Today it is common knowledge that DNA, a nucleic acid, directs the development of cells. Scientists gradually learned about DNA in a curiously twisted fashion that is common in science. For one thing, the discovery of DNA required progress on three separate fronts: cytology (the study of cells through a microscope), genetics, and chemistry.
After Gregor Mendel’s laws of heredity were rediscovered in 1900, considerable interest developed in what causes heredity. The fundamental structures involved –– the chromosomes –– had been discovered and studied by Walther Flemming in the 1880s, but no one knew that they were connected to heredity. They were just long thin structures that appeared when cells were stained during cell division. Also, Friederich Miescher had discovered nucleic acids in cell nuclei as early as 1869, but they were not connected either to heredity or to chromosomes –– although Miescher’s later discovery that salmon sperm are almost entirely nucleic acid should have been a clue to the connection.
In 1907 Thomas Hunt Morgan, who was somewhat skeptical about genetics, began to use fruit flies in breeding experiments. Within a short time he found that Mendel’s laws worked, but also that some inherited characteristics appeared to be linked together. These linkages behaved as if the units of heredity, the genes, lined up in long rows. A suitable long thin part of the cell that could physically contain the genes was the chromosome, as had earlier been suggested on other grounds by August Weismann.
By 1911 Morgan was able to show that genes strung along the chromosomes are the agents of heredity. While this development was occurring on the genetic front, there was also some progress being made in chemistry. In 1909 Phoebus Aaron Theodor Levene was the first to determine that nucleic acids contain a sugar, ribose. Twenty years later, he found that other nucleic acids contain a different sugar, deoxyribose. Hence, there are two types of nucleic acid: ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Levene also worked out the other compounds that were in RNA and DNA. This chemistry was then explored in detail in the 1930s by Alexander Todd.
Chromosomes, like other cell structures, contain proteins. They also contain DNA. Proteins were known to be complex molecules that are biologically very active, so everyone thought that genes must be proteins –– until 1944 when Oswald Avery and coworkers showed that hereditary characteristics could be induced by pure DNA, without a protein involved. By the early 1950s a few scientists from different fronts were tackling the problem of understanding DNA. Among these was Linus Pauling, who was at the time probably the most accomplished chemist. In 1951 Pauling, working with Robert Corey, determined that the structure of a class of proteins is a helix, which is a three-dimensional spiral. This was the first determination of the physical structure of a large biological molecule. At about this time, Pauling turned to the study of DNA, hoping to discover its structure as well.
In England, there were several scientists interested in the structure of DNA. Maurice Wilkins and Rosalind Franklin were doing X-ray diffraction studies of DNA in hopes of elucidating its structure. Diffraction studies had proved successful in analyzing crystal structures, and DNA could be crystallized. Another English scientist interested in the subject was Francis Crick, a 35-year-old graduate student. With an undergraduate degree in physics, he too would have liked to do X-ray diffraction studies; but English custom kept him from competing with Wilkins and Franklin.
A fourth interested scientist was James Watson, an American. Watson was working as a postgraduate student, trying to learn about genetics from studying organisms. But he realized that the solution to the problem was more likely on the chemical front, so he abandoned what he was doing and applied for work in X-ray diffraction. He was lucky to be taken on at the same Cambridge laboratory where Francis Crick was pursuing his degree, not far from London, where Wilkins and Franklin worked. News of Pauling’s discovery of a helical structure in proteins set all the English group (except –– at first –– Franklin) thinking that DNA might be a helix as well. Alec Stokes, who was working with Wilkins, was the first to think DNA might be a helix, an idea he had developed when he first saw the diffraction studies. Wilkins thought it might be several helices twisted together.
Watson and Crick decided to try using the method by which Pauling had found the helix in proteins. He had stuck together models of the subunits of the molecule, rather as one puts a tinker toy set together. The models need to be constructed so that they fit together according to Pauling’s theory of the chemical bond. Watson and Crick acquired a copy of Pauling’s 1939 book on the chemical bond and came up with a model for DNA of three helices twisted together. But when they showed it to Wilkins and Franklin, Franklin pointed out that it disagreed with her diffraction data and had other deficiencies as well.
Watson gradually established to his and Crick’s satisfaction that DNA does have a helical structure. Crick figured out that the bases in DNA are always paired in the same way. Franklin insisted on the correct location of the sugars. Meanwhile, Pauling produced two versions of his model of DNA. It contained three twisted helices and was clearly wrong. One of the best chemists of the century had made a mistake in his chemistry.
After another false step, Watson finally built a model that incorporated two helices, paired bases, and the sugar structure recommended by Franklin. Crick did calculations that showed that this model was feasible. Wilkins and Franklin produced X-ray diffraction calculations that confirmed the structure. On a visit to Cambridge, Pauling agreed. The true nature of DNA had finally been discovered.