History of molecular biology
The history of molecular biology begins in the 1930s with the convergence of various, previously distinct biological and physical disciplines: biochemistry, genetics, microbiology, virology and physics. With the hope of understanding life at its most fundamental level, numerous physicists and chemists also took an interest in what would become molecular biology.
In its modern sense, molecular biology attempts to explain the phenomena of life starting from the macromolecular properties that generate them. Two categories of macromolecules in particular are the focus of the molecular biologist: 1) nucleic acids, among which the most famous is deoxyribonucleic acid proteins, which are the active agents of living organisms. One definition of the scope of molecular biology therefore is to characterize the structure, function and relationships between these two types of macromolecules. This relatively limited definition allows for the estimation of a date for the so-called "molecular revolution", or at least to establish a chronology of its most fundamental developments.
General overview
In its earliest manifestations, molecular biology—the name was coined by Warren Weaver of the Rockefeller Foundation in 1938—was an idea of physical and chemical explanations of life, rather than a coherent discipline. Following the advent of the Mendelian-chromosome theory of heredity in the 1910s and the maturation of atomic theory and quantum mechanics in the 1920s, such explanations seemed within reach. Weaver and others encouraged research at the intersection of biology, chemistry and physics, while prominent physicists such as Niels Bohr and Erwin Schrödinger turned their attention to biological speculation. Schrödinger's 1944 book What Is Life? in particular inspired many to enter the emerging field, including guiding James Watson towards DNA research. However, in the 1930s and 1940s it was by no means clear which—if any—cross-disciplinary research would bear fruit; work in colloid chemistry, biophysics and radiation biology, crystallography, and other emerging fields all seemed promising.In 1940, George Beadle and Edward Tatum demonstrated the existence of a precise relationship between genes and proteins. In the course of their experiments connecting genetics with biochemistry, they switched from the genetics mainstay Drosophila to a more appropriate model organism, the fungus Neurospora; the construction and exploitation of new model organisms would become a recurring theme in the development of molecular biology. In 1944, Oswald Avery, working at the Rockefeller Institute of New York, demonstrated that genes are made up of DNA. In 1952, Alfred Hershey and Martha Chase confirmed that the genetic material of the bacteriophage, the virus which infects bacteria, is made up of DNA. In 1953, James Watson and Francis Crick published a paper about the discovery of the double helical structure of the DNA molecule based on the discoveries made by Rosalind Franklin. In 1961, François Jacob and Jacques Monod demonstrated that the products of certain genes regulated the expression of other genes by acting upon specific sites at the edge of those genes. They also hypothesized the existence of an intermediary between DNA and its protein products, which they called messenger RNA. Between 1961 and 1965, the relationship between the information contained in DNA and the structure of proteins was determined: there is a code, the genetic code, which creates a correspondence between the succession of nucleotides in the DNA sequence and a series of amino acids in proteins.
In April 2023, scientists, based on new evidence, concluded that Rosalind Franklin was a contributor and "equal player" in the discovery process of DNA, rather than otherwise, as may have been presented subsequently after the time of the discovery.
The chief discoveries of molecular biology took place in a period of only about twenty-five years. Another fifteen years were required before new and more sophisticated technologies, united today under the name of genetic engineering, would permit the isolation and characterization of genes, in particular those of highly complex organisms.
The exploration of the molecular dominion
If we evaluate the molecular revolution within the context of biological history, it is easy to note that it is the culmination of a long process which began with the first observations through a microscope. The aim of these early researchers was to understand the functioning of living organisms by describing their organization at the microscopic level. From the end of the 18th century, the characterization of the chemical molecules which make up living beings gained increasingly greater attention, along with the birth of physiological chemistry in the 19th century, developed by the German chemist Justus von Liebig and following the birth of biochemistry at the beginning of the 20th, thanks to another German chemist Eduard Buchner. Between the molecules studied by chemists and the tiny structures visible under the optical microscope, such as the cellular nucleus or the chromosomes, there was an obscure zone, "the world of the ignored dimensions," as it was called by the chemical-physicist Wolfgang Ostwald. This world is populated by colloids, chemical compounds whose structure and properties were not well defined.The successes of molecular biology derived from the exploration of that unknown world by means of the new technologies developed by chemists and physicists: X-ray diffraction, electron microscopy, ultracentrifugation, and electrophoresis. These studies revealed the structure and function of the macromolecules.
A milestone in that process was the work of Linus Pauling in 1949, which for the first time linked the specific genetic mutation in patients with sickle cell disease to a demonstrated change in an individual protein, the hemoglobin in the erythrocytes of heterozygous or homozygous individuals.
The encounter between biochemistry and genetics
The development of molecular biology is also the encounter of two disciplines which made considerable progress in the course of the first thirty years of the twentieth century: biochemistry and genetics. The first studies the structure and function of the molecules which make up living things. Between 1900 and 1940, the central processes of metabolism were described: the process of digestion and the absorption of the nutritive elements derived from alimentation, such as the sugars. Every one of these processes is catalyzed by a particular enzyme. Enzymes are proteins, like the antibodies present in blood or the proteins responsible for muscular contraction. As a consequence, the study of proteins, of their structure and synthesis, became one of the principal objectives of biochemists.The second discipline of biology which developed at the beginning of the 20th century is genetics. After the rediscovery of the laws of Mendel through the studies of Hugo de Vries, Carl Correns and Erich von Tschermak in 1900, this science began to take shape thanks to the adoption by Thomas Hunt Morgan, in 1910, of a model organism for genetic studies, the famous fruit fly. Shortly after, Morgan showed that the genes are localized on chromosomes. Following this discovery, he continued working with Drosophila and, along with numerous other research groups, confirmed the importance of the gene in the life and development of organisms. Nevertheless, the chemical nature of genes and their mechanisms of action remained a mystery. Molecular biologists committed themselves to the determination of the structure, and the description of the complex relations between, genes and proteins.
The development of molecular biology was not just the fruit of some sort of intrinsic "necessity" in the history of ideas, but was a characteristically historical phenomenon, with all of its unknowns, imponderables and contingencies: the remarkable developments in physics at the beginning of the 20th century highlighted the relative lateness in development in biology, which became the "new frontier" in the search for knowledge about the empirical world. Moreover, the developments of the theory of information and cybernetics in the 1940s, in response to military exigencies, brought to the new biology a significant number of fertile ideas and, especially, metaphors.
The choice of bacteria and of its virus, the bacteriophage, as models for the study of the fundamental mechanisms of life was almost natural—they are the smallest living organisms known to exist—and at the same time the fruit of individual choices. This model owes its success, above all, to the fame and the sense of organization of Max Delbrück, a German physicist, who was able to create a dynamic research group, based in the United States, whose exclusive scope was the study of the bacteriophage: the phage group.
The phage group was an informal network of biologists that carried out basic research mainly on bacteriophage T4 and made numerous seminal contributions to microbial genetics and the origins of molecular biology in the mid-20th century. In 1961, Sydney Brenner, an early member of the phage group, collaborated with Francis Crick, Leslie Barnett and Richard Watts-Tobin at the Cavendish Laboratory in Cambridge to perform genetic experiments that demonstrated the basic nature of the genetic code for proteins. These experiments, carried out with mutants of the rIIB gene of bacteriophage T4, showed, that for a gene that encodes a protein, three sequential bases of the gene's DNA specify each successive amino acid of the protein. Thus the genetic code is a triplet code, where each triplet specifies a particular amino acid. They also found that the codons do not overlap with each other in the DNA sequence encoding a protein, and that such a sequence is read from a fixed starting point.
During 1962–1964 phage T4 researchers provided an opportunity to study the function of virtually all of the genes that are essential for growth of the bacteriophage under laboratory conditions. These studies were facilitated by the discovery of two classes of conditional lethal mutants. One class of such mutants is known as amber mutants. Another class of conditional lethal mutants is referred to as temperature-sensitive mutants. Studies of these two classes of mutants led to considerable insight into numerous fundamental biologic problems. Thus understanding was gained on the functions and interactions of the proteins employed in the machinery of DNA replication, DNA repair and DNA recombination. Furthermore, understanding was gained on the processes by which viruses are assembled from protein and nucleic acid components. Also, the role of chain terminating codons was elucidated. One noteworthy study used amber mutants defective in the gene encoding the major head protein of bacteriophage T4. This experiment provided strong evidence for the widely held, but prior to 1964 still unproven, "sequence hypothesis" that the amino acid sequence of a protein is specified by the nucleotide sequence of the gene determining the protein. Thus, this study demonstrated the co-linearity of the gene with its encoded protein.
The geographic panorama of the developments of the new biology was conditioned above all by preceding work. The US, where genetics had developed the most rapidly, and the UK, where there was a coexistence of both genetics and biochemical research of highly advanced levels, were in the avant-garde. Germany, the cradle of the revolutions in physics, with the best minds and the most advanced laboratories of genetics in the world, should have had a primary role in the development of molecular biology. But history decided differently: the arrival of the Nazis in 1933—and, to a less extreme degree, the rigidification of totalitarian measures in fascist Italy—caused the emigration of a large number of Jewish and non-Jewish scientists. The majority of them fled to the US or the UK, providing an extra impulse to the scientific dynamism of those nations. These movements ultimately made molecular biology a truly international science from the very beginnings.