early work on genes cannot be considered molecular bio
12、logy,or even molecular genetics,because early geneticists did not know the molecular nature of genes.In fact,the chemical composition of genes was not know until 1944.At that point,it became possible to study genes as molecules,and the discipline of molecular biology was born.,Conclusion:the genetic
13、 material of phage also is DNA.,Stage 2:Establishing and developing of contemporary Molecular Biology,From early 1950s to early 1970s 从50年代初到70年代初 Central Dogma Further understanding on protein structure and function 对蛋白质结构和功能的进一步认识,Discovery of DNA Double Helix DNA双螺旋结构的发现In 1950，Erwin Chargaff rul
14、e：A=T；G=CIn 1952，Rosalind Franklin,Maurice Wilkins X-ray picture of B-DNAIn 1953，Pauling published DNA triple helix structureIn 1953，Watson&Crick put forward right-handed double helix model of DNA.They won the Nobel Prize in Physiology and Medicine in 1962 with Wilkins.,DNA double helix,“As a boy,Cr
15、ick wor-ried that there wouldnt be anything left for him to discover by the time he grew up and became a scientist.”E.Edelson(Francis Crick and James Watson),对DNA 复制的认识,1953年，在发现DNA双螺旋结构同时，Watson和Crick就提出DNA复制的可能模型，1956年，A.Kornberg首先发现DNA聚合酶；1958年，Meselson及Stahl用同位素标记和超速离心分离实验为DNA半保留模型提出了证明；1968年，Ok
16、azaki（冈畸）提出DNA不连续复制模型；1972年，证实了DNA复制开始需要RNA作为引物；70年代初，获得DNA拓扑异构酶，并对真核DNA聚合酶特性做了分析研究；,对RNA的认识 在研究DNA复制将遗传信息传给子代的同时，提出了RNA在遗传信息传到蛋白质过程中起着中介作用的假说；1958年，Weiss及Hurwitz等发现依赖于DNA的RNA聚合酶；1961年，Sydney Brenner,Francis Jacob,Matthew Meselson 发现了 messenger RNA；1961年，Hall和Spiege-lman用RNA-DNA杂交证明mRNA与DNA序列互补；逐步阐明
17、了RNA转录合成的机理。,对蛋白质的认识 50年代初，Zamecnik等在形态学和分离的亚细胞组分实验中发现微粒体（microsome）是细胞内蛋白质合成的部位；1957年，Hoagland、Zamecnik及Stephenson等分离出tRNA并对它们在合成蛋白质中转运氨基酸的功能提出了假设；1961年，Brenner及Gross等观察了在蛋白质合成过程中mRNA与核糖体的结合；1965年，Holley首次测出了酵母丙氨酸tRNA的一级结构；60年代，Nirenberg、Ochoa以及Khorana等几组科学家的共同努力破译了RNA上编码合成蛋白质的遗传密码，随后研究表明这套遗传密码在生物界
18、具有通用性，从而认识了蛋白质翻译合成的基本过程。,In 1970，Howard Temin&David Baltimore discovered reverse transcriptase-a RNA-dependent DNA polymerase from retrovirus particles.,Stage 3:Primary understanding of the nature of life and modification of life-deep development stage,From late 1970s to 2000s 70年代后至21世纪初 DNA recomb
19、ination技术的建立和发展 Genomics基因组研究的进展 Monoclonal antibody单克隆抗体及基因工程抗体的建立和发展 Regulation of gene expression基因表达调控机理 Mechanisms of signal transduction细胞信号转导机理研究成为新的前沿领域,重组DNA技术的建立和发展,1967-1970年，R.Yuan和等发现的限制性核酸内切酶为基因工程提供了有力的工具；1972年，Berg等将SV-40病毒DNA与噬菌体P22DNA在体外重组成功，转化大肠杆菌，使本来在真核细胞中合成的蛋白质能在细菌中合成,打破了种属界限；197
20、7年，Boyer等首先将人工合成的生长激素释放抑制因子14肽的基因重组入质粒，成功地在大肠杆菌中合成得到这14肽；1978年，Itakura（板仓）等使人生长激素191肽在大肠杆菌中表达成功；1979年，美国基因技术公司用人工合成的人胰岛素基因重组转入大肠杆菌中合成人胰岛素。1982年，Palmiter等将克隆的生长激素基因导入小鼠受精卵细胞核内，培育得到比原小鼠个体大几倍的“巨鼠”，激起了人们创造优良品系家畜的热情。1994年，能比普通西红柿保鲜时间更长的转基因西红柿投放市场。1996年，转基因玉米、转基因大豆相继投入商品生产。2004年，全球转基因抗虫棉播种面积占植棉总面积的80%。,基因
21、组研究的进展,1977年，Sanger测定了X174-DNA全部5375个核苷酸的序列；1978年，Fiers等测出SV-40DNA全部5224对碱基序列；80年代，噬菌体DNA全部48,502碱基对的序列全部测出；一些小的病毒包括乙型肝炎病毒、艾滋病毒等基因组的全序列也陆续被测定；1996年底，许多科学家共同努力测出了大肠杆菌基因组DNA的全序列长4x106碱基对。1990年，人类基因组计划（HumanGenomeProject）开始实施，这是生命科学领域有史以来全球性最庞大的研究计划，目前已测定出人基因组全部DNA3x109碱基对的序列、确定人类约2.5-3万个基因的一级结构，这将使人类能
22、够更好掌握自己的命运。,单克隆抗体及基因工程抗体的建立和发展,1975年Kohler和Milstein首次用B淋巴细胞杂交瘤技术制备出单克隆抗体以来，人们利用这一细胞工程技术研制出多种单克隆抗体，为许多疾病的诊断和治疗提供了有效的手段。80年代以后随着基因工程抗体技术而相继出现的单域抗体、单链抗体、嵌合抗体、重构抗体、双功能抗体等为广泛和有效的应用单克隆抗体提供了广阔的前景。,基因表达调控机理,Jacob和Monod最早提出的操纵元学说打开了人类认识基因表达调控的窗口；60年代，人们主要认识了原核生物基因表达调控的一些规律；70年代，逐渐认识了真核基因组结构和调控的复杂性。1977年，最先发现
23、猴SV40病毒和腺病毒中编码蛋白质的基因序列是不连续的，这种基因内部的间隔区（内含子）在真核基因组中是普遍存在的，揭开了认识真核基因组结构和调控的序幕。1981年，Cech等发现四膜虫rRNA的自我剪接，从而发现核酶（ribozyme）。80-90年代，使人们逐步认识到真核基因的顺式调控元件与反式转录因子、核酸与蛋白质间的分子识别与相互作用是基因表达调控根本所在。,细胞信号转导机理研究成为新的前沿领域,1957年，Sutherland 发现cAMP1965年，提出第二信使学说，是人们认识受体介导的细胞信号转导的第一个里程碑。1977年，Ross等用重组实验证实G蛋白的存在和功能，将G蛋白与腺苷
24、环化酶的作用相联系起来，深化了对G蛋白偶联信号转导途径的认识。70年代中期以后，癌基因和抑癌基因的发现、蛋白酪氨酸激酶的发现及其结构与功能的深入研究、各种受体蛋白基因的克隆和结构功能的探索等，使近10年来细胞信号转导的研究更有了长足的进步。目前，对于某些细胞中的一些信号转导途径已经有了初步的认识，尤其是在免疫活性细胞对抗原的识别及其活化信号的传递途径方面和细胞增殖控制方面等都形成了一些基本的概念。,Stage 4:Post-genome era基因组学(genomics)结构基因组学(structural genomics)功能基因组学(functional genomics)环境基因组学(e
25、nvironmental genomics)营养基因组学(nutritional genomics)药物基因组学(drug genomics)癌症基因组学(cancer genomics)毒理基因组学(toxicological genomics)转录组学(transcriptomics)蛋白质组学(proteomics)代谢组学(metabolomics),相当于约三十个人的基因组,3 Relationship between Molecular Biology and other disciplines,分子生物学Molecular biology,发育生物学 Developmental
26、Biology,Molecular Biology,Extension of Molecular Biology,Joshua Lederberg,1959,James Watson(34y)Francis Crick(46y)Maurice Wilkins(46y),1962,Francois Jacob(44y)Jacques Monod(55y)(French),Lac.Operon Theory,1965,Concept of mRNA,1968,R.Holley H.Gobind Khorana&Marshall Nirenberg pakistan,1969,Max Delbruc
27、k(63y)Alfred Hershey(61y),M.Delbruck,A.Hershey,Reverse transcription,Walter Gilbert(48y),Fredenick Sanger,Mechanism of protein synthesisIsolation of Lac.Operon repressor,1980,DNA sequencing,DNA+SV40 Recombination DNA,Paul Berg,1983.Barbara McClintock(86y),DNA transposable elememt,1998 Furchgott,Igna
28、rro&Murad for their discoveries concerning nitric oxide as as a signalling molecule in the cardiovascular system 1999 Gunter Blobel for for the discovery that proteins have intrinsic signals that govern their transport and localization in the cell 2000 Arvid Carlsson,Paul Greegard&Eric Kandel for th
29、eir discoveries concerning signal transduction in the nervous system.2001 Leland Hartwell,R.Timothy Hunt&Paul Nurse for their discoveries of key regulators of the cell cycle.2002 Sydney Brenner,John E.Sulston&H.Robert Horvits for their discoveries concerning genetic regulation of organ development a
30、nd programmed cell death,2004 Richard Axel&Linda B.Buck for their discoveries of odorant receptors and the organization of the olfactory system organization 发现气味受体和嗅觉系统组织方式2006 AndrewZ.Fire&CraigMello,RNA interference RNA干扰2007 Mario Capecchi,Sir Martin Evans and Oliver Smithies:gene targeting in mi
31、ce 基因打靶技术,4 Prospects of Molecular Biology,individual,cell,molecule,还原论reductionism,整体论System theory,细胞中的定位localization,细胞分化Cell differentiation,神经基质神经通道信息传递,11个抑癌基因被证实（P53,P21,ERBA,WT1,NF1 等）,Human Genome Project（HGP）,Genetic map Physical mapSequence mapExpression map,Gene localization,Comparative
32、genomics,计算计语言,分辨，提取，分析，比较，预测生物信息,生物大分子的结构与功能信息,系统生物学(Systems biology),Systems biology is a relatively new biological study field that focuses on the systematic study of complex interactions in biological systems,thus using a new perspective(integration instead of reduction)to study them.Particularl
33、y from year 2000 onwards,the term is used widely in the biosciences,and in a variety of contexts.Because the scientific method has been used primarily toward reductionism,one of the goals of systems biology is to discover new emergent properties that may arise from the systemic view used by this discipline in order to understand better the entirety of processes that happen in a biological system.,双螺旋成行,Hohhot,Thank you!,
