Paul Doty and the Modern Era of DNA as a Molecule

In april of 1959 The Journal of Molecular Biology was launched. Word of this imminent journal had spread, and manuscripts were promptly readied and sent. The first one to be accepted and published was from the laboratory of the Harvard physical chemist, Paul Doty, and addressed the organization of DNA and protein in isolated chromatin. This prescient paper serves as a point of departure for remembering Paul Doty (1920– 2011) and all that he meant in the foundational years of molecular biology and thereafter (Fig. 1). When it was first discovered by Friedrich Miescher in 1865 as the substance “nuclein,” chromatin behaved as a proteinaceous substance (hence, the suffix “in,” borne by both terms), despite its obvious content of another component that contained phosphorus and nitrogen, later recognized as DNA. For nearly one century, the biochemical composition of chromatin remained ill-defined. The basic proteins, termed histones, were discovered by Albrecht Kossel in 1884, but their relationship to chromatin remained unclear. In the 1940s, Alexander Dounce, at the University of Rochester, rekindled the isolation of chromatin, as did the laboratories of James Bonner at Caltech and Alfred Mirsky at Rockefeller a bit later. These preparations were obtained as viscous gels, and there were uncertainties as to whether this feature was simply a signature of the long DNA or perhaps implied an adventitious coacervate formed during the extraction process. It is to be borne in mind that at those times, the discovery of the structure of DNA was yet to be made, and issues such as the length and number of DNA molecules per chromosome were unknown. Even if DNA and its associated proteins could be isolated at reasonable purity, there was no existing information by which to predict its biophysical properties, such as molecular mass (although broken from chromosomes to be sure), the persistence length of the fragments as a possible clue to the uniformity or spatial irregularity of bound proteins along the DNA, and so on. As an experienced physical chemist of polymers, in the mid-1950s Doty was keenly aware of how little was known about how DNA was organized with proteins in chromosomes. He was not alone in this awareness, but unlike others, he did something about the situation. Geoffrey Zubay in Doty’s lab achieved a soluble preparation of chromatin, and at that moment, he and his mentor knew that they could interrogate it as a particle. Inter alia, they determined the molecular weight of the chromatin pieces from light scattering, and they used optical rotatory dispersion to estimate the -helical content of the chromatin proteins. No publication had had as much influence in the epistemology of chromatin for the simple reason that Zubay and Doty were the first to study chromatin as a particle. The very first paper the Journal of Molecular Biology published might have been from any lab, on anything. It is a tribute to Paul Doty’s prescience, and now to his memory, that the first paper in the inaugural issue of JMB was so far-reaching (1). Doty and colleagues displayed prescience all throughout his career. He attracted brilliant students, postdocs, and visiting scientists. Julius Marmur perfected the isolation of very large DNA from Escherichia coli as a recipe that even inexperienced students could do (as I and thousands of others did in the 1960s). Doty’s lab was among the first to envision that the two strands of DNA could be melted apart and rejoined, forming the basis of all nucleic acid