COMMENTARY Explorations in the land of DNA and beyond Matthew Meselson Like many of my colleagues, I have liked sci- the war was still evident and the Cold War must have had up his sleeve all along: the X- ence for as long as I can remember. Though was starting up. ray diffraction determination of the structure not college educated, my parents were always The following year, with almost no under- of N,N´-dimethylmalonamide. The idea was encouraging, as were two uncles who knew a graduate science credits, I entered the to test the prediction from his resonance the- little chemistry. When I was still in grammar California Institute of Technology, a fresh- ory that its two amide groups are planar, as of school, the basement of our house in Los man all over again. I took Linus Pauling’s course they turned out to be. Angeles became a sizeable laboratory where I general chemistry course and did a research I remember being disappointed at the time built radios, spectroscopes and other instru- project for him to determine the accessibility by Erwin Schrödinger’s little 1945 book, ments, purified radium and rare-earth ele- of the heme group of the hemoglobin of the What Is Life?1.A founder of quantum ments from carnotite and monazite ores by marine worm Urechis to a series of increas- mechanics, Schrödinger had left his native fractional crystallization and ion-exchange ingly large alkyl isocyanides that I synthe- Austria soon after the German occupation in chromatography, and synthesized for neigh- sized. When at the end of the year I showed 1938 and had become a professor at Trinity bors the recently discovered insecticide DDT. Pauling my only partly complete results, College, Dublin. After pointing out that heat The war, though far away, was neverthe- expecting a stern response, he beamed his motion would make assemblages of inde- less the focus of attention then, and it broad smile and said that the important pendent molecules too unstable to account seemed wrong to spend high school vaca- thing for a student to learn from such work for the stability of genes, he concluded that tions solely in recreational activities. So I was that it can take much longer to complete genes, or maybe even entire chromosomes, took a job washing glassware at a vitamin than expected. are huge molecules, the stability of which factory and attended summer school classes I was dissatisfied with undergraduate life derives from their covalent bonds, and that to shorten the time required to earn a at Cal Tech. Except for general chemistry, the their variety corresponds to their various sta- diploma and begin college. To my surprise, courses I took seemed based too much on ble isomeric states. Though couched in quan- however, academic credits were not enough: memory and, after Chicago and half a year in tum-mechanical terms, the concept boiled California law required 3 full years of high Europe, the other students (all males and 4–5 down to what for chemists is a truism—that school physical education. Then I learned of years younger) seemed uninterested in the only covalent bonds can account for the sta- a college that took students without requir- world outside. Eventually, after a year back at bility of the hereditary substance. Yet coming ing the last 2 years of high school—the Chicago taking chemistry and math courses from Schrödinger and written so gracefully, University of Chicago. and a year at Berkeley as a physics graduate with a moving epilog on determinism and Upon entering the College of the student, through great good luck I became free will, it influenced some of the pioneers of University of Chicago in 1946, expecting to Linus Pauling’s last graduate student at Cal molecular biology to enter the field. study chemistry and physics, I found that Tech.Initially, he suggested that for my dis- Schrödinger addressed the question of the undergraduate programs in specialized sub- sertation research I should determine the chemical stability of the genetic material but jects had been abolished in favor of a manda- structures of some tellurium minerals by said nothing about how it might replicate. It tory curriculum based on classical writings in means of X-ray diffraction. He may have was Pauling, in 1948, who grasped the the humanities and the social and natural sci- been only half-serious, because he went on to answer, published at the University of ences. I count this elementary education in caution me that some chemists working with Nottingham as the 21st Sir Jesse Boot what is uninformatively called the ‘liberal tellurium compounds had acquired a horri- Foundation Lecture entitled “Molecular arts’ a piece of good fortune, even though it ble halitosis called ‘tellurium breath,’ isolat- Architecture and the Processes of Life”: got me only a Ph.B. (bachelor of philosophy), ing them from society and driving some of no good at all for admission to a graduate them to suicide. By then wondering how In general, the use of a gene or virus as a school in science. After 3 years, I left Chicago ordinary atoms could be put together to template would lead to the formation of a and spent the next 6 months traveling make self-replicating structures, I asked to be molecule not with identical structure but around Europe, reading and discussing with assigned instead a molecule composed of with complementary structure. It might hap- friends what might lie ahead for America and biologically more important atoms. So pen, of course, that a molecule could be at the the world. It was 1949—the devastation of Pauling suggested another project that he same time identical with and complementary NATURE MEDICINE VOLUME 10 | NUMBER 10 | OCTOBER 2004 xxi COMMENTARY tern.He interpreted the result to mean that and shouted, “The most important develop- the molecule consisted of three chains coiled ment in biology in a decade and you don’t about one another. The calculation appears know about it? Read these and don’t come on a page dated 26 November 1952 in one of back until you have!” I took this as an his research notebooks, followed by the invitation to come back. When I did, Max notation, “Perhaps we have a triple-chain spoke of his difficulty in imagining that the structure!” Of course, the three-chain struc- two polynucleotide chains wound around ture he and Corey published three months each other could come apart during replica- later was wrong. Soon after receiving from tion without breaking—an understandable James Watson and Francis Crick a prepubli- dilemma, because DNA topoisomerases were cation copy of their April 1953 letter to then unknown. How this question led to the Nature describing their double-helical invention of equilibrium density-gradient model of DNA, Pauling wrote to his son centrifugation that formed the second half of Peter, “The structure seems to me to be a my doctoral dissertation, and to the experi- very interesting one and I have no strong ment that Frank Stahl and I then did using argument against it. I do not think their 15N as a density label, demonstrating the arguments against our structure are strong semiconservative replication of DNA, is told ones, either.” He went on to write that if the in detail in a book by Frederick Lawrence specimens from which his data came con- Holmes (Fig. 1)2–4. tained about 30% water, the DNA molecules Density-gradient centrifugation proved in them would have only two chains. useful for attacking other fundamental prob- Figure 1 Matthew Meselson and Frank Stahl in My first knowledge of the great discovery lems posed by the double-helical structure of 1996, standing at the place they met in 1954 at of Watson and Crick came through an act of DNA. Jean Weigle and I used it in 1960 to Woods Hole. From ref 2. violence. Sometime in 1953, after the publi- show that genetically recombinant chromo- cation of the double helix, I went for the first somes of phage lambda contain segments of to the template on which it is moulded. time to talk with Max Delbrück. Immediately parental DNA consistent with a break-and- However, this case seems to me to be too he asked what I thought of the papers Jim join model of recombination rather than unlikely to be valid in general, except in the and Francis had published in Nature in April with the template-switching model called following way. If the structure that serves as a and May. When I replied that I had not heard copy choice5. Earlier that year, Cedric Davern template (the gene or virus molecule) consists of them, Max hurled a stack of reprints at me and I showed by a density-transfer experi- of, say,two parts, which are themselves com- plementary in structure, then each of these parts can serve as the mould for the produc- tion of a replica of the other part, and the complex of two complementary parts thus can serve as the mould for the production of duplicates of itself. Pauling attributed the templating speci- ficity involved in gene duplication, as well as in certain other manifestations of biological specificity, to detailed structural complemen- tarity and the cooperative action of individu- ally rather weak interactions, such as van der Waals attraction and hydrogen bonding. Later, it was learned that the great fidelity of gene duplication is achieved by the repeated application of such interactions in certain error-correction mechanisms. Despite Pauling’s insight requiring the gene to be made of two complementary parts, he proposed a three-strand structure for DNA (and RNA).