The discovery of DNA and the double helix
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 ribose and the other deoxyribose. It was this subsequent discovery that led to the identification and naming of DNA as a substance distinct from RNA.
Friederich 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.
Max Delbrück, Nikolai V. Timofeeff-Ressovsky, and Karl G. Zimmer published results in 1935 suggesting that chromosomes are very large molecules the structure of which can be changed by treatment with X-rays, and that by so changing their structure it was possible to change the heritable characteristics governed by those chromosomes. (Delbrück and Salvador Luria were awarded the Nobel Prize in 1969 for their work on the genetic structure of viruses.) In 1943, Oswald Theodore Avery discovered that traits proper to the "smooth" form of the Pneumococcus could be transferred to the "rough" form of the same bacteria merely by making the killed "smooth" (S) form available to the live "rough" (R) form. Quite unexpectedly, the living R Pneumococcus bacteria were transformed into a new strain of the S form, and the transferred S characteristics turned out to be heritable.
In 1944, the renowned physicist, Erwin Schrödinger, published a brief book entitled What is Life?, in which he maintained that chromosomes contained what he called the "hereditary code-script" of life. He added: "But the term code-script is, of course, too narrow. The chromosome structures are at the same time instrumental in bringing about the development they foreshadow. They are law-code and executive power -- or, to use another simile, they are architect's plan and builder's craft -- in one." He conceived of these dual functional elements as being woven into the molecular structure of chromosomes. By understanding the exact molecular structure of the chromosomes one could hope to understand both the "architect's plan" and also how that plan was carried out through the "builder's craft." Francis Crick, James D. Watson, Maurice Wilkins, Seymour Benzer, et al., took up the physicist's challenge to work out the structure of the chromosomes and the question of how the segments of the chromosomes that were conceived to relate to specific traits could possibly do their jobs.
Just how the presence of specific features in the molecular structure of chromosomes could produce traits and behaviors in living organisms was unimaginable at the time. Because chemical dissection of DNA samples always yielded the same four nucleotides, the chemical composition of DNA appeared simple, perhaps even uniform. Organisms, on the other hand, are fantastically complex individually and widely diverse collectively. Geneticists did not speak of genes as conveyors of "information" in such words, but if they had, they would not have hesitated to quantify the amount of information that genes need to convey as vast. The idea that information might reside in a chemical in the same way that it exists in text--as a finite alphabet of letters arranged in a sequence of unlimited length--had not yet been conceived. It would emerge upon the discovery of DNA's structure, but few researchers imagined that DNA's structure had much to say about genetics.
In the 1950s, only a few groups made it their goal to determine the structure of DNA. These included an American group led by Linus Pauling, and two groups in Britain. At Cambridge University, Crick and Watson were building physical models using metal rods and balls, in which they incorporated the known chemical structures of the nucleotides, as well as the known position of the linkages joining one nucleotide to the next along the polymer. At King's College, London, Maurice Wilkins and Rosalind Franklin were examining x-ray diffraction patterns of DNA fibers.
A key inspiration in the work of all of these teams was the discovery in 1948 by Pauling that many proteins included helical (see alpha helix) shapes. Pauling had deduced this structure from x-ray patterns. Even in the initial crude diffraction data from DNA, 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.
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.
Watson and Crick had begun to contemplate double helical arrangements, and they saw that by reversing the directionality of one strand with respect to the other, they could provide an explanation for Chargaff's puzzling finding. This explanation was the complementary pairing of the bases, which also had the effect of ensuring that the distance between the phosphate chains did not vary along a sequence. Watson and Crick were able to discern that this distance was constant and to measure its exact value of 2 nanometers from an X-ray pattern obtained by Franklin. The same pattern also gave them the 3.4 nanometer-per-10 bp "pitch" of the helix. The pair quickly converged upon a model, which they announced before Franklin herself published any of her work.
The great assistance Watson and Crick derived from Franklin's data has become a subject of controversy, and it has angered people who believe Franklin has not received the credit due to her. The most controversial aspect is that Franklin's critical X-ray pattern was shown to Watson and Crick without Franklin's knowledge or permission. Wilkins showed it to them at his lab while Franklin was away.
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. Their paper 'A Structure for Deoxyribose Nucleic Acid' was published on April 25. 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 Meselson-Stahl experiment. Work by Crick and coworkers deciphered the genetic code not long afterward. These findings represent the birth of molecular biology.
Watson, Crick, and Wilkins were awarded a Nobel Prize in 1962, by which time Franklin had died.
- DNA: The Secret of Life, by James D. Watson. ISBN 0-375-41546-7
Source | Copyright