1. Information School: The information school is mainly composed of a group of physicists who are interested in the intergenerational transmission of genetic information, with Delbrouck as the representative. German physicist from Delbrouck, 1930, went to the Institute of Theoretical Physics in Copenhagen with the support of Rockefeller Foundation in the United States to conduct postdoctoral research with the famous physicist niels bohr. From 65438 to 0932, Bohr delivered a speech on "Light and Life" at the International Phototherapy Conference held in Copenhagen. In his speech, Bohr put forward a new view of understanding life, and thought that the study of life phenomena might find some new physical laws. Deeply influenced by Bohr's thought, Delbrouck decided to turn to biological research. He believes that genes are the best starting point to study the intergenerational transmission mechanism of genetic information. After Delbrouck left Copenhagen and returned to Berlin, he and geneticist Lesovsky (Nikola? Vladimir rove. Timofei-Lysov) and biophysicist Carl. G. Zimmer collaborated to study the relationship between radiation and gene mutation from the perspective of quantum theory, and published a booklet on the nature and structure of gene mutation in 1935. In the book, they use quantum theory to analyze and discuss the law of gene mutation induced by radiation, and give a "quantum mechanical model of gene". This model holds that genes, like molecules, have several different stable energy levels. Mutation is explained as the transition of gene molecules from one energy level steady state to another. According to the calculation, the size of the gene is inferred. This is the famous "three-person theory". Three-person thesis is an article that studies genes completely with physical theories and methods. The significance of this article is not whether its conclusion is correct, but that it makes many young physicists believe that genes can be studied by physical methods, thus promoting a large number of excellent physicists to devote themselves to biological research. The "three-person thesis" later became Erwin. Schr？ Ding Ge) "What is life" is the basis of discussion.
From 65438 to 0937, with the support of Rockwell Fund, Delbrouck came to Morgan Laboratory of California Institute of Technology to conduct genetic research. There, he found that bacteriophages are more suitable materials for genetic research than fruit flies, and cooperated with Emory. Ellis studied the proliferation and replication of phage, and established a quantitative determination method of phage. 1940 At the end of the year, at an annual meeting of physics held in Philadelphia, Delbrouck met luria, an Italian biologist who just came to the United States. Ruglia read The Theory of Three People and admired delbruck very much. At that time, he had just received funding from the Rockwell Foundation, and was going to conduct research on X-ray-induced phage mutation at Columbia University. With interest, they quickly established a cooperative relationship. At that time, there was another American scientist engaged in phage research, hershey of Washington University. 1943, Delbrouck invited him to meet in his laboratory to discuss the cooperative research plan. Thus, a "phage colony" with Delbrouck-luria-hershey as the core was formed.
The research results of phage group are as follows: (1) delbruck and luria's research on bacterial mutation law has opened up a new field of bacterial genetics; 1945, luria and hershey independently discovered the mutant characteristics of phage; 1946, delbruck and hershey independently discovered that two kinds of bacteriophages infected with a bacterium at the same time could undergo gene recombination, which proved that the genetic material from the simplest life to human beings followed the same mechanism. The most boastful achievement of phage group is that it was proved in the early 1950s that the chemical essence of genes is DNA. In 1944, Avery (Oswald. T. Avery) once found that DNA is genetic material through pneumococcal transformation test, but it has not been recognized. Hershey and Martha. 35S (binding to protein) and 32P (binding to DNA) were used to chase the labeled phage, and then they were used to infect bacteria. It was found that only the nucleic acid part of phage entered the bacteria, but not the protein shell. The progeny phage produced by replication in bacteriophage-infected bacteria mainly contains 32P label, while the content of 35S is lower than 1%. This clearly proves that in bacteriophage-infected bacteria, it is phage DNA, not protein, that is related to replication. 1952, this result was widely accepted immediately after publication, which is of great significance for james watson and francis crick to make a breakthrough in determining the double helix structure of DNA.
In addition to studying the transmission mechanism of genetic information, Phage Group has also held seminars in Lengquan Port, Long Island, new york every year since 194 1, and held "Phage Research Class" every summer since 1945. This course is mainly for physicists who are interested in biological research. Through the cold spring port class, the phage research network was expanded, and the position of phage population with delbruck-luria-hershey as the core in the field of gene research was formed and consolidated. By the early 1950s, phage group had become a very influential genetic school.
The early research work of phage group attracted the attention of the famous physicist Schrodinger and caused him to think about life. From 65438 to 0943, he gave a series of speeches at Trinity College in Dublin, Ireland, expounding his thoughts on life. From 65438 to 0944, he compiled these speeches into a book and published it, which is regarded as an epoch-making work of "Uncle Tom's Cabin" in molecular biology. In this book, Schrodinger discusses the research results of the information school, especially Delbrouck's "quantum mechanical model of genes". When discussing these research results, Schrodinger believes that "the events unfolding in the life cycle of organisms show a wonderful law and order. Any kind of inanimate matter we have encountered before cannot be compared with it. " We must be ready to discover the new laws of physics that govern life.
The book What is Life has had a shocking impact on biological research. Gunther. The famous molecular biologist Stent pointed out: "In this book, Schrodinger predicted to his physicists that a new era of biological research is about to begin." "Inspired by the romantic idea that we can discover' other laws of physics' through genetic research, many physicists left their original well-trained professional posts and devoted themselves to the study of the nature of genes." The history of molecular biology shows that those scientists who initiated the molecular biology revolution in 1950' s, including Watson and Crick, the discoverers of DNA double helix structure, were all influenced by Schrodinger's book and turned to study the structure and function of genes.
2. Structural school: Since 1930s, a group of physicists in the field of biology began to study the structure of biological macromolecules, which is called "structural school". The structural school was founded by henry bragg and lawrence bragg, sons of Prague in Cavendish Laboratory, England. At the beginning of the 20th century, they found that different diffraction images can be obtained on the background by irradiating the crystal with X-rays. By analyzing the diffraction image, the crystal structure can be inferred. In this way, they successfully determined the molecular structures of some salts (such as potassium chloride). 19 15, Prague and his son both won the nobel prize in physics. From 65438 to 0938, lawrence bragg became a professor in Cavendish, and began to apply X-ray diffraction technology to the study of the three-dimensional structure of biological macromolecules (protein, nucleic acid). In the early 1950s, under the leadership of Peruz of Cavendish Laboratory, two protein structures were being analyzed. First, the research team led by him studied the structure of hemoglobin; The other is a research team led by Chendru, who conducted the structural analysis of myoglobin. In addition, Maurice Wilkins and Rosalind Franklin of King's College London are studying the structure of nucleic acid by X-ray diffraction, and have achieved many meaningful results. Structural biologists are mainly interested in the structure of biological macromolecules, but less involved in functional research.
3. Biochemical genetics school: Since Mendel's law was rediscovered in 1900, how genes control specific traits has become one of the main problems in genetic research. In 1902, archibald Garaude, a British doctor, found that some sick children suffered from depression, and their urine would turn black when exposed to air. Soon, this chemical that blackens urine was identified, that is, the substance transformed from tyrosine. Jarod's pedigree analysis of patients with melanuria found that the disease was inherited according to Mendel's law. After a series of studies, Jarrod published a book "Congenital Defects of Metabolism" in 1909, pointing out that the metabolic disorder of patients with melanuria is due to the first stage of tyrosine catabolism, that is, benzene ring breakage. Therefore, Jarod believes that benzene ring breakage occurs under the action of an enzyme, and the patient lacks this enzyme, so the symptoms of black urine appear. Therefore, a genetic trait (black urine) is associated with an enzyme (protein). However, this predictive hypothesis of genetic factors and enzymes cannot be confirmed by experiments.
From 65438 to 0940, Biddle and tatum began to study the relationship between genes and enzymes with Streptomyces rubrus. They used X-ray irradiation to induce mutants of Streptomyces, and found that several different Streptomyces lost their synthetic ability. Their genetic analysis of the hybrid offspring of these mutants shows that each mutant is the product of a single gene mutation, and the function of each gene is equivalent to that of an enzyme. Therefore, in 194 1, they put forward the hypothesis of "one gene and one enzyme". According to this hypothesis, genes determine the formation of enzymes, and enzymes control biochemical reactions, thus controlling metabolic processes. 1948, F. Mitchell and J. Lein found that some mutants of Alternaria rubra lacked tryptophan synthase, which provided the first direct evidence for the theory of "one gene, one enzyme". Protein is the most direct phenotype of biological genotype, which determines the expression form of biological traits. Therefore, the theory of "one gene, one enzyme" (later changed to "one gene, one protein") provides a theoretical basis for the "central rule" of DNA→RNA→ protein, which is of great significance for understanding the mechanism of gene controlling genetic traits. 1958, Jarrod and Tatum won the Nobel Prize.
Establishment of DNA double helix structure
195 1 year, Watson attended an academic conference on the structure of biological macromolecules in Italy, where he was very excited to hear Wilkins' report on the research results of X-ray crystallography of DNA. Watson is a graduate student of luria, the leader of phage group. After graduating from the doctor's degree, he was sent by luria to Herman Carker's laboratory in Copenhagen, Denmark, to do research on nucleic acid biochemistry. This made him familiar with the knowledge of nucleic acids quickly and confirmed that the essence of genes is DNA. He realized that to solve the mystery of gene function, we must first understand the structure of DNA. Wilkins' work inspired him a lot. With the support of luria, he came to Cavendish Laboratory in Cambridge, which was the center of the research on the structure of biological macromolecules in the world. Here, he met francis crick. Crick graduated from the Physics Department of University of Coriki in London and studied magnetite in the army during World War II. After the war, under the influence of Schrodinger's book What is Life, he turned to biological research. At that time, as a doctoral student, he was involved in the study of hemoglobin structure in Peruz research group. Watson's arrival made him aware of the new progress in DNA research. They agree that understanding the structure of DNA is the key to reveal the mystery of genes. Wilkins of King's College London is Crick's friend, which makes it easy for them to obtain the new achievements of Wilkins' group in nucleic acid research. The cooperation between Watson and Crick can be regarded as the combination of information school and structure school in biological research. This combination eventually led to the discovery of DNA double helix structure.
When Watson Crick began to study the structure of DNA, the information about DNA structure was still scattered. I knew it then: 1. DNA consists of adenine (a), guanine (g), thymine (t) and cytosine (c). 2。 The sugar gene of each nucleotide combines with the phosphate gene of another nucleotide in the form of valence bond to form a sugar-phosphate skeleton; 3。 These long nucleotide chains have a regular spiral structure and repeat every 3.4 angstroms. However, it is still unclear whether DNA molecules are composed of several nucleotide chains and how to form spiral molecules between the chains. In 195 1, Watson-Crick proposed a triple helix model, and in 1952, Pauling also proposed a triple helix model, but it was rejected immediately because it was inconsistent with the known DNA X-ray diffraction results. The establishment of DNA double helix structure mainly benefits from the following research results: 1. 1952, Watson saw the X-ray diffraction pattern of hydrated DNA taken by Franklin in 195 1 year in Wilkins. The strong reflection in the photo clearly shows that DNA is a double-stranded structure. This picture left a deep impression on Watson, and he decided to build a double-stranded model of DNA. 2。 1952, mathematician J. Griffith gave the evidence of mutual attraction between A and T, G and C by calculating the binding force between bases. At the same time, F. Chargaff's earlier equivalence law of the ratio of purine bases to pyrimidine bases in DNA molecules also ruled out the possibility of isomorphic base pairing. In addition, J. Donohue pointed out the tautomerism of bases. These results confirm the principle of base pairing between A-T and G-C in two nucleotide chains of DNA. 3。 From 65438 to 0952, the X-ray diffraction results of Franklin DNA have accurately inferred that the sugar phosphate skeleton of double-stranded molecules is on the outside and the bases are on the inside. Franklin also speculated that the distance between paired bases was 20 angstroms and the spin distance was 3.4 angstroms.
According to the above data, Watson-Crick proposed the DNA double helix model in 1953. This structure conforms to the known experimental data about DNA, and does not suggest the possible way of DNA molecular replication, so it immediately attracted the attention of the scientific community and was quickly accepted. The discovery of DNA double helix structure marks the birth of molecular biology. In the following 15 years, molecular biology has made rapid progress, among which the major progress is as follows:
1, 1968 Crick put forward that the flow of genetic information is the famous "central rule" of DNA-RNA- protein. 1970, Howard teming and David Baltimore discovered "RNA-dependent DNA transcriptase" (reverse transcriptase) in RNA tumor virus particles respectively, which proved that genetic information can also flow from RNA to DNA, thus perfecting the content of the central rule. 1975, Timin and Baltimore won the Nobel Prize in Physiology or Medicine.
2, 1954 Gamov called the nucleotide combination that determines an amino acid genetic code for the first time, and put forward the hypothesis of "overlapping triple code". He gave 64 possible triple codes through calculation. The problems assumed by Gamov are: 1, overlapping password error; 2. It is wrong to think that DNA directly guides the synthesis of protein. In 196 1, Crick and S.Brenner denied the overlapping of genetic codes through experiments and statistical analysis, and put forward the hypothesis of "non-overlapping triple codes", which was confirmed by experiments. In the same year, nirenberg (M.W.) successfully identified UUUU by biochemical methods and cell-free synthesis system in vitro. It was the codon of phenylalanine for the first time, which opened the prelude to deciphering the triple code. By 1966, the code list of all 20 amino acids was completed, and nirenberg won the Nobel Prize in Physiology or Medicine.
3. Put forward the "operon theory" of gene expression regulation. 1960, French scientists J. Monod and F.Jacob published the paper "Genetic Regulation Mechanism of protein Synthesis". In the article, they formally put forward the operon theory of gene expression. Based on the lactose metabolism regulation system of Escherichia coli, they revealed the gene regulation mechanism of galactosidase production, put forward the concepts of structural gene, regulatory gene and manipulation gene, and proved that the production of galactosidase (protein) was the result of the interaction of these genes. The introduction of operon theory makes the study of genes shift from structural study to functional study, which lays a foundation for further revealing the mechanism of genes controlling biological traits (phenotypes). 1965 Mono and Jacob won the Nobel Prize in Physiology or Medicine. Operon theory strongly confirms the concept of "jumping gene" (transposon) proposed by American scientist B. mcclintock in 195 1, which opens the way for the study of gene regulation in eukaryotic cells. 1983 mcclintock won the nobel prize in physiology or medicine.
4. The birth of genetic engineering. 1962 W.Arber proposed that there is an enzyme in bacteria that can destroy foreign DNA. 1970, H.O.Smith obtained the first DNA restriction endonuclease. Nathans cut SV40 virus DNA into some specific fragments with endonuclease, and obtained the physical map of virus genome. 1978 Albert, Smith and Natans won the Nobel Prize in Physiology or Medicine. Since then, DNA ligase and DNA polymerase have been discovered one after another, and the discovery of these tool enzymes laid the foundation for the emergence of genetic engineering technology. 197 1 year, American scientist P. Berg connected SV40 DNA with the DNA fragment inserted by phage with restriction endonuclease and ligase, and the hybrid molecule was successfully expressed in E.coli, making cross-species DNA recombination a reality. As a new technology, genetic engineering has been born, which not only provides a broad development space for the development of agriculture, animal husbandry and pharmaceutical industry, but also provides technical means for further exploring the origin of life and carrying out the research on artificial life (synthetic biology). Berg's work laid the foundation for the birth of genetic engineering. 1980, Berg won the Nobel Prize in Physiology or Medicine.
Since 1953 discovered the double helix structure of DNA, molecular biology has developed rapidly along the road of reductionism and made many important progress. Since 2 1 Chronicle, the completion of the human genome project and the emergence of various "omics" such as protein have opened up a new direction for understanding basic biological phenomena such as heredity, variation and individual development as a whole. It has long been recognized that there are obvious genetic phenotypic differences between identical twins, which shows the complex relationship between genotype and phenotype. In recent years, the study of epigenetics shows that the genome can change the expression mode of genes through DNA methylation, gene imprinting, maternal effect, gene silencing, RNA editing and so on. In this way, it is possible to deeply understand the relationship between environment and heredity, which will have a far-reaching impact on the development of medical science.