EDITED BY WESLEY FIRST Doubleday & Company, Inc., Garden City, New York t963 _ Francis J. Ryan A great university is measured by the caliber oE the men it can attract and maintain in a free community of scholars. In my own scientific career, one great m3n was a pm-eminent formative Muence-Francis J. 12yx1, professor of Zoology at Columbia University. Ryan was a Columbia man through- out: A.B. (1937), Ph.D. (1941), and then a prokssor until a sudden fatal heart attack in 1963 at the age of forty-seven. I first met Ryan when I was a Columbia College sophomore in 1942. He had just returned from a year's postdoctoral re- JOSHUA LEDERBERG, I944 College,-strrdeltt at Columbia Col- lege of Physicians nrtd Srrrgeolu from 1944 to 1946, ottd Ph.D. from Yule in 1947, WCLT CI Nobel laureate in X958 in physiology and medicine for rescnrch in genetics of bacteria. He is now at Sranford. . . .._ 1L _,,..- ..__... w. ,__ -J...I_ 106 UNlVERS1l-Y ON THE HEIGHTS starch felIowship at Stauford. He had intended to work on embryological physiology in frogs, but there he met G. W. Beadle and E. L. Tatum, who were rapidly pushing ahead after their first epochal findings in the biochemical genetics of Neurospora. He was-perhaps foolhardy to bring this botanical material-the red bread mold-back to a department of Zoology, but he was too good a biologist to be deterred by niceties like plant versus animal in deciding how to study fundamental'issues of lift. Bcsidcs, this mold grew so quickly that it would put up a good race with a lame snail. So one could pretend to imbue it with the animal virtue of locomo- tion. The excitement of a biochemical approach to genetics was infectious, and I soon begged him for a chance to learn the tricks of this new game. He arranged a laboratory job for me, glassware washing at first; later, technical work in micro- biolo,y, that not only helped me through that year of college, but taught me much of the discipline of laboratory rcscarch. Above all, it gave me the opportunity to sharpen my adoles- cent thinking against one of the most versatile, most generous minds I would ever encounter. In retrospect, I can perceive more cIearly what a unique quality he had for focusing on his students' development even at the expense of a profes- sorial ego. He rarely instructed me about anything, but would often lead me into an intellectual trap, then challenge me to find my own way out of it. In 1944, Avery, McCarty, and MacLcod of the Rockefeller Institute published their historic paper on the identiEcation of DNA as the "transforming factor" in certain bacteria. This work aroused great interest as a strong indication that the gene was composed of DNA. It was not yet conclusive for it FRANCIS J. RYAN 107 was still controversial whether bacteria could even be thought of as having a genetics. The details of this bacterial %ans- forming factor" still left very reasonable questions about its analo,gy to the gents of higher orgmisms with well-defined chromosomes, like Ncurospora, fruit flies, or man. In a bull session, Ryan and I soon agreed that it would be exciting to try experiments on the possibility of a similar trausfomring ctlect of DNA in Ncurospora. The advanta,oc of Ncurospora was that, on the one hand, it could bc easily manipulated as laboratory material for micro- bial genetics. Esperiments that would take years with mice, and months with fruit flies, could be done in a few days. Furthermore, one could perform biochemical tests with billions of individual cell nuclei in a small ffask. On the other hand, Neurospora could be cross-bred (unlike, as we theu thought, other simpler microbes) and apparent genetic chan:cs sub- jected to thorough analysis by test crosses, in close analog to the genetics of other well-studied organisms. The experimental design was impeccable-but it never worked. In fact, to this day we have no very clear cxamplc OF the incorporation of purified DNA molecules into existing chromosomes of cells of h@er forms. If we failed to achieve our original aims, however, there wcrc several useful by-prod- ucts. For one thing, we discovered the occasional occurrence of spontaneous reversions of a mutant gene back to the or-i+ nal normal type, and it was an occasion of great pride to co-author this with Ryan as my debut in scientific publication. Far more important, this work laid the methodolo$cal groundwork for systematic searches for rare genetic events occurring in large cell populations. One day I suggested that we ring the changes on our ex- - -WT.-- - .---.-... --.c l 10s UNIVERSITY ON THE Il-fZIGHTS perimental approach. Instead 01 trying to make Neurospora imitate a phenomenon recently worked out in bacteria, we could use similar methods to inquire whether bacteria had geuetic mechanisms similar to Ncurospora. Ryan immediately perceived the potentialities of this ap- proach, and thereafter spared no effort to create the op- portunity for me to explore them. We did start some experi- ments on bacterial recombination at Columbia, but they were inconclusive. (Later we were to know that the particular strains of bacteria wc used then were inappropriate, but there could have been no way to tell this bcforchand.) By this time, I had be,w my training at Columbia Medi- cal School, while continuing part-time research with Ryan at Morningside Heights. By a fortunate coincidence, the mid- quarter of the junior year was allocated to elective work, and Ed Tatum had just then taken a chair at Yale University. During 1945, Ryan had leamcd that Tahrm had already initiated some similar steps toward a bacterial genetics, having already published a brief note on biochemical mutants of Escherichia coli in 1944. Ryan suggested that I ask Tatum to sponsor me as a research felIow at Yale to pursue this work -and of course must have recommended me to him, for I was promptly accepted. When I met Tatum, I found he had already been thinking along similar lines for some time, but his active work on the problem had been disrupted by moving and the reorganiza- tion of a new laboratory. I arrived in New Haven in March 1946, just when he was restarting his own work. This is not the place to recount that happy story; briefly, the fellowship lengthened into a year's leave, and eventually into a dropout from Columbia Medical School. My research with Tatum 4 FRANCIS J. RYAN 109 went too well to be interrupted, and Columbia courses were readily accepted for credit toward a Yale Ph.D. In fact, I was officially registered for elective work (off campus) in the Columbia M.D. program while doing the research that bc- came my Yale Ph.D. dissertation in 1947. Fortunately, these technicalities were overlooked at the time. To my regret, I had only occasional visits with Ryan nftcr that, but they were always a lift to the spirit and a challenge to the mind. In 1958, I was somewhat bewildered to find myself in Stockholm on a platform with Beadle and Tatum, to share a Nobel Prize of which my part was based on these studies on genetic recombination in bacteria. Perhaps only a knowl- edgeable circle knew, as we did, of Ryan's part in them. Any such awards are bound to be arbitrary, and a thoughtful observer will always look for the teacher behind the student. In many ways Ryan was ahead of his time; but he also insisted on keeping a firm hold on traditional biology as well as its innovations in biochemistry and microbiology. He was also keenly alert to the human uses and misuses of scientific knowledSc: for him, biology was one of the essential lmmani- ties. Some of his insights into modem biolo,y were too ad- vanced to get the priority they deserved, even taking account of the pressure of legitimate but conflicting demands on the resources of a great university. The winds of change are blowing again, and he might now look forward with genter . confidence that the university he loved so well would regain its historic preeminence in reserukh and teaching about the fundamentals of life.