Computational Biology and Chemistry 27 (2003) 461–467 Commentary The DNA double helix fifty years on Robert B. Macgregor Jr.∗, Gregory M.K. Poon Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada M5S 2S2 Received 16 June 2003; received in revised form 8 August 2003; accepted 12 August 2003 Abstract This year marks the 50th anniversary of the proposal of a double helical structure for DNA by James Watson and Francis Crick. The place of this proposal in the history and development of molecular biology is discussed. Several other discoveries that occurred in the middle of the twentieth century were perhaps equally important to our understanding of cellular processes; however, none of these captured the attention and imagination of the public to the same extent as the double helix. The existence of multiple forms of DNA and the uses of DNA in biological technologies is presented. DNA is also finding increasing use as a material due to its rather unusual structural and physical characteristics as well as its ready availability. © 2003 Published by Elsevier Ltd. Keywords: DNA; Double helix; Molecular biology; Nanotechnology 1. Introduction netic transmission of characteristics. At about the same time as Mendel was carrying out his studies, DNA was discovered 1953 witnessed the birth of a science icon with the pub- by the Swiss physiologist Friedrich Miescher. For the first lication of James Watson and Francis Crick’s proposal of a several decades after its discovery the role of DNA in cellular double helix structure of DNA in the journal Nature (Watson processes remained unexplained and for the most part unin- and Crick, 1953a). In their original publication they pro- vestigated. During the early part of the 20th century, various posed that DNA consists of two molecules that are wound biochemical pathways and principles were brought to light; around each other to form a right-handed helix that is sta- however, the question remained, which cellular molecule bilized by hydrogen bonding interactions between comple- provides the basis for Mendellian genetics? The different mentary base pairs between the two molecules. They pointed disciplines interested in cellular processes, biochemistry, out that this proposed structure provided a hint as to how genetics, and microbiology took very different approaches DNA could be self-replicating (Watson and Crick, 1953b). in their investigations of this question; however, none fo- The proposal rationalized and accommodated a great deal cused on DNA. Proteins and enzymes were known to be of current experimental information and pointed the way to the molecular phenotype of cells; however, the link between other experiments that could verify it. The process of veri- the gene-carrying molecule and these proteins was anything fication provided additional revelations about the molecular but clear. DNA was generally considered to be chemically, mechanisms of cellular processes, and it provided a model and thus structurally, too simple to contain the presumably on which many other ideas could be based. complex information necessary for heredity. This view changed over the course of about 20 years starting in 1928 when Fred Griffith found that a benign 2. The path to molecular biology strain of pneumococcal bacteria could be transformed into a pathogenic strain by exposure to a cell-free extract of In the 19th century, the Moravian monk Gregor Mendel the pathogenic strain. In the mid 1930s Oswald Avery and had given a solid quantitative grounding to the idea of ge- coworkers set out to purify this transforming factor. Chemi- cal analysis of the extract showed that DNA had transformed ∗ the pneumococcal bacteria and in 1944 he published the first Corresponding author. Tel.: +1-416-978-7332; fax: +1-416-978-8511. results demonstrating that DNA was the genetic material E-mail address: [email protected] (R.B. Macgregor Jr.). (Avery et al., 1944). A few years later, the results of Hershey 1476-9271/$ – see front matter © 2003 Published by Elsevier Ltd. doi:10.1016/j.compbiolchem.2003.08.001 462 R.B. Macgregor Jr., G.M.K. Poon / Computational Biology and Chemistry 27 (2003) 461–467 and Chase (1952) reinforced Avery’s finding by demonstrat- give rise to the proteins for which they code. At that time ing that DNA mediated the production of progeny virus there was no known molecule or mechanism that would link in bacteriophage-infected Escherichia coli bacteria. During these two structures. A proposal by Mahlon Hoagland sug- this time, George Beadle and Edward Tatum had shown in gesting the formation of a complementary structure between the early 1940s that enzyme synthesis in cells was con- DNA and RNA appeared in the magazine Scientific Ameri- trolled by genes and that there was one gene for each en- can in 1959. The next year experimental data from the labo- zyme (Beadle and Tatum, 1941). ratory of Sol Spiegelman (Nomura et al., 1960) showed the Taken together these were extremely important discover- involvement of a DNA–RNA hybrid molecule that was cru- ies putting an end to nearly a century of speculation about the cial to protein synthesis; this molecule was messenger RNA chemical nature of genes. It was interesting to know that ge- (mRNA). Oddly, although RNA was known to form heli- netic information somehow resided in DNA; however, there cal structures similar to DNA, the necessity or likelihood was no way to incorporate it into the current understanding of formation of a transient DNA–RNA hybrid had not been of cellular mechanisms. It was not clear how the genes on considered. With the discovery of mRNA the modern cen- DNA could be transformed into proteins; several pieces of tral dogma of molecular biology, DNA makes RNA makes the puzzle were still missing. This was the state of knowl- protein, was established. edge in biology during which the work on the structure of DNA began. In the early 1950s several prominent scientists had turned 3. The success of the Watson–Crick model their efforts toward elucidating the structure of DNA, the perceived importance and prestige of these studies was Synthesis, verifiability, and extrapolation are hallmarks enhanced by the fact that Linus Pauling, the chemist who of great scientific ideas. Many other experiments in biology received the Nobel Prize for his descriptions of chemi- that occurred after the proposal of the double helix are con- cal bonding, was working on the structure of biological sidered to be direct consequences of the Watson and Crick molecules, including DNA. Studies of the structure of double helix. This may be overstating the case somewhat; molecules had been made possible by the advent of X-ray many seminal discoveries about the molecular biology of diffraction, a technique that had been recently developed the cell had already been made and would have been made by physicists. And although X-ray diffraction worked well with or without a working model for the structure of DNA. for small molecules, work on large biological molecules However, it is clear that their proposal is a major landmark like proteins or DNA was slow for a number of reasons. In in the progression of understanding of biological systems the case of analyzing the structure of DNA the difficulties that began in the 19th century. There have been many other were exacerbated by the fact that there were no crystals of scientific milestones but none have so consistently captured DNA available meaning that the diffraction images were the imagination of the public and scientific community. acquired using oriented fibers of DNA. The diffraction In purely structural terms, the DNA double helix was the patterns obtained using fibers is poor and only gross de- first model for a major macromolecular cellular component tails of the structure can be determined. For example, it and it remains the greatest success of structural biology was known that DNA was helical and that the bases were to date. Although there are currently thousands of protein oriented perpendicular to the axis of the helix. However, structures known and the three dimensional structures of neither the relative orientation of the molecular groups nor the other cellular components have also been elucidated, the handedness of the helix could be ascertained. this was not the case in the 1950s. A working model for any When Watson and Crick combined the known data about large cellular molecule was a great novelty at the time; the DNA, the results of the X-ray diffraction analysis, and a first protein structure was still about ten years away. DNA great deal of imagination they struck upon a structure that is much simpler than any protein and Watson and Crick’s satisfied all of the requirements. Because of the earlier work model was consistent with all the known information about of Avery, Hershey and Chase, and Beadle and Tatum, when the composition and properties of DNA. Although detailed Watson and Crick published their proposed structure the information concerning protein structure is often useful in scientific world was ready. Their two publications in 1953 guiding further experimentation about a particular protein, offered an entirely new way of understanding the molec- such knowledge does not have the generality, and thus, ular mechanisms underlying many cellular processes, such does not have the impact of the originally proposed double as cell division, genetic inheritance, and protein synthesis. helical structure for DNA. This is true because it is very dif- However, despite the fact that the advances between 1927 ficult to extract general principles from most protein data, and 1953 had revolutionized the understanding of the cell a the details are important. In contrast to this the details of number of very large questions had also been raised.