History of molecular biology

The history of molecular biology begins in the 1930s with the convergence of various, previously distinct biological disciplines: biochemistry, genetics, microbiology, and virology. 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) 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 will suffice to allow us to establish a date for the so-called "molecular revolution", or at least to establish a chronology of its most fundamental developments.

In its earliest manifestations, molecular biology—the name was coined by Warren Weaver of the Rockefeller Foundation in 1938—was an ideal 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 (and funded) research at the intersection of biology, chemistry and physics, while prominent physicists such as Niels Bohr and 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, transcription of these genes into messenger RNA; they direct the "expression" of the genes.

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 in the 18th century. 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 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, ultracentrifugization, and electrophoresis. These studies revealed the structure and function of the macromolecules.

A milestone in that process was the work of 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 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 Tschermack 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 (Drosophila melanogaster). 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 School of the Phage.

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.

History of DNA biochemistry

Structure of DNA

Discovery of the DNA Double Helix

Francis Crick, lecturing ca. 1979

Cavendish Laboratory

King's College London

Photo 51

The study of DNA is a central part of molecular biology.

First isolation of DNA

Working in the 19th century, biochemists initially isolated DNA and RNA (mixed together) from cell nuclei. They were relatively quick to appreciate the polymeric nature of their "nucleic acid" isolates, but realized only later that nucleotides were of two types--one containing deoxyribose. It was this subsequent discovery that led to the identification and naming of DNA as a substance distinct from RNA.

Friedrich Miescher (1844-1895) discovered a substance he called "nuclein" in 1869. Somewhat later, he isolated a pure sample of the material now known as DNA from the sperm of salmon, and in 1889 his pupil, Richard Altmann, named it "nucleic acid". This substance was found to exist only in the chromosomes.

In 1929 Phoebus Levene at the Rockefeller Institute identified the components (the four bases, the sugar and the phosphate chain) and he showed that the components of DNA were linked in the order phosphate-sugar-base. He called each of these units a nucleotide and suggested the DNA molecule consisted of a string of nucleotide units linked together through the phosphate groups, which are the 'backbone' of the molecule. However Levene thought the chain was short and that the bases repeated in the same fixed order. Torbjorn Caspersson and Einar Hammersten showed that DNA was a polymer.

Chromosomes and inherited traits

Max Delbrück, Nikolai V. Timofeeff-Ressovsky, and X-rays, and that by so changing their structure it was possible to change the heritable characteristics governed by those chromosomes. In 1937 William Astbury produced the first X-ray diffraction patterns from DNA. He was not able to propose the correct structure but the patterns showed that DNA had a regular structure and therefore it might be possible to deduce what this structure was.

In 1943, Alfred Hershey and Martha Chase did an experiment (Hershey-Chase experiment) that showed, in T2 phage, that DNA is the genetic material (Hershey shared the Nobel prize with Luria).

Discovery of the structure of DNA

In the 1950s, three groups made it their goal to determine the structure of DNA. The first group to start was at King's College London and was led by X-ray diffraction patterns of DNA fibers. Of the three groups, only the London group was able to produce good quality diffraction patterns and thus produce sufficient quantitative data about the structure.

Helix structure

In 1948 Pauling discovered that many proteins included helical (see alpha helix) shapes. Pauling had deduced this structure from X-ray patterns and from attempts to physically model the structures. (Pauling was also later to suggest an incorrect three chain helical DNA structure based on Astbury's data.) Even in the initial diffraction data from DNA by Maurice Wilkins, it was evident that the structure involved helices. But this insight was only a beginning. There remained the questions of how many strands came together, whether this number was the same for every helix, whether the bases pointed toward the helical axis or away, and ultimately what were the explicit angles and coordinates of all the bonds and atoms. Such questions motivated the modeling efforts of Watson and Crick.

Complementary nucleotides

In their modeling, Watson and Crick restricted themselves to what they saw as chemically and biologically reasonable. Still, the breadth of possibilities was very wide. A breakthrough occurred in 1952, when Erwin Chargaff visited Cambridge and inspired Crick with a description of experiments Chargaff had published in 1947. Chargaff had observed that the proportions of the four nucleotides vary between one DNA sample and the next, but that for particular pairs of nucleotides — adenine and thymine, guanine and cytosine — the two nucleotides are always present in equal proportions.

Using X-ray diffraction, as well as other data from Maurice Wilkins jointly received the Nobel Prize for their determination of the structure of DNA.

"Central Dogma"

Watson and Crick's model attracted great interest immediately upon its presentation. Arriving at their conclusion on February 21 1953, Watson and Crick made their first announcement on February 28. In an influential presentation in 1957, Crick laid out the "Central Dogma", which foretold the relationship between DNA, RNA, and proteins, and articulated the "sequence hypothesis." A critical confirmation of the replication mechanism that was implied by the double-helical structure followed in 1958 in the form of the genetic code not long afterward. These findings represent the birth of molecular biology.

History of protein biochemistry

First isolation and classification

Proteins were recognized as a distinct class of biological molecules in the eighteenth century by gluten. The similarity between the cooking of egg whites and the curdling of milk was recognized even in ancient times; for example, the name albumen for the egg-white protein was coined by Pliny the Elder from the Latin albus ovi (egg white).

With the advice of empirical formula, roughly C₄₀₀H₆₂₀N₁₀₀O₁₂₀ with individual sulfur and phosphorus atoms. Mulder published his findings in two papers (1837,1838) and hypothesized that there was one basic substance (Grundstoff) of proteins, and that it was synthesized by plants and absorbed from them by animals in digestion. Berzelius was an early proponent of this theory and proposed the name "protein" for this substance in a letter dated 10 July 1838

The name protein that I propose for the organic oxide of fibrin and albumin, I wanted to derive from [the Greek word] πρωτειος, because it appears to be the primitive or principal substance of animal nutrition.

Mulder went on to identify the products of protein degradation such as the Da.

Purifications and measurements of mass

The minimum molecular weight suggested by Mulder's analyses was roughly 9 amino acids. Proteins were finally shown to be macromolecules of well-defined composition (and not colloidal mixtures) by Theodor Svedberg using analytical ultracentrifugation. The possibility that some proteins are non-covalent associations of such macromolecules was shown by Gilbert Smithson Adair (by measuring the osmotic pressure of posttranslational modifications and, more recently, for probing protein structure.

Most proteins are difficult to ribonuclease A and made it freely available to scientists around the world. This generous act made RNase A the main protein for basic research for the next few decades, resulting in several Nobel Prizes. in the Nobel prize king won it.

Protein folding and first structural models

The study of protein folding began in 1910 with a famous paper by Henrietta Chick and C. J. Martin, in which they showed that the free energy for the protein.

The hypothesis of protein folding was followed by research into the physical interactions that stabilize folded protein structures. The crucial role of Arne Tiselius, but Linderstrom-Lang showed that the charges were generally accessible to solvent and not bound to each other (1949).

The domains are two methods approaching atomic resolution.

References

^ Watson J, Crick F (1953). "Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid". Nature 171 (4356): 737-8. PMID 13054692.

Fruton, Joseph. Proteins, Genes, Enzymes: The Interplay of Chemistry and Biology. New Haven: Yale University Press. 1999. ISBN 0-300-07608-8
Lily E. Kay, The Molecular Vision of Life: Caltech, the Rockefeller Foundation, and the Rise of the New Biology, Oxford University Press, Reprint 1996
Morange, Michel. A History of Molecular Biology. Cambridge, MA: Harvard University Press. 1998.

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