Life In Science.

As a boy in the 1920s and 30s, I was always interested in science. It was an era in which chemists were developing new materials, physicists were developing new instruments and discovering new particles, and engineers were creating new devices (such as radios, airplanes, and refrigerators). As my senior thesis in high school, I researched and wrote a paper on the possibility of transmutation of the elements and of atomic energy. (I did not envision a bomb!) Two high school teachers, one in mathematics and one in chemistry, intrigued and guided my interests, influcening me to enroll at the Massachusetts Institute of Technology (MIT). It was a serious, high-intensity school. During my sophomore year, MIT launched a new program in physical and chemical biology that instantly seized my imagination. After four years’ time out for World War II, (radar research and development) I started work research on nucleic acids in 1946. The nature and mode of action of the gene was mysterious and clearly central to biology. The work of Avery, McLeod, and McCarty (1) with Pneumococcus strongly suggested that the genes were DNA. Uber’s work upon ultraviolet-induced mutation suggested that damage to DNA had genetic effects (2). But the structure of DNA and its biochemistry were essentially unknown. The ultraviolet absorption bands of DNA were broad. We sought to narrow them (so as to be able to produce more specific effects) by taking spectra at low temperatures (liquid nitrogen and liquid hydrogen) (3), but the effects were small. However, upon ultraviolet irradiation of uracil, I discovered a reversible photochemical (4) effect at the same time that Renato Dulbecco discovered a photochemical effect on phage (5). Upon completing my PhD, I obtained a position as Associate Professor of Biophysics at Iowa State (a position earlier held by Uber). To pursue this line of research further it seemed desirable to use deoxynucleotides rather than the purine and pyrimidine bases. At that time the only techniques to isolate deoxynucleotides had yields of about 1%. I developed the technique to obtain 100% yield of nucleotides from DNA (6), and then quantitated and characterized their ultraviolet absorption. I also isolated all of the possible dinucleotides (7). This permitted me to show that (a) the methylcytosine was always adjacent to guanine, and (b) the molar equalities of A and T and of G and C demonstrated by Chargaff (8) could not arise from a sequential order but more likely required two strands of complementary sequence. But I had no proof, only surmise. At this time I realized that if I was to advance further with DNA I needed a biological system in which DNA was active. Bacteriophage, as elucidated by Max Delbruck, was such a system. (Max, at my invitation, had earlier visited at Iowa State to present a series of excellent lectures on bacteriophage.) I was able to take a six month leave of absence from Iowa State, and Max arranged a stipend for me to come to Caltech to learn the arts of phage research. (When I arrived at Caltech, I gave a seminar on the DNA dinucleotide data that Max and Solomon Golomb tried to use to deduce a genetic code!) My Caltech experience went very well. It was an exhilarating environment. When it came time to leave to return to Iowa, Max wanted me to continue to work on the T phages. I wanted to work on the small phages (PhiX and S13), which I thought might be simpler. We compromised. I would do both. My subsequent T phage work resulted in the discovery of the sucrose modifications of the DNA of T2 and T4 (9) in varying amount. We also characterized T7. PhiX seemed more stable than S13, so I concentrated on learning how to culture and purify it, and I began to characterize its DNA using light scattering, ultra-centrifugation, and electron microscopy. At this time I was invited to join Caltech. There I continued with PhiX, resulting iIn a series of discoveries. First it was small. In the electron microscope it was nearly spherical with a diameter of 25 millimicrons. Next I found by light scattering and