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History of Genetics: Modern Genetics

Since the 1950s, studies of the molecular biology of the genehave provided new answers to the fundamental questions about the mechanism of inheritance and the relationship between genes and gene products. Once scientists were able to identify DNA as the genetic material and a model for the three-dimensional structure of DNA was proposed, molecular biologists were able to investigate the biochemical basis of gene structure and function. The term "genetics" was coined at the beginning of the twentieth century to separate new forms of scientific inquiry from previous studies of generation, inheritance, or heredity. Moderngenetics can be seen as the result of the integration of three lines of investigation: classical breeding tests, cytology, and biochemistry. Cytological studies became very sophisticated during the 1930s with the development of ultraviolet microspectrophotometry and special staining techniques. Ingenious use of such techniques provided some insights into the chemical nature of the chromosomes and other subcellular entities. Classical genetics was quite successful in answering questions about how the gene was transmitted. The methods of classical genetics, however, could not answer questions about the chemical nature of the gene or the mechanism of gene action. Some scientists thought it was impossible to imagine that genes could be explained in terms of a specific chemical substance. Others were sure that the gene must be a complex chemical entity, which might act like an enzyme, that is, a catalytic protein. Proteins were made up of about 20 different amino acids and could, therefore, occur in many different forms. Nucleic acids, which were made up of only a few different nucleotide bases, were thought to be too simple to serve as the hereditary material. The nucleic acids were discovered in the 1860s by Johann Friedrich Miescher (1844-1895), who called the material "nuclein." Some scientists thought that nuclein might be identical to "chromatin," the material that made up the chromosomes. Two forms of nuclein were subsequently identified; they are now known as deoxyribonucleic acid (DNA) andribonucleic acid (RNA). In 1944, Oswald T. Avery (1877-1955) and his associates discovered that the transforming principle of certain bacteriaseemed to be DNA. However, it was not possible to explain the apparent biological activity of DNA with prevailing ideas about the chemistry of the nucleic acids. The most important work on the chemistry of DNA had been carried out by Phoebus Aaron Levene (1869-1940). Levene's work suggested that DNA was basically a simple and repetitious polymer. After reading Avery's paper on the transforming principle, Erwin Chargaff (1905-) proved that nucleic acids were actually very interesting and complex chemicals. He also realized that there were certain regularities about the base composition of DNAs from various sources.

Research on bacteria and bacteriophage (bacterial viruses) provided another important approach to understanding the nature of the gene. Although bacterial cells do not have a nucleus, in 1946 Joshua Lederberg (1925-) demonstrated that they do undergo genetic recombination. Max Delbrck (1906-1981), one of the founders of molecular biology, realized that bacteriophages would be useful model systems for geneticists. In 1952 Alfred Hershey (1908-1997) and Martha Chase (1927-) conducted experiments that seemed to prove that DNA was the genetic material. Hershey and Chase found that when bacteriophage attack bacteria, viral DNA entered the host cells, but viral proteins remained outside. James Dewey Watson (1928-), a young member of the "Phage Group," immediately accepted the Hershey-Chase experiment as proof that DNA was the genetic material. Watson found that Francis Crick (1916-) shared his interest in determining the structure of DNA and the nature of the gene. The collaboration between Watson and Crick led to the discovery of the DNA double helix in 1953. Watson and Crick based their model on a combination of model building and x-ray data collected by Rosalind Franklin (1920-1958). The model of DNA structuresuggested by Watson and Crick in 1952 immediately suggested an explanation of its role as the genetic material. In the double helical structure proposed by Watson and Crick, the two chains were held together by hydrogen bonds between the purine and pyrimidine bases. Any sequence of bases could occur on one chain, but the rules of base pairing automatically determined the sequence of bases on the other chain. The Watson-Crick double helix explained Chargaff's data concerning the molar ratios of purines to pyrimidines, because adenine always paired with thymine and guanine paired with cytosine. The double helix also suggested a copying mechanism for the genetic material. Within about five years scientists had confirmed the essential features of the Watson-Crick model. Scientists proved that each old DNA strand became associated with a newly synthesized strand of DNA.Enzymes that catalyze the synthesis of DNA and enzymes that use DNA as a template to synthesize RNA were discovered. Once the chemical nature of the gene was understood, scientists discovered many aspects of how genes work. Watson summarized the fundamental principles of molecular genetics in what was called the central dogma of molecular biology: the flow of genetic information travels from DNA to RNA, where is made into proteins. The process of transferring information from a DNA template to an RNA copy is known as transcription. Transferring information from the language group of nucleic acids to that of proteins is known as translation. The process of protein synthesis involves the use of different forms of RNA known asmessenger RNA, and transfer RNA, and the cytoplasmic entities known as ribosomes, which consist of proteins and another type of RNA, known as ribosomal RNA. Eventually, scientists who were studying certain viruses proved that information could also flow from RNA to DNA by means of an enzyme called reverse transcriptase. These so-called

retroviruses have RNA rather than DNA as their genetic material. HIV (human immunodeficiencyvirus), the virus associated with AIDS, is a retrovirus. In 1965, Franois Jacob (1920-), Jacques Monod (1910-1976), and Andr Lwoff (1902-1994) shared the Nobel Prize for their discoveries about the way genes regulate the synthesis of proteins. Their theoretical framework for genetic regulation was called the operon theory. According to this theory, gene expression involves a structural gene (a gene that codes for a specific protein), a regulator gene (a gene that codes for a repressor), and an operator gene (a region of the chromosomethat is affected by the repressor substance). Although the operon model worked well for bacteria, further research indicated that genetic regulation in higher organisms was considerably more complicated. Moreover, in higher organisms, some traits did not show Mendelian segregation and seemed to be inherited only through the maternal line. In the 1960s, scientists discovered that certain cytoplasmic entities, such as mitochondria and chloroplasts, contain their own DNA. Studies of inherited metabolic diseases (disorders caused by defective enzymes) provided another approach to the biochemical mechanisms of gene action. George W. Beadle (1903-1989) and Edward Tatum (1909-1975) won the Nobel Prize in 1958 for established biochemical genetics and the one gene-one enzymeconcept of gene regulation through their studies of the red bread mold Neurospora crassa. The relationship between genes and enzymes had been suggested in 1908 by Archibald Edward Garrod (1857-1936) on the basis of his studies of four hereditary diseases (alkaptonuria, cystinuria, albinism, and pentosuria). Garrod called these diseases "inborn errors of metabolism." In 1949, Linus Pauling (1901-1994) and his associates established the molecular basis of a genetic disease by analyzing the abnormal hemoglobin produced by patients with sickle cell anemia. This discovery led to the establishment of the "one gene-one polypeptide" principle. Although research on bacteria and viruses revealed many fundamental aspects of the molecular biology of the gene, by the 1970s, studies of reverse transcriptase, ribozymes, transposable genetic elements, recombinant DNA, cell growth anddifferentiation, provided many unexpected insights into the nature of gene regulation in higher organisms. The powerful new techniques of molecular biology made it possible to manipulate the genetic material and provided the basis for gene transfer, genetic engineering, gene therapy, and the cloning of high organisms. The potential benefits of further insights into the gene led to the establishment of the international Human Genome Project in 1994. In 2001, scientists published working drafts of the whole human genome. During the twenty-first century, a new approach to genetics that has been called "genomics" will allow scientists to use the information provided by the Human Genome Project to identify and characterize genes and their arrangement in the chromosomes. Scientists expect genomics to have profound implications for human genetics and medicine.